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The accumulation of sand induced by wind poses a significant challenge to the safety and maintenance of railways in arid and desert regions. Accurate calculation and prediction of sand accumulation are crucial for ensuring continuous railway operation. This research is centered on the region significantly impacted by sand accumulation along the Ganquan Railway. Wind speed, wind direction, and sand carrying capacity data near this section were monitored. Using the collected wind speed, wind direction, and wind-sand flow density data, numerical simulations were conducted using the Computational Fluid Dynamics (CFD) method to predict the amount of sand accumulation within the sand mitigation measures of the Ganquan Railway. Monitoring results indicate that the dominant wind direction in spring and summer is due west, while in autumn and winter it is southwest, with an average wind speed of 12 m/s. A positive correlation was observed between wind-sand flow density and wind speed. The wind-sand flow density above 2 m was nearly zero, indicating that the wind-sand flow structure is concentrated within 2 m from the ground, with an average wind-sand flow density of 3.50×10−5 kg/m3. Through numerical simulation, the characteristics of the wind field and sand accumulation distribution within the calculation domain were determined. A relationship equation between sand accumulation mass and width over time was derived. Initially, the sand accumulation width increases uniformly and then stabilizes, while the sand accumulation mass rises uniformly to a plateau before in-creasing rapidly. From these findings, the optimal period for sand removal was identified as between 350 and 450 days after the sand mitigation measures are put into operation.

Cadmium, as a typical heavy metal, has the potential to induce soil pollution and threaten human health through the soil-plant-human pathway. The conventional evaluation method based on the total content in soil cannot accurately represent the content migrated from the food chain to plants and the human body. Previous studies focused on the process of plant enrichment of heavy metals in soil, and very few studies directly predicted human exposure or risk through the labile state of Cd in soil. Hence, a relatively accurate and convenient prediction model of Cd release and translocation in the soil-rice-human system was developed. This model utilizes available Cd and soil parameters to predict the bioavailability of Cd in soil, as well as the in vitro bioaccessibility of Cd in cooked rice. The bioavailability of Cd was determined by the Diffusive Gradients in Thin-films technology and BCR sequential extraction procedure, offering in-situ quantification, which presents a significant advantage over traditional monitoring methods and aligns closely with the actual uptake of heavy metals by plants. The experimental results show that the prediction model based on the concentration of heavy metal forms measured by BCR sequential extraction procedure and diffusive gradients in thin-films technique can accurately predict the Cd uptake in rice grains, gastric and gastrointestinal phase (R2=0.712, 0.600 and 0.629). This model accurately predicts Cd bioavailability and bioaccessibility across the soil-rice-human pathway, informing actual human Cd intake, offering scientific support for developing more effective risk assessment methods.

An unbalanced protocol recognition method based on the improved Residual U-Net was proposed to solve the challenge of network security posed by the increasing network attacks with the continuous development of the Internet.In the captured network traffic, a small proportion is constituted by malicious traffic, typically utilizing minority protocols.However, existing protocol recognition methods struggle to accurately identify these minority protocols when the class distribution of the protocol data is imbalanced.To address this issue, an unbalanced protocol recognition method was proposed, which utilized the improved Residual U-Net, incorporating a novel activation function and the Squeeze-and-Excitation Networks (SE-Net) to enhance the feature extraction capability.The loss function employed in the proposed model was the weighted Dice loss function.In cases where the recognition accuracies of the minority protocols were low, the loss function value would be high.Consequently, the optimization direction of the model would be dominated by the minority protocols, resulting in improved recognition accuracies for them.During the protocol recognition process, the network flow was extracted from the network traffic and preprocessed to convert it into a one-dimensional matrix.Subsequently, the protocol recognition model extracted the features of the protocol data, and the Softmax classifier predicted the protocol types.Experimental results demonstrate that the proposed protocol recognition model achieves more accurate recognition of the minority protocols compared to the comparison model, while also improving the recognition accuracies of the majority protocols.

Summary: Mutations of TRAPPC12 are associated with progressive childhood encephalopathy including abnormal white matter. However, the underlying pathogenesis is still unclear. Here, we found that Trappc12 deficiency in CG4 and oligodendrocyte progenitor cells (OPCs) affects their differentiation and maturation. In addition, TRAPPC12 interacts with Mea6/cTAGE5, and Mea6/cTAGE5 ablation in OPCs affects their proliferation and differentiation, leading to marked hypomyelination, compromised synaptic functionality, and aberrant behaviors in mice. We reveal that TRAPPC12 is associated with COPII components at ER exit site, and Mea6/cTAGE5 cKO disrupts the trafficking pathway by affecting the distribution and/or expression of TRAPPC12, SEC13, SEC31A, and SAR1. Moreover, we observed marked disturbances in the secretion of pleiotrophin (PTN) in Mea6-deficient OPCs. Notably, exogenous PTN supplementation ameliorated the differentiation deficits of these OPCs. Collectively, our findings indicate that the association between TRAPPC12 and MEA6 is important for cargo trafficking and white matter development.

In order to explore a kind of hot-air drying of Antarctic krill under variable temperature process, the drying time, protein, fat and astaxanthin content were taken as indicators, the effects of first phase of the drying temperature, second phase of the drying temperature and moisture content point on the drying effect of Antarctic krill were studied, the drying effect was evaluated by multi-index comprehensive scoring method, the drying technology of dried Antarctic krill was optimized by orthogonal optimization test based on single factor experiments. The results showed that the optimum hot-air drying of Antarctic krill under variable temperature process were first phase of the drying temperature 55 ℃, second phase of the drying temperature 85 ℃, moisture content point 50%. The dried Antarctic krill obtained by this optimized process were the content of protein, fat, astaxanthin and drying time 69.24%, 19.79%, 232.72 μg/g, 300 min, respectively, and the comprehensive score of drying effect was 99.05.

BackgroundIn sepsis patients, kidney damage is among the most dangerous complications, with a high mortality rate. In addition, major adverse kidney events within 30 days (MAKE30) served as a comprehensive and unbiased clinical outcome measure for sepsis patients due to the recent shift toward targeting patient-centered renal outcomes in clinical research. However, the underlying predictive model for the prediction of MAKE30 in sepsis patients has not been reported in any study.MethodsA cohort of 2,849 sepsis patients from the Medical Information Mart for Intensive Care (MIMIC)-IV database was selected and subsequently allocated into a training set (n = 2,137, 75%) and a validation set (n = 712, 25%) through randomization. In addition, 142 sepsis patients from the Xi’An No. 3 Hospital as an external validation group. Univariate and multivariate logistic regression analyses were conducted to ascertain the independent predictors of MAKE30. Subsequently, a nomogram was developed utilizing these predictors, with an area under curve (AUC) above 0.6. The performance of nomogram was assessed through calibration curve, receiver operating characteristics (ROC) curve, and decision curve analysis (DCA). The secondary outcome was 30-day mortality, persistent renal dysfunction (PRD), and new renal replacement therapy (RRT). MAKE30 were a composite of death, PRD, new RRT.ResultsThe construction of the nomogram was based on several independent predictors (AUC above 0.6), including age, respiratory rate (RR), PaO2, lactate, and blood urea nitrogen (BUN). The predictive model demonstrated satisfactory discrimination for MAKE30, with an AUC of 0.740, 0.753, and 0.821 in the training, internal validation, and external validation cohorts, respectively. Furthermore, the simple prediction model exhibited superior predictive value compared to the SOFA model in both the training (AUC = 0.710) and validation (AUC = 0.692) cohorts. The nomogram demonstrated satisfactory calibration and clinical utility as evidenced by the calibration curve and DCA. Additionally, the predictive model exhibited excellent accuracy in forecasting 30-day mortality (AUC = 0.737), PRD (AUC = 0.639), and new RRT (AUC = 0.846) within the training dataset. Additionally, the model displayed predictive power for 30-day mortality (AUC = 0.765), PRD (AUC = 0.667), and new RRT (AUC = 0.783) in the validation set.ConclusionThe proposed nomogram holds the potential to estimate the risk of MAKE30 promptly and efficiently in sepsis patients within the initial 24 h of admission, thereby equipping healthcare professionals with valuable insights to facilitate personalized interventions.

ABSTRACTBackground: This study aims to evaluate waning effectiveness against severe and fatal COVID-19 with two to three doses of CoronaVac/BNT162b2, where data are limited. Methods: A case–control study included individuals aged ≥18 years, unvaccinated or received two to three doses of CoronaVac/BNT162b2, using electronic healthcare databases in Hong Kong. Those with first COVID-19-related hospitalization, severe complications, or mortality between 1 January and 15 August 2022 were defined as cases and matched with up-to-10 controls by age, sex, index date, and Charlson Comorbidity Index. Vaccine effectiveness (VE) against COVID-19-related outcomes was estimated at different time intervals from second and third-dose vaccination (0–13 up-to 210–240 days) using conditional logistic regression adjusted for comorbidities and medications. Results: By 211–240 days after second dose, VE against COVID-19-related hospitalization reduced to 46.6% (40.7–51.8%) for BNT162b2 and 36.2% (28.0–43.4%) for CoronaVac, and VE against COVID-19-related mortality were 73.8% (55.9–84.4%) and 76.6% (60.8–86.0%). After third dose, VE against COVID-19-related hospitalization decreased from 91.2% (89.5–92.6%) for BNT162b2 and 76.7% (73.7–79.4%) for CoronaVac at 0–13 days, to 67.1% (60.4–72.6%) and 51.3% (44.2–57.5%) at 91–120 days. VE against COVID-19-related mortality for BNT162b2 remained high from 0–13 days [98.2% (95.0–99.3%)] to 91–120 days [94.6% (77.7–98.7%)], and for CoronaVac reduced from 0–13 days [96.7% (93.2–98.4%)] to 91–120 days [86.4% (73.3–93.1%)]. Conclusions: Significant risk reduction against COVID-19-related hospitalization and mortality after CoronaVac or BNT162b2 vaccination was observed for >240 and >120 days after second and third doses compared to unvaccinated, despite significant waning over time. Timely administration of booster doses could provide higher levels of protection.

Abstract A multitude of natural and synthetic chemicals are present in our environment.Through the study of a compound’s cytotoxicity, researchers can carefully set regulations regarding how much of a certain chemical in the ambient environment is tolerable. In the past, research has focused on point measurements such as the LD50. Instead, we consider entire time-dependent cellular response curves through the application of functional mixed effects models. We identify differences in such curves corresponding to the chemical’s mode of action—i.e. how the compound attacks human cells. Through such analysis, we identify curve features to be used for cluster analysis via application of both k-means and self organizing maps. The data is analyzed by making use of functional principal components as a data driven basis and separately by considering B-splines for identifying local-time features. Our analysis can be used to drastically speed up future cytotoxicity research.

Kelp, often referred to as a “sea vegetable”, holds substantial economic significance. Currently, the drying process for kelp in China primarily relies on outdoor sun-drying methods. Detecting kelp in the field presents challenges arising from issues such as overlapping and obstruction. To address these challenges, this study introduces a lightweight model, K-YOLOv5, specifically designed for the precise detection of sun-dried kelp. YOLOv5-n serves as the base model, with several enhancements implemented in this study: the addition of a detection head incorporating an upsampling layer and a convolution module to improve the recognition of small objects; the integration of an enhanced I-CBAM attention mechanism, focusing on key features to enhance the detection accuracy; the replacement of the CBS module in the neck network with GSConv to reduce the computational burden and accelerate the inference speed; and the optimization of the IoU algorithm to improve the identification of overlapping kelp. Utilizing drone-captured images of sun-dried kelp, a dataset comprising 2190 images is curated. Validation on this self-constructed dataset indicates that the improved K-YOLOv5 model significantly enhances the detection accuracy, achieving 88% precision and 78.4% recall. These values represent 6.8% and 8.6% improvements over the original model, respectively, meeting the requirements for the real-time recognition of sun-dried kelp.

Soil organic carbon (SOC) is an important pool in the global carbon cycle, playing a vital role in moderating atmospheric CO2 concentrations. Soil is the largest carbon pool in terrestrial ecosystems and, as the basic unit of soil structure, soil aggregates are key to protecting soil carbon pools. However, the influence of soil aggregate particle size, SOC distribution, and the contribution of different particle sizes to SOC is still unclear, particularly under different land use types. In this study, soil samples were collected from five land use types (slope farmland (SF), forest (FL), grassland (GL), shrubland (SL), and terraced field (TF)) in a typical small watershed in the Loess Plateau, China. We analyzed the soil aggregate particle size, composition, and stability after dry and wet sieving, SOC content of different particle sizes in aggregates, and the effects of different aggregate particle sizes and land use on the distribution of SOC. The results showed that, the surface soil (0 ∼ 20 cm) water-stable aggregates were relatively stable, particularly under FL, the mean weight diameter (MWD) value was 2.16 mm. Deep soil (40 ∼ 60 cm) non-water stable aggregates were more stable, and GL was optimal, the MWD value was 3.94 mm. SOC and total nitrogen (TN) were significantly correlated with water-stable aggregate stability indicators (p 50% to SOC in SF and TF. In deep soil, small aggregates under all five land uses made the largest contribution rate to SOC at 57%. These findings indicate that carbon sequestration in the study area can be improved by a combination of appropriate soil management with ecological construction to increase the content of small aggregates, strengthen the fixation and protection of SOC, and reduce carbon emissions in the soil.

BackgroundUpper limb function reconstruction has been an important issue in the field of stroke rehabilitation. Due to the complexity of upper extremity dysfunction in stroke patients, the clinical efficacy produced by central or peripheral stimulation alone is limited. For this reason, our group has proposed acupuncture synchronized rehabilitation therapy (ASRT), i.e., simultaneous scalp acupuncture and intradermal acupuncture during rehabilitation. Pre-experiments results showed that this therapy can effectively improve the motor and sensory functions of upper limbs in post-stroke patients, but the clinical efficacy and safety of ASRT need to be further verified, and whether there is a synergistic effect between scalp acupuncture and intradermal acupuncture also needs to be studied in depth. Therefore, we designed a randomized controlled trial to compare the efficacy and safety of different therapies to explore a more scientific “synchronous treatment model.”MethodsThis is a single-center, randomized controlled trial using a 2 × 2 factorial design. We will recruit 136 stroke survivors with upper extremity dysfunction and randomize them into four groups (n = 34). All subjects will undergo routine treatment, based on which the Experimental Group 1: rehabilitation training synchronized with intradermal acupuncture treatment of the affected upper limb; Experimental Group 2: rehabilitation training of the affected upper limb synchronized with focal-side scalp acupuncture treatment, and Experimental Group 3: rehabilitation training synchronized with intradermal acupuncture treatment of the affected upper limb synchronized with focal-side scalp acupuncture treatment; Control Group: rehabilitation training of the affected upper limb only. The intervention will last for 4 weeks, 5 times a week. Both acupuncture treatments will be performed according to the Revised Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). The primary outcome indicators for this trial are Fugl-Meyer Assessment-Upper Extremity and Somatosensory Evoked Potential. Secondary outcome indicators include Wolf Motor Function Test, Upper Extremity Function Test, revised Nottingham Sensory Assessment Scale, Diffusion Tensor Imaging, and Modified Barthel Index. The incidence of adverse events will be used as the indicator of safety.DiscussionThe study will provide high-quality clinical evidence on whether ASRT improves upper limb motor and sensory function and activities of daily living (ADL) in stroke patients, and determine whether scalp acupuncture and intradermal acupuncture have synergistic effects.Clinical trial registrationhttps://www.chictr.org.cn/, Chinese Clinical Trial Registry [ChiCTR2200066646].

Quantum Dots (QDs) modified with branched Polyethylene Glycol-amine (6- or 8-arm PEG-amine) coupled with methoxy PEG (mPEG) hold great promise for in vivo biomedical applications due to a long half-life in blood and negligible toxicity. However, the potential risks regarding their concomitant prolonged co-incubation with cardiovascular and blood cells remains inconclusive. In the present study, the feasible, effective and convenient proliferating-restricted cell line models representing the circulatory system were established to investigate the cellular internalization followed by intracellular outcomes and resulting acute/sub-acute cytotoxicity of the 6-arm PEG-amine/mPEG QDs. We found a dose-, time- and cell type-dependent cellular uptake of the 6-arm PEG-amine/mPEG QDs, which was ten-fold lower compared to the traditional linear PEG-modified counterpart. The QDs entered cells via multiple endocytic pathways and were mostly preserved in Golgi apparatus for at least one week instead of degradation in lysosomes, resulting in a minimal acute cytotoxicity, which is much lower than other types of PEG-modified QDs previously reported. However, a sub-acute cytotoxicity of QDs were observed several days post exposure using the concentrations eliciting no-significant acute cytotoxic effects, which was associated with elevated ROS generation caused by QDs remained inside cells. Finally, a non-cytotoxic concentration of the QDs was identified at the sub-acute cytotoxic level. Our study provided important information for clinical translation of branched PEG-amine/mPEG QDs by elucidating the QDs-cell interactions and toxicity mechanism using the proliferation-restricted cell models representing circulatory system. What's more, we emphasized the indispensability of sub-acute cytotoxic effects in the whole biosafety evaluation process of nanomaterials like QDs.

Data regarding protection against mortality and severe complications after Omicron BA.2 infection with CoronaVac and BNT162b2 vaccines remains limited. We conducted a case–control study to evaluate the risk of severe complications and mortality following 1–3 doses of CoronaVac and BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related mortality or severe complications between 1 January and 31 March 2022, matched with up-to 10 controls by age, sex, index date, and Charlson Comorbidity Index. Vaccine effectiveness against COVID-19-related mortality and severe complications by type and number of doses was estimated using conditional logistic regression adjusted for comorbidities and medications. Vaccine effectiveness (95% CI) against COVID-19-related mortality after two doses of BNT162b2 and CoronaVac were 90.7% (88.6–92.3) and 74.8% (72.5–76.9) in those aged ≥65, 87.6% (81.4–91.8) and 80.7% (72.8–86.3) in those aged 50–64, 86.6% (71.0–93.8) and 82.7% (56.5–93.1) in those aged 18–50. Vaccine effectiveness against severe complications after two doses of BNT162b2 and CoronaVac were 82.1% (74.6–87.3) and 58.9% (50.3–66.1) in those aged ≥65, 83.0% (69.6–90.5) and 67.1% (47.1–79.6) in those aged 50–64, 78.3% (60.8–88.0) and 77.8% (49.6–90.2) in those aged 18–50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, with vaccine effectiveness of 98.0% (96.5–98.9) for BNT162b2 and 95.5% (93.7–96.8) for CoronaVac against mortality, 90.8% (83.4–94.9) and 88.0% (80.8–92.5) against severe complications. Both CoronaVac and BNT162b2 vaccination were effective against COVID-19-related mortality and severe complications amidst the Omicron BA.2 pandemic, and risks decreased further with the third dose.

Accruing evidence suggests an increased risk of myocarditis in adolescents from messenger RNA COVID-19 vaccines. However, other potential adverse events remain under-researched. We conducted a retrospective cohort study of adolescents aged 12–18 with a territory-wide electronic healthcare database of the Hong Kong population linked with population-based vaccination records and supplemented with age- and sex-specific population numbers. Two age- and sex-matched retrospective cohorts were formed to observe 28 days following the first and second doses of BNT162b2 and estimate the age- and sex-adjusted incidence rate ratios between the vaccinated and unvaccinated. Thirty AESIs adapted from the World Health Organization’s Global Advisory Committee on Vaccine Safety were examined. Eventually, the first-dose cohort comprised 274,881 adolescents (50.25% received the first dose) and the second-dose cohort 237,964 (50.29% received the second dose). Ninety-four (34.2 per 100,000 persons) adolescents in the first-dose cohort and 130 (54.6 per 100,000 persons) in the second-dose cohort experienced ≥1 AESIs. There were no statistically significant differences in the risk of any AESI associated with BNT162b2 except myocarditis [first-dose cohort: incidence rate ratio (IRR) = 9.15, 95% confidence interval (CI) 1.14–73.16; second-dose cohort: IRR = 29.61, 95% CI 4.04–217.07] and sleeping disturbances/disorders after the second dose (IRR = 2.06, 95% CI 1.01–4.24). Sensitivity analysis showed that, with myocarditis excluded as AESIs, no significantly elevated risk of AESIs as a composite outcome associated with vaccination was observed (P = 0.195). To conclude, the overall absolute risk of AESIs was low with no evidence of an increased risk of AESIs except myocarditis and sleeping disturbances/disorders.

The reclamation coral sand (CS) layer is the survival environment for island reef vegetation in the South China Sea. The root system within the CS bed draws water necessary for vegetation growth, implying that the water-retention capacity of CS plays a pivotal role in determining vegetation viability. Particle size distribution (PSD) significantly influences the water-retention capacity of geomaterials. This study examines the impact of PSD on the water-retention capacity of CS from both macro (soil–water characteristic curve, SWCC) and micro (pore water distribution) perspectives using the pressure plate test and nuclear magnetic resonance technique, and an F&X model was used to analyze the SWCC of CS. The findings indicated that the F&X model aptly describes the SWCC of CS with different PSDs. Both the air entry value and residual water content rise with an increased content of fine grains (d < 0.25 mm), suggesting that the presence of fine grains augments the water-retention capacity of CS. It is considered that a size range of d = 0.075–0.25 mm predominantly impacts the water-retention capacity of CS. The PSD primarily influences the water-retention capacity by affecting the pore size distribution of CS. The volume of small pores swells with the surge of fine-grain content, while the maximum pore size contracts with increasing fine-grain content. Limited pore connectivity in CS means macropores can retain water even under high suction, bolstering the water-retention capacity of CS. These findings offer theoretical guidance for selecting gradation parameters for the planting layer on island reefs.

Background COVID‐19 vaccines have demonstrated effectiveness against SARS‐CoV‐2 infection, hospitalization, and mortality. The association between vaccination and risk of cardiovascular complications shortly after SARS‐CoV‐2 infection among patients with cardiovascular disease remains unknown. Methods and Results A case–control study was conducted with cases defined as patients who had myocardial infarction or stroke within 28 days after SARS‐CoV‐2 infection between January 1, 2022 and August 15, 2022. Controls were defined as all other patients who attended any health services and were not cases. Individuals without history of cardiovascular disease were excluded. Each case was randomly matched with 10 controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Adjusted odds ratio with 95% CI was estimated using conditional logistic regression. We identified 808 cases matched with 7771 controls among all patients with cardiovascular disease. Results showed that vaccination with BNT162b2 or CoronaVac was associated with a lower risk of myocardial infarction or stroke after SARS‐CoV‐2 infection with a dose–response relationship. For BNT162b2, risk decreased from 0.49 (95% CI, 0.29–0.84) to 0.30 (95% CI, 0.20–0.44) and 0.17 (95% CI, 0.08–0.34) from 1 to 3 doses, respectively. Similar trends were observed for CoronaVac, with risk decreased from 0.69 (95% CI, 0.57–0.85) to 0.42 (95% CI, 0.34–0.52) and 0.32 (95% CI, 0.21–0.49) from 1 to 3 doses, respectively. Conclusions Vaccination with BNT162b2 or CoronaVac is associated with a lower risk of myocardial infarction or stroke after SARS‐CoV‐2 infection among patients with cardiovascular disease.

Three-dimensional superhydrophobic materials are characterized by a low surface energy and extremely low strength, and hence require reinforcement for viable applications. An experimental study is presented of the processing and mechanical properties of a graphene-reinforced superhydrophobic siloxane, synthesized by a sol–gel approach integrating alkali activation of metakaolin, hydrolysis of alkoxysilane, dispersion of graphene into the precursor, and co-condensation. To promote uniform dispersion and distribution of graphene, three processing techniques were used: while ultrasonication was adopted to disperse graphene nanoplatelets, accelerated condensation at 50 and 75 °C and varying the precursor’s viscosity used to prevent graphene from floating and re-aggregation. Results of nanoindentation, porosimetry, and unconfined compression show that adding 0.9 wt% graphene increases the strength of the superhydrophobic composites from ∼ 0 to 34 MPa. Slow condensation and curing at 25 °C allow graphene to re-aggregate and float upward in the sol, leading to its heterogeneous distribution. Despite its function in improving microscale dispersion, ultrasonication detrimentally decreases the composite’s strength due to acoustic cavitation. Similarly, curing at elevated temperatures accelerates co-condensation and results in a more uniform distribution of graphene, but induces thermal cavitation and bubble formation, because the threshold for acoustic and thermal cavitations is significantly reduced by superhydrophobicity.

In order to explore the impact of different shucking methods on the efficiency and quality of oysters, five methods such as boiling, steaming, microwave, ultra-high pressure, and electric shock were used to open the oysters. The opening rate and the opening size were used as the evaluation indexes of opening efficiency, the freshness, juice loss rate, and the degree of protein denaturation of the occluder muscle were used as the evaluation indexes of quality. The opening efficiency and quality of several opening methods were comprehensively compared, and the feasibility of applying them to the opening of oysters were analyzed. The research results showed that the efficiency of microwave opening was the fastest, and all oysters could be opened in 30 s, followed by ultra-high pressure, steaming and water boiling. Electric shock could open part of oysters, but the opening rate did not reach 100%, a small number of oysters failed to open their shells from beginning to end; microwave-opened oysters had the largest opening size, followed by steaming and boiling. The proportions of opened oysters above 5 mm were 70%, 50% and 20%, respectively. Oysters opened by ultra-high pressure and electric shock had a smaller opening size, basically below 2 mm; the quality of oyster meat after opening the shell was analyzed, and it was found that the quality of oyster meat after electric shock was the closest to that of fresh open-shell oysters, with the smallest temperature rise and the least juice loss, Ca2+-ATPase activity was the highest, followed by ultra-high pressure, steaming, boiling and microwave. Comprehensive analysis of the efficiency, size, quality and practical operability of the shell opening, the study concluded that ultra-high pressure was suitable for the processing of small batches of raw oysters; microwave opening was suitable for processing of small batches of dried oysters; steaming had higher shell opening efficiency, larger opening size, and better quality, which could take into account efficiency and quality and was currently the most suitable method of oyster shelling for batch processing.

Abstract The global COVID-19 epidemic has spread rapidly around the world and caused the death of more than 5 million people. It is urgent to develop effective strategies to treat COVID-19 patients. Here, we revealed that SARS-CoV-2 infection resulted in the dysregulation of genes associated with NAD+ metabolism, immune response, and cell death in mice, similar to that in COVID-19 patients. We therefore investigated the effect of treatment with NAD+ and its intermediate (NMN) and found that the pneumonia phenotypes, including excessive inflammatory cell infiltration, hemolysis, and embolization in SARS-CoV-2-infected lungs were significantly rescued. Cell death was suppressed substantially by NAD+ and NMN supplementation. More strikingly, NMN supplementation can protect 30% of aged mice infected with the lethal mouse-adapted SARS-CoV-2 from death. Mechanically, we found that NAD+ or NMN supplementation partially rescued the disturbed gene expression and metabolism caused by SARS-CoV-2 infection. Thus, our in vivo mouse study supports trials for treating COVID-19 patients by targeting the NAD+ pathway.

Introduction: We aimed to investigate whether a lower starting dose of roxadustat (∼1–1.4 mg/kg) converted from erythropoiesis-stimulating agent (ESA) could achieve a comparable hemoglobin (Hb) target (≥100 and ≤120 g/l) compared with the standard weight-based dose (∼1.5–2 mg/kg) at week 12 through a peritoneal dialysis (PD) cohort. Methods: A 12-week multicenter randomized, parallel-controlled, open-label, pilot clinical trial enrolled adult patients who had undergone PD treatment for >3 months with renal anemia. Participants were randomized in blocks of 4 in a 1:1 ratio to either the standard-dose group (n = 50) or the low-dose group (n = 50). The primary end point was the proportion of patients achieving the Hb target at week 12. Results: Baseline demographic and clinical characteristics of the 2 groups were comparable. There was no difference in the proportion of patients who met the Hb target at week 12, that is, 26 patients (52%) versus 31 patients (62%) in the low-dose group and standard-dose group, respectively (P = 0.31). The Hb levels significantly increased in both groups from baseline to week 12; the median change of Hb levels was 5.0 (0.0–14.3) g/l (P < 0.001) for the standard-dose group and 6.0 (−3.3 to 16.3) g/l for the low-dose group (P = 0.005) (P = 0.581 for between groups). Conclusion: This study suggests that a lower starting dose of roxadustat effectively achieves the Hb target as standard-dose does among patients on PD. (ClinicalTrials.gov number, NCT04454879).

Adverse events resulting from COVID-19 vaccination are a public health concern and it is not known whether pre-existing conditions may impose an increased risk. Here, using electronic health records from Hong Kong, the authors show that adverse events are rare for all groups, and there is no evidence of risk modification due to multimorbidity.

The fractures of different sizes in rock masses are important for describing rock fragmentation. The distribution dispersion of fracture size influences the blockiness level of the rock masses. Based on a normal statistical distribution, the volume ratio of blocks to rock (B) was obtained to describe the blockiness level. For exploring the effect of the dispersion of fracture size on blockiness level and the representative elementary volume (REV) of rock masses, the laboratory model and numerical simulation were established, and the theory of statistics and the method of analytical solution were applied. In addition, 4,525 practical rock models were established to qualitatively reproduce the behavior of B with changing domain size. The results show that by comparing the degree of convergence, the REV of a rock mass is determined by the fracture size rather than the degree of fracture dispersion. The value of B increases with the distribution dispersion of fracture size, indicating a higher blockiness level. From the experimental analysis of coin tossing, when the number of trials exceeds 69, the random results are nearly stable. In this study, 100 calculations were performed. A formula to calculate the blockiness by considering the dispersion degrees of fracture size was obtained. Moreover, a positive linear correlation between B and the coefficient of variation of fracture size was obtained. The rate of increase in B has a parabolic relationship with the ratio of fracture size to fracture spacing (L).

BackgroundHigh expression of matrix metalloproteinase-11 (MMP11) is associated with various tumors and immune microenvironments. Conversely, poor response to immunotherapy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients is closely related to the characteristics of immune microenvironment.MethodsThe Cancer Genome Atlas (TCGA)-LUAD database and our gathered clinical LUAD samples were used to examine the relationship between MMP11 expression and EGFR mutation. Then the correlation between MMP11 and immune response and the difference of immune cell infiltration in different groups were analyzed. Compared the differences in the immune microenvironment between the MMP11-positive and MMP11-negative expression groups using immunohistochemistry (IHC) and multiplex immunohistochemistry.ResultsThe expression of MMP11 in samples with exon 19 deletions, exon 21 L858R or de novo exon 20 T790M mutations was higher than wild type, but there was no difference between the samples with uncommon mutation and the wild-type. The high MMP11 expression group had a higher Tumor Immune Dysfunction and Exclusion (TIDE) score. Pathways associated with enrichment in the extracellular matrix (ECM) were the main biological functions of differential genes between the high and low MMP11 groups. The IHC score of MMP11 in the EGFR-mutant group was higher than in the EGFR-wild group. In TCGA-LUAD, the high MMP11 group had a lower proportion of T cell CD8+ and NK cells activated. In the clinical samples, the infiltration levels of T cell CD8+ and NK cells in the tumor parenchyma of EGFR-mutant LUAD was lower in the MMP11-positive than in the MMP11-negative group. The expression levels of tumor cell PD-L1 were higher in the MMP11-positive expression group than in the MMP11-negative expression group, and the proportion of PD1+CD8+ T cells infiltrated was reduced in the MMP11-positive group compared to the MMP11-negative group.ConclusionsHigh expression of MMP11 was associated with EGFR mutations. Patients with EGFR-mutant LUAD with high expression of MMP11 responded poorly to immunotherapy, and the percentage of T cell CD8+ and NK cells in immune cell infiltration was lower in MMP11. Consequently, MMP11 is related to the immunological microenvironment of EGFR-mutant lung adenocarcinoma, which may be a predictor of possible immunotherapeutic response.

Summary: Background: COVID-19 vaccines are important for patients with heart failure (HF) to prevent severe outcomes but the safety concerns could lead to vaccine hesitancy. This study aimed to investigate the safety of two COVID-19 vaccines, BNT162b2 and CoronaVac, in patients with HF. Methods: We conducted a self-controlled case series analysis using the data from the Hong Kong Hospital Authority and the Department of Health. The primary outcome was hospitalization for HF and the secondary outcomes were major adverse cardiovascular events (MACE) and all hospitalization. We identified patients with a history of HF before February 23, 2021 and developed the outcome event between February 23, 2021 and March 31, 2022 in Hong Kong. Incidence rate ratios (IRR) were estimated using conditional Poisson regression to evaluate the risks following the first three doses of BNT162b2 or CoronaVac. Findings: We identified 32,490 patients with HF, of which 3035 were vaccinated and had a hospitalization for HF during the observation period (BNT162b2 = 755; CoronaVac = 2280). There were no increased risks during the 0–13 days (IRR 0.64 [95% confidence interval 0.33–1.26]; 0.94 [0.50–1.78]; 0.82 [0.17–3.98]) and 14–27 days (0.73 [0.35–1.52]; 0.95 [0.49–1.84]; 0.60 [0.06–5.76]) after the first, second and third doses of BNT162b2. No increased risks were observed for CoronaVac during the 0–13 days (IRR 0.60 [0.41–0.88]; 0.71 [0.45–1.12]; 1.64 [0.40–6.77]) and 14–27 days (0.91 [0.63–1.32]; 0.79 [0.46–1.35]; 1.71 [0.44–6.62]) after the first, second and third doses. We also found no increased risk of MACE or all hospitalization after vaccination. Interpretation: Our results showed no increased risk of hospitalization for HF, MACE or all hospitalization after receiving BNT162b2 or CoronaVac vaccines in patients with HF. Funding: The project was funded by a Research Grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (Ref. No. COVID19F01). F.T.T.L. (Francisco T.T. Lai) and I.C.K.W. (Ian C.K. Wong)'s posts were partly funded by the D24H; hence this work was partly supported by AIR@InnoHK administered by Innovation and Technology Commission.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays a vital role in sensing viral DNA in the cytosol, stimulating type I interferon (IFN) production and triggering the innate immune response against DNA virus infection. However, viruses have evolved effective inhibitors to impede this sensing pathway. Chicken anemia virus (CAV), a nonenveloped ssDNA virus, is a ubiquitous pathogen causing great economic losses to the poultry industry globally. CAV infection is reported to downregulate type I IFN induction. However, whether the cGAS-STING signal axis is used by CAV to regulate type I IFN remains unclear. Our results demonstrate that CAV infection significantly elevates the expression of cGAS and STING at the mRNA level, whereas IFN-β levels are reduced. Furthermore, IFN-β activation was completely blocked by the structural protein VP1 of CAV in interferon stimulatory DNA (ISD) or STING-stimulated cells. VP1 was further confirmed as an inhibitor by interacting with interferon regulatory factor 7 (IRF7) by binding its C-terminal 143–492 aa region. IRF7 dimerization induced by TANK binding kinase 1 (TBK1) could be inhibited by VP1 in a dose-dependent manner. Together, our study demonstrates that CAV VP1 is an effective inhibitor that interacts with IRF7 and antagonizes cGAS-STING pathway-mediated IFN-β activation. These findings reveal a new mechanism of immune evasion by CAV.

Abstract Background Urinary uromodulin (uUMOD) is one of the novel biomarkers for predicting AKI. However, currently available publications showed inconsistent results. We designed this meta-analysis to evaluate the potential association between uUMOD and AKI. Methods We searched research articles with no language restriction in Medline, Web of Science, Cochrane Library, Embase, and 3 Chinese datasets from inception to February 2021. We used random-effects models to estimate the standardized mean difference (SMD) between patients with AKI or not, while the leave-one-out method and random-effects meta-regression to evaluate the sensitivity and the impact of potential confounders such as age and surgery. Results The meta-analysis comprising 3148 subjects from 11 studies showed that the uUMOD of the AKI group is significantly lower than the non-AKI group (SMD: − 0.71; 95% confidence interval (CI), − 1.00, − 0.42, P

Introduction: Zoledronic acid (ZA) is a widely used bisphosphonate compound for the prevention of skeletal metastasis-associated osteolysis and treatment of post-menopause osteoporosis. Acute kidney injury is one of the commonly described renal complications. Electrolytes disorder has also been reported relevant to ZA exposure and nephrotoxicity. Syndrome of persistent hypophosphatemia, hypokalemia and metabolic acidosis is regarded as the initial signs of acute kidney injury. Case presentation: We reported a 64-year-old female with bone metastasis from lung adenocarcinoma who received a 5-year history of 4-week cycle ZA infusion. She initially presented symptomatic severe hypophosphatemia and was finally identified with ZA-induced generalized tubular dysfunction as Fanconi’s syndrome and distal renal tubular acidosis. Renal pathological findings revealed toxic renal tubular necrosis. The ZA infusion was thus extended to an 8-week cycle with oral phosphate supplementation and alfacalcidol. Although periodic changes pre- and post-ZA infusion existed yet, hypophosphatemia was effectively improved and the rapid decline of eGFR was partially delayed. We reviewed the literature and mainly summarized the characteristics of bisphosphonates-associated hypophosphatemia. Moderate hypophosphatemia was more frequently mentioned in contrast to severe cases being predisposed to be reported. And progressive hypophosphatemia serves as an early sign of kidney injury. Conclusion: Progressive electrolyte disorders and CKD were the long-term renal outcome of the current patient. We would like to arouse more attention to electrolytes imbalance related to early ZA-induced kidney injury and emphasize the significance of close monitoring.

Soil microbes are of great significance to many energy flow and material circulation processes in alpine forest ecosystems. The distribution pattern of soil microbial community along altitudinal gradients is an essential research topic for the Tibetan Plateau. Yet our understanding of linkages between soil microbial communities and key factors along an altitudinal gradient of different slopes remains limited. Here, the diversity, composition and interaction of bacterial and fungal communities and in response to environmental factors were compared across five elevation sites (3,500 m, 3,700 m, 3,900 m, 4,100 m, 4,300 m) on the eastern and western slopes of Mount Segrila, by using Illumina MiSeq sequencing. Our results showed that microbial community composition and diversity were distinct at different elevations, being mainly influenced by soil total nitrogen and carbonate. Structural equation models indicated that elevation had a greater influence than slope upon the soil microbial community. Co-occurrence network analysis suggested that fungi were stable but bacteria contributed more to among interactions of bacterial and fungal communities. Ascomycota was identified as a key hub for the internal interactions of microbial community, which might affect the soil microbial co-occurrence network resilience of alpine forest ecosystems on the Tibetan Plateau.

Background: Many studies demonstrated that roxadustat (FG-4592) could increase hemoglobin (Hb) levels effectively in anemia patients with chronic kidney disease (CKD). However, its safety remains controversial. This study aims to explore the risk of infection for CKD patients treated with roxadustat, especially focused on sepsis.Methods: We thoroughly searched for the randomized controlled trials (RCTs) comparing treatment with roxadustat versus erythropoiesis stimulating agents (ESAs) or placebo in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, European Union Clinical Trials Register. Both on and not on dialysis anemia patients with CKD were included. Primary outcomes contained the incidence rates of sepsis. Secondary outcomes included infection-related consequences (septic shock and other infection events), general safety outcomes [all-cause mortality, treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)] and iron parameters. Moreover, a trial sequential analysis (TSA) was conducted to assess if the results were supposed to be a robust conclusion.Results: Eighteen RCTs (n = 11,305) were included. Overall, the incidence of sepsis (RR: 2.42, 95% CI [1.50, 3.89], p = 0.0003) and cellulitis (RR: 2.07, 95% CI [1.24, 3.44], p = 0.005) were increased in the roxadustat group compared with placebo group. In non-dialysis-dependent (NDD) CKD patients, the incidence of cellulitis (RR 2.01, 95% CI [1.23, 3.28], p = 0.005) was significantly higher in roxadustat group than that in the ESAs or placebo group. Both groups showed similar results in the incidence of septic shock (RR 1.29, 95% CI [0.86, 1.94], p = 0.22). A significant increased risk of all-cause mortality [risk ratios (RR): 1.15, 95% confidence interval (CI) [1.05, 1.26], p = 0.002] was found in roxadustat treatment, and TSA confirmed the result. Compared with ESAs or placebo, both the incident rates of TEAEs (RR:1.03, 95% CI [1.01, 1.04], p = 0.008) and TESAEs (RR: 1.06, 95% CI [1.02, 1.11], p = 0.002) were significantly increased in roxadustat group. As for iron parameters, changes from baseline (Δ) of hepcidin (MD: -26.46, 95% CI [-39.83, -13.09], p = 0.0001), Δ ferritin and Δ TSAT were remarkably lower in the roxadustat group, while Δ Hb, Δ iron and Δ TIBC increased significantly versus those in ESAs or placebo group.Conclusion: We found evidence that incidence rates of sepsis and cellulitis are higher in roxadustat group compared with placebo. This may be the result of improved iron homeostasis. The risk of all-cause mortality, TEAEs and TESAEs in CKD patients also increased in patients treated with roxadustat. We need more clinical and mechanistic studies to confirm whether roxadustat really causes infection.

BackgroundImmunotherapy using programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors seems less effective in non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations. Varied responses to PD-1/PD-L1 inhibitors have recently been observed in NSCLC patients harboring different types of EGFR mutations. Some EGFR-mutated NSCLC patients may benefit from PD-1/PD-L1 inhibitors. At present, PD-L1 expression, tumor mutational burden (TMB), and tumor immune microenvironment (TIME) are biomarkers for predicting the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients. We retrospectively evaluated PD-L1 expression, TMB, and immune cell infiltration in NSCLC patients with EGFR mutation subtypes.MethodsPD-L1 expression, TMB, and the abundance of immune cell infiltration in NSCLC patients were evaluated in public databases and clinical samples. TMB was detected using the NGS technique, PD-L1 was detected using immunohistochemistry, and the abundance of immune cell infiltration in NSCLC samples was detected using multiple immunohistochemistry.ResultsPD-L1 expression and TMB were lower in EGFR-mutated NSCLCs than in wild-type patients. Differences in the abundance of immune cell infiltration were also observed between EGFR-mutated and wild-type NSCLC. The expression of PD-L1, TMB, and abundance of immune cell infiltration were different in patients harboring different subtypes of EGFR mutations. Patients with uncommon EGFR mutations, especially the G719X mutation, showed higher TMB and expressions of PD-L1 than classical EGFR mutations. M1 macrophages were higher in uncommon EGFR mutations than classical EGFR mutations.ConclusionsThe expression of PD-L1 and TMB in uncommon EGFR-mutated NSCLCs, especially the G719X mutation, were higher than those for classical EGFR-mutated NSCLCs and similar to EGFR wild-type. The abundance of immune cell infiltration in uncommon EGFR-mutated NSCLCs was similar to that in EGFR wild-type. Our findings suggest that uncommon EGFR-mutated NSCLCs may benefit from PD-1/PD-L1 inhibitors.

Insect herbivores can adversely impact terrestrial plants throughout ontogeny and across various ecosystems. Simultaneously, the effects of foliar herbivory may extend belowground, to the soil microbial community. However, the responses in terms of the diversity, assembly, and stability of rhizosphere fungi to aboveground herbivory remain understudied. Here, using high-throughput sequencing, the effects of foliar insect herbivory on rhizosphere fungal microbes were investigated in a common garden experiment that manipulated herbivory intensity and time from herbivore removal. The number of observed fungal species was reduced by a greater herbivory intensity, with some species evidently sensitive to herbivory intensity and time since herbivore removal. Rhizofungal assembly processes were altered by both herbivory intensity and time since herbivore removal. Further, we found evidence that both factors strongly influenced fungal community stability: a high intensity of herbivory coupled with a shorter time since herbivore removal resulted in low stability. These results suggest that foliar herbivory can adversely alter fungal diversity and stability, which would in turn be harmful for plant health. Fortunately, the effect seems to gradually diminish with time elapsed after herbivore removal. Our findings provide a fresh, in-depth view into the roles of rhizofungi in enhancing the adaption ability of plants under environmental stress.

Background and AimMetabolic disorders are prevalent in patients with chronic kidney disease (CKD) and may lead to protein energy wasting (PEW). Adipokines improve connections between PEW and energy metabolism. We aimed to determine the relationship between adipokine levels and resting energy expenditure (REE) in patients with CKD.MethodsA total of 208 patients in non-dialyzed CKD stages 3–5 were enrolled in this cross-sectional study. Serum adipokines (leptin, adiponectin, and interleukin 6 (IL-6) were measured using enzyme-linked immunosorbent assay. Patient's REE was measured using indirect calorimetry. Fat mass (FM) and lean tissue mass (LTM) were measured using multiple-frequency bioimpedance analysis. Spearman correlation analyses and multivariate linear regression models were used to assess the association between serum adipokines and REE.ResultsThe mean age was 52.7 ± 14.6 years, and 26.9, 26.4, and 46.7% of our participants had CKD stages 3, 4, and 5, respectively. The median values of serum adiponectin, leptin, and IL-6 were 470.4 (range, 291.1–802.2), 238.1 (range, 187.9–418.4), and 4.0 (range, 2.4–9.5) pg/mL, respectively. The male participants had significantly lower FM% (P = 0.001) and lower leptin levels (P < 0.001) than the female participants. After adjusting for age, diabetes, high-sensitivity C-reactive protein, intact parathyroid hormone, LTM, and FM, multiple linear regression analysis revealed that serum leptin levels were significantly positively associated with REE in men rather than in women (P < 0.05). Serum adiponectin levels were inversely associated with REE in men, but this association disappeared while FM was additionally adjusted. Adiponectin levels in women were not correlated with REE (P > 0.05). IL-6 was not significantly associated with REE in either men or women.ConclusionsA sex-specific relationship between serum adipokines (leptin and adiponectin) and REE was observed in patients with CKD stages 3–5, which was partly confounded by FM.

Abstract Background Sarcopenia is common and contributes to a high risk of mortality among general population. There is no consensus regarding the cut-off values for sarcopenia in terms of mortality among chronic kidney disease patients. This study aimed to explore and validate cut-off points of handgrip strength (HGS) and lean mass index (LMI) for estimating the risk of mortality in peritoneal dialysis (PD) patients. Methods This single-center prospective cohort study enrolled 1089 incident PD patients between October 2002 and July 2019. All patients were followed until death, transfer to hemodialysis, receiving renal transplantation or the end date of study (December 2019). All participants were randomly sampled to development cohort (70% participants) and validation cohort (30% participants), matched by gender and diabetes. Lean body mass was calculated by using the equation published by our center. Cubic spline regression analysis was used to examine the relationship between HGS or LMI values and mortality, and explore the cut-off points after adjusting for age, diabetes, cardiovascular disease and serum albumin in the development cohort. The derived cut-off values were verified by the agreement rate for predicting mortality and then compared with cut-off values from various clinical guidelines in the validation cohort. Results All 1089 patients were followed up with the median of 36.0 (18.0, 71.0) months. In the development cohort, cut-off points for predicting the higher mortality were derived as 24.5 kg and 14 kg of HGS for males and females, 16.7 kg/m2 and 13.8 kg/m2 of LMI for males and females respectively. In the validation cohort, these cut-off values significantly predicted worse outcomes, with HR 1.96 (1.35, 2.84) of HGS and HR 1.76 (1.26, 2.47) of LMI for all-cause mortality after multivariate adjustment. The newly derived cut-off points of HGS have numerically higher prognostic values in all-cause mortality compared with those from current clinical guidelines, and agreement rates of HGS were 65.2 versus 62.5–64.6 respectively. Conclusions The derived cut-off values of HGS and LMI have sufficient and better prognostic value in predicting all-cause mortality in PD patients compared with the cut-off values in the existing guidelines. These cut-off values are only validated in a single population, thus limiting the generalizability.

Abstract Background As global warming continues, heat stress (HS) is becoming an increasingly significant factor limiting plant growth and reproduction, especially for cool-season grass species. The objective of this study was to determine the transcriptional regulatory network of Cleistogenes songorica under HS via transcriptome profiling, identify of gene families and comparative analysis across major Poaceae species. Results Physiological analysis revealed significantly decreased leaf relative water content (RWC) but increased proline (Pro) content in C. songorica under 24 h of HS. Transcriptome profiling indicated that 16,028 and 14,645 genes were differentially expressed in the shoots and roots of C. songorica under HS, respectively. Two subgenomes of C. songorica provide equal contribution under HS on the basis of the distribution and expression of differentially expressed genes (DEGs). Furthermore, 216 DEGs were identified as key evolutionarily conserved genes involved in the response to HS in C. songorica via comparative analysis with genes of four Poaceae species; these genes were involved in the ‘response to heat’ and ‘heat acclimation’. Notably, most of the conserved DEGs belonged to the heat-shock protein (HSP) superfamily. Similar results were also obtained from co-expression analysis. Interestingly, hub-genes of co-expression analysis were found to overlap with conserved genes, especially heat-shock protein (HSP). In C. songorica, 84 HSP and 32 heat-shock transcription factor (HSF) genes were identified in the allotetraploid C. songorica genome, and might have undergone purifying selection during evolutionary history based on syntenic and phylogenetic analysis. By analysing the expression patterns of the CsHSPs and CsHSFs, we found that the transcript abundance of 72.7% of the CsHSP genes and of 62.5% of the CsHSF genes changed under heat stress in both the shoots and roots. Finally, a core regulatory network of HS was constructed on the basis of the CsHSP, CsHSF and other responsive genes in C. songorica. Conclusions Regulatory network and key genes were comprehensively analysed and identified in C. songorica under HS. This study improves our knowledge of thermotolerance mechanisms in native grasses, and also provides candidate genes for potential applications in the genetic improvement of grasses.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a monoclonal B cell lymphocytosis that produces nephrotoxic monoclonal immunoglobulin (MIg). However, the role of MIg in CLL and how it affects CLL patient survival are still unknown. Here, we report a case of MIg with renal significance (MGRS) associated with CLL. A 59-year-old Chinese woman complaining of abdominal pain, skin purpura, and typical soy-colored urine was admitted to the hospital for investigation. Laboratory tests revealed that she had microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury (AKI), and hypocomplementemia. She also reported cryoglobulinemia, thrombotic microangiopathy (TMA), and AKI 2 years previously. Peripheral blood smears at that time showed 4% schistocytes, a negative Coombs' test, and elevated lactate dehydrogenase (LDH). Based on a diagnosis of complement-mediated TMA, the patient was treated by plasmapheresis and achieved clinical disease remission. However, the serum hypocomplement 4 and cryoglobulinemia persisted. Further investigation showed elevated B lymphocytes and monoclonal serum IgMκ; however, the cryoprecipitate contained monoclonal IgMκ and polyclonal IgG, as well as immunoglobulins κ and λ. After plasmapheresis, her LDH, platelets, and complement 3 (C3) levels returned to normal. Biopsies of the bone marrow and an enlarged subclavicular lymph node revealed CLL/SLL. Renal pathological findings indicated significant arteriolar endothelial cells myxoid edema and glomerular endothelial cells swelling, however no thromboli, cryoglobulin formation and vasculitis were observed. We also found mild mesangial proliferative C3 glomerulonephritis and renal interstitial CLL cells infiltration. Collectively, these clinical and pathological manifestations were attributed to monoclonal IgMκ, which triggered C3 activation. MGRS associated with CLL was finally confirmed. Six cycles of rituximab, cyclophosphamide, verodoxin, and dexamethasone therapy were administered, after which she received ibrutinib. The patient experienced disease remission, and her serum C4 level returned to normal. Cryoglobulin and IgMκ were not detected. This is a special presentation of CLL/SLL with monoclonal IgMκ, which is a type of MGRS. Activation of the complement system by MIg led to TMA with C3 glomerulonephritis. Treatment for TMA and CLL/SLL should be initiated in a timely manner to improve patient prognosis.

The expression level of BCMA in bone marrow of 54 MM patients was detected in this study to explore the relationship between the BCMA expression and the classification, stage, and prognostic factors of MM. The BCMA expression level of the stable group and remission group was lower than that of the newly diagnosed group and relapse group (P=0.001). There was no significant difference in BCMA expression of MM patients in different types and stages (P>0.05), but it was found that for the newly diagnosed MM patients, the BCMA expression level of IgG patients was higher than that of IgA or light-chain patients (rank average 11.20 vs 5.44, P=0.014). There was no significant correlation between the BCMA expression and the age and serum creatinine of MM patients (P>0.05). And there was no significant difference in BCMA expression between patients with different levels of age and serum creatinine (P>0.05). But it was found that the BCMA expression level of the newly diagnosed MM patients was moderately positively correlated with their age (P=0.025, r=0.595). There was no significant correlation between the BCMA expression and serum β2-microglobulin, serum lactate dehydrogenase, free kap/lam ratio, and urine β2-microglobulin (P>0.05). But we found that the BCMA expression of patients with high serum β2-microglobulin was higher than that of patients with low serum β2-microglobulin (rank average 28.89 vs 17.54, P=0.017). And the BCMA expression of patients with abnormal serum free kap/lam ratio was higher than that of patients with normal ratio (rank average 28.49 vs 13.55, P=0.004). The BCMA expression was strongly positively correlated with 24-h urine protein, was moderately positively correlated with serum M protein and the percentage of plasma cells in bone marrow, was moderately negatively correlated with albumin and hemoglobin count, and was weakly positively correlated with serum corrected calcium (P0.05).

Abstract Background Transcription factors act as important regulators of transcription networks. Basic leucine zipper (bZIP) transcription factors have been shown to be involved in multiple biological processes in plants. However, no information is available for the bZIP family in Cleistogenes songorica, which is an important xerophytic and allotetraploid grass in desert grasslands. Results In this study, 86 CsbZIPs were identified in the allotetraploid C. songorica genome. For location analysis, CsbZIPs were distributed evenly across two subgenomes of C. songorica. Phylogenetic tree analysis among three species indicated that CsbZIPs were evolutionarily more closely related to OsbZIPs than AtbZIPs. Syntenic and phylogenetic analyses confirmed that the CsbZIPs were mainly expanded by whole-genome duplication events. Furthermore, it was determined that rice and C. songorica might have undergone purified selection during their long evolutionary history by calculating the Ks values and Ka/Ks ratios of orthologous gene pairs. By analysing the expression patterns of CsbZIPs in different tissues and under abiotic stresses, 21 CsbZIP genes were differentially expressed between chasmogamous (CH) and cleistogamous (CL) flowers, including two FLOWERING LOCUS D (FD) genes. In shoots and roots, 79.1 and 87.2% of the CsbZIP genes, respectively, displayed transcript changes under at least one stress treatment, such as heat, cold, drought and salt. Strikingly, 17 common CsbZIP genes showed differential expression under stress response and during CL flowering. Co-expression network, GO annotation and real-time quantitative reverse transcription PCR (qRT-PCR) analyses revealed a close relationship between CL flowering-associated genes and abiotic stress-related genes. Conclusions BZIP TFs were comprehensively analysed and identified in allotetraploid C. songorica. Our results provide insights into the evolutionary history of the bZIP family in C. songorica and provide abiotic stress-responsive and CL-associated candidate CsbZIP genes for potential applications in the genetic improvement of plants.

Abstract Background The aim of this systematic review was to synthesise peer-reviewed literature assessing the impact of electronic prescribing (eP) systems on the working practices of healthcare professionals (HCPs) in the inpatient setting and identify implications for practice and research. Methods We searched PubMed, Medline, Embase, Cochrane and the Cumulative Index to Nursing Allied Health Literature databases for studies published from inception to November 2018. We included controlled, uncontrolled, observational and descriptive studies that explored the effect of eP on HCPs’ working practices in an inpatient setting. Data on setting, eP system and impact on working practices were extracted. Methodological quality was assessed using the Mixed Methods Appraisal Tool. Emergent themes were identified and subjected to narrative synthesis. The protocol was registered with PROSPERO (registration CRD42017075804). Results Searches identified 1301 titles and abstracts after duplicate removal. 171 papers underwent full-text review. A total of 25 studies met the inclusion criteria, from nine different countries. Nineteen were of commercial eP systems. There were a range of study designs; most (n = 14) adopted quantitative methods such as cross-sectional surveys, ten adopted qualitative approaches and a further one used mixed methods. Fourteen of the 25 studies were deemed to be of high quality. Four key themes were identified: communication, time taken to complete tasks, clinical workflow, and workarounds. Within each theme, study findings differed as to whether the effects of eP on HCPs’ working practices were positive or negative. Conclusion There is a lack of consensus within the literature on the impact of eP on HCPs’ working practices. Future research should explore the strategies resulting in a positive impact on HCPs’ working practices and learn from those that have not been successful.

Abstract Background Water stress seriously constrains plant growth and yield. Long non-coding RNAs (lncRNAs) serve as versatile regulators in various biological regulatory processes. To date, the systematic screening and potential functions of lncRNA have not yet been characterized in Cleistogenes songorica, especially under water stress conditions. Results In this study, we obtained the root and shoot transcriptomes of young C. songorica plants subjected to different degrees of water stress and recovery treatments by Illumina-based RNA-seq. A total of 3397 lncRNAs were identified through bioinformatics analysis. LncRNA differential expression analysis indicated that the higher response of roots compared to shoots during water stress and recovery. We further identified the 1644 transcription factors, 189 of which were corresponded to 163 lncRNAs in C. songorica. Though comparative analyses with major Poaceae species based on blast, 81 water stress-related orthologues regulated to lncRNAs were identified as a core of evolutionary conserved genes important to regulate water stress responses in the family. Among these target genes, two genes were found to be involved in the abscisic acid (ABA) signalling pathway, and four genes were enriched for starch and sucrose metabolism. Additionally, the 52 lncRNAs were predicted as target mimics for microRNAs (miRNAs) in C. songorica. RT-qPCR results suggested that MSTRG.43964.1 and MSTRG.4400.2 may regulate the expression of miRNA397 and miRNA166, respectively, as target mimics under water stress and during recovery. Finally, a co-expression network was constructed based on the lncRNAs, miRNAs, protein-coding genes (PCgenes) and transcription factors under water stress and during recovery in C. songorica. Conclusions In C. songorica, lncRNAs, miRNAs, PCgenes and transcription factors constitute a complex transcriptional regulatory network which lncRNAs can regulate PCgenes and miRNAs under water stress and recovery. This study provides fundamental resources to deepen our knowledge on lncRNAs during ubiquitous water stress.

BackgroundS100A8 plays a key role in many cellular processes and is highly expressed in various solid cancers. However, the prognostic role of S100A8 has not been well defined. Therefore, we conducted a quantitative meta-analysis to investigate whether or not S100A8 could be used as a prognostic biomarker in solid tumors.MethodsPubMed, Web of Science, Embase, and Cochrane library were searched to acquire relevant studies that evaluated the association between expression of S100A8 and prognosis of cancer patients. Pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were extracted to evaluate the association between S100A8 overexpression and Overall Survival (OS), Disease-Free Survival (DFS), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS). The expression of S100A8 was also validated by Flow cytometry, immunohistochemistry (IHC), and western blot.ResultsA total of 2,817 patients from 13 independent studies, ranging from 43 to 1,117 patients in size, were statistically analyzed. Our results indicated that a high level of S100A8 expression was significantly associated with poor OS, poor DFS, and poor PFS/RFS. In term of clinical pathological characteristics, a high expression level of S100A8 was significantly associated with differentiation grades, lymphatic metastasis, ER statue, and PR statue. The validation studies showed that the expression of S100A8 was at high levels in MDA-MB-231 (79.7%), MDA-MB-453 (89.2%), HTB-9 (70.2%), and T24 (53.3%) cells and it was higher in breast cancer tissue and bladder cancer tissue than their corresponding para-carcinoma tissue.ConclusionsS100A8 overexpression was significantly associated with poor clinical prognosis in cancer patients. S100A8 is potential a prognostic biomarker in breast cancer and bladder cancer. More well-designed studies with adequate prognostic data are needed to confirm the prognostic role of S100A8 revealed in this study.

Listeriolysin O (LLO) is a cholesterol-dependent cytolysin that mediates escape of L. monocytogenes from phagosomes and enables the bacteria to grow within the host. LLO is a versatile tool allowing Listeria to trigger several cellular responses. In this study, rapid phosphorylation of ERK1/2 on Caco-2 cells caused by Listeria infection was demonstrated to be highly dependent on LLO activity. The effect could be strongly induced by adding purified recombinant LLO alone and could be inhibited by exogenous cholesterol. Lack of the PEST sequence, known to tightly control cytotoxicity of LLO, did not affect ERK1/2 activation. However, the recombinant non-cytolytic LLOT515AL516A, with mutations in the cholesterol-binding motif, was unable to trigger this response. Recombinant LLON478AV479A, which lacks most of the cytolytic activity, also failed to activate ERK1/2 phosphorylation, and this effect could be rescued when the protein concentration reached a cytolytic level. Infection with an LLO-deficient mutant (Δhly) or the mutant complementing LLOT515AL516A abrogated the capacity of the bacteria to activate ERK1/2. However, infection with the Δhly mutant complementing LLON478AV479A, which retained partial pore-forming ability and could grow intracellularly, was capable of triggering ERK1/2 phosphorylation. Collectively, these data suggest that ERK1/2 activation by L. monocytogenes depends on the permeabilization activity of LLO and more importantly correlates with the cholesterol-binding motif of LLO.

Circulating tumor cells (CTCs) in cancer patients’ peripheral blood have been demonstrated to be a significant biomarker for metastasis detection, disease prognosis, and therapy response. Due to their extremely low concentrations, efficient enrichment and non-destructive release are needed. Herein, an FTO chip modified with multifunctional gelatin nanoparticles (GNPs) was designed for the specific capture and non-destructive release of CTCs. These nanoparticles share a similar dimension with the microvilli and pseudopodium of the cellular surface; thus, they can enhance adhesion to CTCs, and then GNPs can be degraded by the enzyme matrix metalloproteinase (MMP-9), gently releasing the captured cells. In addition, the transparency of the chip makes it possible for fluorescence immunoassay identification in situ under a microscope. Our chip attained a high capture efficiency of 89.27%, a release efficiency of 91.98%, and an excellent cellular viability of 96.91% when the concentration of MMP-9 was 0.2 mg/mL. Moreover, we successfully identified CTCs from cancer patients’ blood samples. This simple-to-operate, low-cost chip exhibits great potential for clinical application.

Abstract In this paper, we study the multiplicity of periodic solutions of one kind of planar Hamiltonian systems with a nonlinear term satisfying semilinear conditions. Using a generalized Poincaré–Birkhoff fixed point theorem, we prove that the system has infinitely many periodic solutions, provided that the time map tends to zero.

This article starts from the point of view that handwriting examination is dependent on empiricism and by analyzing the core steps of handwriting identification explains that it might be influenced by subjective bias. In practice, examiners cannot avoid biases in decision-making; instead, we must accept the existence of subjective bias in handwriting identification and then discuss its impact; for instance, feature selection in the process of comprehensive evaluation, which involves a comparison of the number and quality of similarities and differences between a questioned sample and the references. While we conclude that comprehensive evaluation is the most important step in the identification process, industries in China do not stipulate explicit and transparent criteria for it, making it hard to numerically quantify the characteristics of handwriting identification. In this article, forensic examiners' opinions on handwriting identification were obtained through a survey. One finding was that most handwriting examiners believe that handwriting identification is subject to subjective bias. In addition, they believe that the subjective cognition of handwriting identification can somehow help actively produce the correct opinion; before the examination, most handwriting examiners think that they should understand the context and so on. Finally, through the questionnaire, which contained variations such as the same case with different background information, different cases with the same background information, and the same case with or without context, it was concluded that handwriting identification does have certain subjectivity. However, which kind of factors influence this subjectivity is not presently clear. Furthermore, it is difficult to control uncertainties when forming an opinion on identification. An alternative way is to perform scrutiny after the formulation of handwriting opinions; for example, internal and external reviews such as appearing in court.

Abstract In this paper, we look for periodic solutions of planar Hamiltonian systems { x ′ = f ( y ) + p 1 ( t , y ) , y ′ = − g ( x ) + p 2 ( t , x ) . $$\left \{ \textstyle\begin{array}{l} x'=f(y)+p_{1}(t,y),\\ y'=-g(x)+p_{2}(t,x). \end{array}\displaystyle \right . $$ By using the Poincaré-Birkhoff twist theorem, we prove the existence and multiplicity of periodic solutions of the given system when f satisfies an asymmetric condition and the related time map satisfies an oscillating condition.

The eastern coast of China provides a network of Important Bird Areas (IBAs) as feeding and breeding habitats, as well as migratory corridors for a large variety of waterbirds. However, long-term coastal reclamation has greatly encroached on coastal wetlands and undermined their functions as waterbird habitats. To identify the impacts of coastal reclamation on waterbird habitats in 2014, we analyzed coastal wetland modifications that have been caused by various reclamation types in 38 IBAs along China's coastline by using remotely sensed data. The distribution data of major waterbird families in 15 IBAs were collected to explore their population responses to habitat modification. The densities of their population were calculated to compare the habitat preferences to the natural and modified habitats. In addition, the index of Reclamation Intensity was used to evaluate the comprehensive impacts of coastal reclamation on waterbirds. The results show that more than half of the wetland areas in the 38 IBAs have undergone modification from various types of land use. The different habitat preferences indicate that the original habitat suitability for waterbirds has been perturbed considerably by the coastal reclamation. Our findings revealed that there are still notable conservation gaps for waterbirds along China's coastline and the opportunity exists for trading off waterbird conservation versus socioeconomic benefits by wise use of artificial wetlands as alternative and provisional habitats for waterbirds. Keywords: Habitat modification, Coastal reclamation, Waterbird distribution, Habitat preference, Important bird area

Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-activated protein kinase kinase kinase 3 (MEKK3) forms a complex with WDR62 to promote c-Jun N-terminal kinase (JNK) signaling synergistically in the control of neurogenesis. The deletion of Mekk3, Wdr62, or Jnk1 resulted in phenocopied defects, including premature NPC differentiation. We further showed that WDR62 protein is positively regulated by MEKK3 and JNK1 in the developing brain and that the defects of wdr62 deficiency can be rescued by the transgenic expression of JNK1. Meanwhile, WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. Our findings demonstrate that the coordinated reciprocal and bidirectional regulation among MEKK3, FBW7, WDR62, and JNK1, is required for fine-tuned JNK signaling for the control of balanced NPC self-renewal and differentiation during cortical development.

Melilotus is an important genus of legumes with industrial and medicinal value, partly due to the production of coumarin. To explore the genetic diversity and population structure of Melilotus, 40 accessions were analyzed using long terminal repeat (LTR) retrotransposon-based markers. A total of 585,894,349 bp of LTR retrotransposon sequences, accounting for 55.28% of the Melilotus genome, were identified using bioinformatics tools. A total of 181,040 LTR retrotransposons were identified and classified as Gypsy, Copia, or another type. A total of 350 pairs of primers were designed for assessing polymorphisms in 15 Melilotus albus accessions. Overall, 47 polymorphic primer pairs were screened for their availability and transferability in 18 Melilotus species. All the primer pairs were transferable, and 292 alleles were detected at 47 LTR retrotransposon loci. The average polymorphism information content (PIC) value was 0.66, which indicated that these markers were highly informative. Based on unweighted pair group method with arithmetic mean (UPGMA) dendrogram cluster analysis, the 18 Melilotus species were classified into three clusters. This study provides important data for future breeding programs and for implementing genetic improvements in the Melilotus genus.

Listeria monocytogenes is a food-associated bacterium that is responsible for food-related illnesses worldwide. In the L. monocytogenes EGD-e genome, FlhB, FliM, and FliY (encoded by lmo0679, lmo0699, and lmo0700, respectively) are annotated as putative flagella biosynthesis factors, but their functions remain unknown. To explore whether FlhB, FliM, and FliY are involved in Listeria flagella synthesis, we constructed flhB, fliM, fliY, and other flagellar-related gene deletion mutants using a homologous recombination strategy. Then, we analyzed the motility, flagella synthesis, and protein expression of these mutant strains. Motility and flagella synthesis were completely abolished in the absence of flhB, fliM, or fliY. These impaired phenotypes were fully restored in the complemented strains CΔflhB, CΔfliM, and CΔfliY. The transcriptional levels of flagellar-related genes, including flaA, fliM, fliY, lmo0695, lmo0698, fliI, and fliS, were downregulated markedly in the absence of flhB, fliM, or fliY. Deletion of flhB resulted in the complete abolishment of FlaA expression, while it decreased FliM and FliY expression. The expression of FlaA was abolished completely in the absence of fliM or fliY. No significant changes were found in the expression of FlhF and two flagella synthesis regulatory factors, MogR and GmaR. We demonstrate for the first time that FlhB, FliM, and FliY not only mediate Listeria motility, but also are involved in regulating flagella synthesis. This study provides novel insights that increase our understanding of the roles played by FlhB, FliM, and FliY in the flagellar type III secretion system in L. monocytogenes.

Listeria monocytogenes is a facultative intracellular pathogen that secretes the cytolysin listeriolysin O (LLO), which enables the bacteria to cross the phagosomal membrane. L. monocytogenes regulates LLO activity in the phagosome and minimizes its activity in the host cytosol. Mutants that fail to compartmentalize LLO activity are cytotoxic and have attenuated virulence. Here, we showed that residues N478 and V479 of LLO are required for LLO hemolytic activity and bacterial virulence. A single N478A mutation (LLON478A) significantly increased the hemolytic activity of LLO at a neutral pH, while no difference was observed at the optimum acidic pH, compared with wild-type LLO. Conversely, the mutant LLOV479A exhibited lower hemolytic activity at the acidic pH, but not at the neutral pH. The double mutant LLON478AV479A showed a greater decrease in hemolytic activity at both the acidic and neutral pHs. Interestingly, strains producing LLON478A or LLOV479A lysed erythrocytes similarly to the wild-type strain. Surprisingly, bacteria-secreting LLON478AV479A had barely detectable hemolytic activity, but exhibited host cell cytotoxicity, escaped from the phagosome, grew intracellularly, and spread cell-to-cell with the same efficiency as the wild-type strain, but were highly attenuated in virulence in mice. These data demonstrate that these two residues are required for LLO hemolytic activity and pathogenicity in mice, but not for escape from the phagosome and cell-to-cell spreading. The finding that the nearly non-hemolytic LLON478AV479A mutant grew intracellularly indicates that mutagenesis of a virulence determinant is a novel approach for the development of live vaccine strains.