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Abstract Nucleic acid tests are essential for the accurate diagnosis and control of infectious diseases. However, current assays are not easily scalable for a large population, due to the requirement of laboratory settings or special equipment. Here, we developed an integrated box for instant nucleic acid screening which fully integrates nucleic acid release, amplification, and results visualization for self-service standalone test. Importantly, the operation of the box runs on a novel gamepad-like interface, which allows deployment of the box in home settings and operation by users without any prior professional training. The performance of the box is empowered by an RNA extraction-free sample inactivation process and nested recombinase polymerase amplification chemistry and exhibits sensitivity comparable to reverse transcription-quantitative polymerase chain reaction with high specificity for severe acute respiratory syndrome coronavirus 2 RNA in a reaction time of 30 minutes directly from fresh swab sample to results. These innovations make the box a novel platform for a convenient, accurate, and deployable point-of-care testing scheme.

Volatile organic compounds (VOCs) are crucial precursors in the formation of ozone (O3). The sources of pollution are complex and significantly impact O3 generation. Long-term exposure to high-concentration O3 environments causes serious damage to organisms. High-altitude areas experience continuous high temperatures and strong solar radiation, which can easily produce O3 through photochemical reactions, making these areas prone to frequent air pollution. This study utilizes the National Positioning Station of the Yinchuan Urban Ecosystem in Ningxia to conduct field synchronous observations, gathering data on VOCs, meteorological variables, and O3. By employing machine learning algorithms, we examined the seasonal distribution characteristics of VOCs, their pollution sources, and their impact on O3. The results show that the seasonal distribution of VOCs areas is low in spring and autumn and high in summer and winter. The components with higher volume fraction contribution are m-tolualdehyde in spring and summer, ethane in autumn, and acetylene in winter. The main emission sources of VOCs pollution are hydrocarbon volatile emission in spring and winter, solvent volatilization emission in summer, and industrial sources in autumn. VOCs have a negative effect on O3, with a greater impact in winter and spring, evidenced by standardized effect values of −0.26 and −0.24. The key components affecting O3 in VOCs vary by season. Aromatic hydrocarbons are the key components in spring and winter, with contribution rates of 22 % and 21.3 %. Alkenes are the key components in summer and autumn (24.5 % and 26.8 %). Among meteorological variables, temperature is the key factor affecting O3, while wind speed is the key factor affecting O3 only in winter. This study aims to clarify the sources of VOCs pollution in different seasons and their impact on O3, providing a theoretical basis and technical support for the prevention and control of VOCs and O3 pollution in high-altitude areas.

A synthetic jet piezo (PE) pump with an inlet channel structured akin to a diffuser/nozzle, featuring smoothed walls, was developed. The synthetic jet was characterized by analyzing the internal flow field of the PE pump. Furthermore, the flow performance of this novel PE pump was compared with that of a basic PE pump, thereby demonstrating the advantages of the proposed design. Utilizing regression equations and standardized effect plots derived from the response surface method, both the main and interaction effects of parameters on the flow rate were assessed. Subsequently, the flow performance of the optimized PE pump was evaluated through experimental testing. Additionally, air impact cooling experiments were conducted, focusing on the influence of the impact distance on cooling performance. The findings indicated that the PE pump's open cavity height, closed cavity height, outlet diameter, and orifice diameter were 1.3 mm, 0.5 mm, 1.5 mm, and 0.8 mm, respectively. The proposed synthetic jet PE pump achieved a flow rate of 1832.3 ml/min at 50 Vpp and 4.6 kHz. Furthermore, it was observed that the operation of the PE pump reduced the temperature of the heater by 63 % at an impact distance of 20 mm.

Abstract Epithelial ovarian cancer (EOC) is an often‐fatal malignancy marked by the development of resistance to platinum‐based chemotherapy. Thus, accurate prediction of platinum drug efficacy is crucial for strategically selecting postoperative interventions to mitigate the risks associated with suboptimal therapeutic outcomes and adverse effects. Tissue‐derived extracellular vesicles (tsEVs), in contrast to their plasma counterparts, have emerged as a powerful tool for examining distinctive attributes of EOC tissues. In this study, 4D data‐independent acquisition (DIA) proteomic sequencing was performed on tsEVs obtained from 58 platinum‐sensitive and 30 platinum‐resistant patients with EOC. The analysis revealed a notable enrichment of differentially expressed proteins that were predominantly associated with immune‐related pathways. Moreover, pivotal immune‐related proteins (IRPs) were identified by LASSO regression. These factors, combined with clinical parameters selected through univariate logistic regression, were used for the construction of a model employing multivariate logistic regression. This model integrated three tsEV IRPs, CCR1, IGHV_35 and CD72, with one clinical parameter, the presence of postoperative residual lesions. Thus, this model could predict the efficacy of initial platinum‐based chemotherapy in patients with EOC post‐surgery, providing prognostic insights even before the initiation of chemotherapy.

The application of a diammonium phosphate coating effectively mitigates direct contact between the phosphate fertilizer and the soil, thus minimizing phosphorus fixation. Humic acid holds a pivotal role in augmenting soil quality and activating the soil’s phosphorus reserves. Notably, when combined with humic acid, diammonium phosphate significantly enhances the utilization efficiency of phosphate fertilizer. However, there is a paucity of literature exploring the dynamics of nutrient transport in soil when humic acid is paired with coated phosphate fertilizers. To assess the impact of the combined application of coated diammonium phosphate and humic acid on wheat yield enhancement, we conducted pot experiments along with leaching and ammonia volatilization simulation tests, aiming to elucidate the effects of this combination on nutrient transport. The study explored the effects of three distinct treatments: coated diammonium phosphate (CP), coated diammonium phosphate combined with humic acid (PHA), and coated diammonium phosphate combined with humic acid (CPHA). The investigation focused on analyzing their impacts on wheat yield, ammonia volatilization, soil-available phosphorus, nitrate nitrogen, ammonium nitrogen, soil-available potassium, as well as the mobilization and transport of calcium and magnesium in the soil. (1) Compared to the P treatment, the PHA and CP treatments significantly increased grain yield by 17.2% and 13.5%, respectively. The PHA treatment also increased effective panicle number by 12.9%. Overall, the CP, PHA, and CPHA treatments improved grain yield by 13.5%, 17.2%, and 19.1% compared to the P treatment. (2) The CP and PHA treatments reduced available phosphorus by 95.6% and 49.2%, calcium by 2.0% and 67.0%, and magnesium by 11.6% and 46.1% compared to the P treatment. Ammonium nitrogen decreased by 37.0% and 64.3%, while nitrate nitrogen increased by 14.0% in CP and slightly decreased by 0.8% in PHA. In the leaching solution, PHA and CP treatments reduced available phosphorus by 96.7% and 62.5%, increased calcium by 5.0% and 78.9%, decreased ammonium nitrogen by 2.2% and 43.4%, and decreased nitrate nitrogen by 10.6% and 13.0%. The PHA and CPHA treatments increased available phosphorus in the 0–20 cm soil layer by 1.4 times and 25.8%, respectively. (3) The CP treatment reduced ammonia volatilization by 87.0% compared to the P treatment, while the CPHA treatment further reduced it by 87.5% compared to the PHA treatment. The application of coated diammonium phosphate efficiently delays nutrient release and reduces nutrient leaching in the soil. Additionally, the integration of humic acid significantly improves the availability of phosphorus in the soil, minimizing phosphorus loss. Notably, the combined application of humic acid and coated diammonium phosphate leads to a significant increase in soil phosphorus content, subsequently enhancing soil nutrient availability, conserving fertilizer, and ultimately resulting in an improved wheat yield.

DOX/TPOR4@CB[7]4 was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of photodynamic therapy on SH-SY5Y cells was assessed using the MTT assay, while flow cytometry analysis was employed to detect cell apoptosis. Confocal laser scanning microscopy was utilized to observe the intracellular distribution of DOX/TPOR4@CB[7]4 in SH-SY5Y cells. Additionally, fluorescence imaging of DOX/TPOR4@CB[7]4 in nude mice bearing SH-SY5Y tumors and examination of the combined effects of photodynamic and chemical therapies were conducted. The incorporation of CB[7] significantly enhanced the optical properties of DOX/TPOR4@CB[7]4, resulting in increased ROS production and pronounced toxicity towards SH-SY5Y cells. Moreover, both the apoptotic and mortality rates exhibited significant elevation. In vivo experiments demonstrated that tumor growth inhibition was most prominent in the DOX/TPOR4@CB[7]4 group. π–π interactions facilitated the binding between DOX and photosensitizer TPOR, with TPOR’s naphthalene hydrophilic groups encapsulated within CB[7]’s cavity through host–guest interactions with CB[7]. Therefore, CB[7] can serve as a nanocarrier to enhance the combined application of chemical therapy and photodynamic therapy, thereby significantly improving treatment efficacy against neuroblastoma tumors.

Purpose: Patients with genetic diseases often seek testing to reach a firm diagnosis. Based on clinical phenotypes, exome sequencing for small-nucleotide variations or array-based methods for copy-number variations (CNVs) are commonly offered to identify the underlying causative genetic variants. In this study, we investigated whether data from a standard ES test could be used to additionally identify pathogenic CNVs and increase diagnostic yield. Methods: Prospectively, 134 patients presenting with a skin condition suspected of being genetic in origin were offered the next-generation variant exon screening (ngVES) test. Sequencing data were analyzed for both single-nucleotide variants and CNVs using established algorithms. Results: The positive detection rate for skin diseases using ngVES was 66% (88/134) with the most common diagnoses being neurofibromatosis type1 (n = 48) and tuberous sclerosis type2 (n = 12). The diagnostic increased yield from 58% to 66% was the result of additional detection of pathogenic CNVs. Each of the 9 CNVs were verified by independent genetic tests. Conclusion: The advances in the ngVES bioinformatics pipeline are proofs of concept, which improved identification of genetic variants associated with skin disease. Simultaneous single-nucleotide variants/INDEL and CNV detection by this approach demonstrates ngVES potential as a first-tier screen for any suspected genetic disease.

High-temperature aerogels have garnered significant attention as promising insulation materials in various industries such as aerospace, automotive manufacturing, and beyond, owing to their remarkable thermal insulation properties coupled with low density. With advancements in manufacturing techniques, the thermal resilience of aerogels has considerable improvements. Notably, polyimide-based aerogels can endure temperatures up to 1000 °C, zirconia-based aerogels up to 1300 °C, silica-based aerogels up to 1500 °C, alumina-based aerogels up to 1800 °C, and carbon-based aerogels can withstand up to 2500 °C. This paper systematically discusses recent advancements in the thermal insulation performance of these five materials. It elaborates on the temperature resistance of aerogels and elucidates their thermal insulation mechanisms. Furthermore, it examines the impact of doping elements on the thermal conductivity of aerogels and consolidates various preparation methods aimed at producing aerogels capable of withstanding temperatures. In conclusion, by employing judicious composition design strategies, it is anticipated that the maximum tolerance temperature of aerogels can surpass 2500 °C, thus opening up new avenues for their application in extreme thermal environments.

Abstract Objective Facial expressions have been served as clinical symptoms to convey mental conditions in psychiatry. This paper proposes to recognize patients with schizophrenia (SCZ) using their facial images based on deep learning algorithm, and to investigate objective differences in facial expressions between SCZ patients and healthy controls using deep learning algorithm and statistical analyses. Methods The study consists of two parts. The first part recruited 106 SCZ patients and 101 healthy controls, and videotaped their facial expressions through a fixed experimental paradigm. The video data were randomly divided into two sets, one for training a convolutional neural network (CNN) with the classification of “healthy control” or “SCZ patient” as output and the other for evaluating the classification result of the trained CNN. In the second part, all facial images of the recruited participants were put into another CNN separately, which was priorly trained with a facial expression database and will output the most likely facial expressions of the recruited participants. Statistical analyses were performed on the obtained facial expressions to find out the objective differences in facial expressions between the two recruited groups. Results The trained CNN achieved an overall accuracy of 95.18% for classifying “healthy control” or “SCZ patient.” Statistical results on the obtained facial expressions demonstrated that the objective differences between the two recruited groups were statistically significant (p

Summary: Small extracellular vesicles (sEVs) and large extracellular vesicles (lEVs), play vital roles in intercellular communication. We optimized a method that extracts EVs from epithelial ovarian cancer (EOC) tissues for the purpose of investigating whether cryopreservation of EOC tissues affects the phenotypes, contents, and biological functions of extracted EVs. EV morphology, the number and size distribution of EVs, and EV-related markers were analyzed. Storage of lysates at −80°C decreased lEV yield and increased sEV yield, whereas storage of tissues at −80°C increased both sEV and lEV yields; neither changed the morphology or particle mass ratio of EVs. The two cryopreservation groups retained over 90% of proteins and 80% of miRNAs detected in the “fresh” group. EVs extracted following lysate/tissue storage at −80°C could also promote angiogenesis and invasive migration ability in human endothelial cells. Cryopreserved EOC tissue may benefit clinical applications for studies of tissue-derived EVs, especially EV proteins-related ones.

Conventional potassium chloride granules have inefficient applications in agricultural production due to particle irregularity and low fluidity. The application of controlled-release potassium chloride could increase the potassium-use efficiency and alleviate the shortage of potassium ore resources. In this study, a well-rounded potassium chloride fertilizer core was prepared, using the graft modification of polyurea to enhance the coating rate and release performance. The adhesive and tensile characteristics of the modified polyurea binder, as well as the granule properties of modified polyurea binder potassium chloride, were studied to determine the ideal lignin-grafted ratio. The effect of the modified polyurea binder with potassium chloride on the properties of coated fertilizer was investigated. The findings, shown by radar maps of the binder’s properties, demonstrated that the ideal mass ratio of the modified lignin polyurea binder to urea is 1:2. The Fourier-transform infrared spectroscopy results demonstrated that the amino functional groups of lignin were enhanced, improving the product’s interfacial compatibility with the polyurea matrix. Compared to humic acid (HA; 12%) and bentonite (Ben; 30%) treatments, the granule intensity of the 9.9%—1:2 treatment considerably increased by 139.10% and 38.86%, respectively, while the static angle of the granules reduced by 16.67% and 3.81%. The 28-day cumulative release rate of the modified polyurea (9.9%—2:1) with a 5% coating thickness was the lowest (28%), 42% lower than that of the lowest conventional treatment. In summary, the creation of a bio-lignin polyurea binder under the optimum conditions reduced the need for petrochemical-based materials, allowed the preparation of fertilizer with granules of increased fluidity, and enabled the successful coating of a high-salt potassium fertilizer, offering a novel technique for the high-value application of potash fertilizer coating.

Many factors have been identified as having the ability to affect the sensitivity of rapid antigen detection (RAD) tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to identify the impact of sample processing on the sensitivity of the RAD tests. We explored the effect of different inactivation methods, viral transport media (VTM) solutions, and sample preservation on the sensitivity of four RAD kits based on two SARS-CoV-2 strains. Compared with non-inactivation, heat inactivation significantly impacted the sensitivity of most RAD kits; however, β-propiolactone inactivation only had a minor effect. Some of the VTM solutions (VTM2, MANTACC) had a significant influence on the sensitivity of the RAD kits, especially for low viral-loads samples. The detection value of RAD kits was slightly decreased, while most of them were still in the detection range with the extension of preservation time and the increase of freeze–thaw cycles. Our results showed that selecting the appropriate inactivation methods and VTM solutions is necessary during reagent development, performance evaluation, and clinical application.

Abstract The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors show survival benefits in ovarian cancer patients with BRCA1/2 mutation or homologous recombination (HR) deficiency, but only limited efficacy in HR-proficient ones. Another drug, arsenic trioxide (ATO) or arsenic drug (RIF), exerts antitumor effects via inducing DNA damage. Here, we investigated the combined therapeutic effects of the PARP inhibitors and the arsenic compound in HR-proficient ovarian cancer. The combined treatment of niraparib, olaparib, or fluazolepali with ATO showed a significant suppression in tumor cell viability and colony formation. The drug treatment also induced synergistic inhibition of cell proliferation and DNA damage, and acceleration of cell apoptosis in two HR-proficient ovarian cancer cell lines SKOV3 and CAOV3, either by simultaneous or sequential administration. The mechanism underlying these synergistic effects were reflected by the significantly increased ratio of cleaved-PARP/total PARP and decreased ratio of p-AKT/total AKT. Consistently, the combination of olaparib with RIF synergistically reduced the tumor growth in mouse xenograft models. In conclusion, the arsenic compound greatly sensitizes HR-proficient ovarian cancer cells to the PARP inhibitors, and our findings provide an evidence for the clinical treatment development of this combination in HR-proficient ovarian cancer patients.

Omicron (B.1.1.529) was first detected in a sample collected in Botswana on November 11, 2021, and has rapidly replaced Delta as the dominant global variant given the robust transmissibility. Moreover, it displays a lower virulence than other variants. However, the pathogenicity of Omicron appears to be underestimated in view of the increasing levels of herd immunity through natural infection or vaccination. Additionally, the volume of hospitalizations and deaths increase in proportion to the number of cases due to the high transmissibility of Omicron. Therefore, vaccination remains an important public health priority. Notably, a series of important mutations in the Omicron spike protein, especially in the receptor-binding domain and N-terminal domain, appears to be associated with immune escape capacity, reducing the willingness of people to receive vaccines. Herein, we provide an in-depth discussion to assess the effectiveness of the second and third vaccination against Omicron variant. On the one hand, the two-dose vaccination program adopted by many countries is insufficient to prevent Omicron infection given the mutations correlated with immune escape and the decline in vaccine efficacy over time. On the other hand, booster dose significantly increases the protective efficacy against Omicron infection. Most importantly, heterologous third dose vaccination induces a more robust immune response than homologous booster dose. Therefore, under the special background of this pandemic, there is an urgent need to accelerate the third dose of vaccination, especially providing better booster vaccination strategies, to combat emerging Omicron variant.

A large surface area dendritic mesoporous silica material (KCC-1) was successfully synthesized and used as a support to confine SnO2 nanoparticles (NPs). Owing to the large specific surface area and abundant mesoporous structure of dendritic KCC-1, the SnO2 NPs were highly dispersed, resulting in significantly improved CO catalytic oxidation activity. The obtained Snx/KCC-1 catalysts (x represents the mass fraction of SnO2 loading) exhibited excellent CO catalytic activity, with the Sn7@KCC-1 catalyst achieving 90% CO conversion at about 175 °C. The SnO2 NPs on the KCC-1 surface in a highly dispersed amorphous form, as well as the excellent interaction between SnO2 NPs and KCC-1, positively contributed to the catalytic removal process of CO on the catalyst surface. The CO catalytic removal pathway was established through a combination of in situ diffuse reflectance infrared transform spectroscopy and density-functional theory calculations, revealing the sequential steps: ① CO → CO32−ads, ② CO32−ads → CO2free+SnOx−1, ③ SnOx−1+O2 → SnOx+1. This study provides valuable insights into the design of high-efficiency non-precious metal catalysts for CO catalytic oxidation catalysts with high efficiency.

The membrane-associated RING-CH (MARCH) proteins are E3 ligases regulating stability of plasma membrane (PM) proteins. Here, Liu et al. show that MARCH8 suppresses Influenza A virus infection in vitro and in vivo through redirecting M2 protein from the PM to lysosomes for degradation.

Abstract Background Metastasis is the key cause of death in ovarian cancer patients. To figure out the biological nature of cancer metastasis is essential for developing effective targeted therapy. Here we investigate how long non-coding RNA (lncRNA) SPOCD1-AS from ovarian cancer extracellular vesicles (EVs) remodel mesothelial cells through a mesothelial-to-mesenchymal transition (MMT) manner and facilitate peritoneal metastasis. Methods EVs purified from ovarian cancer cells and ascites of patients were applied to mesothelial cells. The MMT process of mesothelial cells was assessed by morphology observation, western blot analysis, migration assay and adhesion assay. Altered lncRNAs of EV-treated mesothelial cells were screened by RNA sequencing and identified by qRT-PCR. SPOCD1-AS was overexpressed or silenced by overexpression lentivirus or shRNA, respectively. RNA pull-down and RNA immunoprecipitation assays were conducted to reveal the mechanism by which SPOCD1-AS remodeled mesothelial cells. Interfering peptides were synthesized and applied. Ovarian cancer orthotopic implantation mouse model was established in vivo. Results We found that ovarian cancer-secreted EVs could be taken into recipient mesothelial cells, induce the MMT phenotype and enhance cancer cell adhesion to mesothelial cells. Furthermore, SPOCD1-AS embedded in ovarian cancer-secreted EVs was transmitted to mesothelial cells to induce the MMT process and facilitate peritoneal colonization in vitro and in vivo. SPOCD1-AS induced the MMT process of mesothelial cells via interacting with G3BP1 protein. Additionally, G3BP1 interfering peptide based on the F380/F382 residues was able to block SPOCD1-AS/G3BP1 interaction, inhibit the MMT phenotype of mesothelial cells, and diminish peritoneal metastasis in vivo. Conclusions Our findings elucidate the mechanism associated with EVs and their cargos in ovarian cancer peritoneal metastasis and may provide a potential approach for metastatic ovarian cancer therapeutics.

Abstract Background Distal 8p duplication is rare but clinically significant. Duplication syndrome results in variable phenotypes, such as developmental delay, intellectual disability, and malformation of the heart. We aimed to provide a better understanding of the phenotypes by studying duplication and its effects in a single family. Methods In a family with a previously induced labor (second fetus) at 12 weeks gestation due to increased nuchal translucency (3.5 mm), copy number variation sequencing (CNV-seq) revealed a 16.22 Mb deletion of 8p23.3p22. For their subsequent pregnancy, the family requested a prenatal diagnosis as well as CNV-seq, karyotyping and FISH testing of all family members. Results The first and third children were found to have a 16.22 Mb duplication of 8p23.3p22, containing the 8p23.1 duplication syndrome region. The duplication was inherited from their father, a carrier with a translocation of 8p22 and 22q13. We confirmed that the duplication site was located on chromosome 22q13 by combining the results of CNV-seq, karyotype and FISH. The first child is a 7.5-year-old boy. At one month old, he was diagnosed with a ventricular septal defect and treated surgically at age four. His growth and intelligence developed well, and he performed well in school. His primary issue is an inability to distinguish between the blade alveolars and retroflexes in speech. The third fetus had a normal ultrasound index from beginning until birth. The family elected to continue the pregnancy, and the baby was born healthy, providing us the opportunity to evaluate the effects of 8p23.3p22 duplication by comparison with the brother. Conclusion Our study makes a significant contribution to the literature because this relatively rare condition can have significant phenotypical consequences, and an understanding of the inheritance and variability of phenotypes caused by this mutation is essential to an increased understanding of the condition.

The association between a high-fat diet (HFD) consumption and emotional/cognitive disorders is widely documented. One distinctive feature of the prefrontal cortex (PFC), a kernel emotion- and cognition-related brain region, is its protracted adolescent maturation, which makes it highly vulnerable to the detrimental effects of environmental factors during adolescence. Disruption of the PFC structure and function is linked to emotional/cognitive disorders, especially those that emerge in late adolescence. A HFD consumption is common among adolescents, yet its potential effects on PFC-related neurobehavior in late adolescence and any related underlying mechanisms are yet to be established. In the present study, adolescent (postnatal days 28–56) male C57BL/6J mice were fed a control diet (CD) or a HFD and underwent behavioral tests in addition to Golgi staining and immunofluorescence targeting of the medial PFC (mPFC). The HFD-fed adolescent mice exhibited anxiety- and depression-like behavior and abnormal mPFC pyramidal neuronal morphology accompanied by alterations in microglial morphology indicative of a heightened state of activation and increased microglial PSD95+ inclusions signifying excessive phagocytosis of the synaptic material in the mPFC. These findings offer novel insights into the neurobehavioral effects due to adolescent HFD consumption and suggest a contributing role in microglial dysfunction and prefrontal neuroplasticity deficits for HFD-associated mood disorders in adolescents.

The preservation of image details in the defogging process is still one key challenge in the field of deep learning. The network uses the generation of confrontation loss and cyclic consistency loss to ensure that the generated defog image is similar to the original image, but it cannot retain the details of the image. To this end, we propose a detail enhanced image CycleGAN to retain the detail information during the process of defogging. Firstly, the algorithm uses the CycleGAN network as the basic framework and combines the U-Net network’s idea with this framework to extract visual information features in different spaces of the image in multiple parallel branches, and it introduces Dep residual blocks to learn deeper feature information. Secondly, a multi-head attention mechanism is introduced in the generator to strengthen the expressive ability of features and balance the deviation produced by the same attention mechanism. Finally, experiments are carried out on the public data set D-Hazy. Compared with the CycleGAN network, the network structure of this paper improves the SSIM and PSNR of the image dehazing effect by 12.2% and 8.1% compared with the network and can retain image dehazing details.

Abstract Objective To investigate the detailed roles and mechanisms of tumor-derived exosomes in progression and metastasis of ovarian cancer in vitro. Methods Exosomes were isolated by differential centrifugation method; the morphology, size and biological markers of exosomes were separately defined by transmission electron microscopy, nanoS90 and Western blotting; Trans-well chambers assay was used to assess the ability of migration and invasion of recipient cells uptaking the exosomes from HO8910PM cells. The downstream molecule was screened by mass spectrometry.CD44 was identified by western blotting and the function of CD44 was identified by trans-well chambers assay and CCK8 assay. Results Exosomes derived from HO8910PM cells could be transferred to HO8910 cells and promote cell migration and invasion in the recipient cells of ovarian cancer. And CD44 could be transferred to the HO8910 cells through exosomes from HO8910PM cells and influence the migration and invasion ability of HO8910 cells. Conclusion The more aggressive subpopulation can transfer a metastatic phenotype to the less one via secreting exosomes within a heterogeneous tumor. CD44 may be a potential therapeutic approach for ovarian cancer.

Seasonal human coronaviruses (HCoVs) including HCoV-229E, -OC43, -NL63, and -HKU1 widely spread in global human populations. However, the relevance of humoral response against seasonal HCoVs to COVID-19 pathogenesis is elusive. In this study, we profiled the temporal changes of IgG antibody against spike proteins (S-IgG) of SARS-CoV-2 and seasonal HCoVs in 838 plasma samples collected from 344 COVID-19 patients. We tested the antigenic cross-reactivities of S protein between SARS-CoV-2 and seasonal HCoVs and evaluated the correlations between the levels of HCoV-OC43 S-IgG and the disease severity in COVID-19 patients. We found that SARS-CoV-2 S-IgG titres mounted until days 22–28, whereas HCoV-OC43 antibody titres increased until days 15–21 and then plateaued until day 46. However, IgG titres against HCoV-NL63, −229E, and -HKU1 showed no significant increase. A two-way cross-reactivity was identified between SARS-CoV-2 and HCoV-OC43. Neutralizing antibodies against SARS-CoV-2 were not detectable in healthy controls who were positive for HCoV-OC43 S-IgG. HCoV-OC43 S-IgG titres were significantly higher in patients with severe disease than those in mild patients at days 1–21 post symptom onset (PSO). Higher levels of HCoV-OC43 S-IgG were also observed in patients requiring mechanical ventilation. At days 1–10 PSO, HCoV-OC43 S-IgG titres correlated to disease severity in the age group over 60. Our data indicate that there is a correlation between cross-reactive antibody against HCoV-OC43 spike protein and disease severity in COVID-19 patients.

Lili Ren et al. investigate antibody response from 176 COVID-19 patients who presented different stages of their disease. This study suggests the late onset of antibody response as a risk factor for disease severity and a limited role of antibody titers in predicting the disease severity of COVID-19.

Here, using a humanized phage display library with recombinant SARS- CoV-2 receptor binding domain (RBD) proteins, the authors identify a number of single domain antibodies (sdAbs) that neutralize SARS-CoV-2 in vitro by inhibiting the interaction of the RDB with the host entry receptor ACE2.

Wenzhou virus (WENV) was first identified in rodents and Asian house shrews in Wenzhou, Zhejiang Province, China. However, little is known about the prevalence of WENV infections in humans in China. To determine the threat that WENV may pose to humans, we determine the seroprevalence of WENV in healthy individuals in China in this study. Cross-reactivities of nucleoprotein (NP) were detected between Lymphocytic choriomeningitis virus (LCMV) and WENV using Western blot and ELISA assy. The prevalence of specific IgG antibodies against WENV NP was investigated in different age groups of 830 healthy individuals aged 0–70 years old in China using a competition ELISA assay. The results indicate that WENV and LCMV share cross-reactive epitopes between NPs. The total seroprevalence of WENV in healthy adults was 4.6%, with 3.6% (8/221) for individuals 15–44 years of age, 5.4% (17/317) for individuals 45–59 years of age, and 4.1% (4/98) for older adults over 60. The total seroprevalence of WENV in children under age 15 was 1.5%, with 2.9% (1/34) in children aged 2–5 years, and 2.2% in 5–14 years (2/91). The finding suggests that WENV or WENV-like virus may sporadically infect humans of China.

The pandemic of SARS-CoV-2 post a significant threat to public health. Here the authors show, by screening 23 viral proteins, that both structural and non-structural SARS-CoV-2 proteins are capable of modulating host innate immunity and type interferon responses, with this information serves to warrant further studies on SARS-CoV-2 pathogenesis.

ABSTRACTTo identify the association between the kinetics of viral load and clinical outcome in severe coronavirus disease 2019 (COVID-19) patients, a retrospective study was performed by involved 188 hospitalized severe COVID-19 patients in the LOTUS China trial. Among the collected 578 paired throat swab (TS) and anal swab (AS) samples, viral RNA was detected in 193 (33.4%) TS and 121 (20.9%) AS. A higher viral RNA load was found in TS than that of AS, with means of 1.0 × 106 and 2.3 × 105 copies/ml, respectively. In non-survivors, the viral RNA in AS was detected earlier than that in survivors (median of 14 days vs 19 days, P = 0.007). The positivity and viral load in AS were higher in non-survivors than that of survivors at week 2 post symptom onset (P = 0.006). A high initial viral load in AS was associated with death (OR 1.368, 95% CI 1.076–1.741, P = 0.011), admission to the intensive care unit (OR 1.237, 95% CI 1.001–1.528, P = 0.049) and need for invasive mechanical ventilation (OR 1.340, 95% CI 1.076–1.669, P = 0.009). Our findings indicated viral replication in extrapulmonary sites should be monitored intensively during antiviral therapy.

Non-uniform temperature distributions in ovens affect the quality of baked goods and raise concerns regarding food safety. Traditional research on oven performance focuses on the heating mechanisms in simulated ovens and does not involve quantitative analysis of baked goods. This study proposes a model for calculating the uniformity of baked goods based on image processing technology, to quantitatively assess the distribution uniformity of different baked states and digitally express the internal temperature field distribution in the oven. First, the image of the baked goods is captured using a digital camera. Then, it is preprocessed to obtain an image containing only the region showing the baked goods. Subsequently, the simple linear iterative clustering segmentation algorithm is employed to extract the baked states. Finally, a meshing model is applied to calculate the distribution variance of each baked state, and the evaluation index describing the uniformity of the baked goods image is obtained by normalizing the variance in the distribution. The simple linear iterative clustering segmentation algorithm expresses the color features of acquired baked goods images in the form of superpixels. By determining the distribution and proportion of different baked states, the proposed method can qualitatively and quantitatively reflect the spatial distribution of the temperature fields inside the oven corresponding to the baked goods image. This provides a strong basis for further evaluation of the heat distribution field inside the oven.

Abstract Although purely organic room‐temperature phosphorescence (RTP) has drawn widespread attention in recent years, regulatable phosphorescence resonance energy transfer (PRET) supramolecular switch is still rare. Herein, single molecular dual‐fold supramolecular light switches, which are constructed by phenylpyridinium salts modified diarylethene derivatives (DTE‐Cn, n = 3, 5) and cucurbit[8]uril (CB[8]) are reported. Significantly, biaxial [3]pseudorotaxane displayed efficiently reversible RTP after binding with CB[8] and the phosphorescence quenching efficiency is calculated up to be 99%. Furthermore, the binary supramolecular assembly can coassemble with Cy5 to form ternary supramolecular assembly showing efficiently PRET, which is successfully applied in switchable near infrared (NIR) mitochondria‐targeted cell imaging and photocontrolled data encryption. This supramolecular strategy involving energy transfer provides a convenient approach for phosphorescent application in biology and material fields.

BackgroundThe relatively high incidence and the clinical symptoms of sex chromosome aneuploidies (SCAs) make prenatal screening of SCAs an attractive option for pregnant women. However, limited studies have assessed the clinical performance of noninvasive prenatal testing (NIPT) for screening SCAs. This study was performed to evaluate the clinical performance of NIPT for SCAs in singleton pregnancies in central China.MethodsNoninvasive prenatal testing was performed using next-generation sequencing. Standard Z-score analysis was used to identify fetal SCAs. NIPT-positive results were confirmed by invasive prenatal diagnosis (IPD).ResultsA total of 42,164 pregnant women with singleton pregnancies were recruited in this study. They were divided into the following five groups with different clinical indications: with ultrasound soft index abnormalities (9.23%, 3,892/42,164); with advanced maternal age (22.14%, 9,336/42,164); with high risk for maternal serum screening (MSS) (18.35%, 7,738/42,164); with an intermediate risk for MSS (26.6%, 11,215/42,164); and with low risk (23.68%, 9,983/42,164). In all, 223 women had a high risk for SCAs by NIPT with a positive rate of 0.53%. There was no significant difference associated with the five groups in the positive rate. Of all of the positive results, 89 were 45,X (39.91%), 38 were 47,XXX (17.04%), 31 were 46,XY,del(X) (13.90%), 50 were 47,XXY (22.42%,), and 15 were 47,XYY (6.73%). Finally, 147 participants (65.92%) chose to undergo IPD, and 47 cases were confirmed. The combined positive predictive value (PPV) of NIPT for SCA was 31.97% (47/147). PPV was high for 47,XYY (100%, 11/11), moderate for 47,XXX (42.86%, 9/21) and 47,XXY (45.45%, 15/33), but low for 45,X (16.13%, 10/62) and 46,XY,del(X) (10%, 2/20). The termination rates of Turner syndrome and 47,XXY syndrome were higher than 47,XXX and 47,XYY syndromes.ConclusionIn this relatively large cohort, we evaluated the value of NIPT for SCAs. Our data showed that with informed consent and subsequent professional genetical consulting, NIPT can be a useful method to screen SCAs.

Background: The overconsumption of a high-fat diet (HFD) has been repeatedly blamed as being a possible contributor to the global prevalence of emotional problems in modern society. Our group recently demonstrated the deleterious effect of a chronic HFD throughout adulthood on both emotional behavior and neuroplasticity markers in mice. As a heightened preference for palatable HFDs from the time of the juvenile period (when the brain is particularly vulnerable to environmental insults) is universal among populations around the world, a comparison of the consequences of chronic HFDs starting from juveniles or adults will assist in obtaining better knowledge of the impact that chronic HFDs have on mental health, thus potentially leading to the discovery of more effective strategies for reducing the incidence of psychiatric disorders. Methods: In the present study, male C57BL/6J mice with an initial age of 4 weeks (IA-4 W) or 8 weeks (IA-8 W) were separately assigned to two subgroups and fed either a control diet (CD, 10 kJ% from fat) or HFD (60 kJ% from fat) for 9 months followed by an analysis focused on metabolic, emotional behavioral, and neuroplastic profiles. Results: The results illustrated that, in addition to abnormal glucolipid metabolism and insulin sensitivity, mice on a chronic HFD exhibited increased levels of anxiety and depression-like behaviors and aberrant hippocampal neuroplasticity. When compared with IA-8 W mice, several changes indicating systemic metabolic disturbance and neurobehavioral disorder after chronic HFD consumption were aggravated in IA-4 W mice, accompanied by exaggerated impairments in hippocampal insulin sensitivity and neurogenesis. Conclusions: These results not only provide in vivo evidence that the juvenile stage is a critical period of vulnerability to detrimental effects of HFD consumption on metabolic and neuronal function but also suggest dampened hippocampal insulin signaling as a potential link between prolonged HFD consumption and negative neurobehavioral outcomes. Considering the substantial burden posed by psychiatric disorders and the high prevalence of HFD among youth, these observations are meaningful for raising awareness of the harmful effects of excessive dietary fat intake and developing strategy for preventing mental disorders.

Abstract Background Chromosome 18p deletion syndrome is a disease caused by the complete or partial deletion of the short arm of chromosome 18, there were few cases reported about the prenatal diagnosis of 18p deletion syndrome. Noninvasive prenatal testing (NIPT) is widely used in the screening of common fetal chromosome aneuploidy. However, the segmental deletions and duplications should also be concerned. Except that some cases had increased nuchal translucency or holoprosencephaly, most of the fetal phenotype of 18p deletion syndrome may not be evident during the pregnancy, 18p deletion syndrome was always accidentally discovered during the prenatal examination. Case presentations In our case, we found a pure partial monosomy 18p deletion during the confirmation of the result of NIPT by copy number variation sequencing (CNV-Seq). The result of NIPT suggested that there was a partial or complete deletion of X chromosome. The amniotic fluid karyotype was normal, but result of CNV-Seq indicated a 7.56 Mb deletion on the short arm of chromosome 18 but not in the couple, which means the deletion was de novo deletion. Finally, the parents chose to terminate the pregnancy. Conclusions To our knowledge, this is the first case of prenatal diagnosis of 18p deletion syndrome following NIPT.NIPT combined with ultrasound may be a relatively efficient method to screen chromosome microdeletions especially for the 18p deletion syndrome.

Noise-induced hearing loss (NIHL) is one of the most prevalent forms of acquired hearing loss, and it is associated with aberrant microglial status and reduced hippocampal neurogenesis; however, the nature of these associations is far from being elucidated. Beyond its direct effects on the auditory system, exposure to intense noise has previously been shown to acutely activate the stress response, which has increasingly been linked to both microglial activity and adult hippocampal neurogenesis in recent years. Given the pervasiveness of noise pollution in modern society and the important implications of either microglial activity or hippocampal neurogenesis for cognitive and emotional function, this study was designed to investigate how microglial status and hippocampal neurogenesis change over time following acoustic exposure and to analyze the possible roles of the noise exposure-induced stress response and hearing loss in these changes. To accomplish this, adult male C57BL/6J mice were randomly assigned to either a control or noise exposure (NE) group. Auditory function was assessed by measuring ABR thresholds at 20 days post noise exposure. The time-course profile of serum corticosterone levels, microglial status, and hippocampal neurogenesis during the 28 days following noise exposure were quantified by ELISA or immunofluorescence staining. Our results illustrated a permanent moderate-to-severe degree of hearing loss, an early but transient increase in serum corticosterone levels, and time-dependent dynamic alterations in microglial activation status and hippocampal neurogenesis, which both present an early but transient change and a late but enduring change. These findings provide evidence that both the stress response and hearing loss contribute to the dynamic alterations of microglia and hippocampal neurogenesis following noise exposure; moreover, noise-induced permanent hearing loss rather than noise-induced transient stress is more likely to be responsible for perpetuating the neurodegenerative process associated with many neurological diseases.

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4–6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

SARS-CoV-2 has become a global threat to public health. Infected individuals can be asymptomatic or develop mild to severe symptoms, including pneumonia, respiratory distress, and death. This wide spectrum of clinical presentations of SARS-CoV-2 infection is believed in part due to the polymorphisms of key genetic factors in the population. In this study, we report that the interferon-induced antiviral factor IFITM3 inhibits SARS-CoV-2 infection by preventing SARS-CoV-2 spike-protein-mediated virus entry and cell-to-cell fusion. Analysis of a Chinese COVID-19 patient cohort demonstrates that the rs12252 CC genotype of IFITM3 is associated with SARS-CoV-2 infection risk in the studied cohort. These data suggest that individuals carrying the rs12252 C allele in the IFITM3 gene may be vulnerable to SARS-CoV-2 infection and thus may benefit from early medical intervention.

Adolescence is a developmental epoch characterized by massive neural circuit remodeling; thus, the brain is particularly vulnerable to environmental influences during this period. Excessive high-fat diet (HFD) consumption, which is very common among adolescents, has long been recognized as a potent risk factor for multiple mood disorders, including depression and anxiety. However, the precise mechanisms underlying the influences of HFD consumption in adolescence on emotional health are far from clear. In the present study, C57BL/6 mice were fed a control diet (CD) or HFD for about 4 weeks from postnatal day (P) 28 to P60, spanning most of the adolescence period, and then subjected to behavioral assessments and histological examinations. HFD mice exhibited elevated levels of depression and anxiety, decreased hippocampal neurogenesis, and excessive microglial activation in the ventral hippocampus. Furthermore, in HFD-fed mice, microglia showed increased DCX+ inclusions, suggesting aberrant microglial engulfment of newborn neurons in HFD-fed adolescents. To our knowledge, this is the first observation suggesting that the negative effects of HFD consumption in adolescence on emotion and neuroplasticity may be attributed at least in part to aberrant microglial engulfment of nascent neurons, extending our understanding of the mechanism underlying HFD-related affective disorders in young people.

Abstract Introduction Exosomal microRNA (miRNA) as a mediator of intercellular communication plays an essential part in tumor‐relevant angiogenesis. Therapy against angiogenesis has been demonstrated to have a remarkable antitumor efficacy in various malignancies, but not as expected in ovarian cancer. Methods Exosomes were isolated by ultracentrifugation. Exosomal miRNA sequencing and gene function experiments were used to identify the differential expressed miRNAs in exosomes and their mRNA targets. SKOV3 cell line that stably overexpressed miR‐92b‐3p was constructed by lentivirus. In vitro, angiogenesis was analyzed by tube formation assay and migration assay. The angiogenic and antitumor effects in vivo were assessed in zebrafish and nude mouse models. Combination index was calculated to assess the synergetic inhibition of angiogenesis between miR‐92b‐3p and Apatinib. Peptides were conjugated with exosomal membranes to obtain engineered exosomes. Results Ovarian cancer cell‐derived exosomes facilitated the angiogenesis and migration capability of vascular endothelial cells in vitro and in vivo. The expression of miR‐92b‐3p was much lower in ovarian cancer cell‐derived exosomes than that in immortalized ovarian epithelial cell‐derived exosomes. The exosomal miR‐92b‐3p modulated tumor‐associated angiogenesis via targeting SOX4. Besides, Peptide‐engineered exosomes with overexpressed miR‐92b‐3p showed the stronger abilities of anti‐angiogenesis and antitumor than parental exosomes, whether alone or combined with Apatinib. Conclusions Our findings demonstrate the effect and mechanism of exosomal miR‐92b‐3p from ovarian cancer cells on tumor‐associated angiogenesis and the potential of artificially generated exosomes with overexpressed miR‐92b‐3p to be used as anti‐angiogenic agent, which may provide a new approach for anti‐angiogenic therapy of ovarian cancer.

Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3.

COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.

Melanoma is a life-threatening cancer with limited treatments. Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern recognition receptor (PRR) crucial to RNA virus sensing, interferon production, and tumor suppression. Quercetin, a natural flavonoid, has particularly therapeutic interests to prevent and treat cancer, for its pharmacological effects against oxidant, inflammation, and angiogenesis. Quercetin was investigated for its anti-melanoma activity and potential mechanisms in this study. We found that quercetin inhibited mouse melanoma growth in vivo, and suppressed proliferation and promoted apoptosis of both B16 and A375 cells in vitro. Quercetin upregulated IFN-α and IFN-β expression through activating RIG-I promoter in B16 cells. The induction of IFN-α and IFN-β, which could be severely impaired by silencing RIG-I induced interferon stimulated genes (ISGs). Moreover, RIG-I likely amplifies antitumor effects by activating signal transduction and activator of transcription 1 (STAT1) in the IFN-JAK-STAT pathway in an autocrine and paracrine manner. Our study provided novel insights regarding biological and anti-proliferative activities of quercetin against melanoma, and we identified RIG-I as a potential target in anti-tumor therapies.

Disruptive behavior by passengers delayed at airport terminals not only affects personal safety but also reduces civil aviation efficiency and passenger satisfaction. This study investigated the causal mechanisms of disruptive behavior by delayed passengers in three aspects: environmental, managerial, and personal. Data on flight delays at Shenzhen Airport in 2018 were collected and analyzed. The main factors leading to disruptive behavior by delayed passengers were identified, and an early warning model for disturbances was developed using multiple logistic regression and a back-propagation(BP) neural network. The results indicated that the proposed model and method were feasible. Compared to the logistic regression model, the BP neural network model had advantages in predicting disturbances by delayed passengers, showing higher prediction accuracy. The BP network weight analysis method was used to obtain the influence weight of each factor on behavior change of delayed passengers. The influence weight of different factors was obtained, providing an assistant decision-making method to address disruption from flight-delayed passengers.

Abstract: MAPKs play important roles in platelet activation. However, the molecular mechanisms by which MAPKs are regulated in platelets remain largely unknown. Real-time polymerase chain reaction and western blot data showed that MEKK3, a key MAP3K family member, was expressed in human and mouse platelets. Then, megakaryocyte/platelet-specific MEKK3-deletion (MEKK3−/−) mice were developed to elucidate the platelet-related function(s) of MEKK3. We found that agonist-induced aggregation and degranulation were reduced in MEKK3−/− platelets in vitro. MEKK3 deficiency significantly impaired integrin αIIbβ3–mediated inside-out signaling but did not affect the outside-in signaling. At the molecular level, MEKK3 deficiency led to severely impaired activation of extracellular signal–regulated kinases 1/2 (ERK1/2) and c-Jun NH2-terminal kinase 2 but not p38 or ERK5. In vivo, MEKK3−/− mice showed delayed thrombus formation following FeCl3-induced carotid artery injury. Interestingly, the tail bleeding time was normal in MEKK3−/− mice. Moreover, MEKK3−/− mice had fewer microthrombi, reduced myocardial infarction (MI) size, and improved post-MI heart function in a mouse model of MI. These results suggest that MEKK3 plays important roles in platelet MAPK activation and may be used as a new effective target for antithrombosis and prevention of MI expansion.

The SPX domain-encoding proteins are believed to play important roles in phosphorus (Pi) homeostasis and signal transduction in plants. However, the overall information and responses of SPXs to phosphorus deficiency in pines, remain undefined. In this study, we screened the transcriptome data of Pinus massoniana in response to phosphorus deprivation. Ten SPX domain-containing genes were identified. Based on the conserved domains, the P. massoniana SPX genes were divided into four different subfamilies: SPX, SPX-MFS, SPX-EXS, and SPX-RING. RNA-seq analysis revealed that PmSPX genes were differentially expressed in response to phosphorus deprivation. Furthermore, real-time quantitative PCR (RT-qPCR) showed that PmSPX1 and PmSPX4 showed different expression patterns in different tissues under phosphorus stress. The promoter sequence of 2284 bp upstream of PmSPX1 was obtained by the genome walking method. A cis-element analysis indicated that there were several phosphorus stress response-related elements (e.g., two P1BS elements, a PHO element, and a W-box) in the promoter of PmSPX1. In addition, the previously obtained PmSPX2 promoter sequence contained a W-box, and it was shown that PmWRKY75 could directly bind to the PmSPX2 promoter using yeast one-hybrid analysis in this study. These results presented here revealed the foundational functions of PmSPXs in maintaining plant phosphorus homeostasis.

Abstract Background The sources and variants types of the copy number variations (CNVs) in prenatal fetal, and the critical role of parental origin on the interpretation of fetal CNVs are unclear. Methods One hundred and forty‐one prenatal core families with abnormal CNVs were selected and performed by low‐coverage massively parallel CNV sequencing (CNV‐seq). Results The data showed that 72.3% of fetal CNVs were derived from parents, and 27.7% were new variations. Sixty‐three cases were heterozygous deletion, 70 cases were threefold duplication, six cases were complex deletion and duplication, and two cases were fourfold repeats. That means the rate of heterozygous deletion and duplication was approximate one. In addition, in parental‐derived fetal abnormal CNVs reports, before validating parental origin, 62 CNVs were variants of uncertain significance (VUS), 15 CNVs were likely benign, 20 CNVs were likely pathogenic, and 5 CNVs were pathogenic. However, after validating parental origin, the total clinical significance changed into 12 VUS, 89 likely benign, 1 likely pathogenic, and 0 pathogenic. The clinical interpretation of 78.4% fetal CNVs was changed and tended to be benign after parental CNVs were detected. Besides, we followed up all families. 93.3% parental‐derived fetal and 30.3% fetus in new mutation group were born healthy. Conclusion Parental origin verification has an important significance for interpretation on the clinical significance of fetal CNVs.

Abstract Background Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. The large sizes of these genes and the absence of mutation hot spots have complicated mutational analysis by routine PCR‐based approaches. In recent years, the development of next‐generation sequencing (NGS) has made possible the time‐ and cost‐effective and accurate analysis of the three genes in a single step. Methods Here, we analyze COL4A3, COL4A4, and COL4A5 simultaneously in 29 AS patients using NGS. Candidate mutations were validated by classic Sanger sequencing and Real‐time PCR. Results Twenty two new mutations and 10 known mutations were detected. Of those novel mutations, 18, 3, and 1 mutations were detected in COL4A5, COL4A4, and COL4A3, respectively. Twenty six patients showed X‐linked inheritance, one showed autosomal recessive inheritance and two showed digenic inheritance (DI). Conclusion A comparison of the clinical manifestations caused by different types of mutations in COL4A5 suggested that large fragment mutations are relatively more severe than the other missense mutations and AS by some mutations may show inter‐ and intra‐familial phenotypic variability. It is important to consider these transmission patterns in the clinical evaluation according to the results of genetic testing, especially for DI. Twenty two new mutations can expand the genotypic spectrum of AS.

Vascular protein sorting-associated protein 33B (VPS33B) plays important roles in hepatic polarity, which directly maintains the functional structure of the liver. It has reported that VPS33B has close association with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome. Unfortunately, no further studies were conducted to reveal the role of Vps33b in the homeostasis of bile acids. In the current study, hepatic Vps33b-depleted male mice were used to investigate the metabolomics and lipidomics profiles of hepatic Vps33b deficiency based on ultrahigh-performance liquid chromatography coupled with an electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS) system. Hepatic Vps33b-depleted male mice displayed cholestasis and slight liver damage with increased serum levels of ALT, AST, ALP and T-Bili compared to wild-type mice. Targeted metabolomics analysis of bile acids revealed that increased taurine-conjugated bile acids accumulated in the serum of hepatic Vps33b-depleted mice, while unconjugated bile acids were prone to decrease, accompanied by the regulation of bile acid homeostasis-related genes. In addition, lipid profiles were significantly altered with the lack of Vps33b in the liver. A variety of lipids, such as triglycerides and sphingomyelins, were significantly decreased in the liver and increased in the serum of hepatic Vps33b-depleted mice compared to those in wild-type mice. Our study demonstrated that Vps33b influences the progress of liver metabolism both in bile acid circulation and lipid metabolism, which is involved in the progression of liver cholestasis in mice.

The seipin gene (BSCL2) was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2). Neuronal seipin-knockout (seipin-nKO) mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG) and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT) mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi). In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1) and neurogenic differentiation 1 (NeuroD1) mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705) was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice.