The role of hydraulic conductivity in the Pine Island Glacier's subglacial water distribution.

Global climate warming leads to ever-increasing glacier mass loss. Pine Island Glacier in Antarctica is one of the largest contributors to global sea level rise (SLR). One of the biggest uncertainties in the assessment of glacier contribution to SLR at present are subglacial hydrology processes which are less well known than other ice dynamical processes. We use the Glacier Drainage System (GlaDS) model which couples both distributed and channelized components to simulate the basal hydrology of Pine Island Glacier with basal sliding and meltwater production taken from a full-Stokes Elmer/Ice model fitting observed surface velocities. We find ≈100 km long Rothlisberger channels up to 26 m in diameter extending up glacier from the grounding line along the main trunk of Pine Island Glacier delivering 51 m3 s-1 of fresh water to the grounding line. Channelization occurs at high water pressure because of high basal melt rates (maximum of 1 m a-1) caused by high rates of shear heating in regions with fast ice flow (>1000 m a-1). We simulate a shallow "swamp" of 0.8 m water depth where flow transitions from a distributed system into the channels. We performed a set of 38 sensitivity experiments varying sheet and channel conductivity over 4 orders of magnitude. We find a threshold behavior in distributed sheet conductivity above which basal water pressures are unaffected by changing channel conductivities. Our findings suggest a strong need to better understand controls on basal water conductivity through the distributed system. This issue is critical to improve model-based predictive capability for the Pine Island Glacier and, more generally, the Antarctic Ice Sheet.

Resveratrol attenuates cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in the rat mesenteric artery.

Cyclosporin A, an immunosuppressive agent, is extensively utilized for the prevention of transplant rejection and treat autoimmune disease in the clinic, despite its association with a high risk of hypertension development among patients. Resveratrol is a kind of non-flavonoid phenolic compound that widely exists in many plants. The aim of the present study was to investigate the mechanism by which resveratrol ameliorates cyclosporin A-induced hypertension. The arterial rings of the mesentery were incubated with cyclosporin A and resveratrol in vitro. Rats were administered cyclosporin A and/or resveratrol for 3 weeks in vivo. Blood pressure was measured via the tail arteries. Vasoconstriction curves were recorded using a sensitive myograph. The protein expression was evaluated through Western blotting. This study demonstrated that resveratrol mitigated the cyclosporin A-induced increase in blood pressure in rats. Furthermore, resveratrol markedly inhibited the cyclosporin A-induced upregulation of thromboxane A2 receptor-mediated vasoconstriction in the rat mesenteric artery both in vitro and in vivo. Moreover, resveratrol activated AMPK/SIRT1 and inhibited the MAPK/NF-κB signaling pathway. In conclusion, resveratrol restored the cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in rats.

CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses.

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.

Honokiol regulates ovarian cancer cell malignant behavior through YAP/TAZ pathway modulation.

BACKGROUND: Ovarian cancer (OVCA) stands as one of the most fatal gynecological malignancies. Honokiol (HNK) has been substantiated by numerous studies for its anti-tumor activity against malignancies including OVCA. Consequently, this work was designed to elucidate the impact of HNK-mediated modulation of the YAP/TAZ pathway on the biological functions of OVCA cells. METHODS: OVCA cells were subjected to treatment with varying concentrations (0, 25, 50, 75, and 100 µM) of HNK, concomitant with the administration of YAP agonist (XMU). Assessment of cellular viability was executed employing the CCK-8 assay, while quantification of cellular proliferation transpired via colony formation assays. Apoptosis was ascertained using flow cytometry, and expression of apoptosis-related proteins (caspase-3, Bcl-2, Bax), EMT-related proteins (E-cadherin, N-cadherin), migration-associated proteins (MMP-2, MMP-9), and YAP/TAZ pathway-related proteins was evaluated by western blot. Transwell experiments were conducted to assess cellular migratory and invasive propensities. Xenograft tumor models were built to observe tumor growth (volume and weight), apoptosis was assessed by TUNEL staining, and Ki67 expression was evaluated through IHC. RESULTS: HNK exerted inhibitory effects on the viability and proliferative capacity of OVCA cells, elicited apoptotic responses, curtailed the migratory and invasive tendencies of cells, and downregulated the YAP/TAZ pathway. Stimulation with YAP agonist (XMU-MP-1) partially attenuated the impacts of HNK on OVCA cell biology. Experiments in vivo confirmed that HNK inhibited OVCA tumor growth. CONCLUSION: The outcomes of this investigation conclusively established that HNK orchestrated the modulation of the YAP/TAZ pathway, thereby exerting control over the malignant phenotypic manifestations of OVCA cells. The ascertained function of HNK in restraining cellular proliferation and tumor progression provided novel evidence of its anti-proliferative activity within OVCA cells.

ReHoGCNES-MDA: prediction of miRNA-disease associations using homogenous graph convolutional networks based on regular graph with random edge sampler.

Numerous investigations increasingly indicate the significance of microRNA (miRNA) in human diseases. Hence, unearthing associations between miRNA and diseases can contribute to precise diagnosis and efficacious remediation of medical conditions. The detection of miRNA-disease linkages via computational techniques utilizing biological information has emerged as a cost-effective and highly efficient approach. Here, we introduced a computational framework named ReHoGCNES, designed for prospective miRNA-disease association prediction (ReHoGCNES-MDA). This method constructs homogenous graph convolutional network with regular graph structure (ReHoGCN) encompassing disease similarity network, miRNA similarity network and known MDA network and then was tested on four experimental tasks. A random edge sampler strategy was utilized to expedite processes and diminish training complexity. Experimental results demonstrate that the proposed ReHoGCNES-MDA method outperforms both homogenous graph convolutional network and heterogeneous graph convolutional network with non-regular graph structure in all four tasks, which implicitly reveals steadily degree distribution of a graph does play an important role in enhancement of model performance. Besides, ReHoGCNES-MDA is superior to several machine learning algorithms and state-of-the-art methods on the MDA prediction. Furthermore, three case studies were conducted to further demonstrate the predictive ability of ReHoGCNES. Consequently, 93.3% (breast neoplasms), 90% (prostate neoplasms) and 93.3% (prostate neoplasms) of the top 30 forecasted miRNAs were validated by public databases. Hence, ReHoGCNES-MDA might serve as a dependable and beneficial model for predicting possible MDAs.

Honokiol induces ferroptosis in ovarian cancer cells through the regulation of YAP by OTUB2.

BACKGROUND: Ovarian cancer (OVCA) is prevalent in female reproductive organs. Despite recent advances, clinical outcomes remain poor, warranting fresh treatment avenues. Honokiol has an inhibitory effect on proliferation, invasion, and survival of cancer cells in vitro and in vivo. Therefore, this study intended to explore specific molecular mechanism by which honokiol affected OVCA progression. METHODS: Bioinformatics analyzed the drug honokiol that bound to OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2). Cellular thermal shift assay (CETSA) verified the binding relationship between honokiol and OTUB2. Cell counting kit 8 (CCK-8) tested the IC50 value and cell viability of OVCA cells after honokiol treatment. Corresponding assay kits determined malonic dialdehyde (MDA) and Fe2+ levels in OVCA cells. Flow cytometry measured reactive oxygen species levels. Western blot detected OTUB2, SLC7A11, and transcriptional co-activators Yes-associated protein (YAP) expression, and quantitative polymerase chain reaction (qPCR) detected OTUB2 expression. Immunohistochemistry (IHC) detected the expression level of Ki67 protein in tumor tissues. RESULTS: Honokiol was capable of inducing ferroptosis in OVCA cells. CETSA confirmed that honokiol could bind to OTUB2. Further cell functional and molecular experiments revealed that honokiol induced ferroptosis in OVCA cells via repression of YAP signaling pathway through binding to OTUB2. In addition, in vivo experiments have confirmed that honokiol could inhibit the growth of OVCA. CONCLUSION: Honokiol induced ferroptosis in OVCA cells via repression of YAP signaling pathway through binding to OTUB2, implicating that OTUB2 may be an effective target for OVCA treatment, and our study results may provide new directions for development of more effective OVCA treatment strategies.

[New research direction of organ dysfunction caused by hemorrhagic shock: mechanisms of mitochondrial quality control].

Hemorrhagic shock (HS) is one of the leading causes of death among young adults worldwide. Multiple organ dysfunction in HS is caused by an imbalance between tissue oxygen supply and demand, which is closely related to the poor prognosis of patient. Mitochondrial dysfunction is one of the key mechanisms contributing to multiple organ dysfunction in HS, while mitochondrial quality control regulates mitochondrial function through a series of processes, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial-derived vesicles, and mitochondrial protein homeostasis. Modulating mitochondrial quality control can improve organ dysfunction. This review aims to summarize the effects of mitochondrial dysfunction on organ function in HS and discuss the potential mechanisms of mitochondrial quality control, providing insights into the injury mechanisms underlying HS and guiding clinical management.

Artificial intelligence technology improves the accuracy of preoperative planning in primary total hip arthroplasty.

OBJECTIVE: Successful total hip arthroplasty relies on accurate preoperative planning. However, the conventional preoperative planning, a two-dimensional method using X-ray template, has shown poor reliability of predicting component size. To our knowledge, artificial intelligence technology assisted three-dimensional preoperative planning is promising to improve the accuracy of preoperative planning but there is a dearth of clinical evidence. Therefore, in this study we compared the prediction accuracy of these two maneuvers. METHODS: We conducted a prospective study consisting of 117 consecutive patients who underwent a primary cementless total hip arthroplasty to compare the prediction accuracy of these two methods. The two-dimensional and artificial intelligence assisted three-dimensional planning results of the same patient were compared with the definitive implant size respectively. RESULTS: The prediction accuracy of artificial intelligence assisted three-dimensional planning for cup and the stem sizes were 66.67% (78/117) and 65.81% (77/117), two-dimensional planning was 30.77% (36/117) and 37.61% (44/117) (p < 0.05). There were poor prediction results of two-dimensional planning in patients with hip dysplasia (p = 0.004, OR = 7.143) and excessive femoral anteversion (p = 0.012, OR = 1.052), meanwhile the failure risk of stem side two-dimensional planning increased as patients got older (p = 0.003, OR = 1.118). The accuracy of artificial intelligence assisted three-dimensional planning cannot be affected by above factors. CONCLUSIONS: We confirmed that artificial intelligence assisted three-dimensional preoperative planning showed higher accuracy and stability than two-dimensional preoperative planning in primary cementless total hip arthroplasty. We believe artificial intelligence assisted three-dimensional preoperative planning technology provides surgeons a new reliable choice and offers advantages whether in simple or complicated cases.

Associations between the built environment and physical activity in children, adults and older people: A narrative review of reviews.

BACKGROUND: Physical activity is essential for promoting public health, and it is affected by the built environment at population level. Extensive evidence exists on the associations between the built environment and physical activity, but results are inconclusive for different age groups. Therefore, we conducted a narrative review summarizing existing reviews on the associations between the built environment and physical activity for children, adults and older people and synthesized their findings. METHODS: We followed the PRISMA 2020 review procedure and searched for systematic reviews published between January 2010 and April 2022 in seven databases (Scopus, Web of Science, Medline, PsycINFO, EMBASE, SocIndex and Cochrane Library) using keywords related to the built environment, urban interventions, physical activity and health. RESULTS: The selection process yielded 29 reviews with moderate to high quality. From these reviews, we identified 21 built environment characteristics, several of which were positively related to physical activity. For example, children and older people's physical activity was positively associated with pedestrian-friendly features and general safety. Furthermore, adults and older people's physical activity was positively related to the availability and accessibility of shops/commercial services and parks/open spaces. Lastly, the walkability index was positively associated with physical activity in every age group. CONCLUSION: Our findings provide valuable information on creating health-promoting urban environments for practitioners. Further research is needed to understand which characteristics make urban environments age friendly for physical activity. Special attention should be paid to less explored promising characteristics such as street lighting and the quality of green spaces.

Correction: Zhang et al. Experimental and Numerical Studies on Hot Compressive Deformation Behavior of a Cu-Ni-Sn-Mn-Zn Alloy. Materials 2023, 16, 1445.

In the original publication [...].

Improved global 250 m 8-day NDVI and EVI products from 2000-2021 using the LSTM model.

Satellite vegetation index (VI) products, such as normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI), have been widely used. However, they are severely contaminated by clouds and other factors and provide false signals of the surface vegetation conditions. In this study, the new global seamless 250 m, eight-day NDVI and EVI products from 2000-2021 were developed from Moderate Resolution Imaging Spectroradiometer (MODIS) surface reflectance data using a long short-term memory (LSTM) neural network method. High-quality globally representative time series VI samples were constructed to train the model using a combination of the Savitzky-Golay filter (SG), Global LAnd Surface Satellite (GLASS) leaf area index (LAI) fitting and upper envelope methods. To evaluate the proposed method and the 250 m VI products, the MODIS VI product (MOD13Q1) was used for the inter-comparisons using four widely used VI reconstruction methods. Assuming that the MODIS VI data of high quality represents the true values, the root mean square error (RMSE) for NDVI and EVI generated by the LSTM model are 0.0734 and 0.0509, respectively.

Spatiotemporal variation of drought in the Western Sichuan Plateau based on standardized precipitation evapotranspiration index.

Drought is a destructive natural disaster in the Western Sichuan Plateau. Understanding its spatiotemporal variations has important practical significance for drought prevention, ensuring agricultural production safety, and maintaining ecosystem health in the region. Based on the daily meteorological data from 48 meteorological stations in the Western Sichuan Plateau from 1980 to 2020, we used the Penman-Monteith model to calculate potential evapotranspiration and standardized precipitation evapotranspiration index (SPEI). The temporal and spatial variations of drought in the Western Sichuan Plateau were analyzed using linear trend analysis and drought characteristics analysis methods. The results showed that the annual and spring SPEI of the Western Sichuan Plateau showed a weak wetting trend from 1980 to 2020, while summer, autumn, and winter showed a drought trend. The southwest mountains and northeast grasslands in the study region were prone to drought. The range of interannual drought impact in the study area was weakly increasing, with a decreasing trend in spring and an increasing trend in summer, autumn, and winter. The overall drought frequency in the whole region was relatively high. The areas drought of low-frequency were mainly located in parts of west and northeast of the Western Sichuan Plateau, while the rest were high frequency areas.

Propensity score-matched analysis comparing hippocampus-avoidance whole-brain radiotherapy plus simultaneous integrated boost with hippocampus­avoidance whole-brain radiotherapy alone for multiple brain metastases-a retrospective study in multiple institutions.

BACKGROUND: The optimal treatment for multiple brain metastases has been recently controversially discussed.This study was aimed to explore the feasibility of Hippocampus-Avoidance Whole-Brain Radiotherapy plus a simultaneous integrated boost (HA-WBRT + SIB) in patients with multiple brain metastases and assess tumor control in comparison with Hippocampus-Avoidance Whole-Brain Radiotherapy (HA-WBRT) alone for brain metastases. METHODS: In this study, 63 patients with multiple brain metastases (≥ 4 metastases) had undergone HA-WBRT + SIB between January 2016 and December 2020 in the observation group:HA-WBRT (30 Gy in 12 fractions, the maximum dose of the hippocampus ≤ 14 Gy) plus a simultaneous integrated boost (48 Gy in 12 fractions) for brain metastases.Overall Survival (OS), Median survival,intracranial control (IC = control within the entire brain), intracranial progression-free survival (iPFS) and adverse events were compared with the control group (a HA-WBRT retrospective cohort) by propensity score matching analysis. RESULTS: After 1:1 propensity score matching,there were 56 patients in each group (the observation group, the control group). OS, median survival and iPFS were significantly longer in the observation group (18.4 vs. 10.9 months, P<0.001), (13.0 vs. 8.0 months, P<0.001), (13.9 vs.7.8 months, P<0.001). In comparison of 1-year-IC rates, the observation group also demonstrated higher than the control group (51.8% vs. 21.4%, P = 0.002), respectively. Seven hippocampal metastases were found in the control group (4/56,7.1%) and the observation group (3/56,5.4%) after HA-WBRT. The death rate of intracranial progression were 23.2% in the observation group and 37.5% in the control group.All adverse events were not significant difference between the two groups (P>0.05). CONCLUSIONS: HA-WBRT + SIB resulted in better OS,median survival, IC, iPFS, an acceptable risk of radiation response, and a potential way of declining neurocognitive adverse events, which may be a better treatment for patients with multiple brain metastases.

Endothelial progenitor cells derived from embryonic stem cells prevent alveolar simplification in a murine model of bronchopulmonary dysplasia.

Introduction: Vascular remodeling and compromised alveolar development are hallmarks of chronic pulmonary diseases such as bronchopulmonary dysplasia (BPD). Despite advances in neonatal healthcare the number of BPD cases worldwide continues to increase. One approach to overcoming the premature arrest in lung development seen in BPD is to stimulate neonatal angiogenesis via delivery and engraftment of endothelial progenitor cells (EPCs). One such population is resident to the pulmonary microvasculature and expresses both FOXF1 and c-KIT. Previous studies have shown that c-KIT+FOXF1+ EPCs are highly sensitive to elevated levels of oxygen (hyperoxia) and are decreased in premature infants with BPD and hyperoxia-induced BPD mouse models. We hypothesize that restoring EPCs through transplantation of c-KIT+FOXF1+ EPCs derived in vitro from pluripotent embryonic stem cells (ESCs), will stimulate neonatal angiogenesis and alveolarization in mice with hyperoxia-induced lung injury. Methods: Utilizing a novel ESC line with a FOXF1:GFP reporter, we generated ESC-derived c-KIT+FOXF1+ EPCs in vitro. Using a second ESC line which contains FOXF1:GFP and tdTomato transgenes, we differentiated ESCs towards c-KIT+FOXF1+ EPCs and tracked them in vivo after injection into the neonatal circulation of hyperoxia-injured mice. After a recovery period in room air conditions, we analyzed c-KIT+FOXF1+ EPC engraftment and quantified the number of resident and circulating endothelial cells, the size of alveolar spaces, and the capillary density after EPC transplantations. Results and conclusion: Herein, we demonstrate that addition of BMP9 to the directed endothelial differentiation protocol results in very efficient generation of c-KIT+FOXF1+ EPCs from pluripotent ESCs. ESC-derived c-KIT+FOXF1+ EPCs effectively engraft into the pulmonary microvasculature of hyperoxia-injured mice, promote vascular remodeling in alveoli, increase the number of resident and circulating endothelial cells, and improve alveolarization. Altogether, these results provide a proof-of-principle that cell therapy with ESC-derived c-KIT+FOXF1+ EPCs can prevent alveolar simplification in a hyperoxia-induced BPD mouse model.

Effects of Policy Intervention on Food System Resilience to Emergency Risk Shock: Experience from China during COVID-19 Pandemic.

Achieving the goal of zero hunger within the goal of sustainable development requires improving the resilience of food systems to various types of risk shocks; food systems have shown significant vulnerability to COVID-19 outbreaks and transmission. By analyzing the impact of China's lockdown policy and food security emergency policy in 2020 on food prices during the COVID-19 pandemic, we can clarify the role of policy intervention in enhancing the resilience of the food system, which can provide guidance, using China's experience, for dealing with global food safety emergencies in the future. Firstly, we selected Beijing, Shanghai and Guangdong as food-consuming areas, and Shandong, Henan, and Hubei as food-producing areas. We also collected food security emergency policy data from the Chinese government website during the COVID-19 pandemic. Secondly, a difference-in-difference method was used to observe that Chinese cabbage and pork prices in the main food-producing areas and food-consuming areas rose more obviously after the adoption of lockdown policy, and Chinese cabbage and pork prices in the food-consuming areas increased more obviously than those in food-producing areas. However, staple food prices have not risen significantly. Thirdly, the response of four kinds of food prices to the food security emergency policy is analyzed quantitatively and graphically using the food price volatility index and food price increase rate; we observed that the response of food prices to the food security emergency policy is related to the food types and regions. For food types, the fluctuation degree and increase in Chinese cabbage and pork prices decreased significantly after the adoption of the food security emergency policy. For regions, when the food security emergency policy was adopted, the food prices in the main food-consuming areas fluctuated more obviously than those in food-producing areas. Finally, we found that the implementation of the transport policy and the joint supply emergency policy in the main producing and consuming areas has played a very significant and positive role in stabilizing food prices.

Enantioselective Effect of Chiral Small Molecules in SARS-CoV-2 Vaccine-Induced Immune Response.

Although numerous chiral small molecules have been discovered and synthesized, the investigation on their enantioselective immunological effects remains limited. In this study, we designed and synthesized a pair of small molecule enantiomers (R/S-ResP) by covalently bonding two immunostimulators (resiquimod/Res) onto a planar chiral framework (paracyclophane/P). Notably, we found that S-ResP exhibits a 4.05-fold higher affinity for toll-like receptor 7 (TLR7) than R-ResP, thereby more effectively enhancing the functions of dendritic cells and macrophages in cytokine secretion and antigen internalization. Furthermore, we observed that S-ResP significantly enhances RBD antigen-induced cross-neutralization against various SARS-CoV-2 strains compared to R-ResP. These findings demonstrate the enantioselective effects of small molecules on regulating vaccine-induced immune responses and emphasize the significance of chirality in designing small molecular adjuvants.

Spatiotemporal variations and impact factors of nutrients in the Sanya Bay, northern South China Sea.

Nutrients play a fundamental role in maintaining coastal ecosystem stability. Based on two cruise observations in the winter of 2020 and the summer of 2021, the spatiotemporal variations of dissolved inorganic nitrogen (DIN) and orthophosphate (PO43-) and their influencing factors in Sanya Bay were analyzed. Results show that the mean DIN concentrations in the bay are 2.36 µmol/L in winter and 1.73 µmol/L in summer, and the mean PO43- concentrations are 0.08 µmol/L in winter and 0.04 µmol/L in summer. The nutrient concentrations and composition are significantly affected by the Sanya River. The surface DIN concentrations at the Sanya River estuary are 15.80 and 5.25 times than those inside the bay in winter and summer, respectively. Meanwhile, a high proportion of NO3- (74%) and a low proportion of NH4+ (20%) in DIN appear near the river estuary, while a low proportion of NO3- (37%) and a high proportion of NH4+ (53%) occur away from the estuary. In addition, the thermocline promotes the accumulation of NH4+ at the bottom layer in summer. The high proportion of NO3- is likely not favorable for the survival of coral reefs in eastern bay. Compared with the previous nutrient concentrations, the DIN concentration in the bay has a decrease after 2014, which might benefit from the implementation of the environmental protection policy by government.

Analysis on the properties of hydrolyzed amino acids in typical municipal sludge.

In this study, amino acids, proteins, and microbial communities in sludge from different wastewater treatment plants (WWTPs) were analyzed. The results showed that the bacterial communities of different sludge samples were similar at the phylum level, and the dominant bacterial species in sludge samples with the same treatment process were the consistent. The main amino acids in EPS of different layers were different, and the amino acid results of different sludge samples were quite different, but the content of hydrophilic amino acids in all samples was higher than that of hydrophobic amino acids. And the total content of glycine, serine, and threonine related to sludge dewatering was positively correlated with protein content in sludge. In addition, the content of nitrifying bacteria and denitrifying bacteria in sludge was also positively correlated with the content of hydrophilic amino acids. In this study, the correlations between proteins, amino acids, and microbial communities in sludge were analyzed respectively, and the internal relationship was found. And it provided ideas for further study of sludge dewatering characteristics in the future.

Demonstration of Safety in Wild Type Mice of npFOXF1, a Novel Nanoparticle-Based Gene Therapy for Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins.

Introduction: Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins (ACDMPV) is a fatal congenital disease resulting from a pulmonary vascular endothelial deficiency of FOXF1, producing abnormal morphogenesis of alveolar capillaries, malpositioned pulmonary veins and disordered development of lung lobes. Affected neonates suffer from cyanosis, severe breathing insufficiency, pulmonary hypertension, and death typically within days to weeks after birth. Currently, no treatment exists for ACDMPV, although recent murine research in the Kalinichenko lab demonstrates nanoparticle delivery improves survival and reconstitutes normal alveolar-capillary architecture. The aim of the present study is to investigate the safety of intravenous administration of FOXF1-expressing PEI-PEG nanoparticles (npFOXF1), our pioneering treatment for ACDMPV. Methods: npFOXF1 was constructed, validated, and subsequently administered in a single dose to postnatal day 14 (P14) mice via retro-orbital injection. Biochemical, serologic, and histologic safety were monitored at postnatal day 16 (P16) and postnatal day 21 (P21). Results: With treatment we observed no lethality, and the general condition of mice revealed no obvious abnormalities. Serum chemistry, whole blood, and histologic toxicity was assayed on P16 and P21 and revealed no abnormality. Discussion: In conclusion, npFOXF1 has a very good safety profile and combined with preceding studies showing therapeutic efficacy, npFOXF1 can be considered as a good candidate therapy for ACDMPV in human neonates.

The activation of gastric inhibitory peptide/gastric inhibitory peptide receptor axis via sonic hedgehog signaling promotes the bridging of gapped nerves in sciatic nerve injury.

Schwann cells play an essential role in peripheral nerve regeneration by generating a favorable microenvironment. Gastric inhibitory peptide/gastric inhibitory peptide receptor (GIP/GIPR) axis deficiency leads to failure of sciatic nerve repair. However, the underlying mechanism remains elusive. In this study, we surprisingly found that GIP treatment significantly enhances the migration of Schwann cells and the formation of Schwann cell cords during recovery from sciatic nerve injury in rats. We further revealed that GIP and GIPR levels in Schwann cells were low under normal conditions, and significantly increased after injury demonstrated by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Wound healing and Transwell assays showed that GIP stimulation and GIPR silencing could affect Schwann cell migration. In vitro and in vivo mechanistic studies based on interference experiment revealed that GIP/GIPR might promote mechanistic target of rapamycin complex 2 (mTORC2) activity, thus facilitating cell migration; Rap1 activation might be involved in this process. Finally, we retrieved the stimulatory factors responsible for GIPR induction after injury. The results indicate that sonic hedgehog (SHH) is a potential candidate whose expression increased upon injury. Luciferase and chromatin immunoprecipitation (ChIP) assays showed that Gli3, the target transcription factor of the SHH pathway, dramatically augmented GIPR expression. Additionally, in vivo inhibition of SHH could effectively reduce GIPR expression after sciatic nerve injury. Collectively, our study reveals the importance of GIP/GIPR signaling in Schwann cell migration, providing a therapeutic avenue toward peripheral nerve injury.