Considering climate change impact on the global potential geographical distribution of the invasive Argentine ant and little fire ant.

The Argentine ant (Linepithema humile) and the little fire ant (Wasmannia auropunctata) are among the top 100 invasive alien species globally, causing significant ecological and economic harm. Therefore, it is crucial to study their potential geographic distribution worldwide. This study aimed to predict their global distribution under current and future climate conditions. We used distribution data from various sources, including CABI, GBIF, and PIAKey, and key climate variables selected from 19 environmental factors to model their potential geographic distribution using MaxEnt. The AUC values were 0.925 and 0.937 for L. humile and W. auropunctata, respectively, indicating good predictive performance. Suitable areas for L. humile were mainly in southern North America, northern South America, Europe, central Asia, southern Oceania, and parts of Africa, while W. auropunctata suitable areas were mostly in southern North America, most of South America, a small part of Europe, southern Asia, central Africa, and some parts of Oceania. Under climate change scenario, suitable areas for L. humile increased, while highly suitable areas for W. auropunctata decreased. The top four countries with the largest areas of overlapping suitable habitat under current climate were Brazil, China, Australia, and Argentina, while under future SSP585 climate scenario, the top four countries were Brazil, China, Indonesia, and Argentina. Some countries, such as Estonia and Finland, will see an overlapping adaptation area under climate change. In conclusion, this study provides insight into controlling the spread and harm of L. humile and W. auropunctata.

Macrophage-Inspired marine antifouling coating with dynamic surfaces based on regulation of dynamic covalent bonds.

Macrophages can kill bacteria and viruses by releasing free radicals, which provides a possible approach to construct antifouling coatings with dynamic surfaces that release free radicals if the breaking of dynamic covalent bonds is precisely regulated. Herein, inspired by the defensive behavior of macrophages of releasing free radicals to kill bacteria and viruses, a marine antifouling coating composed of polyurethane incorporating dimethylglyoxime (PUx-DMG) is prepared by precise regulation of dynamic oxime-urethane covalent bonds. The obtained alkyl radical (R·) derived from the cleavage of the oxime-urethane bonds manages to effectively suppress the attachment of marine biofouling. Moreover, the intrinsic dynamic surface makes it difficult for biofouling to adhere and ultimately achieves sustainable antifouling property. Notably, the PU50-DMG coating not only presents efficient antibacterial and antialgae properties, but also prevents macroorganisms from settling in the sea for up to 4 months. This provides a pioneer broad-spectrum strategy to explore the marine antifouling coatings.

Loading of Single Atoms of Iron, Cobalt, or Nickel to Enhance the Electrocatalytic Hydrogen Evolution Reaction of Two-Dimensional Titanium Carbide.

The rational design of advanced electrocatalysts at the molecular or atomic level is important for improving the performance of hydrogen evolution reactions (HERs) and replacing precious metal catalysts. In this study, we describe the fabrication of electrocatalysts based on Fe, Co, or Ni single atoms supported on titanium carbide (TiC) using the molten salt method, i.e., TiC-FeSA, TiC-CoSA, or TiC-NiSA, to enhance HER performance. The introduction of uniformly distributed transition-metal single atoms successfully reduces the overpotential of HERs. Overpotentials of TiC-FeSA at 10 mA cm-2 are 123.4 mV with 61.1 mV dec-1 Tafel slope under acidic conditions and 184.2 mV with 85.1 mV dec-1 Tafel slope under alkaline conditions, which are superior to TiC-NiSA and TiC-CoSA. TiC samples loaded with transition-metal single atoms exhibit high catalytic activity and long stability under acidic and basic conditions. Density functional theory calculations indicate that the introduction of transition-metal single atoms effectively reduces the HER barrier of TiC-based electrocatalysts.

Smart exosomes enhance PDAC targeted therapy.

Exosomes continue to attract interest as a promising nanocarrier drug delivery technology. They are naturally derived nanoscale extracellular vesicles with innate properties well suited to shuttle proteins, lipids, and nucleic acids between cells. Nonetheless, their clinical utility is currently limited by several major challenges, such as their inability to target tumor cells and a high proportion of clearance by the mononuclear phagocyte system (MPS) of the liver and spleen. To overcome these limitations, we developed "Smart Exosomes" that co-display RGD and CD47p110-130 through CD9 engineering (ExoSmart). The resultant ExoSmart demonstrates enhanced binding capacity to αvß3 on pancreatic ductal adenocarcinoma (PDAC) cells, resulting in amplified cellular uptake in in vitro and in vivo models and increased chemotherapeutic efficacies. Simultaneously, ExoSmart significantly reduced liver and spleen clearance of exosomes by inhibiting macrophage phagocytosis via CD47p110-130 interaction with signal regulatory proteins (SIRPα) on macrophages. These studies demonstrate that an engineered exosome drug delivery system increases PDAC therapeutic efficacy by enhancing active PDAC targeting and prolonging circulation times, and their findings hold tremendous translational potential for cancer therapy while providing a concrete foundation for future work utilizing novel peptide-engineered exosome strategies.

Hierarchical Nanoheterostructure of HFIP-Grafted α-Fe2O3@Multiwall Carbon Nanotubes as High-Performance Chemiresistive Sensors for Nerve Agents.

New and efficient sensors of nerve agents are urgently demanded to prevent them from causing mass casualties in war or terrorist attacks. So, in this work, a novel hierarchical nanoheterostructure was synthesized via the direct growth of α-Fe2O3 nanorods onto multiwall carbon nanotube (MWCNT) backbones. Then, the composites were functionalized with hexafluoroisopropanol (HFIP) and successfully applied to detect dimethyl methylphosphonate (DMMP)-sarin simulant gas. The observations show that the HFIP-α-Fe2O3@MWCNT hybrids exhibit outstanding DMMP-sensing performance, including low operating temperature (220 °C), high response (6.0 to 0.1 ppm DMMP), short response/recovery time (8.7 s/11.9 s), as well as low detection limit (63.92 ppb). The analysis of the sensing mechanism demonstrates that the perfect sensing performance is mainly due to the synergistic effect of the chemical interaction of DMMP with the heterostructure and the physical adsorption of DMMP by hydrogen bonds with HFIP that are grafted on the α-Fe2O3@MWCNTs composite. The huge specific surface area of HFIP-α-Fe2O3@MWCNTs composite is also one of the reasons for this enhanced performance. This work not only offers a promising and effective method for synthesizing sensitive materials for high-performance gas sensors but also provides insight into the sensing mechanism of DMMP.

Comparison of Anti-Icing, Antifouling, and Anticorrosion Performances of the Superhydrophobic and Lubricant-Infused Coatings Based on a Hollow-Structured Kapok Fiber.

The superhydrophobic surface and slippery liquid-infused porous surface (SLIPS)/lubricant-infused surface (LIS) have attracted increasing attention owing to their multifunctionality. However, their practical applications face several problems such as complex and inefficient preparation technology, loss of lubricant, and fragile microstructures. Therefore, new strategies for preparing microstructures must be developed for constructing superhydrophobic and lubricant-infused coatings. Herein, a low-cost and high-efficiency method for developing superhydrophobic and lubricant-infused coatings based on in situ grown TiO2 on the surface of a hollow kapok fiber (KF) is reported. The anti-icing, antifouling, and anticorrosion performance of the superhydrophobic and lubricant-infused coatings are compared. The superhydrophobic coating reduces the formation and accumulation of ice. The lubricant-infused coating exhibits an extremely low ice adhesion strength and durable anti-icing properties. The superhydrophobic and lubricant-infused coatings show the outstanding antifouling property of diatom; the superhydrophobic surface exhibits superior stability over LIS without an external force field. The lubricant-infused coating shows excellent corrosion resistance and durability when immersed in a 3.5% NaCl solution. The superhydrophobic coating loses its protection as a result of the corrosion media permeating the metal substrate via the electrolytic cell and coating interface, and the lubricant-infused coating provides lasting corrosion resistance because of the lubricant filling into the interface. Although the superhydrophobic coating is fragile and the lubricant-infused coating will lose lubricant, this simple and convenient approach can be repeated to keep the coatings active. This study provides new inspiration for the fabrication of superhydrophobic surfaces and LIS based on natural products.

High mechanical property and hydrophilic electrospun poly amidoxime/poly acrylonitrile composite nanofibrous mats for extraction uranium from seawater.

Seawater reserves about 4.5 billion tons of uranium, if properly extracted, could be a sustainable green energy resource for hundreds of years, alternating its limited terrestrial ore and reducing the CO2 emitted from fossil fuels. The current seawater uranium adsorbents suffer neither economically viable nor adsorption efficiency, requiring more development to harvest satisfactorily uranium from seawater. Amidoxime-based fibrous adsorbents are the most promising adsorbents of seawater uranium due to abundant chelating sites. However, they suffer from severe shrinkage and stiffness once they dry, losing porous architecture and mechanical properties. Herein, an economical and scalable two-nozzle electrospinning technology was applied to produce poly amidoxime nanofibers (PAO NFs) supported by Poly acrylonitrile nanofibers (PAN NFs) as composite PAO/PAN nanofibrous mats with high structure stability. These PAO/PAN mats, with rapid wettability and excellent mechanical strength, show promising uranium adsorption capacities of 369.8 mg/g at seawater pH level, much higher than PAO and PAN NFs. The uranium adsorption capacity of the PAO/PAN mat reached 5.16 mg/g after 7 days of circulating (10 ppm uranium) spiked natural seawater. Importantly, the composite mat maintained its fibrous structure after five adsorption-desorption cycles with more than 80 % of its adsorption capacity, confirming its recyclability and stability. Therefore, the composite PAO/PAN mat fulfills the basic requirements for effectively and economically trapping uranium from seawater, which could be a matrix for further development.

Latent tuberculosis infection status among freshmen in boarding middle schools in Longgang District of Shenzhen City / 中国学校卫生

Objective@#To analyze the current status of latent tuberculosis infection (LTBI) among freshmen in boarding middle schools in Longgang District, Shenzhen, so as to provide reference for formulating tuberculosis prevention and control strategies in the next stage.@*Methods@#Data for tuberculosis health examination conducted among primary and secondary school students in Longgang District of Shenzhen in September 2022 to May 2023 were utilized to analyze the latent tuberculosis infection rate, and to explore the differences in latent tuberculosis infection rate among different grades, school nature, school categories and school levels.@*Results@#The latent tuberculosis infection rate among freshmen in boarding secondary schools in Longgang District, Shenzhen in 2022 was 2.45%. The infection rate among full middle school (6.45%) and high school (3.37%) were higher than that in boarding junior high school (0.28%), nine year education school (0) and twelve year education school (1.00%) ( P <0.01). Moreover, the infection rate of high school freshmen (2.68%) was higher than that of bording junior high school (0.33%), and the rate of public schools (2.87%) and municipal schools (3.24%) were higher than those of private schools (1.78%) and distric-level schools (2.13%) respectively, with statistical significance observed for all differences( χ 2=43.58, 25.15, 22.69, P <0.01).@*Conclusions@#The latent tuberculosis infection rate among new boarding secondary students is relatively low in Longgang District of Shenzhen. However, the infection rate is higher in high school, public and municipal school. School should fully guarantee sports participation of students, enhance students awareness of tuberculosis through health knowledge lectures, and reduce the incidence of tuberculosis among students.

Small Molecule Inhibitors Targeting the "Undruggable" Survivin: The Past, Present, and Future from a Medicinal Chemist's Perspective.

Survivin, a homodimeric protein and a member of the IAP family, plays a vital function in cell survival and cycle progression by interacting with various proteins and complexes. Its expression is upregulated in cancers but not detectable in normal tissues. Thus, it has been regarded and validated as an ideal cancer target. However, survivin is "undruggable" due to its lack of enzymatic activities or active sites for small molecules to bind/inhibit. Academic and industrial laboratories have explored different strategies to overcome this hurdle over the past two decades, with some compounds advanced into clinical testing. These strategies include inhibiting survivin expression, its interaction with binding partners and homodimerization. Here, we provide comprehensive analyses of these strategies and perspective on different small molecule survivin inhibitors to help drug discovery targeting "undruggable" proteins in general and survivin specifically with a true survivin inhibitor that will prevail in the foreseeable future.

Study on Respiratory Function and Hemodynamics of AIDS Patients with Respiratory Failure.

Objective: We performed a comparative analysis of respiratory function and hemodynamics among patients with Acquired Immunodeficiency Syndrome (AIDS)-associated respiratory failure and those with non-AIDS-associated respiratory failure. Methods: Data were collected from critically ill patients diagnosed with Acquired Immunodeficiency Syndrome who were admitted to the Intensive Care Unit (ICU) of Beijing Ditan Hospital, affiliated with Capital Medical University, between January 1, 2019, and December 31, 2019. We simultaneously gathered data from non-AIDS patients admitted to the ICU of Beijing Liangxiang Hospital within the same timeframe. A comparative study was performed to analyze clinical data from these two patient groups, encompassing parameters related to respiratory mechanics and hemodynamic indicators. Results: A total of 12 patients diagnosed with Acquired Immunodeficiency Syndrome (AIDS) and experiencing respiratory failure, along with 23 patients with respiratory failure independent of AIDS, were included in our study. Subsequently, a comparative analysis of clinical information was conducted between the two patient cohorts. Our findings demonstrate non-statistically significant differences between the two patient groups when assessing various indicators, encompassing peak airway pressure, plateau pressure, mean pressure, compliance, oxygenation index, and arterial partial pressure of carbon dioxide (P>0.05). Additionally, the comparison of multiple indicators encompassing mean arterial pressure, central venous pressure, cardiac output index, intrathoracic blood volume index, global end-diastolic volume index, extravascular lung water content, and pulmonary vascular permeability index revealed no statistically significant differences between the two patient groups (P>0.05). Ultimately, the Galileo respiratory system was utilized to assess the pressure-volume (P-V) curve of the experimental cohort, revealing a consistent and seamless trajectory devoid of noticeable points of inflection. Conclusion: No statistically significant differences were found in the respiratory function and hemodynamic profiles between patients diagnosed with AIDS presenting respiratory failure and those experiencing respiratory failure unrelated to AIDS. Additionally, the pressure-volume curve of individuals diagnosed with AIDS presenting respiratory failure displayed a seamless and uninterrupted trajectory devoid of discernible points of inflection. Hence, there might be constraints when utilizing P-V curve-based adjustments for positive end-expiratory pressure (PEEP) during mechanical ventilation in individuals diagnosed with AIDS presenting respiratory failure.

A closed-loop catalytic nanoreactor system on a transistor.

Precision chemistry demands miniaturized catalytic systems for sophisticated reactions with well-defined pathways. An ideal solution is to construct a nanoreactor system functioning as a chemistry laboratory to execute a full chemical process with molecular precision. However, existing nanoscale catalytic systems fail to in situ control reaction kinetics in a closed-loop manner, lacking the precision toward ultimate reaction efficiency. We find an inter-electrochemical gating effect when operating DNA framework-constructed enzyme cascade nanoreactors on a transistor, enabling in situ closed-loop reaction monitoring and modulation electrically. Therefore, a comprehensive system is developed, encapsulating nanoreactors, analyzers, and modulators, where the gate potential modulates enzyme activity and switches cascade reaction "ON" or "OFF." Such electric field-effect property enhances catalytic efficiency of enzyme by 343.4-fold and enables sensitive sarcosine assay for prostate cancer diagnoses, with a limit of detection five orders of magnitude lower than methodologies in clinical laboratory. By coupling with solid-state electronics, this work provides a perspective to construct intelligent nano-systems for precision chemistry.

Anti-GPIb/IX autoantibodies are associated with poor response to dexamethasone combined with rituximab therapy in primary immune thrombocytopenia patients.

This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. One-hundred twenty-six ITP patients were included and retrospectively analyzed, 66.7% of anti-GPIb/IX and 65.9% of anti-GPIIb/IIIa autoantibodies. Results showed that overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at 4 weeks (OR: 73.8% vs. 47.6%, CR: 50.0% vs. 26.2%; P < 0.05) and 6 months (OR: 71.4% vs. 45.2%, CR: 42.9% vs. 25.0%; P < .05). Furthermore, patients with anti-GPIb/IX single-positivity exhibited higher resistance to DXM-RTX than patients with anti-GPIIb/IIIa single-positivity at 4 weeks (OR: 37.5% vs. 78.3%; P < .05) and 6 months (OR: 29.2% vs. 78.3%; P < .05). Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies and megakaryocytes were associated with the OR rate of patients at both 4 weeks and 6 months, and anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX (F = 9.128, P = .003). Therefore, platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX in ITP patients.

What is the context?The safety and efficacy of high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) are gradually recognized; however, there still needs to be an adequate clinical trial to predict its efficacy. Autoantibodies against platelet glycoproteins (GPs) are proven to be associated with a variety of therapeutic responses in ITP. Such as anti-GPIb/IX autoantibodies predict poor response to intravenous immunoglobulin G therapy and rhTPO therapy in ITP patients. Therefore, a retrospective study was needed to verify whether anti-GP autoantibodies can expect a response to DXM-RTX therapy in ITP patients.What is new?This study identified that anti-GPIb/IX autoantibodies were a predictive factor for poor response to DXM-RTX in ITP patients. It mainly manifested in the following aspects: (1) Overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at four weeks and six months. (2) Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies at both four weeks and six months were associated with the OR rate of patients.What is the impact?Our study suggests that ITP patients with anti-GPIb/IX positive autoantibodies respond poorly to DXM-RTX therapy. Platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX therapy in ITP patients.

Synergistic adsorption and photocatalysis reduction of uranium by UiO-66 (Ce)-CdS/PEI-modified chitosan composite sponge.

Uranium is a critical element of the nuclear industry, and while extracting it from seawater is considered the most promising way to meet the growing demand for uranium, there are still some problems that still need to be solved. This work designed a UiO-66(Ce)-CdS/PEI-modified chitosan composite sponge (USPS) with an adsorption-photocatalytic synergistic effect to extract uranium efficiently. On the one hand, the drawback that the powder material is difficult to be recycled is solved. On the other hand, the uranium extraction capacity of the substrate sponge is improved. Compared with the unmodified PCS sponge, the uranium extraction capacity of the USPS-4 composite sponge is 1.63 fold higher than that of the PCS sponge. In addition, the USPS-4 composite sponge exhibits excellent selectivity and regenerability. The mechanism of uranium extraction can be summarized as the coordination chelation of uranium with active functional groups in the adsorption process and the reduction of hexavalent uranium by photogenerated electrons in the photocatalytic process. This study provides a new strategy for designing and preparing a novel material with high uranium extraction performance, easy separation, and recovery.

Effect of high-flow nasal cannula versus non-invasive ventilation after extubation on successful extubation in obese patients: a retrospective analysis of the MIMIC-IV database.

BACKGROUND: The pathophysiological characteristics of the respiratory system of obese patients differ from those of non-obese patients. Few studies have evaluated the effects of high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) on the prognosis of obese patients. We here compared the effects of these two techniques on the prevention of reintubation after extubation for obese patients. METHODS: Data were extracted from the Medical Information Mart for Intensive Care database. Patients who underwent HFNC or NIV treatment after extubation were assigned to the HFNC or NIV group, respectively. The reintubation risk within 96 hours postextubation was compared between the two groups using a doubly robust estimation method. Propensity score matching was performed for both groups. RESULTS: This study included 757 patients (HFNC group: n=282; NIV group: n=475). There was no significant difference in the risk of reintubation within 96 hours after extubation for the HFNC group compared with the NIV group (OR 1.50, p=0.127). Among patients with body mass index ≥40 kg/m2, the HFNC group had a significantly lower risk of reintubation within 96 hours after extubation (OR 0.06, p=0.016). No significant differences were found in reintubation rates within 48 hours (15.6% vs 11.0%, p=0.314) and 72 hours (16.9% vs 13.0%, p=0.424), as well as in hospital mortality (3.2% vs 5.2%, p=0.571) and intensive care unit (ICU) mortality (1.3% vs 5.2%, p=0.108) between the two groups. However, the HFNC group had significantly longer hospital stays (14 days vs 9 days, p=0.005) and ICU (7 days vs 5 days, p=0.001) stays. CONCLUSIONS: This study suggests that HFNC therapy is not inferior to NIV in preventing reintubation in obese patients and appears to be advantageous in severely obese patients. However, HFNC is associated with significantly longer hospital stays and ICU stays.

The First Human Infection Case of Macacine Alphaherpesvirus 1 Virus in China.

BACKGROUND: Macacine alphaherpesvirus 1 (BV) was first reported in the 1930s and only about 60 cases have been diagnosed since then. METHODS: A 53-year-old male who worked as a veterinary surgeon, developed a fever with nausea and vomiting in April 2021 in Beijing, China. Real-time polymerase chain reaction (PCR) and metagenomics Next Generation Sequencing (mNGS) were used for diagnosis. RESULTS: BV DNA was confirmed by mNGS and PCR. The case died 51 days after onset, due to the damage to the brain and spinal cord caused by a viral infection and hypoxic-ischemic encephalopathy. The typical BV inclusion bodies in the brain were found for the first time. CONCLUSIONS: Here we reported the first human infection case of BV in China. This fatal case highlights the potential threat of BV to occupational workers and the essential role of surveillance.

Proline Isomerization: From the Chemistry and Biology to Therapeutic Opportunities.

Proline isomerization, the process of interconversion between the cis- and trans-forms of proline, is an important and unique post-translational modification that can affect protein folding and conformations, and ultimately regulate protein functions and biological pathways. Although impactful, the importance and prevalence of proline isomerization as a regulation mechanism in biological systems have not been fully understood or recognized. Aiming to fill gaps and bring new awareness, we attempt to provide a wholistic review on proline isomerization that firstly covers what proline isomerization is and the basic chemistry behind it. In this section, we vividly show that the cause of the unique ability of proline to adopt both cis- and trans-conformations in significant abundance is rooted from the steric hindrance of these two forms being similar, which is different from that in linear residues. We then discuss how proline isomerization was discovered historically followed by an introduction to all three types of proline isomerases and how proline isomerization plays a role in various cellular responses, such as cell cycle regulation, DNA damage repair, T-cell activation, and ion channel gating. We then explore various human diseases that have been linked to the dysregulation of proline isomerization. Finally, we wrap up with the current stage of various inhibitors developed to target proline isomerases as a strategy for therapeutic development.

Phosphorylated S6K1 and 4E-BP1 play different roles in constitutively active Rheb-mediated retinal ganglion cell survival and axon regeneration after optic nerve injury.

Ras homolog enriched in brain (Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory axons after spinal cord injury by activating downstream effectors of mTOR. S6K1 and 4E-BP1 are important downstream effectors of mTORC1. In this study, we investigated the role of Rheb/mTOR and its downstream effectors S6K1 and 4E-BP1 in the protection of retinal ganglion cells. We transfected an optic nerve crush mouse model with adeno-associated viral 2-mediated constitutively active Rheb and observed the effects on retinal ganglion cell survival and axon regeneration. We found that overexpression of constitutively active Rheb promoted survival of retinal ganglion cells in the acute (14 days) and chronic (21 and 42 days) stages of injury. We also found that either co-expression of the dominant-negative S6K1 mutant or the constitutively active 4E-BP1 mutant together with constitutively active Rheb markedly inhibited axon regeneration of retinal ganglion cells. This suggests that mTORC1-mediated S6K1 activation and 4E-BP1 inhibition were necessary components for constitutively active Rheb-induced axon regeneration. However, only S6K1 activation, but not 4E-BP1 knockdown, induced axon regeneration when applied alone. Furthermore, S6K1 activation promoted the survival of retinal ganglion cells at 14 days post-injury, whereas 4E-BP1 knockdown unexpectedly slightly decreased the survival of retinal ganglion cells at 14 days post-injury. Overexpression of constitutively active 4E-BP1 increased the survival of retinal ganglion cells at 14 days post-injury. Likewise, co-expressing constitutively active Rheb and constitutively active 4E-BP1 markedly increased the survival of retinal ganglion cells compared with overexpression of constitutively active Rheb alone at 14 days post-injury. These findings indicate that functional 4E-BP1 and S6K1 are neuroprotective and that 4E-BP1 may exert protective effects through a pathway at least partially independent of Rheb/mTOR. Together, our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity. Phosphorylated S6K1 and 4E-BP1 promote axon regeneration but play an antagonistic role in the survival of retinal ganglion cells.

Reversible promoter demethylation of PDGFD confers gemcitabine resistance through STAT3 activation and RRM1 upregulation.

Drug resistance is a major problem in cancer treatment with traditional or targeted therapeutics. Gemcitabine is approved for several human cancers and the first line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, gemcitabine resistance frequently occurs and is a major problem in successful treatments of these cancers and the mechanism of gemcitabine resistance remains largely unknown. In this study, we identified 65 genes that had reversible methylation changes in their promoters in gemcitabine resistant PDAC cells using whole genome Reduced Representation Bisulfite Sequencing analyses. One of these genes, PDGFD, was further studied in detail for its reversible epigenetic regulation in expression and shown to contribute to gemcitabine resistance in vitro and in vivo via stimulating STAT3 signaling in both autocrine and paracrine manners to upregulate RRM1 expression. Analyses of TCGA datasets showed that PDGFD positively associates with poor outcome of PDAC patients. Together, we conclude that the reversible epigenetic upregulation plays an important role in gemcitabine resistance development and targeting PDGFD signaling alleviates gemcitabine resistance for PDAC treatment.

Artesunate protects against ocular fibrosis by suppressing fibroblast activation and inducing mitochondria-dependent ferroptosis.

Artesunate, a derivative from extracts of Artemisia annua, has recently been reported to alleviate fibrosis recently. Here, in this study, we sought to determine the anti-fibrosis effect of artesunate in rabbit glaucoma filtration surgery (GFS) model and illuminate underlying mechanisms. Our results showed that artesunate subconjunctival injection alleviated bleb fibrosis by inhibiting fibroblast activation and inducing ferroptosis. Further mechanistic investigation in primary human ocular fibroblasts (OFs) showed that artesunate abrogated fibroblast activation by inhibiting TGF-ß1/SMAD2/3 and PI3K/Akt pathways and scavenged OFs by inducing mitochondria-dependent ferroptosis. Mitochondrial dysfunction, mitochondrial fission, and iron-dependent mitochondrial lipid peroxidation were observed in artesunate-treated OFs. Besides, mitochondria-localized antioxidants inhibited artesunate-induced cell death, suggesting a critical role of mitochondria in artesunate-induced ferroptosis. Our study also found that expression of mitochondrial GPX4 but no other forms of GPX4 was decreased after artesunate treatment and that mitochondrial GPX4 overexpression rescued artesunate-induced lipid peroxidation and ferroptosis. Other cellular ferroptosis defense mechanisms, including cellular FSP1 and Nrf2, were also inhibited by artesunate. In conclusion, our study demonstrated that artesunate protects against fibrosis through abrogation of fibroblast activation and induction of mitochondria-dependent ferroptosis in OFs, which may offer a potential treatment for ocular fibrosis.

Regional Citrate Anticoagulation or Heparin Anticoagulation for Renal Replacement Therapy in Patients With Liver Failure: A Systematic Review and Meta-Analysis.

In patients with liver failure complicated by acute kidney injury, renal replacement therapy (RRT) is often required to improve the internal environment. The use of anticoagulants for RRT in patients with liver failure remains controversial. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies. The methodological quality of the included studies was assessed using the Methodological Index for Nonrandomized Studies. A meta-analysis was performed using R software (version 3.5.1) and Review Manager (version 5.3.5). During RRT, 348 patients from 9 studies received regional citrate anticoagulation (RCA), and 127 patients from 5 studies received heparin anticoagulation (including heparin and LMWH). Among patients who received RCA, the incidence of citrate accumulation, metabolic acidosis, and metabolic alkalosis were 5.3% (95% confidence interval [CI]: 0%-25.3%), 26.4% (95% CI: 0-76.9), and 1.8% (95% CI: 0-6.8), respectively. The potassium, phosphorus, total bilirubin (TBIL), and creatinine levels were lower, whereas the serum pH, bicarbonate, base excess levels, and total calcium/ionized calcium ratio were higher after treatment than before treatment. Among patients who received heparin anticoagulation, the TBIL levels were lower, whereas the activated partial thromboplastin clotting time and D-dimer levels were higher after treatment than before treatment. The mortality rates in the RCA and heparin anticoagulation groups were 58.9% (95% CI: 39.2-77.3) and 47.4% (95% CI: 31.1-63.7), respectively. No statistical difference in mortality was observed between the 2 groups. For patients with liver failure, the administration of RCA or heparin for anticoagulation during RRT under strict monitoring may be safe and effective.