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Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

Summary RNA editing is widely involved in stem cell differentiation and development; however, RNA editing events during human cardiomyocyte differentiation have not yet been characterized and elucidated. Here, we identified genome-wide RNA editing sites and systemically characterized their genomic distribution during four stages of human cardiomyocyte differentiation. It was found that the expression level of ADAR1 affected the global number of adenosine to inosine (A-to-I) editing sites but not the editing degree. Next, we identified 43, 163, 544, and 141 RNA editing sites that contribute to changes in amino acid sequences, variation in alternative splicing, alterations in miRNA-target binding, and changes in gene expression, respectively. Generally, RNA editing showed a stage-specific pattern with 211 stage-shared editing sites. Interestingly, cardiac muscle contraction and heart-disease-related pathways were enriched by cardio-specific editing genes, emphasizing the connection between cardiomyocyte differentiation and heart diseases from the perspective of RNA editing. Finally, it was found that these RNA editing sites are also related to several congenital and noncongenital heart diseases. Together, our study provides a new perspective on cardiomyocyte differentiation and offers more opportunities to understand the mechanisms underlying cell fate determination, which can promote the development of cardiac regenerative medicine and therapies for human heart diseases., Graphical abstract, This study provides a comprehensive identification and characterization of RNA editing events during four human pluripotent-to-cardiomyocyte differentiation stages, which can promote the development of cardiac regenerative medicine and offer new ideas for the therapies of human heart diseases.

Background Alport syndrome (ATS) is a rare hereditary disease caused by mutations in genes such as COL4A3, COL4A4, and COL4A5. ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities. Although ATS can be combined with other diseases or syndromes, ATS combined with lupus nephritis has not been reported before. Case summary A Chinese family with ATS was recruited for the current study. Clinical characteristics (including findings from renal biopsy) of ATS patients were collected from medical records, and potential causative genes were explored by whole-exome sequencing. A heterozygous substitution in intron 22 of COL4A3 (NM_000091 c.2657-1G>A) was found in the patients, which was further confirmed by quantitative polymerase chain reaction. Conclusion Heterozygous substitution of a COL4A3 gene splice site was identified by whole-exome sequencing, revealing the molecular pathogenic basis of this disorder. In general, identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.

Spirofluorenexanthanes (SFXs), as burgeoning second-generation spiro compounds beyond spirobifluorenes (SBFs), can serve as versatile scaffolds for low-cost organic semiconductors in various fluore...

Mitochondrial dysfunction causes energy deficiency and nigrostriatal neurodegeneration which is integral to the pathogenesis of Parkinson disease (PD). Clearance of defective mitochondria involves fission and ubiquitin-dependent degradation via mitophagy to maintain energy homeostasis. We hypothesize that LRRK2 (leucine-rich repeat kinase 2) mutation disrupts mitochondrial turnover causing accumulation of defective mitochondria in aging brain. We found more ubiquitinated mitochondria with aberrant morphology associated with impaired function in aged (but not young) LRRK2R1441G knockin mutant mouse striatum compared to wild-type (WT) controls. LRRK2R1441G mutant mouse embryonic fibroblasts (MEFs) exhibited reduced MAP1LC3/LC3 activation indicating impaired macroautophagy/autophagy. Mutant MEFs under FCCP-induced (mitochondrial uncoupler) stress showed increased LC3-aggregates demonstrating impaired mitophagy. Using a novel flow cytometry assay to quantify mitophagic rates in MEFs expressing photoactivatable mito-PAmCherry, we found significantly slower mitochondria clearance in mutant cells. Specific LRRK2 kinase inhibition using GNE-7915 did not alleviate impaired mitochondrial clearance suggesting a lack of direct relationship to increased kinase activity alone. DNM1L/Drp1 knockdown in MEFs slowed mitochondrial clearance indicating that DNM1L is a prerequisite for mitophagy. DNM1L knockdown in slowing mitochondrial clearance was less pronounced in mutant MEFs, indicating preexisting impaired DNM1L activation. DNM1L knockdown disrupted mitochondrial network which was more evident in mutant MEFs. DNM1L-Ser616 and MAPK/ERK phosphorylation which mediate mitochondrial fission and downstream mitophagic processes was apparent in WT using FCCP-induced stress but not mutant MEFs, despite similar total MAPK/ERK and DNM1L levels. In conclusion, aberrant mitochondria morphology and dysfunction associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in mutant LRRK2 MEFs and mouse brain.Abbreviations: ATP: adenosine triphosphate; BAX: BCL2-associated X protein; CDK1: cyclin-dependent kinase 1; CDK5: cyclin-dependent kinase 5; CQ: chloroquine; CSF: cerebrospinal fluid; DNM1L/DRP1: dynamin 1-like; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LAMP2A: lysosomal-associated membrane protein 2A; LRRK2: leucine-rich repeat kinase 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MMP: mitochondrial membrane potential; PAmCherry: photoactivatable-mCherry; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; RAB10: RAB10, member RAS oncogene family; RAF: v-raf-leukemia oncogene; SNCA: synuclein, alpha; TEM: transmission electron microscopy; VDAC: voltage-dependent anion channel; WT: wild type; SQSTM1/p62: sequestosome 1.

Salidroside (Sal), the major active constituent of

This paper investigates the main scale analysis of the aerodynamic noise in the foremost bogie area by the large-eddy simulation (LES) and the Ffowcs Williams-Hawkings (FW-H) analogy. The mechanism of the aerodynamic noise in this area has been excavated. The aerodynamic excitation results show that the bogie divides the bogie compartment into two cavities, each of which contains a large circulating flow and presents multi-peak characteristics in the frequency domain. The far-field noise results suggest that in the speed range of 200–350 km/h, the aerodynamic noise mechanism in the bogie area is the same. Cavity noise is the main noise mechanism in the foremost bogie area, and the bogie divides the bogie cabin into two cavities, thereby changing the aerodynamic noise in this area.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a therapeutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.

Xiaoqun Fang,1 Shulei Jia,2 Qiuyan Wang,1 Hui-fang Liu,1 Yumei Zhou,1 Lingling Zhang,1 Tanghua Dai,1 Hui Luo,1 Hui Peng,1 Jun Yuan,2 Huyan Zhou2 1Department of Rehabilitation Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2School of Nursing, Nanchang University, Nanchang, 330006, People’s Republic of ChinaCorrespondence: Shulei JiaSchool of Nursing, Nanchang University, No. 461 of Ba Yi Road, Donghu District, Nanchang, 330006, People’s Republic of ChinaTel +86 1579 786 1504Fax +86 791 86360530Email jiashulei2021@163.comObjective: This study investigated clinicians’ perspectives on the feasibility and effectiveness of using telemedicine in the context of providing first aid. It is crucial to identify and explore clinicians’ attitudes and awareness of tele-first-aid in China to keep pace with ongoing global trends.Design: This was a qualitative study. Data gathered from in-depth interviews with 22 clinicians were coded into themes and analyzed.Participants: Participants included hospital-based clinicians: four clinical specialists, eight emergency nurses, four emergency doctors, three general practitioners, and three clinical administrators.Setting: The study was conducted in university-affiliated hospitals.Results: All clinicians who were invited to participate believed that the use of telemedicine in first aid was promising and effective. Participants stated that relevant technology should be designed to synergize the chain of existing platforms in the industry and that it should be determined who has the authority to utilize such technology and how it should be used to achieve the sought-after benefits. The use of such technology refreshes the role of clinicians and their relationship with patients. Additionally, participants believed that the government could play an important role especially in the reform of medical systems.Conclusion: Telemedicine can facilitate the provision of conventional first aid and systematically exploit existing resources due to its feasibility and effectiveness. The social benefits of using tele-first-aid in clinical and community applications, especially when used in coordination with existing resources, make its adoption an inevitable trend in the field.Keywords: telemedicine, first aid, qualitative study, clinicians

To improve the proinsecticidal activity and phloem mobility of amino acid–tralopyril conjugates further, nine conjugates were designed and synthesized by introducing glutamic acid to tralopyril, and the length of the linker between glutamic acid and tralopyril ranged from 2 atoms to 10 atoms. The results of insecticidal activity against the third-instar larvae of P. xylostella showed that conjugates 42, 43, 44,and 45 (straight-chain containing 2–5 atoms) exhibited good insecticidal activity, and their LC50 values were 0.2397 ± 0.0366, 0.4413 ± 0.0647, 0.4400 ± 0.0624, and 0.4602 ± 0.0655 mM, respectively. The concentrations of conjugates 43–45 were higher than that of conjugate 42 in the phloem sap at 2 h, and conjugate 43 showed the highest concentration. The introduction of glutamic acid can improve phloem mobility. The in vivo metabolism of conjugates 42 and 43 was investigated in P. xylostella, and the parent compound tralopyril was detected at concentrations of 0.5950 and 0.3172 nmol/kg, respectively. According to the above results, conjugates 42 and 43 were potential phloem mobile pro-insecticide candidates.

This article aims to investigate the ameliorative effect of Linderae Radix ethanol extract on hyperlipidemia rats induced by high-fat diet and to explore its possible mechanism from the perspective of reverse cholesterol transport(RCT). SD rats were divided into normal group, model group, atorvastatin group, Linderae Radix ethanol extract(LREE) of high, medium, low dose groups. Except for the normal group, the other groups were fed with a high-fat diet to establish hyperlipidemia rat models; the normal group and the model group were given pure water, while each administration group was given corresponding drugs by gavage once a day for five weeks. Serum total cholesterol(TC), triglyceride(TG), high density lipoprotein-cholesterol(HDL-c), low density lipoprotein-cholesterol(LDL-c), alanine aminotransferase(ALT), and aspartate aminotransferase(AST) levels were measured by automatic blood biochemistry analyzer; the contents of TC, TG, total bile acid(TBA) in liver and TC and TBA in feces of rats were detected by enzyme colorimetry. HE staining was used to observe the liver tissue lesions; immunohistochemistry was used to detect the expression of ATP-binding cassette G8(ABCG8) in small intestine; Western blot and immunohistochemistry were used to detect the expression of peroxisome proliferator-activated receptor gamma/aerfa(PPARγ/α), liver X receptor-α(LXRα), ATP-binding cassette A1(ABCA1) pathway protein and scavenger receptor class B type Ⅰ(SR-BⅠ) in liver. The results showed that LREE could effectively reduce serum and liver TC, TG levels, serum LDL-c levels and AST activity, and increase HDL-c levels, but did not significant improve ALT activity and liver index; HE staining results showed that LREE could reduce liver lipid deposition and inflammatory cell infiltration. In addition, LREE also increased the contents of fecal TC and TBA, and up-regulated the protein expressions of ABCG8 in small intestine and PPARγ/α, SR-BⅠ, LXRα, and ABCA1 in liver. LREE served as a positive role on hyperlipidemia model rats induced by high-fat diet, which might be related to the regulation of RCT, the promotion of the conversion of cholesterol to the liver and bile acids, and the intestinal excretion of cholesterol and bile acids. RCT regulation might be a potential mechanism of LREE against hyperlipidemia.

Formaldehyde emitted from formaldehyde-based adhesive profoundly affects human health. Accordingly, increasing attention has been paid to developing effective source-control measures to reduce the amount of formaldehyde released from plywood. In this study, the formaldehyde removal performance of a combined ammonia and electric field plywood treatment method was investigated. By performing orthogonal experiments, the respective influences of the concentration of ammonium hydroxide solution, intensity of the electric field, heating temperature, and heating time were analyzed. It was found that the concentration of formaldehyde released from the plywood was reduced by 48% using the ammonia and electric-field method. In addition, the treatment method was applied to high-emitting plywood. Here, it was found that a higher formaldehyde concentration within the untreated samples corresponded to a higher removal rate. The intensity of the electric field was the most influential factor affecting the performance of the method. The optimal operating conditions for the orthogonal experiment corresponded to a 12.5% concentration of ammonium hydroxide solution, an electric field intensity of 25 V, a heating temperature of 343 K and a heating time of 150 min. The ammonia and electric field treatment method can effectively reduce the concentration of formaldehyde emitted from plywood. Therefore, it can be applied as a promising method for pollution source control.

Parkinson disease (PD) is an age-related neurodegenerative disorder associated with misfolded SNCA/α-synuclein accumulation in brain. Impaired catabolism of SNCA potentiates formation of its toxic oligomers. LRRK2 (leucine-rich repeat kinase-2) mutations predispose to familial and sporadic PD. Mutant LRRK2 perturbs chaperone-mediated-autophagy (CMA) to degrade SNCA. We showed greater age-dependent accumulation of oligomeric SNCA in striatum and cortex of aged LRRK2R1441G knockin (KI) mice, compared to age-matched wildtype (WT) by 53% and 31%, respectively. Lysosomal clustering and accumulation of CMA-specific LAMP2A and HSPA8/HSC70 proteins were observed in aged mutant striatum along with increased GAPDH (CMA substrate) by immunohistochemistry of dorsal striatum and flow cytometry of ventral midbrain cells. Using our new reporter protein clearance assay, mutant mouse embryonic fibroblasts (MEFs) expressing either SNCA or CMA recognition ‘KFERQ’-like motif conjugated with photoactivated-PAmCherry showed slower cellular clearance compared to WT by 28% and 34%, respectively. However, such difference was not observed after the ‘KFERQ’-motif was mutated. LRRK2 mutant MEFs exhibited lower lysosomal degradation than WT indicating lysosomal dysfunction. LAMP2A-knockdown reduced total lysosomal activity and clearance of ‘KFERQ’-substrate in WT but not in mutant MEFs, indicating impaired CMA in the latter. A CMA-specific activator, AR7, induced neuronal LAMP2A transcription and lysosomal activity in MEFs. AR7 also attenuated the progressive accumulation of both intracellular and extracellular SNCA oligomers in prolonged cultures of mutant cortical neurons (DIV21), indicating that oligomer accumulation can be suppressed by CMA activation. Activation of autophagic pathways to reduce aged-related accumulation of pathogenic SNCA oligomers is a viable disease-modifying therapeutic strategy for PD. Abbreviations: 3-MA: 3-methyladenine; AR7: 7-chloro-3-(4-methylphenyl)-2H-1,4-benzoxazine; CMA: chaperone-mediated autophagy; CQ: chloroquine; CSF: cerebrospinal fluid; DDM: n-dodecyl β-D-maltoside; DIV: days in vitro; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GWAS: genome-wide association studies; HSPA8/HSC70: heat shock protein 8; KFERQ: CMA recognition pentapeptide; KI: knockin; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LDH: lactate dehydrogenase; LRRK2: leucine-rich repeat kinase 2; MEF: mouse embryonic fibroblast; NDUFS4: NADH:ubiquinone oxidoreductase core subunit S4; NE: novel epitope; PD: Parkinson disease; RARA/RARα: retinoic acid receptor, alpha; SNCA: synuclein, alpha; TUBB3/TUJ1: tubulin, beta 3 class III; WT: wild-type

Post-translational modification (PTM)-based regulation can be mediated not only by the modification of a single residue but also by the interplay of different modifications. Accurate prediction of PTM cross-talk is a highly challenging issue and is in its infant stage. Especially, less attention has been paid to the structural preferences (except intrinsic disorder and spatial proximity) of cross-talk pairs and the characteristics of individual residues involved in cross-talk, which may restrict the improvement of the prediction accuracy. Here we report a structure-based algorithm called PCTpred to improve the PTM cross-talk prediction. The comprehensive residue- and residue pair-based features were designed for paired PTM sites at the sequence and structural levels. Through feature selection, we reserved 23 newly introduced descriptors and 3 traditional descriptors to develop a sequence-based predictor PCTseq and a structure-based predictor PCTstr, both of which were integrated to construct our final prediction model. According to pair- and protein-based evaluations, PCTpred yielded area under the curve values of approximately 0.9 and 0.8, respectively. Even when removing the distance preference of samples or using the input of modeled structures, our prediction performance was maintained or moderately reduced. PCTpred displayed stable and reliable improvements over the state-of-the-art methods based on various evaluations. The source code and data set are freely available at https://github.com/Liulab-HZAU/PCTpred or http://liulab.hzau.edu.cn/PCTpred/.

Most city trees in Nanjing are Platanus acerifolia and Populus nigra, which generate many whirling willow catkins in the air during the transitional season, yet little attention has been paid to the health risks, including itchy skin and respiratory infections, on occupants of roadside buildings. Since the air quality of these indoor spaces cannot meet WHO guidelines during the transitional season due to the influence of plant pollutants, a suitable ventilation scheme, together with air filtration measures, is urgently needed. Hence, four ventilation schemes were compared: natural ventilation, no ventilation with the door and windows closed, recirculating ventilation with a ceiling cassette fan-coil unit but no air filter, and recirculating ventilation with a ceiling cassette fan-coil unit and F7 filter. The performance of these modes was evaluated by comparing the effects of outdoor particulate matter on the indoor air quality. The results showed that the larger the particle size, the lower the I/O ratio. Furthermore, the influence of the occupants’ activities on indoor particle concentrations cannot be ignored, particularly for large particles, which varied more than small particles according to indoor human activity. Therefore, we suggest operating the ceiling cassette fan-coil unit with an air filter for this application, which can reduce the indoor particle concentration to an acceptable level and decrease the potential health risk posed by plant pollutants.

We aim to study the characteristics and mechanism of the aerodynamic noise sources for a high-speed train in a tunnel at the speeds of 50 m/s, 70 m/s, 83 m/s, and 97 m/s by means of the numerical wind tunnel model and the nonreflective boundary condition. First, the large eddy simulation model was used to simulate the fluctuating flow field around a 1/8 scale model of a high-speed train that consists of three connected vehicles with bogies in the tunnel. Next, the spectral characteristics of the aerodynamic noise source for the high-speed train were obtained by performing a Fourier transform on the fluctuating pressure. Finally, the mechanism of the aerodynamic noise was studied using the sound theory of cavity flow and the flow field structure. The results show that the spectrum pattern of the sound source energy presented broadband and multipeak characteristics for the high-speed train. The dominant distribution frequency range is from 100 Hz to 4 kHz for the high-speed train, accounting for approximately 95.1% of the total sound source energy. The peak frequencies are 400 Hz and 800 Hz. The sound source energy at 400 Hz and 800 Hz is primarily from the bogie cavities. The spectrum pattern of the sound source energy has frequency similarity for the bottom structure of the streamlined part of the head vehicle. The induced mode of the sound source energy is probably the dynamic oscillation mode of the cavity and the resonant oscillation mode of the cavity for the under-car structure at 400 Hz and 800 Hz, respectively. The numerical computation model was checked by the wind tunnel test results.

Noroviruses are the leading cause of acute gastroenteritis and food-borne diseases worldwide. Thus, a rapid, accurate, and easy-to-implement detection method for controlling infection and monitoring progression is urgently needed. In this study, we constructed a novel sandwich-type electrochemical biosensor integrated with two specific recognition elements (aptamer and peptide) for human norovirus (HuNoV). The electrochemical biosensor was fabricated using magnetic covalent organic framework/pillararene heterosupramolecular nanocomposites (MB@Apt@WP5A@Au@COF@Fe3O4) as the signal probes. The sensor showed high accuracy and selectivity. The detection method does not need the extraction and amplification of virus nucleic acid and has a short turn-around time. Intriguingly, the proposed biosensor had a limit of detection of 0.84 copy mL-1 for HuNoV, which was the highest sensitivity among published assays. The proposed biosensor showed higher sensitivity and accuracy compared with immunochromatographic assay in the detection of 98 clinical specimens. The biosensor was capable of determining the predominant infection strain of GII.4 and also GII.3 and achieved 74% selectivity for HuNoV GII group. This study provides a potential method for point-of-care testing and highlights the integrated utilization of Apt and peptide in sensor construction.

This paper was aimed to observe the interventional effect of Sedum sarmentosum total flavanones on hepatic fibrosis and its possible mechanism through the subcutaneous injection of CCl_4 in rats. Sixty male SD rats were randomly divided into normal control group, model group, low-dose, medium-dose, high-dose S. sarmentosum total flavanones groups(100, 200, 400 mg·kg~(-1)) and silymarin group(200 mg·kg~(-1)). The model of liver fibrosis was established by subcutaneous injection of rats with 40% CCl_4. After the modeling, the drug groups were intragastrically administered with corresponding drugs once a day for consecutively five weeks, while the normal group and the model group were given 0.9% sodium chloride solution during the same period. After the experiment, the general conditions of rats and the pathological changes of liver tissues were observed, and the contents of serum ALT, AST, HA and LN were measured. Besides, the expressions of the protein and relevant mRNA of Smad2/3, Smad4 and α-SMA in rats were detected. Compared with model group, S. sarmentosum total flavanones could significantly increase the rats' body weight, inhibit the increase of liver and spleen index in rats of liver fibrosis, reduce the levels of ALT, AST, HA and LN, and alleviate pathological changes. Meanwhile, compared with the model group, the protein expressions of Smad2/3, Smad4 and α-SMA as well as relevant mRNA expressions in S. sarmentosum total flavanones group were obviously decreased, while Smad7 expression was markedly increased. As a result, S. sarmentosum total flavanones could significantly alleviate CCl_4-induced liver fibrosis, and its anti-hepatic fibrosis mechanism may be related to intervention with Smads pathway, so as to inhibit the activation of HSC.

Objective This study investigated the correlations of digit ratio (relative length of second and fourth fingers, 2D: 4D) and muscular strength with the progression of chronic obstructive pulmonary disease (COPD). Methods In total, 164 patients with COPD were enrolled in this prospective study. In all patients, the following parameters were measured: body compartments, pulmonary function, digit ratio (i.e., 2D: 4D), muscle function, and levels of partial pressure of oxygen and partial pressure of carbon dioxide in arterial blood. Results The right-hand digit ratio (R2D: 4D) was associated with dominant hand muscle dysfunction, non-dominant hand muscle dysfunction, and inspiratory muscle dysfunction. Logistic regression analysis showed that right-hand 2D: 4D (odds ratio [ OR ] = 0.01) and dominant hand muscle dysfunction ( OR = 5.60) were significantly associated with past hospital admission. After adjustment for forced expiratory volume in 1 second, the following factors were associated with present acute exacerbations: right-hand 2D: 4D ( OR = 0.01), dominant hand muscle dysfunction ( OR = 3.83), expiratory muscle dysfunction ( OR = 3.80), and inspiratory muscle dysfunction ( OR = 3.61). Conclusions Lower digit ratio may be associated with higher prevalence of muscle dysfunction. This factor could be used to identify patients with COPD who are at higher risk of acute exacerbation.

It remains challenging to accurately discriminate between biological and crystal interfaces. Most existing analyses and algorithms focused on the features derived from a single side of the interface. However, less attention has been paid to the properties of residue pairs across protein interfaces. To address this problem, we defined a novel co-evolutionary feature for homodimers through integrating direct coupling analysis and image processing techniques. The residue pairs across biological homodimeric interfaces were significantly enriched in co-evolving residues compared to those across crystal contacts, resulting in a promising classification accuracy with area under the curves (AUCs) of >0.85. Considering the availability of co-evolutionary feature, we also designed other residue pair based features that were useful for both homodimers and heterodimers. The most informative residue pairs were identified to reflect the interaction preferences across protein interfaces. Regarding the other extant properties, we designed the new descriptors at the interface residue level as well as at the pairwise contact level. Extensive validation showed that these single properties can be used to identify biological interfaces with AUCs ranging from 0.60 to 0.88. By integrating co-evolutionary feature with other residue pair based properties, our final prediction model output excellent performance with AUCs of >0.91 on different datasets. Compared to existing methods, our algorithm not only yielded better or comparable results but also provided complementary information. An easy-to-use web server is freely accessible at http://liulab.hzau.edu.cn/RPAIAnalyst.

Hepatocellular carcinoma (HCC) remains the third cause of cancer-related mortality. Resection and transplantation are the only curative treatments available but are greatly hampered by high recurrence rates and development of metastasis, the initiation of cancer metastasis requires migration and invasion of cells, which is enabled by epithelial-mesenchymal transitions (EMT). TGF-β1 is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis. TGF-β1 is known as a major inducer of EMT, and it was reported that TGF-β1 induced EMT via Smad-dependent and Smad-independent pathways. However, the extrinsic signals of TGF-β1 regulated the EMT in hepatoma cells remains to be elucidated, and searching drugs to inhibit TGF-β1 induced EMT may be considered to be a potentially effective therapeutic strategy in HCC. Fortunately, in this study, we found that curcumin inhibited TGF-β1-induced EMT in hepatoma cells. Furthermore, we demonstrated that curcumin inhibited TGF-β1-induced EMT via inhibiting Smad2 phosphorylation and nuclear translocation, then suppressing Smad2 combined with the promoter of Snail which inhibited the transcriptional expression of Snail. These findings suggesting curcumin could be a useful agent for antitumor therapy and also a promising drug combined with other strategies to preventing and treating HCC.

Based on direct absorption spectroscopy (DAS), a portable methane (CH4) detection device was implemented. The device mainly includes a dual-channel non-dispersive infrared sensor (integrated with an infrared light source, light path and pyroelectric detector), a driving circuit of the sensor, an ARM11 embedded WinCE system, and a LabVIEW-based data-processing platform. Experiments were carried out with prepared CH4 samples to investigate the sensing performance. The relative detection error is less than 9.14% within the measuring range of 0—7×10-2. For a CH4 sample with concentration of 0 (i.e., pure nitrogen), the measured concentration fluctuation range is −1.2×10-5—+2×10-5. An Allan deviation analysis on the gas sample with concentration of 0 indicates that the 1σ limit of detection (LoD) of the device is 4.8×10-6 with an average time of 1 s. Experiments were performed on three CH4 samples with different concentrations to test the response time, which is validated to be less than 20 s. Due to the small size of the ARM11 embedded system and the powerful data processing capability of the LabVIEW platform, the proposed portable and miniaturized CH4 sensor shows a good application prospect in mining operations and some other industrial fields.

The calcium phosphate [Ca3(PO4)2] precipitation was used for improving the clarification efficiency in harvest process of the monoclonal antibody (mAb) containing cell culture fluid (CCF) with high turbidity and product titer. The flocculation conditions (concentration, addition order of flocculants, pH, and operation time), and the effect of flocculants on the mAb physical chemical properties (such as distribution of charge variants and aggregates) and process-related impurities removal (such as DNA and CHOP) were evaluated in this study. The results showed that the turbidity of CCF supernatant was significantly reduced at pH 7, 120 min with addition of phosphate ions first, while a high mAb recovery yield was kept in the CCF supernatant after flocculation. Addition of calcium ions at 15-60 mM was sufficient for flocculation in this study. A relationship between turbidity/mAb recovery yield and the concentration of calcium ions was established. More than 85% DNA in the CCF were effectively removed by the addition of optimal concentration of flocculants. Flocculation process of Ca3(PO4)2 is an effective pretreatment method in purification processes of mAbs from the CCF with high turbidity and product titer.

Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC). Patients with intermediate and advanced stage NPC receiving only radiotherapy have limited survival, so newer immunotherapeutic approaches are sought. The major impediment to better clinical outcomes is tumor immune tolerance. Indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme, is a major inducer of immune tolerance during tumor development; therefore, inhibition of the IDO pathway is an important modality for cancer treatment. We show that bortezomib, a proteasomal inhibitor, inhibited the pathways leading to STAT1 and IRF-1 activation, both of which are necessary for IDO expression. Bortezomib downregulated IFNγ-induced IDO expression via inhibition of STAT1 phosphorylation and nuclear translocation, thereby suppressing STAT1-driven IDO transcription in NPC cells. Bortezomib also promoted IκB-α phosphorylation-ubiquitination, which released NF-κB from IκB-α. However, the released NF-κB could not enter the nucleus to conduct its biological effects and accumulated in the cytoplasm. Negative feedback inhibited the transcription of NF-κB, which is important for activating IRF-1 expression. IDO expression is regulated by two important transcription factor binding sites, ISREs, which bind STAT1 and IRF-1, and GASs, which binds STAT1. Bortezomib upregulated IRF-1 protein by inhibiting its proteasome-dependent degradation, but it also inhibited STAT1 phosphorylation, which directly inhibited the activation of GAS and indirectly inhibited the activation of ISRE, which needs both STAT1 and IRF-1. These discoveries provide a mechanism for the antitumor action of bortezomib and have implications for the development of clinical cancer immunotherapy for preventing and treating NPC. Cancer Immunol Res; 5(1); 42–51. ©2016 AACR.

In order to systematically know the operating characteristics and further improve accuracy of precision magnetostrictive actuator used in precision and ultra precision machining fields, a model considering magnetization hysteresis mechanism and kinematics is established based on the domain wall magnetization essential theory. Magnetization, magnetostriction and kinematical characteristics, and the origin of hysteresis are discussed. According to input energy per unit volume of magnetostrictive materials is the sum of static magnetic energy and hysteresis loss energy, magnetization is divided into reversible and irreversible processes. Moreover, hysteresis loop is represented as an offset of irreversible magnetization relative to anhysteretic magnetization. Actuator’s model is deduced through dividing working process into four stages. Experiments show that the predicted values show good agreement with experimental data and average relative error of displacement is less than 5%. Magnetic hysteresis is derived from irreversible process in which magnetic domain cannot return back to initial distribution state completely. And hysteresis is more serious with the increasement of frequency. Research results reveal magnetization and kinematic characteristics from intrinsic physical mechanism, thus it provides a theoretical guidance for further improve the accuracy of magnetostrictive actuator and promotes the practical application of actuator in precision and ultra precision machining fields.

Background Parkinson’s disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies (LB). During the course of disease, misfolded α-synuclein, the major constituent of LB, spreads to different regions of the brain in a prion-like fashion, giving rise to successive non-motor and motor symptoms. Etiology is likely multifactorial, and involves interplay among aging, genetic susceptibility and environmental factors. Main body The prevalence of PD rises exponentially with age, and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death. However, the majority of those over the age of 80 do not have PD, thus other factors in addition to aging are needed to cause disease. Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk. Nevertheless, the causality of most environmental factors is not conclusively established, and alternative explanations such as reverse causality and recall bias cannot be excluded. The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD. Rare mutations as well as common variants in genes such as SNCA, LRRK2 and GBA are associated with risk of PD, but Mendelian causes collectively only account for 5% of PD and common polymorphisms are associated with small increase in PD risk. Heritability of PD has been estimated to be around 30%. Thus, aging, genetics and environmental factors each alone is rarely sufficient to cause PD for most patients. Conclusion PD is a multifactorial disorder involving interplay of aging, genetics and environmental factors. This has implications on the development of appropriate animal models of PD which take all these factors into account. Common converging pathways likely include mitochondrial dysfunction, impaired autophagy, oxidative stress and neuroinflammation, which are associated with the accumulation and spread of misfolded α-synuclein and neurodegeneration. Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

To investigate the effect of ILC2s on Th2-type adaptive immunity during the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), the study enrolled healthy people, stable COPD patients, and AECOPD patients. Flow cytometry was used to detect Th1, Th2, and ILC2 in the peripheral blood and CD80 and MHC II levels on ILC2. The mRNA levels of GATA3, RORα, and CRTH2 of ILC2s were detected by RT-PCR. In addition, ILC2s from the peripheral blood of AECOPD patients were cocultured with CD4+ T cells from the peripheral blood of healthy controls. Cytokine levels in serum of the three groups and the in vitro coculture supernatants were measured by ELISA. Compared with the stable COPD group or the healthy control group, Th2 in the peripheral blood of AECOPD group increased dramatically, inducing an increase of Th2/Th1 ratio in AECOPD patients. Meanwhile, the level of IL-4 in the serum of this group was also increased. However, we also detected ILC2s in the peripheral blood of the AECOPD group and found that it was also increased, alone with the increased GATA3, RORα, and CRTH2 mRNA levels. We also found that the CD80 and MHC II on ILC2 were significantly upregulated and the proportion of MHC II+ ILC2 cells was significantly positively correlated with the proportion of Th2 cells in AECOPD patients. To further demonstrate the effect of ILC2 on Th2 cells, we cocultured ILC2 with CD4+ T cells in vitro, which also showed a significant increase of Th2 ratio as well as Th2-associated cytokines IL-4, IL-5, and IL-13. However, we found that this effect of ILC2s on Th2 cells could be inhibited by the addition of anti-MHC II. The Th2/Th1 balance shifts to Th2 in AECOPD. ILC2s may function as APC by the upregulation of MHC II and regulate adaptive immunity shift to Th2-type response in AECOPD.

// Guan-Min Jiang 1,* , Wei Xu 2,* , Jun Du 3 , Kun-Shui Zhang 4 , Qiu-Gui Zhang 2 , Xiao-Wei Wang 1 , Zhi-Gang Liu 5 , Shuang-Quan Liu 2 , Wan-Ying Xie 2 , Hui-Fang Liu 2 , Jing-Shi Liu 6 and Bai-Ping Wu 1 1 Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China 2 Department of Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China 3 Department of Microbial and Biochemical Pharmacy School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China 4 Department of Pharmacy, The Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 5 Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China 6 Department of Anesthesia, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China * These authors have contributed equally to this work Correspondence to: Guan-Min Jiang, email: // Bai-Ping Wu, email: // Jing-Shi Liu, email: // Keywords : fibroblast activation protein α, tumor microenvironment, immune suppression, immunotherapy Received : December 04, 2015 Accepted : February 28, 2016 Published : March 15, 2016 Abstract Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein α (FAP α) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP α has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP α-expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP α antibody, FAP α vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP α is an adaptive tumor-associated antigen. This review highlights the role of FAP α in tumor development, explores the relationship between FAP α and immune suppression in the TME, and discusses FAP α as a potential immunotherapeutic target.

By adopting a distributed feedback laser (DFBL) centered at 1.654 μm, a near-infrared (NIR) methane (CH4) detection system based on tunable diode laser absorption spectroscopy (TDLAS) is experimentally demonstrated. A laser temperature control as well as wavelength modulation module is developed to control the laser’s operation temperature. The laser’s temperature fluctuation can be limited within the range of −0.02—0.02 °C, and the laser’s emitting wavelength varies linearly with the temperature and injection current. An open reflective gas sensing probe is realized to double the absorption optical path length from 0.2 m to 0.4 m. Within the detection range of 0—0.01, gas detection experiments were conducted to derive the relation between harmonic amplitude and gas concentration. Based on the Allan deviation at an integral time of 1 s, the limit of detection (LoD) is decided to be 2.952×10-5 with a path length of 0.4 m, indicating a minimum detectable column density of ~1.2×10-5 m. Compared with our previously reported NIR CH4 detection system, this system exhibits some improvement in both optical and electrical structures, including the analogue temperature controller with less software consumption, simple and reliable open reflective sensing probe.