[Retracted] Downregulation of CKS1B restrains the proliferation, migration, invasion and angiogenesis of retinoblastoma cells through the MEK/ERK signaling pathway.

Following the publication of the above paper, it has been drawn to the Editors' attention by a concerned reader that certain of the lumen formation assay data shown in Fig. 5A on p. 112 were strikingly similar to data appearing in different form in another article written by different authors at different research institute, which had already been published in the journal Biomedicine & Pharmacotherapy prior to the submission of this paper to International Journal of Molecular Medicine, and which has also subsequently been retracted. In view of the fact that the contentious data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 103­114, 2019; DOI: 10.3892/ijmm.2019.4183].

SARS-CoV-2 Infection, Hospitalization, and Associated Factors Among People Living With HIV in Southeastern China From December 2022 to February 2023: Cross-Sectional Survey.

BACKGROUND: Limited studies have explored the impact of the Omicron variant on SARS-CoV-2 infection, hospitalization, and associated factors among people living with HIV, particularly in China. The adjustment of preventive policies since December 2022 in China presents an opportunity to evaluate the real-world factors influencing SARS-CoV-2 infection and related hospitalization among people living with HIV. OBJECTIVE: This study aimed to investigate SARS-CoV-2 infection, hospitalization rates, and associated factors among people living with HIV following the adjustment of preventive policies from December 2022 to February 2023 in southeastern China. METHODS: A cross-sectional telephone or web-based survey was conducted among people living with HIV in 5 cities in southeastern China from December 2022 to February 2023. Demographic information, SARS-CoV-2 infection and related hospitalization, and HIV-specific characteristics were collected from existing databases and special investigations. Multivariate logistic regression analyses were conducted to determine the associated factors for infection and hospitalization rates of SARS-CoV-2. Additionally, subgroup analyses were conducted for the association between vaccination and infection across different vaccination statuses and time since the last vaccination. RESULTS: Among people living with HIV with a COVID-19 testing history, the SARS-CoV-2 infection rate was 67.13% (95% CI 65.81%-68.13%), whereas the hospitalization rate was 0.71% (95% CI 0.46%-0.97%). Factors such as age, latest CD4 cell count, latest HIV viral load, and transmission route were found to be associated with SARS-CoV-2 infection, while age, cancer, latest CD4 cell count, and latest HIV viral load were associated with SARS-CoV-2 hospitalization. In terms of SARS-CoV-2 vaccination, compared to unvaccinated people living with HIV, there was a lower infection rate among those who had been vaccinated for <3 months in the booster vaccination group (adjusted odds ratio [aOR] 0.72, 95% CI 0.53-0.98; P=.04); and there was also a lower risk of hospitalization among people living with HIV who had received vaccination in the past 6-12 months (aOR 0.33, 95% CI 0.14-0.81; P=.02) and more than 12 months ago (aOR 0.22, 95% CI 0.07-0.72; P=.01). CONCLUSIONS: After the ease of prevention and control measures in China, we observed a high SARS-CoV-2 infection rate but a low hospitalization rate. General risk factors, such as higher age and vaccination status, and HIV-related parameters, such as the latest CD4 cell count and HIV viral load, were associated with SARS-CoV-2 infection and hospitalization. A booster vaccination campaign for booster doses should be considered among people living with HIV in confronting possible COVID-19 epidemic emergencies in the near future.

The differential impact of iron on ferroptosis, oxidative stress, and inflammatory reaction in head-kidney macrophages of yellow catfish (Pelteobagrus fulvidraco) with and without ammonia stress.

Ammonia toxicity in fish is closely related to ferroptosis, oxidative stress, and inflammatory responses. Iron is an essential trace element that plays a key role in many biological processes for cells and organisms, including ferroptosis, oxidative stress response, and inflammation. This study aimed to investigate the effect of iron on indicators of fish exposed to ammonia, specifically on the three aspects mentioned above. The head kidney macrophages of yellow catfish were randomly assigned to one of four groups: CON (normal control), AM (0.046 mg L-1 total ammonia nitrogen), Fe (20 µg mL-1 FeSO4), and Fe + AM (20 µg mL-1 FeSO4, 0.046 mg L-1 total ammonia nitrogen). The cells were pretreated with FeSO4 for 6 h followed by ammonia for 24 h. The study found that iron supplementation led to an excessive accumulation of iron and ROS in macrophages, but it did not strongly induce ferroptosis, oxidative stress, or inflammatory responses. This was supported by a decrease in T-AOC, and the downregulation of SOD, as well as an increase in GSH levels and the upregulation of TFR1, CAT and Nrf2. Furthermore, the mRNA expression of HIF-1, p53 and the anti-inflammatory M2 macrophage marker Arg-1 were upregulated. The results also showed that iron supplementation increased the progression of some macrophages from early apoptosis to late apoptotic cells. However, the combined treatment of iron and ammonia resulted in a stronger intracellular ferroptosis, oxidative stress, and inflammatory reaction compared to either treatment alone. Additionally, there was a noticeable increase in necrotic cells in the Fe + AM and AM groups. These findings indicate that the biological functions of iron in macrophages of fish may vary inconsistently in the presence or absence of ammonia stress.

Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.

Natural ocean iron fertilization and climate variability over geological periods.

Marine primary producers are largely dependent on and shape the Earth's climate, although their relationship with climate varies over space and time. The growth of phytoplankton and associated marine primary productivity in most of the modern global ocean is limited by the supply of nutrients, including the micronutrient iron. The addition of iron via episodic and frequent events drives the biological carbon pump and promotes the sequestration of atmospheric carbon dioxide (CO2 ) into the ocean. However, the dependence between iron and marine primary producers adaptively changes over different geological periods due to the variation in global climate and environment. In this review, we examined the role and importance of iron in modulating marine primary production during some specific geological periods, that is, the Great Oxidation Event (GOE) during the Huronian glaciation, the Snowball Earth Event during the Cryogenian, the glacial-interglacial cycles during the Pleistocene, and the period from the last glacial maximum to the late Holocene. Only the change trend of iron bioavailability and climate in the glacial-interglacial cycles is consistent with the Iron Hypothesis. During the GOE and the Snowball Earth periods, although the bioavailability of iron in the ocean and the climate changed dramatically, the changing trend of many factors contradicted the Iron Hypothesis. By detangling the relationship among marine primary productivity, iron availability and oceanic environments in different geological periods, this review can offer some new insights for evaluating the impact of ocean iron fertilization on removing CO2 from the atmosphere and regulating the climate.

[Effects of Combined Application of Different Nitrogen Fertilizers and Biochar on Cadmium Uptake by Pakchoi (Brassica chinensis L.) in Cadmium Contaminated Soil].

Nitrogen is an essential nutrient element for crop growth, and biochar is a good material for soil remediation. In this study, a pakchoi (Brassica chinensis L.) pot experiment was conducted to investigate the effects of the combined application of three nitrogen fertilizers, including urea, ammonium sulfate, calcium nitrate, and biochar on pakchoi growth and cadmium (Cd) uptake from cropland soil contaminated by Cd. The results showed that the application of nitrogen fertilizers and biochar prompted pakchoi growth, and the biomass of pakchoi in the treatments of single applications of urea, ammonium sulfate, calcium nitrate, and biochar were significantly increased by 5.02%-32.9%, as compared with that in the control treatment without nitrogen fertilizer application. The biomass of pakchoi in the treatments of the combined application of nitrogen fertilizers and biochar were significantly increased by 8.84%-50.8%, as compared with that in the treatment of the single application of nitrogen fertilizer. Compared with that under the control treatment without nitrogen fertilizer application, the single application of urea significantly reduced soil pH by 0.27 and significantly increased the content of soil available Cd by 30.0%. The single application of ammonium sulfate significantly reduced soil pH by 0.33 and significantly increased Cd content in pakchoi by 29.2%, as compared with that in the control treatment. The single application of calcium nitrate had no significant effect on soil pH or Cd content in pakchoi, whereas the single application of biochar significantly increased soil pH by 0.35 and significantly decreased the content of soil available Cd and content of Cd in pakchoi by 57.4% and 53.7%, respectively, as compared with that in the control treatment. Soil pH in the treatments of the combined application of nitrogen fertilizers and biochar was significantly increased by 0.14-0.28, the contents of soil available Cd were decreased by 16.5%-30.1%, and the contents of Cd in pakchoi were reduced by 15.3%-28.6%, as compared with that in the treatment of single application of nitrogen fertilizers. In general, the application of biochar could adjust the effects of different nitrogen fertilizers on Cd availability in the contaminated soil. During the remediation process of heavy metal-contaminated cropland, nitrogen fertilizer should be selected and applied reasonably to obtain the maximum economic and environmental benefits.

Attitudes toward ophthalmology as a prospective career among pre-clinical medical students in China.

BACKGROUND: A questionnaire was developed and administered to 450 medical students at the Xiangya Medical College, Central South University in Changsha, China to understand the attitudes among medical students in China toward different medical specialties and to find the factors that influenced their choice of career in ophthalmology. PARTICIPANTS: Fourth-year medical students in the five-year program and sixth-year medical students in the eight-year program. METHODS: All the students were asked to rate the importance of nine possible factors in choosing a specialty as their vocation and their first ranked future specialty career choice. RESULTS: When asked about the reasons for choosing to go to medical school, the top four reasons are the ability to help patients, interesting and challenging work, prestige, and job stability. When asked about the reasons for choosing a specialty, the top four reasons are the ability to find employment, financial reward, career upward mobility, and professional pressure. About the first career choice of the future specialty, for clinical medicine students, ophthalmology is the fifth ranked choice for clinical medicine students. 5.6% (five-year) and 3.4% (eight-year) of them choose ophthalmology as their top ranked specialty for their career. For anesthesia medicine and oral medicine students, most of them preferred to choose the same specialty as before. 1.5% (anesthesia) and 4.5% (oral) of them chose ophthalmology as their top ranked specialty. CONCLUSIONS: Medical students in China have numerous factors that motivate their choice in a specialty. Ophthalmology is the fifth ranked choice among clinical medicine students.

Rapid-Hardening and High-Strength Steel-Fiber-Reinforced Concrete: Effects of Curing Ages and Strain Rates on Compressive Performance.

High-strength steel-fiber-reinforced concrete (HSFRC) has become increasingly popular as a cast-in-place jointing material in precast concrete bridges and buildings due to its excellent tensile strength and crack resistance. However, working conditions such as emergency repairs and low-temperature constructions require higher demands on the workability and mechanical properties of HSFRC. To this end, a novel rapid-hardening HSFRC has been proposed, which is produced using sulphoaluminate cement (SC) instead of ordinary Portland cement. In this study, quasi-static and dynamic tests were carried out to compare the compressive behavior of conventional and rapid-hardening HSFRCs. The key test variables included SC replacement ratios, concrete curing ages, and strain rates. Test results showed: (1) Rapid-hardening HSFRC exhibited high early strengths of up to 33.14 and 44.9 MPa at the curing age of 4 h, respectively, but its compressive strength and elastic modulus were generally inferior to those of conventional HSFRC. (2) The strain rate sensitivity of rapid-hardening HSFRC was more significant compared to its conventional counterpart and increased with increasing curing ages and strain rates. This study highlights the great potential of rapid-hardening HSFRC in rapid bridge construction.

Identification of Hypoxia-Associated Signature in Colon Cancer to Assess Tumor Immune Microenvironment and Predict Prognosis Based on 14 Hypoxia-Associated Genes.

Purpose: Colon cancer is the main malignant tumor of the digestive tract. Hypoxia is highly related to the occurrence, progression and tumor immune microenvironment (TIME) of cancer. The aim of this study was to identify a hypoxia-associated signature with high accuracy for predicting the prognosis and TIME of colon cancer. Methods: Download colon cancer data from the GEO and TCGA databases. A novel hypoxia risk model was identified to predict the prognosis of colon cancer patients. Subsequently, GSEA, TIME and mutation analysis were performed in the hypoxia high and low risk score groups. Finally, the signature gene ANKZF1 was selected for functional verification at the cellular level. Results: A novel hypoxia risk model was identified. The risk score was significantly associated with poorer overall survival in colon cancer, and could be used as an independent prognostic factor for colon cancer. GSEA analysis found that the processes related to stimulate tumor proliferation and anti-apoptosis were significantly enriched in the hypoxia high risk score group. The expression of immunosuppressive cells and most immune checkpoints in the high risk score group was significantly higher than that in the low risk score group. In vitro cell experiments showed that knockdown the expression of ANKZF1 could inhibit the proliferation, migration and invasion of colon cancer cells. Conclusion: Hypoxia plays an important role in evaluating the TIME and predicting the prognosis of colon cancer.

MiRNA-1976 Regulates the Apoptosis of Dopaminergic Neurons by Targeting the PINK1 Gene.

INTRODUCTION: Parkinson's disease (PD), which is a neurodegenerative disease, requires urgently needed biomarkers to explore its mechanism. We screened for differences in the expression of microRNAs (miRNAs) and identified miR-1976 as a possible biomarker. METHODS: Twenty-three patients and 30 controls were included in this study. Dopaminergic neurons from C57/BL mice were cultured. The miRNA expression profiles were analyzed using an miRNA microarray. MiR-1976 was identified as an miRNA that was differentially expressed between PD patients and age-matched controls. Lentiviral vectors were constructed, then apoptosis in dopaminergic neurons was analyzed using MTS (multicellular tumor spheroids) and flow cytometry. Transfection of miR-1976 mimics into MES23.5 cells was performed, and target genes and biological effects were analyzed. RESULTS: Overexpression of miR-1976 increased apoptosis and mitochondrial damage in dopaminergic neurons. PINK1 (PINK1-induced kinase 1) was the most common target protein of miR-1976, and silencing of PINK1 caused mitochondrial damage and increased apoptosis of MES23.5 cells. CONCLUSIONS: MiR-1976 is a newly discovered miRNA that exhibits a high degree of differential expression with respect to the apoptosis of dopaminergic neurons. Given these results, increased expression of miR-1976 may increase the risk of PD by targeting PINK1 and may therefore be a useful biomarker for PD.

Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate ovariectomy-induced bone loss.

INTRODUCTION: Osteoporosis is the most common bone disorder where the hyperactive osteoclasts represent the leading role during the pathogenesis. Targeting hyperactive osteoclasts is currently the primary therapeutic strategy. However, concerns about the long-term efficacy and side effects of current frontline treatments persist. Alternative therapeutic agents are still needed. OBJECTIVES: Obacunone (OB) is a small molecule with a broad spectrum of biological activities, particularly antioxidant and anti-inflammatory effects. This study aims to examine OB's therapeutic potential on osteoporosis and explore the rudimentary mechanisms. METHODS: Osteoclast formation and osteoclastic resorption assays were carried out to examine OB's inhibitory effects in vitro, followed by the in-vivo studies of OB's therapeutic effects on ovariectomy-induced osteoporotic preclinical model. To further study the underlying mechanisms, mRNA sequencing and analysis were used to investigate the changes of downstream pathways. The molecular targets of OB were predicted, and in-silico docking analysis was performed. Ligand-target binding was verified by surface plasmon resonance (SPR) assay and Western Blotting assay. RESULTS: The results indicated that OB suppressed the formation of osteoclast and its resorptive function in vitro. Mechanistically, OB interacts with macrophage migration inhibitory factor (MIF) which attenuates receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF-κB pathway, and mitogen-activated protein kinases (MAPKs). These effects eventually caused the diminished expression level of the master transcriptional factor of osteoclastogenesis, nuclear factor of activated T cells 1 (NFATc1), and its downstream osteoclast-specific proteins. Furthermore, our data revealed that OB alleviated estrogen deficiency-induced osteoporosis by targeting MIF and thus inhibiting hyperactive osteoclasts in vivo. CONCLUSION: These results together implicated that OB may represent as a therapeutic candidate for bone disorders caused by osteoclasts, such as osteoporosis.

Diversity and Evolution of Iron Uptake Pathways in Marine Cyanobacteria from the Perspective of the Coastal Strain Synechococcus sp. Strain PCC 7002.

Marine cyanobacteria contribute to approximately half of the ocean primary production, and their biomass is limited by low iron (Fe) bioavailability in many regions of the open seas. The mechanisms by which marine cyanobacteria overcome Fe limitation remain unclear. In this study, multiple Fe uptake pathways have been identified in a coastal strain of Synechococcus sp. strain PCC 7002. A total of 49 mutants were obtained by gene knockout methods, and 10 mutants were found to have significantly decreased growth rates compared to the wild type (WT). The genes related to active Fe transport pathways such as TonB-dependent transporters and the synthesis and secretion of siderophores are found to be essential for the adaptation of Fe limitation in Synechococcus sp. PCC 7002. By comparing the Fe uptake pathways of this coastal strain with other open-ocean cyanobacterial strains, it can be concluded that the Fe uptake strategies from different cyanobacteria have a strong relationship with the Fe bioavailability in their habitats. The evolution and adaptation of cyanobacterial iron acquisition strategies with the change of iron environments from ancient oceans to modern oceans are discussed. This study provides new insights into the diversified strategies of marine cyanobacteria in different habitats from temporal and spatial scales. IMPORTANCE Iron (Fe) is an important limiting factor of marine primary productivity. Cyanobacteria, the oldest photosynthetic oxygen-evolving organisms on the earth, play crucial roles in marine primary productivity, especially in the oligotrophic ocean. How they overcome Fe limitation during the long-term evolution process has not been fully revealed. Fe uptake mechanisms of cyanobacteria have been partially studied in freshwater cyanobacteria but are largely unknown in marine cyanobacterial species. In this paper, the characteristics of Fe uptake mechanisms in a coastal model cyanobacterium, Synechococcus sp. PCC 7002, were studied. Furthermore, the relationship between Fe uptake strategies and Fe environments of cyanobacterial habitats has been revealed from temporal and spatial scales, which provides a good case for marine microorganisms adapting to changes in the marine environment.

A Novel Tumor-Promoting Role for Nuclear Factor IX in Glioblastoma Is Mediated through Transcriptional Activation of GINS1.

Our previous study illustrated that nuclear factor IX (NFIX) promotes glioblastoma (GBM) progression by inducing migration and proliferation of GBM cells. However, the underlying mechanism of how NFIX regulates GBM cell proliferation remains obscure. In this study, we uncovered that Go-Ichi-Ni-San 1 (GINS1) is upregulated and positively correlated with NFIX in human GBM specimen. NFIX silencing downregulates the expression of GINS1, which is pivotal for cell-cycle progression and proliferation of GBM cells. Replenishment of GINS1 largely rescues the NFIX-null effect on GBM cell proliferation. Mechanistic investigation revealed that NFIX transcriptionally actives GINS1 expression by directly binding to promoter region (-1779 to -1793bp) of the GINS1 gene. Furthermore, knockdown of NFIX sensitizes GBM cells to DNA damage-inducing agents including doxorubicin and temozolomide, in a GINS1-dependent manner. IMPLICATIONS: Our study highlights that targeting NFIX-GINS1 axis could be a novel and potential therapeutic approach for GBM treatment.

CDH17 nanobodies facilitate rapid imaging of gastric cancer and efficient delivery of immunotoxin.

BACKGROUND: It is highly desirable to develop new therapeutic strategies for gastric cancer given the low survival rate despite improvement in the past decades. Cadherin 17 (CDH17) is a membrane protein highly expressed in cancers of digestive system. Nanobody represents a novel antibody format for cancer targeted imaging and drug delivery. Nanobody targeting CHD17 as an imaging probe and a delivery vehicle of toxin remains to be explored for its theragnostic potential in gastric cancer. METHODS: Naïve nanobody phage library was screened against CDH17 Domain 1-3 and identified nanobodies were extensively characterized with various assays. Nanobodies labeled with imaging probe were tested in vitro and in vivo for gastric cancer detection. A CDH17 Nanobody fused with toxin PE38 was evaluated for gastric cancer inhibition in vitro and in vivo. RESULTS: Two nanobodies (A1 and E8) against human CDH17 with high affinity and high specificity were successfully obtained. These nanobodies could specifically bind to CDH17 protein and CDH17-positive gastric cancer cells. E8 nanobody as a lead was extensively determined for tumor imaging and drug delivery. It could efficiently co-localize with CDH17-positive gastric cancer cells in zebrafish embryos and rapidly visualize the tumor mass in mice within 3 h when conjugated with imaging dyes. E8 nanobody fused with toxin PE38 showed excellent anti-tumor effect and remarkably improved the mice survival in cell-derived (CDX) and patient-derived xenograft (PDX) models. The immunotoxin also enhanced the anti-tumor effect of clinical drug 5-Fluorouracil. CONCLUSIONS: The study presents a novel imaging and drug delivery strategy by targeting CDH17. CDH17 nanobody-based immunotoxin is potentially a promising therapeutic modality for clinical translation against gastric cancer.

Subcellular Partitioning of Arsenic Trioxide Revealed by Label-Free Imaging.

Subcellular partitioning of therapeutic agents is highly relevant to their interactions with target molecules and drug efficacy, but studying subcellular partitioning is an enormous challenge. Here, we describe the application of nanoscale secondary ion mass spectrometry (NanoSIMS) analysis to define the subcellular pharmacokinetics of a cytotoxic chemotherapy drug, arsenic trioxide (ATO). We reasoned that defining the partitioning of ATO would yield valuable insights into the mechanisms underlying ATO efficacy. NanoSIMS imaging made it possible to define the intracellular fate of ATO in a label-free manner─and with high resolution and high sensitivity. Our studies of ATO-treated cells revealed that arsenic accumulates in the nucleolus. After prolonged ATO exposure, ∼40 nm arsenic- and sulfur-rich protein aggregates appeared in the cell nucleolus, nucleus, and membrane-free compartments in the cytoplasm, and our studies suggested that the partitioning of nanoscale aggregates could be relevant to cell survival. All-trans retinoic acid increased intracellular ATO levels and accelerated the nanoscale aggregate formation in the nucleolus. This study yielded fresh insights into the subcellular pharmacokinetics of an important cancer therapeutic agent and the potential impact of drug partitioning and pharmacokinetics on drug activity.

A protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism.

GPIHBP1, a protein of capillary endothelial cells (ECs), is a crucial partner for lipoprotein lipase (LPL) in the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1, which contains a three-fingered cysteine-rich LU (Ly6/uPAR) domain and an intrinsically disordered acidic domain (AD), captures LPL from within the interstitial spaces (where it is secreted by parenchymal cells) and shuttles it across ECs to the capillary lumen. Without GPIHBP1, LPL remains stranded within the interstitial spaces, causing severe hypertriglyceridemia (chylomicronemia). Biophysical studies revealed that GPIHBP1 stabilizes LPL structure and preserves LPL activity. That discovery was the key to crystallizing the GPIHBP1-LPL complex. The crystal structure revealed that GPIHBP1's LU domain binds, largely by hydrophobic contacts, to LPL's C-terminal lipid-binding domain and that the AD is positioned to project across and interact, by electrostatic forces, with a large basic patch spanning LPL's lipid-binding and catalytic domains. We uncovered three functions for GPIHBP1's AD. First, it accelerates the kinetics of LPL binding. Second, it preserves LPL activity by inhibiting unfolding of LPL's catalytic domain. Third, by sheathing LPL's basic patch, the AD makes it possible for LPL to move across ECs to the capillary lumen. Without the AD, GPIHBP1-bound LPL is trapped by persistent interactions between LPL and negatively charged heparan sulfate proteoglycans (HSPGs) on the abluminal surface of ECs. The AD interrupts the HSPG interactions, freeing LPL-GPIHBP1 complexes to move across ECs to the capillary lumen. GPIHBP1 is medically important; GPIHBP1 mutations cause lifelong chylomicronemia, and GPIHBP1 autoantibodies cause some acquired cases of chylomicronemia.

Effects of Steel Fiber and Specimen Geometric Dimensions on the Mechanical Properties of Ultra-High-Performance Concrete.

Ultra-high-performance concrete (UHPC) is an advanced concrete with superior mechanical strength, ductility and durability properties. However, the influence of steel fiber on its constitutive laws and the specimen geometric dimension effect on its strength had not been paid enough attention. To investigate the effect of steel fibers on the properties of UHPC, specimens with different fiber volume contents and fiber types were tested. Meanwhile, the mechanical properties of UHPC at different ages from 3 days to 28 days were conducted. Moreover, specimens with various geometric dimensions were also prepared to study the effect of specimen geometric dimensions (dog-bone-shaped, prism and cylinder specimens) on the properties of UHPC. The results indicated that elastic modulus, tensile peak stress and the corresponding strain increased as the fiber volume content and curing age increased. Specimens with hooked-end fibers exhibited better tensile performance than those with straight fibers. Furthermore, different geometric dimensions of specimens significantly influenced the tensile properties of UHPC. Based on the experimental results, conversion factors were suggested for the transformation of strength obtained from specimens with different geometric dimensions to reference specimens. In addition, both compressive and tensile constitutive laws were proposed to generate the stress-strain relationship of UHPC.

Gas Diffusion Layer with a Regular Hydrophilic Structure Boosts the Power Density of Proton Exchange Membrane Fuel Cells via the Construction of Water Highways.

The gas diffusion layer (GDL) is an essential carrier for the mass transmission of proton exchange membrane fuel cells (PEMFCs), which decides the peak power density of PEMFCs. Herein, a gas diffusion layer with a regularly arranged hydrophilic and hydrophobic pattern structure was prepared by a template method combined with the ultrasonic spray process. The peak power density was enhanced by 30% (from 520 to 678 mW/cm2) compared to an unpatterned structure, and the breakthrough pressure of the GDL was reduced from 13.61 to 2.96 kPa. In addition, the finite element analysis (FEA) results indicate that the polarization curve of calculation was highly consistent with the experimental results. Importantly, the capillary pressure of the hydrophilic area was about 0.3 kPa, much lower than that of the hydrophobic area (2 kPa), demonstrating that the hydrophilic and hydrophobic synergistic structure reduced the water transmission resistance in separating water and oxygen and builds a high-speed channel for water transmission.

Epigallocatechin-3-O-gallate promotes extracellular matrix and inhibits inflammation in IL-1ß stimulated chondrocytes by the PTEN/miRNA-29b pathway.

CONTEXT: Epigallocatechin-3-O-gallate (EGCG) exhibits anti-arthritic activity. MiR-29b-3p provokes chondrocyte apoptosis and promotes the initiation and development of osteoarthritis (OA). OBJECTIVE: To explore the roles of EGCG and miR-29b-3p in interleukin-1ß (IL-1ß)-stimulated chondrocytes. MATERIALS AND METHODS: HE and Safranin O staining were used to detect the pathological changes of cartilage tissue in OA patients and healthy people. OA-like chondrocyte injury was mimicked by 5 ng/mL IL-1ß stimulation for 24 h in vitro, and after transfection with miR-29b-3p mimics and pcDNA-PTEN, IL-1ß-stimulated chondrocytes were pre-treated with EGCG (20 and 50 µM) for 2 h. Cell viability, colony numbers, apoptosis rate, the levels of IL-6 and matrix metalloproteinase-13 (MMP-13), miR-19b-3p, PTEN and apoptosis-associated proteins in chondrocytes were evaluated. RESULTS: MiR-29b-3p level was upregulated in cartilage tissues of OA patients (3.5-fold change, p < 0.001) and IL-1ß stimulated chondrocytes (two fold change, p < 0.001). The matrix staining was weakened and unevenly distributed, and the chondrocytes were arranged disorderly in the tissues of patients with OA. EGCG (20 and 50 µM) increases viability and decreases the levels of miR-29b-3p and MMP-13 and IL-6 in IL-1ß stimulated chondrocytes (p < 0.05). MiR-29b-3p mimics reversed the effects above 50 µM EGCG (p < 0.05). Furthermore, PTEN overexpression abrogated the effects of miR-29b-3p mimics on viability, colony numbers, apoptosis rate and the levels of Bcl-2, MMP-13, IL-6, Bax and cleaved caspase 3 in IL-1ß-stimulated chondrocytes (p < 0.01). DISCUSSION AND CONCLUSIONS: EGCG is a potential candidate for the treatment of OA, which also can be explored in a novel therapeutic method for other degenerative or inflammatory disorders.

Special roles for efflux systems in iron homeostasis of non-siderophore-producing cyanobacteria.

In oligotrophic oceans, low bioavailability of Fe is a key factor limiting primary productivity. However, excessive Fe in cells leads to the Fenton reaction, which is toxic to cells. Cyanobacteria must strictly maintain intracellular Fe homeostasis. Here, we knocked out a series of genes encoding efflux systems in Synechocystis sp. PCC 6803, and found eight genes that are required for high Fe detoxification. Unexpectedly, the HlyBD-TolC efflux system plays an important role in the adaptation of Synechocystis under Fe-deficient conditions. Mutants of HlyD and TolC grew worse than the wild-type strain under low-Fe conditions and showed significantly lower intracellular Fe contents than the wild-type strain. We excluded the possibility that the low Fe sensitivity of the HlyBD-TolC mutants was caused by a loss of the S-layer, the main extracellular protein secreted via this efflux system. Inactivation of the HlyD protein influenced type IV pili formation and direct inactivation of type IV pili related genes affected the adaptation to low-Fe conditions. HlyBD-TolC system is likely involved in the formation of type IV pili and indirectly influenced Fe acquisition. Our findings suggest that efflux system in non-siderophore-producing cyanobacteria can facilitate Fe uptake and help cells adapt to Fe-deficient conditions via novel pathways.