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APP misexpression plays a crucial role in triggering a complex pathological cascade, leading to Alzheimer’s disease (AD). But how the expression of APP is regulated in pathological conditions remains poorly understood. In this study, we found that the exosomes isolated from AD mouse brain promoted APP expression in neuronal N2a cells. Moreover, exosomes derived from N2a cells with ectopic expression of APP (APP-EXO) also induced APP dysregulation in normal N2a cells. Surprisingly, the effects of APP-EXO on APP expression in recipient cells were not mediated by the direct transferring of APP gene products. Instead, the effects of APP-EXO were highly likely mediated by the reduction of the expression levels of exosomal miR-185-5p. We found that the 3′UTR of APP transcripts binds to miR-185-5p, therefore inhibiting the sorting of miR-185-5p to exosomes. N2a cell-derived exosomes with less amount of miR-185-5p exert similar roles in APP expression to APP-EXO. Lastly, we demonstrated a significant decline of serum exosomal miR-185-5p in AD patients and AD mice, versus the corresponding controls. Together, our results demonstrate a novel mechanism in the exosome-dependent regulation of APP, implying exosomes and exosomal miRNAs as potential therapeutic targets and biomarkers for AD treatment and diagnosis, respectively.

The Lewy bodies (LBs) are the pathological hallmark of Parkinson's disease (PD). More than 90% of α-synuclein (α-syn) within LBs is phosphorylated at the serine-129 residue [pSer129 α-syn (p-α-syn)]. Although various studies have revealed that this abnormally elevated p-α-syn acts as a pathological biomarker and is involved in the pathogenic process of PD, the exact pathophysiological mechanisms of p-α-syn are still not fully understood. Therefore, the development of specific and reliable tools for p-α-syn detection is important. In this study, we generated a novel p-α-syn mouse monoclonal antibody (C140S) using hybridoma technology. To further identify the characteristics of C140S, we performed several in vitro assays using recombinant proteins, along with ex vivo assays utilizing the brains of Thy1-SNCA transgenic (Tg) mice, the preformed fibril (PFF)-treated neurons, and the brain sections of patients with PD. Our C140S specifically recognized human and mouse p-α-syn proteins both in vitro and ex vivo, and similar to commercial p-α-syn antibodies, the C140S detected higher levels of p-α-syn in the midbrain of the Tg mice. Using immunogold electron microscopy, these p-α-syn particles were partly deposited in the cytoplasm and colocalized with the outer mitochondrial membrane. In addition, the C140S recognized p-α-syn pathologies in the PFF-treated neurons and the amygdala of patients with PD. Overall, the C140S antibody was a specific and potential research tool in the detection and mechanistic studies of pathogenic p-α-syn in PD and related synucleinopathies.

Single-cell RNA-seq (scRNA-seq) is being widely used to resolve cellular heterogeneity. Here, the authors present a cell-querying method built on a neural network-based generative model and a customized cell-to-cell similarity metric.

Abstract Background Since SCD (plus) was standardized, little is known about its demographic characteristics and its outcomes of neuropsychological assessments, including the SCD questionnaire 9 (SCD‐Q9). Objective To characterize SCD (plus) by comparing the neuropsychological features among its subgroups and with normal controls (NC). Also, to explore its demographics and to understand the relation of the chief complaints and the scores of SCD‐Q9. Methods Multistage stratified cluster random sampling was conducted to select participants. As a result, 84 NC and 517 SCD (plus) were included. SCD (plus) was further classified into several subgroups (SCD‐C: concerned cognitive decline; SCD‐F: complaints about SCD within the past five years; SCD‐P: feeling performance being not as good as their peers; SCD+: presented> 3 of SCD (plus) features; SCD‐: presented ≤ 3 of SCD (plus) features (see the diagnostic criteria for the details)) and between‐group comparisons of neuropsychological scores were conducted. Point‐biserial correlation and binary logistic regression analyses were performed to investigate the demographic characteristics of its subgroups. Finally, Spearman correlation was used to better understand the relation of SCD (plus) to SCD‐Q9. Results (1) Scores of AVLT‐LR (AVLT‐LR: Auditory Verbal Learning Test‐Long Delayed Recall) and MoCA‐B (MoCA: Montreal Cognitive Assessment‐Basic) were lower in the SCD‐P group than those in the NC group, and the SCD+ group scored lower in the MoCA‐B and CDT(CDT: Clock Drawing Test) than the SCD‐ group. (2) Females were more concerned than male participants. Individuals with lower education level felt that their cognitive performance were worse than their peers. Also, younger people might express concerns more than the more elderly. People who had complaints of SCD‐P might be more likely to report SCD‐C, but less likely to report SCD‐F. (3) Positive correlations were found between the chief complaints of SCD (plus) and some items of SCD‐Q9. Conclusions SCD (plus) may be related to demographic factors. Individuals with SCD (plus) already exhibited cognitive impairment, which can be detected by SCD‐Q9.

Abstract The roles of some long non-coding RNAs (lncRNAs) in intracranial aneurysm (IA) have been investigated in many studies. The aim of this study is to elucidate the mechanism of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-143 (miR-143)/vascular endothelial growth factor-A (VEGFA) signal axis in vascular endothelial injury-induced IA. MALAT1, miR-143, and VEGFA expression in IA tissues and normal arterial tissues were detected. Matrix metalloproteinase 9 (MMP-9) in tissues, von Willebrand factor (vWF) in serum and tissues, and endothelin-1 (ET-1) in serum were detected. The modeled IA rats were injected with silenced or overexpressed MALAT1 for detecting vascular endothelial injury. Vascular endothelial cells from patients with IA were abstracted and transfected with silenced or overexpressed MALAT1 to verify the impacts of MALAT1 on cell viability and apoptosis. The connections among MALAT1, miR-143, and VEGFA were verified by online prediction, luciferase activity, and RNA-pull down assays. Overexpression of MALAT1 and VEGFA and poor expression of miR-143 were found in IA tissues. Downregulation of MALAT1 inhibited blood pressure, the expression of ET-1, vWF, and MMP-9, as well as the apoptotic index of vascular endothelial cells of rats with IA. Downregulated MALAT1 inhibited apoptosis and promoted viability of vascular endothelial cells in IA. MALAT1 bound to miR-143 and miR-143 targeted VEGFA. This study suggests that MALAT1 elevates VEGFA expression through competitive binding to miR-143, thereby boosting apoptosis and attenuating viability of vascular endothelial cells in IA.

Abstract Background Fatty liver is a reversible status, but also an origin stage to develop to other metabolic syndromes, such as diabetes and heart disease that threatens public health worldwide. Ascorbate deficiency is reported to be correlated with increasing risks for metabolic syndromes, but whether ascorbate has a therapeutic effect is unknown. Here, we investigated if ascorbate treatment alone could work on protecting from the development of steatosis and mechanisms beyond. Methods Guinea pigs were fed with a chow diet or a high palm oil diet (HPD) respectively. HPD induced animals were administered different concentrations of ascorbate in different time intervals through water. Besides, hepatocyte-like cells derived from human embryonic stem cells and HepG2 cells were treated with palmitic acid (PA) to induce lipid accumulation for molecular mechanism study. Results We find that ascorbate rescues HPD and PA induced steatosis and insulin tolerance in vivo and in vitro. We demonstrate that ascorbate changes cellular lipid profiles via inhibits lipogenesis, and inhibits the expression of SOCS3 via STAT3, thus enhances insulin signal transduction. Overexpression of SOCS3 abolishes the ascorbate rescue effects on insulin signal and lipid accumulation in hepatic cells. Conclusions Ascorbate ameliorates hepatic steatosis and improves insulin sensitivity through inhibiting lipogenesis and SOCS3.

Abstract Background Heterogeneity of oil-bearing formations is one of major contributors to low oil recovery efficiency globally. Long-term water flooding will aggravate this heterogeneity by resulting in many large channels during the exploitation process. Thus, injected water quickly flows through these large channels rather than oil-bearing areas, which ultimately leads to low oil recovery. This problem can be solved by profile control using polymer plugging. However, non-deep profile control caused by premature plugging is the main challenge. Here, a conditional bacterial cellulose-producing strain, namely Enterobacter sp. FY-0701, was constructed for deep profile control to solve the problem of premature plugging. Its deep profile control and oil displacement capabilities were subsequently identified and assessed. Results The conditional bacterial cellulose-producing strain Enterobacter sp. FY-0701 was constructed by knocking out a copy of fructose-1, 6-bisphosphatase (FBP) encoding gene in Enterobacter sp. FY-07. Scanning electron microscope observation showed this strain produced bacterial cellulose using glucose rather than glycerol as the sole carbon source. Bacterial concentration and cellulose production at different locations in core experiments indicated that the plugging position of FY-0701 was deeper than that of FY-07. Moreover, enhanced oil recovery by FY-0701 was 12.09%, being 3.86% higher than that by FY-07 in the subsequent water flooding process. Conclusions To our knowledge, this is the first report of conditional biopolymer-producing strains used in microbial enhance oil recovery (MEOR). Our results demonstrated that the conditional bacterial cellulose-producing strain can in situ produce biopolymer far from injection wells and plugs large channels, which increased the sweep volume of injection water and enhance oil recovery. The construction of this strain provides an alternative strategy for using biopolymers in MEOR.

AIM: To discuss the correlation between fixation nature and macular thickness, in addition, to investigate the variations of macular thickness and other related factors in hyperopic ametropic amblyopic children ranged from 4 to 8 years old by measuring each area's macular thickness, fixation nature and length of optic axis.METHODS: Prospective, non-randomized, contemporaneous controlled study trials. Totally 44 children with 57 eyes who admitted to the hospital for the first time without any amblyopia training before from September 2018 to December were included in this study.36 eyes from hyperopic ametropic amblyopic children were enrolled in hyperopia group and 21 eyes from children with normal vision were enrolled in healthy controls. The optical coherence tomography(OCT)was used to measure the macular retinal thickness in both. Meanwhile, the OCT was also used to measure the macular retinal thickness in 29 central fixation patients(32 eyes)and 15 eccentric fixation(25 eyes)which examined by direct ophthalmoscope, and the data were analyzed by SPSS19.0 statistical software.RESULTS: The length of optic axis in hyperopic amblyopic eyes is shorter than it in normal eyes(PPPP>0.05)CONCLUSION: The retinal thickness of central sector and nasal quadrant in inner ring of central fixation children was increase. Hyperopia amblyopia children's retinal thickness of central sector or region and nasal、inferior quadrant in inner ring and superior quadrant in outer ring was increase. The length of optic axis in hyperopic amblyopic children is decrease.

Objective To analyze the correlation between the Kellgren–Lawrence (K‐L) score of knee osteoarthritis (KOA) patients with different degrees and their urine concentration of C‐terminal telopeptide of collagen type II (CTX‐II) and interleukin‐1β (IL‐1β), and to further evaluate the diagnostic value of CTX‐II and IL‐1β during the pathological process by producing an experimental osteoarthritis (OA) model in rabbits. Methods From 1 January 2017 to 31 December 2018, a total of 34 subjects (7 mild, 9 moderate, 9 severe arthritis patients, and 9 healthy individuals) comprising 16 men and 18 women were included in this study. Patients were diagnosed according to the American College of Rheumatology (ACR) criteria. The urine of all subjects was collected to detect the concentration of CTX‐II and IL‐1β. The rabbits in the KOA group were subjected to protease (control group with saline) injection into the articular cavity of their right knees and immobilization with gypsum. We used radiological and histological examination to identify the KOA model. ELISA was applied to investigate the concentrations of CTX‐II and IL‐1β in urine and serum, and Spearman's rank correlation analysis was used to analyze the correlation. Results There was no significant difference in the mean ages and body mass index (BMI) between groups. The mean ages of mild, moderate, and severe arthritis patients and healthy individuals were 54.29 ± 5.76, 58.44 ± 6.44, 59.89 ± 6.75, and 56.67 ± 4.18 years, respectively. The mean BMI of mild, moderate, and severe arthritis patients and healthy individuals were 23.59 ± 1.56, 23.57 ± 2.06, 24.46 ± 1.64, and 23.42 ± 1.35 kg/m2, respectively. The Kellgren–Lawrence (K‐L) score was higher with the aggravation of KOA. The K‐L scores of mild, moderate, and severe KOA patients were 1.14 ± 0.38, 2.56 ± 0.53, and 3.63 ± 0.52, respectively. The KOA symptoms of patients became more severe, with not only increased K‐L scores but also elevated concentrations of CTX‐II and IL‐1β. Moreover, there was a positive correlation between CTX‐II and IL‐1β of all subjects (r = 0.974, P

The rapid development of medical micromotors draws a beautiful blueprint for the noninvasive or minimally invasive diagnosis and therapy. By combining stimuli-sensitive hydrogel materials, micromotors are bestowed with new characteristics such as stimuli-responsive shape transformation/morphing, excellent biocompatibility and biodegradability, and drug loading ability. Actuated by chemical fuels or external fields (e.g., magnetic field, ultrasound, light, and electric field), hydrogel-based stimuli-responsive (HBSR) micromotors can be utilized to load therapeutic agents into the hydrogel networks or directly grip the target cargos (e.g., drug-loaded particles, cells, and thrombus), transport them to sites of interest (e.g., tumor area and diseased tissues), and unload the cargos or execute a specific task (e.g., cell capture, targeted sampling, and removal of blood clots) in response to a stimulus (e.g., change of temperature, pH, ion strength, and chemicals) in the physiological environment. The high flexibility, adaptive capacity, and shape morphing property enable the HBSR micromotors to complete specific medical tasks in complex physiological scenarios, especially in confined, hard-to-reach tissues, and vessels of the body. Herein, this review summarizes the current progress in hydrogel-based medical micromotors with stimuli responsiveness. The thermo-responsive, photothermal-responsive, magnetocaloric-responsive, pH-responsive, ionic-strength-responsive, and chemoresponsive micromotors are discussed in detail. Finally, current challenges and future perspectives for the development of HBSR micromotors in the biomedical field are discussed.

Short-term traffic flow prediction is an important component of intelligent transportation systems, which can support traffic trip planning and traffic management. Although existing predicting methods have been applied in the field of traffic flow prediction, they cannot capture the complex multifeatures of traffic flows resulting in unsatisfactory short-term traffic flow prediction results. In this paper, a multifeature fusion model based on deep learning methods is proposed, which consists of three modules, namely, a CNN-Bidirectional GRU module with an attention mechanism (CNN-BiGRU-attention) and two Bidirectional GRU modules with an attention mechanism (BiGRU-attention). The CNN-BiGRU-attention module is used to extract local trend features and long-term dependent features of the traffic flow, and the two BiGRU-attention modules are used to extract daily and weekly periodic features of the traffic flow. Moreover, a feature fusion layer in the model is used to fuse the features extracted by each module. And then, the number of neurons in the model, the loss function, and other parameters such as the optimization algorithm are discussed and set up through simulation experiments. Finally, the multifeature fusion model is trained and tested based on the training and test sets from the data collected from the field. And the results indicate that the proposed model can better achieve traffic flow prediction and has good robustness. Furthermore, the multifeature fusion model is compared and analyzed against the baseline models with the same dataset, and the experimental results show that the multifeature fusion model has superior predictive performance compared to the baseline models.

Gemcitabine (GEM) is the gold-standard therapeutic regimen for patients with pancreatic cancer (PC); however, patients may receive limited benefits due to the drug resistance of GEM. LncRNA SNHG6 is reported to play key roles in drug resistance, but its role and molecular mechanism in PC remain incompletely understood. We found that LncRNA SNHG6 is drastically downregulated in GEM-resistant PC and is positively correlated with the survival of PC patients. With the help of bioinformatic analysis and molecular approaches, we show that LncRNA SNHG6 can sponge miR-944, therefore causing the upregulation of the target gene KPNA5. In vitro experiments showed that LncRNA SNHG6 and KPNA5 suppress PC cell proliferation and colony formation. The Upregulation of LncRNA SNHG6 and KPNA5 increases the response of GEM-resistant PANC-1 cells to GEM. We also show that the expression of KPNA5 is higher in patients without GEM resistance than in those who developed GEM resistance. In summary, our findings indicate that the LncRNA SNHG6/miR944/KPNA5 axis plays a pivotal role in overcoming GEM resistance, and targeting this axis may contribute to an increasing of the benefits of PC patients from GEM treatment.

The frequency of intratympanic (IT) steroid injection varies from once daily to once weekly or less among studies and does not reach a uniform standard. This study investigated the potential association between the number of IT steroid injections and hearing recovery to determine the optimal number in sudden sensorineural hearing loss (SSNHL) patients. A retrospective study involving 233 SSNHL patients receiving IT steroids plus batroxobin within 7 days of onset was performed. Patients were followed up for 3 months. More than 15 dB of HL improvement in the pretreatment pure tone average (PTA) was defined as effective. The effective group had a higher IT injection numbers than the ineffective group (≥ 6 times: 84.6 vs. 61.1, p < 0.001). Regardless of the unadjusted model or adjusted model, patients who received more frequent IT steroid injections seemed more likely to recover hearing (unadjusted model, OR, 95% CI: 1.25, 1.06–1.48; p = 0.007; adjusted model, OR, 95% CI: 1.21, 1.01–1.45; p = 0.044). Six IT injections had the highest rate of hearing recovery (79.1%). In conclusion, IT injection number was an independent factor that was positively associated with hearing recovery, and the optimal number of IT steroid injections was 6. Batroxobin plus higher number of IT steroid injections showed more effective for treating SSNHL.

Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.

The large-caliber steady-state magnetic-field testing system is an important device for the International Thermonuclear Experimental Reactor, which is mainly used for electromagnetic compatibility tests in a strong magnetic field environment. The uniform magnetic field area needs to be measured to ensure the correctness of the design after the completion of the platform. This paper mainly analyzes the relationship between the magnetic field probe and error, studies the detection effect of different arrangement methods of magnetic field probe points, and obtains a more accurate probe arrangement method through comparative analysis. Then, the principle and structure of the acquisition and detection system are studied, and the multipoint synchronous Hall array magnetic field detection system of the magnetic field is built by using the Hall probe to realize the omnidirectional measurement of the magnetic field. Finally, the Hall probe is calibrated and tested by experiments, and a test platform is built to test the magnetic field. The results verify the correctness of the analysis.

Chenodeoxycholic acid (CDCA), a primary bile acid (BA), has been demonstrated to play an important role as a signaling molecule in various physiological functions. However, the role of CDCA in regulating intestinal epithelial cell (IEC) function remains largely unknown. Herein, porcine intestinal epithelial cells (IPEC-J2) were used as an in vitro model to investigate the effects of CDCA on IEC proliferation and explore the underlying mechanisms. IPEC-J2 cells were treated with CDCA, and flow cytometry and transcriptome analysis were adopted to investigate the effects and potential molecular mechanisms of CDCA on the proliferation of IECs. Our results indicated that adding 50 μmol/L of CDCA in the media significantly increased the proliferation of IPEC-J2 cells. In addition, CDCA treatment also hindered cell apoptosis, increased the proportion of G0/G1 phase cells in the cell cycle progression, reduced intracellular ROS, and MDA levels, and increased mitochondrial membrane potential, antioxidation enzyme activity (T-AOC and CAT), and intracellular ATP level (p < 0.05). RNA-seq results showed that CDCA significantly upregulated the expression of genes related to cell cycle progression (Cyclin-dependent kinase 1 (CDK1), cyclin G2 (CCNG2), cell-cycle progression gene 1 (CCPG1), Bcl-2 interacting protein 5 (BNIP5), etc.) and downregulated the expression of genes related to mitochondrial biogenesis (ND1, ND2, COX3, ATP6, etc.). Further KEGG pathway enrichment analysis showed that CDCA significantly enriched the signaling pathways of DNA replication, cell cycle, and p53. Collectively, this study demonstrated that CDCA could promote IPEC-J2 proliferation by regulating cell cycle progression and mitochondrial function. These findings provide a new strategy for promoting the intestinal health of pigs by regulating intestinal BA metabolism.

Hereditary gingival fibromatosis [HGF, (MIM 135300)], a rare benign oral condition, has several adverse consequences such as aesthetic changes, malocclusion, speech impediments, and abnormal dentition. However, relatively few studies have addressed the beneficial effects of thick gingival tissues in resisting external stimuli. In this report, we present a unique case of a family affected by HGF that manifests as a ‘healthy’ gingiva. Human β-defensins (hBDs) are known to play a pivotal role in the clearance and killing of various microbes, and contribute to maintaining a healthy oral environment, which is currently emerging research area. However, the expression pattern and localisation of hBDs in patients with HGF have not yet been reported. hBD-2 and hBD-3 in the pedigree we collected had relatively elevated expression. High hBD levels in the gingival tissue of patients from the family may be beneficial in protecting oral tissue from external stimuli and promoting periodontal regeneration, but their role and the mechanisms underlying HGF need to be clarified.

Valuable furfuryl alcohol (FFA) and 2,5-dihydroxymethylfuran (DHMF) could be produced by selective hydrogenation of biomass-derived furfural (FF) and 5-hydroxymethylfurfural (HMF) with high atom economy. In this study, SBA-15 (a kind of mesoporous silica molecular sieve)-supported low metal loading (3 wt% total metal content) PtNi alloy catalyst (PtNi/SBA-15) was synthesized via two steps, including the generation of PtNi alloy by hydrothermal method, and the immobilization of PtNi alloy on SBA-15. PtNi/SBA-15 has ordered mesoporous structure with high surface area, and high dispersion of the PtNi alloy with the formation of Ptδ−-Niδ+ surface pairs on SBA-15, which benefit hydrogen activation and selective carbonyl hydrogenation. The selective hydrogenation of FF and HMF over PtNi/SBA-15 in water solvent at 303 K with 1.5 MPa H2 within 2 h, could respectively yield 64.6% FFA with 77.0% selectivity, and 68.2% DHMF with 81.9% selectivity. Besides, PtNi/SBA-15 exhibited a satisfactory water resistance and stability after recycling at least five runs.

Rice (Oryza sativa) OsMADS58 is a C-class MADS box protein, and characterization of a transposon insertion mutant osmads58 suggested that OsMADS58 plays a role in stamen development. However, as no null mutation has been obtained, its role has remained unclear. Here, we report that the CRISPR knockout mutant osmads58 exhibits complex altered phenotypes, including anomalous diploid germ cells, aberrant meiosis, and delayed tapetum degeneration. This CRISPR mutant line exhibited stronger changes in expression of OsMADS58 target genes compared with the osmads58 dSpm (transposon insertion) line, along with changes in multiple pathways related to early stamen development. Notably, transcriptional regulatory circuits in young panicles covering the stamen at stages 4–6 were substantially altered in the CRISPR line compared to the dSpm line. These findings strongly suggest that the pleiotropic effects of OsMADS58 on stamen development derive from a potential role in stabilizing gene regulatory circuits during early stamen development. Thus, this work opens new avenues for viewing and deciphering the regulatory mechanisms of early stamen development from a network perspective.

Wind and rainfall climatic erosivities are important parameters with which to assess the possible effects of climatic conditions on erosion. In this study, wind erosion climatic erosivity (C-factor) and rainfall erosivity (Rday-factor) were calculated for the period 1970–2020 based on data from 50 meteorological stations in Qinghai Province. The Mann–Kendall test, trend analysis, and K-means clustering method were used to explore the spatiotemporal characteristics of regional wind/rainfall climatic erosivity. Results showed that the annual mean value of the C-factor was 25.8 over the past 51 years, with an obvious trend of decline of 6.5/10a. The mean annual value of the Rday-factor was 491.6 MJ·mm/(hm2·h·a), with an obvious trend of increasing of 24.0 MJ·mm/(hm2·h·10a). Strong seasonality was found in both the C-factor and the Rday-factor. The highest values of the C-factor were found in late winter and spring, accounting for a substantial proportion of the annual C-factor (48.6%). Rainfall erosivity occurred mainly April–October, with the highest values in summer, accounting for a substantial proportion of the annual Rday-factor (72.9%). Wind-erosion climatic erosivity and rainfall erosivity were obviously asynchronous on an annual basis, and the period of their combination extended the time of soil erosion. Through k-means clustering analysis, climatic erosivity in Qinghai Province was divided into three regions: the first dominated by wind-erosion climatic erosivity, the second dominated by rainfall erosivity, and the third dominated by their combination. The most serious land erosion occurred in the third region, accounting for 34.3% of the entire land area of Qinghai Province, where annual rainfall was found to be broadly consistent at 300–400 mm. Wind speed, temperature, rainfall, and sunshine duration are key factors known to impact the variation in wind-erosion climatic erosivity, while annual erosive rainfall, number of rainy days, and sunshine duration are the main factors known to impact the variation in rainfall erosivity. The findings of this study represent a robust reference for ecoenvironmental protection, sustainable development, and soil protection.

The objective of the present work is to evaluate the influence of material color on mechanical properties of fused deposition modeling (FDM) parts. The performance of the products is evaluated by testing eight different colors of acrylonitrile butadiene styrene (ABS) and polylactic acid (PLA) material in terms of tensile strength, compressive strength, and flexural strength. The analysis of data shows a significant difference in mechanical characteristics of prints depending on filament color. For different colors, these three strengths almost follow the same rising and falling tendency. In order to explore the relationship between mechanical strengths and filament colors, the color-mixing theory and the least-squares method are adopted to fit the best ratio coefficients of different color combinations. Results are presented showing that the strength value (e.g., tensile) of the mixed color can be evaluated through that of primary colors by fitting the other strength (e.g., compressive or flexural). It is shown that the predicted value is always no more than 7% error compared with the actual strength, in spite of two-color or three-color mixtures. An additional confirmation test with seven colored PLA filaments from different suppliers was conducted to focus on the extensibility. The outcomes show the maximum fitting errors of strengths for mixed colors in all cases are within 5%, proving the effectiveness and applicability of this predicted approach. This study can bring a detailed analysis that enables better estimation of the function of material color and contributes to improving the property of FDM printed products for consumers by choosing the suitable filament color.

In recent years, much research has been conducted on time series based human activity recognition (HAR) using wearable sensors. Most existing work for HAR is based on the manual labeling. However, the complete time serial signals not only contain different types of activities, but also include many transition and atypical ones. Thus, effectively filtering out these activities has become a significant problem. In this paper, a novel machine learning based segmentation scheme with a multi-probability threshold is proposed for HAR. Threshold segmentation (TS) and slope-area (SA) approaches are employed according to the characteristics of small fluctuation of static activity signals and typical peaks and troughs of periodic-like ones. In addition, a multi-label weighted probability (MLWP) model is proposed to estimate the probability of each activity. The HAR error can be significantly decreased, as the proposed model can solve the problem that the fixed window usually contains multiple kinds of activities, while the unknown activities can be accurately rejected to reduce their impacts. Compared with other existing schemes, computer simulation reveals that the proposed model maintains high performance using the UCI and PAMAP2 datasets. The average HAR accuracies are able to reach 97.71% and 95.93%, respectively.

In the present study, a comparison of two widely used optimization approaches for fused deposition modeling (FDM), that is, Taguchi method in contrast with response surface method (RSM), was investigated. Four operating parameters, namely extrusion temperature, layer thickness, raster width, print speed, and their interaction terms, were identified as control variables with three levels, while tensile strength and compressive strength were selected responses. L27 orthogonal array and face-centered central composite design (FCCCD) were used for the experimental approach for Taguchi and RSM, respectively. The signal-to-noise (S/N) ratio and analysis of variance (ANOVA) were employed to find the optimal FDM parameter combination as well as the main factor that affect the performance of the PLA samples. Based on experimental results, it was observed that conclusions about significant ranking of parameters on FDM process from these two methods were different. However, both the Taguchi method and RSM succeed in predicting better results compared with the original groups. In addition, the optimum combinations for tensile strength and compressive strength obtained from the RSM were 2.11% and 8.15% higher than Taguchi method, respectively.

Ripened oriental melon (Cucumis melo) with orange-colored flesh is rich in β-carotene. Lycopene β-cyclase (LCYB) is the synthetic enzyme that directly controls the massive accumulation of β-carotene. However, the regulatory mechanism underlying the CmLCYB-mediated β-carotene accumulation in oriental melon is fairly unknown. Here, we screened and identified a transcription factor, CmNAC34, by combining bioinformatics analysis and yeast one-hybrid screen with CmLCYB promoter. CmNAC34 was located in the nucleus and acted as a transcriptional activator. The expression profile of CmNAC34 was consistent with that of CmLCYB during the fruit ripening. Additionally, the transient overexpression of CmNAC34 in oriental melon fruit promoted the expression of CmLCYB and enhanced β-carotene concentration, while transient silence of CmNAC34 in fruit was an opposite trend, which indicated CmNAC34 could modulate CmLCYB-mediated β-carotene biosynthesis in oriental melon. Finally, the yeast one-hybrid (Y1H), electrophoretic mobility shift assay (EMSA), β-glucuronidase (GUS) analysis assay, and luciferase reporter (LUC) assay indicated that CmNAC34 could bind to the promoter of CmLCYB and positively regulated the CmLCYB transcription level. These findings suggested that CmNAC34 acted as an activator to regulate β-carotene accumulation by directly binding the promoter of CmLCYB, which provides new insight into the regulatory mechanism of carotenoid metabolism during the development and ripening of oriental melon.

Single-cell ATAC-seq data is challenging to analyse for reasons such as high dimensionality and sparsity. Here, the authors develop SCALE, a deep learning method that leverages latent feature extraction for various tasks of scATACseq data analysis.

Stripe rust is a serious threat to wheat production. Here, the authors reveal that the resistance gene, only present in the wheat progenitor Aegilops tauschii and its derived synthetic wheat, encodes a nucleotide oligomerization domain-like receptor and confers resistance in common wheat and barley.

Abstract Background High risk human papillomaviruses (HPV) plays important roles in the development of cervical cancer, a number of other anogenital cancer and they are increasingly found in oropharyngeal squamous cell carcinoma (OPSCC), however there has not been comprehensive analysis about the role how these viruses play in the development of OPSCC. Methods To characterize the physical status of HPV within OPSCC and to determine the effect this has throughout the host genome, we have performed 30-40X whole genome sequencing (WGS) on the BGI sequencing platform on 34 OPSCCs: 28 of which were HPV positive. We then examined the sequencing data to characterize the HPV copy number and HPV physical status to determine what effect they have on both HPV and human genome structural changes. Results WGS determined the HPV copy number across the viral genome. HPV copy number ranged from 1 copy to as high as 150 copies in each individual OPSCC. Independent of HPV copy number, most tumors had either a small or a very large deletion in the viral genome. We discovered that these deletions were the result of either HPV integration into the human genome or HPV-HPV sequence junctions. WGS revealed that ~ 70% of these tumors had HPV integrations within the human genome and HPV integration occurred independent of HPV copy number. Individual HPV integrations were found to be highly disruptive resulting in structural variations and copy number changes at or around the integration sites. Conclusions WGS reveals that there is a great complexity in both HPV sequences present and the HPV integrations events in HPV positive OPSCCs tumors. Thus HPV may be playing different roles in the development of different OPSCCs and this further challenge the HPV-driven carcinogenesis model first proposed for cervical cancer.

Abstract Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. Cytosolic TERC-53 levels respond to mitochondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53 functions downstream of mitochondria as a signal of mitochondrial functions. Here, we show that cytosolic TERC-53 plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53 levels affects cellular senescence and cognition decline in 10 months old mouse hippocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc −/− cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals.

Abstract Background Lipoxygenases (LOXs) play significant roles in abiotic stress responses, and identification of LOX gene promoter function can make an important contribution to elucidating resistance mechanisms. Here, we cloned the CmLOX08 promoter of melon (Cucumis melo) and identified the main promoter regions regulating transcription in response to signalling molecules and abiotic stresses. Results The 2054-bp promoter region of CmLOX08 from melon leaves was cloned, and bioinformatic analysis revealed that it harbours numerous cis-regulatory elements associated with signalling molecules and abiotic stress. Five 5′-deletion fragments obtained from the CmLOX08 promoter—2054 (LP1), 1639 (LP2), 1284 (LP3), 1047 (LP4), and 418 bp (LP5)—were fused with a GUS reporter gene and used for tobacco transient assays. Deletion analysis revealed that in response to abscisic acid, salicylic acid, and hydrogen peroxide, the GUS activity of LP1 was significantly higher than that of the mock-treated control and LP2, indicating that the − 2054- to − 1639-bp region positively regulates expression induced by these signalling molecules. However, no deletion fragment GUS activity was induced by methyl jasmonate. In response to salt, drought, and wounding treatments, LP1, LP2, and LP4 promoted significantly higher GUS expression compared with the control. Among all deletion fragments, LP4 showed the highest GUS expression, indicating that − 1047 to − 1 bp is the major region regulating promoter activity and that the − 1047 to − 418-bp region positively regulates expression induced by salt, drought, and wounding, whereas the − 1284 to − 1047-bp region is a negative regulatory segment. Interestingly, although the GUS activity of LP1 and LP2 was not affected by temperature changes, that of LP3 was significantly induced by heat, indicating that the − 1284- to − 1-bp region is a core sequence responding to heat and the − 2054- to − 1284-bp region negatively regulates expression induced by heat. Similarly, the − 1047- to − 1-bp region is the main sequence responding to cold, whereas the − 2054- to − 1047-bp region negatively regulates expression induced by cold. Conclusions We cloned the CmLOX08 promoter and demonstrated that it is a signalling molecule/stress-inducible promoter. Furthermore, we identified core and positive/negative regulatory regions responding to three signalling molecules and five abiotic stresses.

Considering the tradable credits' characteristics of public goods, this paper incorporated public pricing method into the tradable credits pricing analysis. Also, in view of budget imbalance of marginal cost pricing, we tried to make a price for the tradable credit by using an average pricing method. This paper constructed an average pricing method of tradable credits by the angles of travel behavior and economics. The main work of this paper is listed as follows: (1) Consumers and producers of tradable credits in the traffic network are defined, and their mathematical constraints are given; (2) Under the tradable credits scheme, the production cost function of producers and demanding function of consumers are analyzed; (3) The mathematical description of average pricing is given; and (4) At last, the process of average pricing on tradable credits are reappeared by a simple numerical example, which average pricing's efficiency on tradable credits. In a word, average cost pricing pushes the application of tradable credits scheme in urban traffic management forward, which has certain theoretical and practical significance to improve the urban traffic demand management.

This paper applies the reference-dependent utility theory (RDUT) to model traveler's route choice behaviors under travel time variability and develops a user equilibrium (UE) model based on RDUT for stochastic traffic networks. The proposed model explicitly considers both the absolute utility (or consumption utility) and the relative utility (or gain-loss utility) in the travelers' path choice decision procedure. The former is determined by the stochastic path travel time while the latter is measured by the actual path travel time relative to a reference time point. Subsequently, the RDUT-based UE model, which can be equivalently formulated as a variational inequality problem and solved by a heuristic algorithm, is employed to explore how risk aversion and reference-dependent preference jointly determine network equilibrium patterns. Both the features and applicability of the proposed RDUT-UE model and the designed solution algorithm are demonstrated in two numerical examples. This paper further establishes an RDUT-based dynamic traffic system which incorporates commuters' learning, choosing, and renewing process in dynamic path choices and captures the day-to-day dynamic traffic flows. Another numerical example is presented to show how the dynamic traffic system evolves to the UE status.

In transport planning and urban planning, some standard traffic indicators are proposed to measure the level of urban transportation system. In early days, household traffic survey data is almost the only dataset in traffic indicators evaluation. However, numerous facts have proved that household traffic survey is expensive and dangerous. To our delight, with the development of social networking, mobile internet, electronic commerce and so on, various data are growing exponentially. The vast amount of data provides some new methods with better visualization, easier to understand and more efficient in measuring the level of urban transportation system. This paper tries to have an analysis on traffic evaluation indicators in transport planning based on the multi-source data, i.e., household traffic survey data, license plate recognition data, smart card data and location based service (LBS) data. Results show that household travel survey data has the strongest applicability, which can be used to all indicators calculation. However, due to the limitations of data content, only parts of indicators can be calculated based on license plate recognition data, smart card data and LBS data. After comparing with the standard indicators, the following results are obtained: (1) In Qingdao city, the well-run public transport system has not yet formed. Statistics found that the whole trip time of public transport in central urban area (full day) is 2.5 times that of individual motor vehicle, which don’t meet the standard requirement (i.e., 1.5 times). (2) Parts of residents’ travel distance is too far. Results show that the average travel distance of the top 15% travelers is about 3.3 times of the average travel distance of urban residents, which don’t satisfy the standard requirement (i.e., 2.5 times). (3) Bus passengers and car users spend too much time on travelling compared other travel modes. Especially bus passengers need to spend 52 minutes to travel (the standard value is 40 minutes). (4) In Qingdao city, the proportion of public transport had been increasing. On the contrary, the non-motor travel has been decreasing.

This study is to investigate the role of Sphingosine-1-phosphate (S1P) in the asthma progression, and the involvement of autophagy. Airway remodeling mice were subjected to the HE, PAS, and Masson staining. Protein expression levels in the tissues, samples and model cells were detected with ELISA, Western blot analysis, and immunohistochemical/immunofluorescent analysis. The S1P2 receptor antagonist JTE-013 decreased the inflammatory cell infiltration and goblet cell production in asthmatic mice tissues. The IL-1, IL-4, IL-5 and serum IgE contents were decreased in bronchoalveolar lavage fluid, while the Beclin1 expression in lung tissues was decreased. The LC3B1 to LC-3B2 conversion was decreased, with increased P62 accumulation and decreased p-P62 expression. In airway remodeling mice, JTE-013 significantly decreased collagen deposition in lung tissues and decreased smooth muscle cell smooth muscle activating protein expression. In lung tissue, the expression levels of Beclin1 were decreased, with decreased LC3B1 to LC-3B2 conversion, as well as the increased P62 accumulation and decreased p-P62 expression. However, these effects were reversed by the RAC1 inhibitor EHT 1864. Similar results were observed for the silencing of S1P2 receptor in the cells, as shown by the decreased Beclin1 expression, decreased LC3B1 to LC-3B2 conversion, increased P62 accumulation, and decreased p-P62 expression. The smooth muscle activators were significantly decreased in the JTE-013 and EHT1864 groups, and the EHT 1864 + S1P2-SiRNA expression level was increased. S1P is involved in the progression of asthma and airway remodeling, which may be related to the activation of S1PR2 receptor and inhibition of autophagy through RAC1.

The reasonable accessibility assessment method is an important basis for the measurement of the level of prehospital emergency medical services. There is no general model for prehospital emergency care in traditional accessibility evaluation, and its supply-demand characteristics have also been ignored. Based on the three-step floating catchment area (3SFCA) model, the supply-demand three-step floating catchment area (SD3SFCA) model is proposed in this paper, which can express the difference between supply and demand of prehospital emergency medical services and accurately simulate unified dispatching of emergency centers. The unified dispatching behavior of emergency centers is simulated based on the potential service capacity of emergency stations with a supply-demand difference. The supply capacity of different emergency facilities is quantified from the perspective of infrastructure and technical quality. The needs of typical population densities are taken into account and adjusted by the weighting index. The validity of the model is verified, with the prehospital emergency medical service in the West Coast New District of Qingdao as an example. The results show that the model can effectively measure the accessibility level of prehospital emergency services and truly reflect the characteristics of supply and demand. Compared with previous models, the model has been significantly improved, which can provide an important reference for optimizing the allocation of prehospital emergency resources.

Short-term traffic flow prediction can provide a basis for traffic management and support for travelers to make decisions. Accurate short-term traffic flow prediction also provides necessary conditions for the sustainable development of the traffic environment. Although the application of deep learning methods for traffic flow prediction has achieved good accuracy, the problem of combining multiple deep learning methods to improve the prediction accuracy of a single method still has a margin for in-depth research. In this article, a combined deep learning prediction (CDLP) model including two paralleled single deep learning models, CNN-LSTM-attention model and CNN-GRU-attention model, is established. In the model, a one-dimensional convolutional neural network (1DCNN) is used to extract traffic flow local trend features and RNN variants (LSTM and GRU) with attention mechanism are used to extract long temporal dependencies trend features. Moreover, a dynamic optimal weighted coefficient algorithm (DOWCA) is proposed to calculate the dynamic weights of CNN-LSTM-attention and CNN-GRU-attention with the goal of minimizing the sum of squared errors of the CDLP model. Then, the neuron number, loss function, optimization algorithm, and other parameters of the CDLP model are discussed and set through experiments. Finally, the training set and test set for the CDLP model are established through the processing of traffic flow data collected from the field. The CDLP model is trained and tested, and the prediction results of traffic flow are obtained and analyzed. It indicates that the CDLP model can fit the change trend of traffic flow very well and has better performance. Furthermore, under the same dataset, the results from the CDLP model are compared with baseline models. It is found that the CDLP model has higher prediction accuracy than baseline models.

Radio telescopes play an important role in lunar exploration projects, manned space flight projects, and navigation systems. China is constructing a giant 110 m aperture ground-based fully steerable radio telescope in Qitai County, Xinjiang Uygur Autonomous Region. In this paper, a 110 m aperture fully steerable radio telescope prestressed back frame structure is proposed and optimized to improve the reflector accuracy and to reduce the weight of the telescope. First, prestressed cables are introduced into the back frame structure, and three innovative cable layout schemes are presented. Second, for stress state analysis, the wind pressure distribution on the main reflector is explored using wind tunnel experiments. Third, some improvements in genetic algorithms for addressing computational complexity are explained. Finally, the effects of prestressed cables on the weight reduction and reflector accuracy improvement are analysed. Additionally, in order to evaluate the safety of the prestressed back frame structure, its strength has been checked, and the internal force and displacement under static conditions and in earthquakes are interpreted in detail.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum in vitro blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.

BackgroundOur previous study showed that guanine nucleotide exchange factor T (GEFT) was highly expressed in colorectal cancer (CRC) tissues and CRC patients with high GEFT expression had a poor prognosis, and suggested the close link of GEFT expression and CRC tumorigenesis/metastasis. In this text, the roles and upstream regulatory mechanisms of GEFT in the development and progression of CRC were further investigated.MethodsExpression levels of GEFT mRNA and LINC00355 was measured by RT-qPCR assay. Protein levels of lin-28 homologue A (LIN28A) and GEFT were determined by western blot assay. Cell proliferative, migratory, and invasive capacities were assessed by CCK-8, Transwell migration and invasion assays, respectively. The effect of GEFT knockdown on CRC tumorigenesis was examined by mouse xenograft experiments in vivo. GEFT mRNA stability was examined by actinomycin D assay. The relationships of LINC000355, LIN28A, and GEFT were explored by RNA pull down and RIP assays.ResultsGEFT was highly expressed in CRC tissues and cell lines. GEFT knockdown inhibited CRC cell proliferation, migration, and invasion, and hindered CRC xenograft tumor growth. GEFT overexpression alleviated the detrimental effects of LINC00355 loss on CRC cell proliferation, migration, and invasion. LINC00355 promoted GEFT expression and enhanced GEFT mRNA stability via LIN28A. LIN28A knockdown weakened the promotive effect of LINC00355 on CRC cell proliferation, migration, and invasion.ConclusionLINC00355 facilitated CRC tumorigenesis and progression by increasing GEFT expression via LIN28A, deepening our understanding on roles and upstream regulatory mechanisms of GEFT in CRC development and progression.

Due to the availability of materials and low cost for production, fused deposition modeling is becoming the most widely used additive manufacturing (AM) technology. However, the reasonable choice of process parameters for FDM is a significant task that directly affects the performance of the printed part. Therefore, it is necessary to investigate the influences of various process parameters on the quality characteristics of the components. The objectives of this study are to thoroughly review the current state of research that characterizes, estimates the effects of process parameters on mechanical properties, and summarizes the conclusions of existing works. In addition, some general issues of the presented research are summarized, and the need for future development is also emphasized. Finally, the research proposes several areas that deserve further study in this field.

Photocrosslinked Gelatin–Methacryloyl (GelMA) has been widely used in the field of 3D bioprinting due to its excellent biological properties, but its properties are not yet optimized. With the advent of embedded printing, the balance between hydrogel printability and cell viability is expected to be achieved. Agarose microgel is a good support material because of its simple preparation, good biocompatibility, high melting point, and good rheology. In this study, aiming at realizing a GelMA/Agarose suspension printing system, the printing effect of the suspension process was explored, and a suitable process printing window was defined. The resulting scaffolds showed better water absorption and elasticity, but larger deformation during printing. This study explored some potential roles of suspension baths in embedded printing, paving the way for the preparation of good suspension structures that can be convenient for customized tissue engineering applications.

Precise classification of bacteria facilitates prediction of their ecological niche. The genus Enterobacter includes pathogens of plants and animals but also beneficial bacteria that may require reclassification. Here, we propose reclassification of Enterobacter FY-07 (FY-07), a strain that has many plant-growth-promoting traits and produces bacterial cellulose (BC), to the Kosakonia genera. To re-examine the taxonomic position of FY-07, a polyphasic approach including 16S rRNA gene sequence analysis, ATP synthase β subunit (atpD) gene sequence analysis, DNA gyrase (gyrB) gene sequence analysis, initiation translation factor 2 (infB) gene sequence analysis, RNA polymerase β subunit (rpoB) gene sequence analysis, determination of DNA G + C content, average nucleotide identity based on BLAST, in silico DNA–DNA hybridization and analysis of phenotypic features was applied. This polyphasic analysis suggested that Enterobacter sp. FY-07 should be reclassified as Kosakonia oryzendophytica FY-07. In addition, the potential of FY-07 to promote plant growth was also investigated by detecting related traits and the colonization of FY-07 in rice roots.

As the leading causes of global death, cardiovascular diseases are generally initiated by artery-related disorders such as atherosclerosis, thrombosis, and aneurysm. Although clinical treatments have been developed to rescue patients suffering from artery-related disorders, the underlying pathologies of these arterial abnormalities are not fully understood. Biofabrication techniques pave the way to constructing diseased artery in vitro models using human vascular cells, biomaterials, and biomolecules, which are capable of recapitulating arterial pathophysiology with superior performance compared with conventional planar cell culture and experimental animal models. This review discusses the critical elements in the arterial microenvironment which are important considerations for recreating biomimetic human arteries with the desired disorders in vitro. Afterward, conventionally biofabricated platforms for the investigation of arterial diseases are summarized, along with their merits and shortcomings, followed by a comprehensive review of advanced biofabrication techniques and the progress of their applications in establishing diseased artery models.

Zebrafish are widely used to investigate candidate genes for human diseases. While the emergence of CRISPR-Cas9 technology has revolutionized gene editing, the use of individual guide RNAs limits the efficiency and application of this technology in functional genetics research. Multiplexed genome editing significantly enhances the efficiency and scope of gene editing. Herein, we describe an efficient multiplexed genome editing strategy to generate zebrafish mutants. Following behavioural tests and histological examination, we identified one new candidate gene (tmem183a) for hearing loss. This study provides a robust genetic platform to quickly obtain zebrafish mutants and to identify candidate genes by phenotypic readouts.

Sulfide and methane emissions always simultaneously exist in natural environment and constitute a major topic of societal concern. However, the metabolic environments between sulfate-reducing bacteria (SRB) and methanogenic archaea (MA) exist a great difference, which seems to be opposite to the coexisting phenomenon. To explore this issue, the comprehensive biofilm structures, substrate consuming and metabolism pathways of SRB and MA were investigated in a case study of urban sewers. The results showed that, due to the stricter environmental requirements of MA than SRB, SRB became the preponderant microorganism which promoted the rapid generation of sulfide in the initial period of biofilm formation. According to a metagenomic analysis, the SRB appeared to be more preferential than MA in sewers, and the preponderant SRB could provide a key medium (Methyl-coenzyme M) for methane metabolism. Therefore, the diversity of MA gradually increased, and the symbiosis system formed preliminarily. In addition, via L-cysteine, methane metabolism also participated in sulfide consumption which was involved in cysteine and methionine metabolism. This phenomenon of sulfide consumption led to the forward reaction of sulfide metabolism, which could promote sulfide generation while stabilizing the pH value (H+ concentration) and S2- concentrations which should have inhibited SRB and MA production. Therefore, the heavily intertwined interactions between sulfide and methane metabolism provided environmental security for SRB and MA, and completely formed the symbiosis between SRB and MA. Based on these findings, an ecological model involving synergistic mechanism between sulfide and methane generation is proposed and this model can also improve understanding on the symbiosis of SRB and MA in the natural environment.

Understanding the molecular mechanism of drug resistance helps to identify an effective target for breast cancer therapy. In this study we investigated the regulatory role of Obg-like ATPase 1 which is involved in multiple uses of drug resistance against breast cancer. Paclitaxel resistant cell line (MCF-7-PTR) was developed by a continuous increasing paclitaxel concentration. MTT assay was used to validate either acquired resistant or OLA1 modified cell lines. qRT-PCR, western blotting, apoptosis, and cell cycle assays were executed to evaluate gene and protein expression in cell lines. A series of in vitro assays was performed in the cells with RNAi-mediated knockdown to expound the regulatory function of OLA1 in breast cancer. We demonstrated that OLA1 was highly correlated with either acquired or intrinsic resistance of breast cancer. Further study showed that escalated expression of OLA1 promoted the EMT process in tumor cells through TGF-β/Smad signaling cascades, resulting in the enhanced expression of anti-apoptosis-related proteins (cleaved caspase3, Bax, Bcl-2) and the strengthening depolymerization of microtubules in tumor cells. Our findings revealed that OLA1 enhanced the anti-apoptotic ability and elucidated a regulatory role of OLA1 in promoting chemotherapy resistance of breast cancer. Chemo-sensitivity of the disease can be thus enhanced significantly by knocked down OLA1, which led to the inactivation of the TGF-β/Smad signaling cascades, polymerized microtubules, and promoted cell apoptosis. Our data suggest that OLA1 may be developed as a potential target to improve chemotherapy of patients with breast cancer.

Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release in vitro. However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.

Taxi as a door-to-door, all-weather way of travel is an important part of the urban transportation system. A fundamental understanding of temporal-spatial variation and its related influential factors are essential for taxi regulation and urban planning. In this paper, we explore the correlation between taxi demand and socio-economic, transport system and land use patterns based on taxi GPS trajectory and POI (point of interest) data of Qingdao City. The geographically weighted regression (GWR) model is used to describe the influence factors of spatial heterogeneity of the taxi demand and visualize the spatial distributions of parameter estimations. Results indicate that during the peak hours, there are some differences in taxi demand between workdays and weekends. Residential density and housing prices increase the number of taxi trips. Road density, parking lot density and bus station density are positively associated with the taxi demand. It is also found that the higher of the proportion of commercial area and public service area, the greater of the taxi demand, while the proportion of residential area and the land use mix have a negative impact on taxi demand. This paper provides some references for understanding the internal urban environmental factors generating from the taxi travel demand, and provides insights for reducing the taxi vacancy rate, forecasting taxi temporal-spatial demand and urban public transportation system planning.

Accessibility could reflect people’s travel convenience, cities’ livability and sustainability, and reduce the negative impacts on the environment and safety. It is therefore a key concept in city sustainable development policies across the world. Based on the multi-source data, this paper tries to have an empirical analysis on the urban accessibility of Qingdao city from the angles of spatial linkage strength, job-hosting ratio and distributions of large-scale hospitals and schools. The multisource data includes navigation data, location based service (LBS) data, Point of Interest (POI) data and the census data. The inter-city linkage strength and internal-external linkage strength are used to evaluate the spatial linkages of the urban agglomeration. Results show that the spatial connectivity and public facilities have a very strong positive correlation with the inter-city accessibility. Meanwhile, providing transport infrastructure and services could greatly strengthen the accessibility between two areas. Job-housing ratio is used to analyze the distribution of residents and jobs. Results show that the job-housing ratio declines gradually from the central urban areas to the surrounding areas. Distributions of large-scale hospitals and schools are used to estimate the service capacity of public facilities. Results show that public service facilities are mainly concentrated in the developed areas. On the contrary, the other areas developed slowly due to lack of supporting service facilities.

Generally, road characteristics (such as the longitudinal slope and pavement damage) have an important effect on logistics distribution path, not only the vehicle fuel economy and driving safety but also the benefits and efficiency of logistics companies. It is necessary to explore the influence of road characteristics on logistics distribution path planning. First, a road characteristics evaluation value is defined to quantify road characteristics. With the application of analytic hierarchy process (AHP), the road characteristics evaluation index system with three criteria and eleven indices was built, and then the calculation of the road characteristics evaluation value is proposed based on the fuzzy comprehensive evaluation method. Secondly, a mathematical model of logistics distribution path planning is proposed, in which road characteristics and distance are comprehensively considered. Thirdly, an adaptive genetic algorithm (AGA) is presented with customized crossover operator for the solution of the mathematical model. Finally, through simulation by a real example, the influences of road characteristics and distance on the optimal distribution path are discussed, and the results show the model considering the road characteristics and distance comprehensively achieves superior distribution paths to that considering the distance or road characteristics only.

The worldwide rise in heatwave frequency poses a threat to plant survival and productivity. Determining the new marker phenotypes that show reproducible response to heat stress and contribute to heat stress tolerance is becoming a priority. In this study, we describe a protocol focusing on the daily changes in plant morphology and photosynthetic performance after exposure to heat stress using an automated noninvasive phenotyping system. Heat stress exposure resulted in an acute reduction of the quantum yield of photosystem II and increased leaf angle. In longer term, the exposure to heat also affected plant growth and morphology. By tracking the recovery period of the WT and mutants impaired in thermotolerance (hsp101), we observed that the difference in maximum quantum yield, quenching, rosette size, and morphology. By examining the correlation across the traits throughout time, we observed that early changes in photochemical quenching corresponded with the rosette size at later stages, which suggests the contribution of quenching to overall heat tolerance. We also determined that 6 h of heat stress provides the most informative insight in plant’s responses to heat, as it shows a clear separation between treated and nontreated plants as well as the WT and hsp101. Our work streamlines future discoveries by providing an experimental protocol, data analysis pipeline, and new phenotypes that could be used as targets in thermotolerance screenings.