Effects of apolipoprotein H downregulation on lipid metabolism, fatty liver disease, and gut microbiota dysbiosis.

Apolipoprotein H (APOH) downregulation can cause hepatic steatosis and gut microbiota dysbiosis. However, the mechanism by which APOH-regulated lipid metabolism contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) remains undetermined. Herein, we aim to explore the regulatory effect of APOH, mediated through various pathways, on metabolic homeostasis and MASLD pathogenesis. We analyzed serum marker levels, liver histopathology, and cholesterol metabolism-related gene expression in global ApoH-/- C57BL/6 male mice. We used RNA sequencing and metabolomic techniques to investigate the association between liver metabolism and bacterial composition. Fifty-two differentially expressed genes were identified between ApoH-/- and WT mice. The mRNA levels of de novo lipogenesis genes were highly upregulated in ApoH-/- mice than in WT mice. Fatty acid, glycerophospholipid, sterol lipid, and triglyceride levels were elevated, while hyodeoxycholic acid levels were significantly reduced in the liver tissues of ApoH-/- mice than in those of WT mice. Microbial beta diversity was lower in ApoH-/- mice than in WT mice, and gut microbiota metabolic functions were activated in ApoH-/- mice. Moreover, ApoH transcripts were downregulated in patients with MASLD, and APOH-related differential genes were enriched in lipid metabolism. Open-source transcript-level data from human metabolic dysfunction-associated steatohepatitis livers reinforced a significant association between metabolic dysfunction-associated steatohepatitis and APOH downregulation. In conclusion, our studies demonstrated that APOH downregulation aggravates fatty liver and induces gut microbiota dysbiosis by dysregulating bile acids. Our findings offer a novel perspective on APOH-mediated lipid metabolic dysbiosis and provide a valuable framework for deciphering the role of APOH in fatty liver disease.

Co-delivery of Brinzolamide and Timolol from Micelles-laden Contact Lenses: In vitro and In Vivo Evaluation.

PURPOSE: Traditional eye drops exhibit a modest bioavailability ranging from 1 to 5%, necessitating recurrent application. Thus, a contact lens-based drug delivery system presents substantial benefits. Nonetheless, pharmaceutical agents exhibiting poor solubility may compromise the quintessential characteristics of contact lenses and are, consequently, deemed unsuitable for incorporation. To address this issue, the present study has engineered a novel composite drug delivery system that amalgamates micellar technology with contact lenses, designed specifically for the efficacious conveyance of timolol and brinzolamide. METHODS: Utilizing mPEG-PCL as the micellar material, this study crafted mPEG-PCL micelles loaded with brinzolamide and timolol through the film hydration technique. The micelle-loaded contact lens was fabricated employing the casting method; a uniform mixture of HEMA and EGDMA with the mPEG-PCL micelles enshrouding brinzolamide and timolol was synthesized. Following the addition of a photoinitiator, 50 µL of the concoction was deposited into a contact lens mold. Subsequently, the assembly was subjected to polymerization under 365 nm ultraviolet light for 35 min, resulting in the formation of the micelle-loaded contact lenses. RESULTS: In the present article, we delineate the construction of a micelle-loaded contact lens designed for the administration of brinzolamide and timolol in the treatment of glaucoma. The study characterizes crucial properties of the micelle-loaded contact lenses, such as transmittance and ionic permeability. It was observed that these vital attributes meet the standard requirements for contact lenses. In vitro release studies revealed that timolol and brinzolamide could be gradually liberated over periods of up to 72 and 84 h, respectively. In vivo pharmacodynamic evaluation showed a significant reduction in intraocular pressure and a relative bioavailability of 10.84 times that of commercially available eye drops. In vivo pharmacokinetic evaluation, MRT was significantly increased, and the bioavailability of timolol and brinzolamide was 2.71 and 1.41 times that of eye drops, respectively. Safety assessments, including in vivo irritation, histopathological sections, and protein adsorption studies, were conducted as per established protocols, confirming that the experiments were in compliance with safety standards. IN CONCLUSION: The manuscript delineates the development of a safe and efficacious micelle-loaded contact lens drug delivery system, which presents a novel therapeutic alternative for the management of glaucoma.

A Lotus Seedpods-Inspired Interfacial Solar Steam Generator with Outstanding Salt Tolerance and Mechanical Properties for Efficient and Stable Seawater Desalination.

Interfacial solar steam generators (ISSGs) can capture solar energy and concentrate the heat at the gas-liquid interface, resulting in efficient water evaporation. However, traditional ISSGs have limitations in long-term seawater desalination processes, such as limited light absorption area, slow water transport speed, severe surface salt accumulation, and weak mechanical performance. Inspired by lotus seedpods, a novel ISSG (rGO-SA-PSF) is developed by treating a 3D warp-knitted spacer fabric with plasma (PSF) and combining it with sodium alginate (SA) and reduces graphene oxide (rGO). The rGO-SA-PSF utilizes a core-suction effect to achieve rapid water pumping and employs aerogel to encapsulate the plasma-treated spacer yarns to create the lotus seedpod-inspired hydrophilic stems, innovatively constructing multiple directional water transport channels. Simultaneously, the large holes of rGO-SA-PSF on the upper layer form lotus seedpod-inspired head concave holes, enabling efficient light capture. Under 1 kW m-2 illumination, rGO-SA-PSF exhibits a rapid evaporation rate of 1.85 kg m-2  h-1 , with an efficiency of 96.4%. Additionally, it shows superior salt tolerance (with no salt accumulation during continuous evaporation for 10 h in 10% brine) and self-desalination performance during long-term seawater desalination processes. This biomimetic ISSG offers a promising solution for efficient and stable seawater desalination and wastewater purification.

NIST Interlaboratory Study on Glycosylation Analysis of Monoclonal Antibodies: Comparison of Results from Diverse Analytical Methods.

Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submitted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide community-derived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods.

Alcohol-dependent downregulation of apolipoprotein H exacerbates fatty liver and gut microbiota dysbiosis in mice.

BACKGROUND: Alcohol-related liver disease (ALD) is a major chronic liver ailment caused by alcohol overconsumption and abuse. Apolipoprotein H (APOH) participates in lipid metabolism and might have a potential regulatory role in ALD. Therefore, this study aimed to explore the effects of ApoH on alcohol-induced liver injury and gut microbiota dysbiosis. METHODS: ApoH-/- mice were generated and the synergic alcoholic steatohepatitis mouse model was constructed, which were used to assess liver function and pathological changes. RESULTS: ApoH-/- mice clearly exhibited spontaneous steatohepatitis. Severe hepatic steatosis was observed in alcohol-fed WT and ApoH-/- mice, in which ApoH expression was reduced post alcohol consumption. Moreover, RNA-seq and KEGG pathway analyses indicated that differential expression genes enriched in lipid metabolism and oxidation-reduction process between in alcohol-fed ApoH-/- mice and pair-fed control mice. Finally, gut microbiota diversity and composition were assessed by 16S rRNA Illumina next-generation sequencing. Alpha diversity of enterobacteria was lower in ApoH-/- mice with ethanol feeding than in ethanol-fed WT mice and all control-fed mice (P < 0.05). Moreover, KEGG enrichment analysis, using PICRUSt software, revealed that metabolic functions were activated in the gut microorganisms of ApoH-/- mice with ethanol feeding (P < 0.05). CONCLUSIONS: Alcohol-downregulated ApoH expression, leading to the progress of fatty liver disease and gut microbiota dysbiosis.

General Synthesis of Amorphous PdM (M = Cu, Fe, Co, Ni) Alloy Nanowires for Boosting HCOOH Dehydrogenation.

Noble metal-based nanomaterials with amorphous structures are promising candidates for developing efficient electrocatalysts. However, their synthesis remains a significant challenge, especially under mild conditions. In this paper, we report a general strategy for preparing amorphous PdM nanowires (a-PdM NWs, M = Fe, Co, Ni, and Cu) at low temperatures by exploiting glassy non-noble metal (M) nuclei generated by special ligand adsorption as the amorphization dictator. When evaluated as electrocatalysts toward formic acid oxidation, a-PdCu NWs can deliver the mass and specific activities as high as 2.93 A/mgPd and 5.33 mA/cm2, respectively; these are the highest values for PdCu-based catalysts reported thus far, far surpassing the crystalline-dominant counterparts and commercial Pd/C. Theoretical calculations suggest that the outstanding catalytic performance of a-PdCu NWs arises from the amorphization-induced high surface reactivity, which can efficiently activate the chemically stable C-H bond and thereby significantly facilitate the dissociation of HCOOH.

Effect of air pollution on health care expenditure: Evidence from respiratory diseases.

Recent reports show that at least 95% of the world's population is breathing polluted air. However, the impact of air quality on air pollution-related medical expenditure and utilization is sparse. This study estimates the short-term health care cost impacts of air pollution using a meteorological phenomenon-thermal inversion-as an instrumental variable for air quality. Using information on outpatient care for respiratory diseases from universal health insurance claim data in Taiwan during 2006-2012, our estimates suggest that a one-unit reduction in the air quality index (AQI) leads to NT$2.3 billion (nearly US$74 million) of savings in respiratory-related outpatient expenditure per year. Given that the average AQI is equal to 32 during our study period, completely removing air pollution would reduce the national health expenditure by approximately 8% annually. Our results provide the important implication that the cost of controlling air pollutant emissions can be offset by curtailing health care expenditure.

Haemin pre-treatment augments the cardiac protection of mesenchymal stem cells by inhibiting mitochondrial fission and improving survival.

The cardiac protection of mesenchymal stem cell (MSC) transplantation for myocardial infarction (MI) is largely hampered by low cell survival. Haem oxygenase 1 (HO-1) plays a critical role in regulation of cell survival under many stress conditions. This study aimed to investigate whether pre-treatment with haemin, a potent HO-1 inducer, would promote the survival of MSCs under serum deprivation and hypoxia (SD/H) and enhance the cardioprotective effects of MSCs in MI. Bone marrow (BM)-MSCs were pretreated with or without haemin and then exposed to SD/H. The mitochondrial morphology of MSCs was determined by MitoTracker staining. BM-MSCs and haemin-pretreated BM-MSCs were transplanted into the peri-infarct region in MI mice. SD/H induced mitochondrial fragmentation, as shown by increased mitochondrial fission and apoptosis of BM-MSCs. Pre-treatment with haemin greatly inhibited SD/H-induced mitochondrial fragmentation and apoptosis of BM-MSCs. These effects were partially abrogated by knocking down HO-1. At 4 weeks after transplantation, compared with BM-MSCs, haemin-pretreated BM-MSCs had greatly improved the heart function of mice with MI. These cardioprotective effects were associated with increased cell survival, decreased cardiomyocytes apoptosis and enhanced angiogenesis. Collectively, our study identifies haemin as a regulator of MSC survival and suggests a novel strategy for improving MSC-based therapy for MI.

LINC00324 affects non-small cell lung cancer cell proliferation and invasion through regulation of the miR-139-5p/IGF1R axis.

Long non-coding RNAs (lncRNAs) are proved to perform critical function in regulating cancer cell behavior. It is reported that LINC00324 promotes lung adenocarcinoma development by regulating miR-615-5p/AKT1 axis. This study aimed to demonstrate whether LINC00324 participates in non-small cell lung cancer (NSCLC) pathogenesis through other molecular mechanism. Relative mRNA, lncRNA, and microRNA levels were analyzed using quantitative real-time-polymerase chain reaction (qRT-PCR). Western blot was used to detect protein level. MTT assay shown proliferation ability and transwell assay shown invasive ability. Luciferase reporter assay illustrated the interaction between RNA molecules. In NSCLC, the high expression of LINC00324 had correlation with the poor prognosis. LINC00324 promoted the proliferation and invasion of NSCLC cells while miR-139-5p inhibited these behaviors. LINC00324 overexpression promoted insulin-like growth factor 1 receptor (IGF1R) expression via absorbing miR-139-5p. The tumor-promoting effects of LINC00324 were attenuated through miR-139-5p overexpression. Highly expressed LINC00324 in NSCLC through sponged miR-139-5p to elevate IGF1R expression and promoted cell proliferation and invasion. This research demonstrated that LINC00324 is a potential NSCLC diagnosis and therapy target.

Activation of Src mediates acquired cisplatin resistance in human lung carcinoma cells.

Cisplatin (CDDP) is the most effective chemotherapeutic drug against lung carcinoma. However, the emergence of resistant clones has severely limited its clinical application. We found that the cisplatin-resistant lung carcinoma cell line A549/CDDP had increased levels of the phosphorylated gap junction protein Cx43 and SRC tyrosine kinase, and low levels of total Cx43 protein and reduced gap junction formation. The SRC kinase inhibitor PP2 increased the expression of total Cx43 protein and enhanced cisplatin sensitivity, indicating that activated SRC kinase induces chemoresistance by decrease total Cx43 level. Furthermore, Cx43 gene silencing in the drug-resistant cell lines abrogated the sensitizing effect of PP2. Taken together, targeting SRC kinase by PP2 reverses cisplatin resistance by upregulating Cx43 protein levels, indicating a novel pathway of cisplatin resistance that may be amenable to therapeutic intervention.

Engineering Surface Structure of Pt Nanoshells on Pd Nanocubes to Preferentially Expose Active Surfaces for ORR by Manipulating the Growth Kinetics.

Synthesis of Pt nanoshells on substrates can increase the utilization efficiency of Pt atoms and reduce the amount of Pt used in the applications. However, it is still an enormous challenge in tailoring the required crystal facets of Pt nanoshells on a given substrate. In this work, we demonstrate a facile and convenient approach capable for generating Pt octahedral islands with tunable sizes and densities on Pd nanocubes by manipulating the deposition rate. The key to this synthesis is the fine control over the deposition rate of Pt on Pd seeds. Because of the different reactivities at the surface sites, the deposition of Pt can be controlled at a certain site by carefully tuning the deposition rate. With a low concentration of reductant (8.33 mg/mL of glucose), surface diffusion dominates the process, and thus the Pt cubic shells form on Pd cubic seeds. In contrast, when a higher amount of the reductant (16.67 mg/mL of glucose) is added, the deposition starts to dominate the growth of Pt shells. In this case, the deposition would be controlled at the corners, forming eight large Pt octahedra on a cubic Pd seed. Further increasing the deposition rate can induce much higher deposition rates, in which case, the deposition of Pt would likely take place not only at the corners, but also the edge and surface sites of the seeds. Not surprisingly, this growth habit can result in the formation of high-density octahedral islands on Pd cubic seeds. With the same amount of precursor supply, the higher the densities of Pt islands, the smaller the size of the octahedral islands on Pd nanocubes. Unlike other synthetic methods, the size of the octahedral islands on Pd seeds can be even controlled to be smaller than 3 nm by controlling the amount of the Pt precursor. Considering the excellent performance of {111} facets of Pt catalysts toward ORR, the Pt nanocages with small octahedral islands on the surfaces can exhibit a high activity with a mass activity 0.68 A/mg, as high as 5.2 times of that of commercial Pt/C.

[Synergistic Effect of 2-deoxy-D-glucose Combined with Hydroxycamptothecin on Apoptosis of Breast Cancer Cells].

OBJECTIVE: To investigate the effect of 2-deoxy-d-glucose (2-DG) combined with hydroxycamptothecin (HCPT) on anti-tumor activity of breast cancer cells and its mechanism. METHODS: MDA-MB-231 and MCF-7 breast cancer cells were incubated with varying concentrations of 2-DG (0, 1.25, 2.5, 5, 10, 20 mmol/L), HCPT(0, 5, 10, 20, 40 µmol/L) and 2-DG (5 mmol/L) combined with HCPT. Cell viability was measured using the MTT assay; Propidium iodide (PI) detected the apoptosis of MDA-MB-231 cells by 5 mmol/L 2-DG, 10 µmol/L HCPT alone or in combination; MDA-MB-231 cells were treated with 2-DG (0, 2.5, 5, 10, 20 mmol/L) and the level of ATP was detected by ATP kit; the expression of Akt, p-Akt, Bcl-2/Bax, PARP, Caspase-8 and Caspase-3 proteins in MDA-MB-231 cells were measured by Western blot assay. RESULTS: The combination of 2-DG (5 mmol/L) and HCPT had a synergistic effect. The 48 h combination index (CI < 1) was higher than that of the single-use group (P < 0.05). At the same time, the combination of the two drugs inhibits the phosphorylation of Akt protein and increases the activation of Caspase-3 protein, thereby increasing the cleavage of PARP proteins. CONCLUSION: The combination of 2-DG and HCPT can synergistically induce the apoptosis of breast cancer cells, which may be caused by inhibiting the energy generation of tumor cells, inhibiting the phosphorylation of Akt protein and enhancing the activity of caspase-3 protein.

Toward Automated Identification of Glycan Branching Patterns Using Multistage Mass Spectrometry with Intelligent Precursor Selection.

Glycans play important roles in a variety of biological processes. Their activities are closely related to the fine details of their structures. Unlike the simple linear chains of proteins, branching is a unique feature of glycan structures, making their identification extremely challenging. Multistage mass spectrometry (MS n) has become the primary method for glycan structural identification. The major difficulty for MS n is the selection of fragment ions as precursors for the next stage of scanning. Widely used strategies are either manual selection by experienced experts, which requires considerable expertise and time, or simply selecting the most intense peaks by which the product-ion spectrum generated may not be structurally informative and therefore fail to make the assignment. We here report a glycan "intelligent precursor selection" strategy (GIPS) to guide MS n experiments. Our approach consists of two key elements, an empirical model to calculate candidate glycan's probability and a statistical model to calculate fragment ion's distinguishing power in order to select the structurally most informative peak as the precursor for next-stage scanning. Using 15 glycan standards, including three pairs with isomeric sequences and eight variously fucosylated oligosaccharides on linear or branched hexasaccharide backbones isolated from a human milk oligosaccharide fraction by HPLC, we demonstrate its successful application to branching pattern analysis with improved efficiency and sensitivity and also the potential for automated operation.

Glycan analysis of colorectal cancer samples reveals stage-dependent changes in CEA glycosylation patterns.

BACKGROUND: Carcinoembryonic antigen (CEA) is a glycoprotein associated with colorectal cancer (CRC). While the functions of its gene and protein have been fully characterized, its post-translational modifications in the context of CRC development remain undefined. METHODS: To show the correlation between the different stages of CRC development and changes in the glycosylation patterns of CEA, we analyzed CEA in tumor tissues (CEA-T) and paired tumor-adjacent normal tissues (CEA-A) from 53 colorectal cancer patients using a high-density lectin microarray containing 56 plant lectins. RESULTS: We detected higher expression levels of fucose, mannose and Thomsen-Friedenreich antigen, and lower expression levels of N-acetylgalactosamine, N-acetylglucosamine, galactose, branched and bisecting N-glycans on CEA in the tumor tissues relative to the tumor-adjacent normal tissues. Furthermore, a combinatorial assessment of 9 lectins is sufficient to distinguish CRC tumor tissues from tumor-adjacent normal tissues with 83% sensitivity and ~ 90% specificity. Moreover, the levels of N-acetylgalactosamine, mannose, galactose, N-acetylglucosamine on CEA showed a downward trend after first experiencing an increase at Stage II with the stages of CRC. CONCLUSIONS: Our insights into the changing CEA glycosylation patterns and their role in the development of CRC highlight the importance of glycan variants on CEA for early clinical detection and staging of CRC.

[Effect of SRC Kinase on Adriamycin Resistance and Invasion and Metastasis in Human Breast Cancer Cells].

OBJECTIVE: To investigate the role of SRC kinase inhibitor PP2 in drug resistance to adriamycin (ADM) in breast cancer cells and invasion, metastasis of cells. METHODS: MTT assay was used to detect the inhibitory effect of ADM on MCF-7 and MCF-7/ADM cells. The 50% inhibitory concentration (IC50) and resistance index (RI) of cells were calculated. The expression of MDR1, connexin 43 (Cx43) and SRC proteins in breast cancer cells were detected by Western blot assay. Transwell experiment and cell scratch test were used to determine the invasion and migration of cells respectively [MCF-7, MCF-7/ADM, PP2 (1, 2, 4 µmol/L)]. Standard colony formation assay was used to detect the cytotoxicity effect of 4 µmol/L PP2 pretreatment on ADM. RESULTS: ADM inhibited the proliferation of MCF-7 more than MCF-7/ADM cells (P<0.01). The IC50 of MCF-7/ADM cells was 24.55 µmol/L, the IC50 of MCF-7/ADM cells was 770.57 µmol/L, the RI was 31. Compared with MCF-7 cells, expressions of the multidrug resistance proteins MDR1 and SRC were significantly increased (P<0.01). The invasion and migration ability of the MCF-7/ADM cells was stronger than that of the sensitive cells (P<0.01). When MCF-7/ADM was exposed to SRC inhibitor PP2, the invasion and metastasis ability of cells were inhibited (P<0.01) and the rate of colony formation was decreased, that is, more sensitivity to ADM (P<0.01). CONCLUSION: The resistance of MCF-7 to ADM is accompanied by increased expression of SRC. SRC inhibitor PP2 can reduce the cell resistance, ability of invasion and metastasis.

Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death.

Interleukin-22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS, and effects on alcohol-induced hepatocyte cell death are unexplored and were examined in this study. Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5-fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration-dependent manner with a maximum reduction of 5-fold. LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacological inhibitor of c-Jun NH2-terminal kinase (JNK) and by JNK knockdown. Next, we explored whether macrophage-derived IL-22 regulated ethanol-induced hepatocyte death. Conditioned media from IL-10-stimulated macrophages attenuated ethanol-induced hepatocyte caspase-3/7 activity, and apoptosis as assessed by fluorometric assay and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy-drinking controls, implying a state of IL-22 resistance in human AH. Macrophage-derived IL-22 protects hepatocytes from ethanol-induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH.

Characterization of IgG glycosylation in rheumatoid arthritis patients by MALDI-TOF-MSn and capillary electrophoresis.

An analytical method based on the combination of multistage mass spectrometry (MSn) and capillary electrophoresis (CE) was developed for the analysis of immunoglobulin G (IgG) glycosylation in rheumatoid arthritis (RA) patients. It has been recently suggested that IgG glycosylation defect may be involved in RA immunopathogenesis. Complete characterization of glycans, including both qualitative and quantitative analysis, requires a combination of different techniques, and accurate, robust, sensitive, and high-throughput methodologies are important for analysis of clinical samples. In the present study, N-glycosylation of IgG in RA patients and in healthy people was characterized through identification of the released glycans using multistage matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MSn), and quantitation by CE. Assignment of the IgG N-glycan structures was made through branching pattern analysis by MSn with high-throughput. Further accurate quantitation indicated that galactosylation and sialylation of IgG N-glycans in RA cases were significantly lower than in healthy subjects. The results indicate that CE coupled with MSn can identify abnormal glycosylation of IgG in RA patients compared with healthy people, and that the present work is useful for RA mechanism studies and RA diagnosis. Graphical Abstract Qualitative and quantitative analysis of IgG glycosylation in rheumatoid arthritis patients by MALDI-TOF-MSn and capillary electrophoresis.

Exploring the relationship between nursing hours per patient day and mortality rate of hospitalised patients in Taiwan.

AIM: To investigate the relationship between nursing hours per patient day and the inpatient mortality rate in Taiwan. BACKGROUND: Nursing hours per patient day has been associated with better patient outcomes. The literature is inconclusive on the relationship between nursing hours per patient day and the inpatient mortality rate, and no studies have yet examined this issue in Taiwan. METHODS: A retrospective longitudinal study analysed data from the 'Nursing Utilization of Resources, Staffing and Environment on Outcome Study: NURSE-outcome study'. Hierarchical regression estimated the relationship between nursing hours per patient day and in-hospital mortality rate after controlling for confounding variables. RESULTS: The mean nursing hours per patient day in Taiwan was 2.3, while the mean inpatient mortality rate was 0.73% higher nursing hours per patient day was associated with a lower inpatient mortality rate after controlling for confounding variables. The total explained variance of this study in inpatient mortality rate was 19.9%. Significant relationships to inpatient mortality were found in levels of hospitals, seasonal variation and nurses' work experience. CONCLUSION: Nursing hours per patient day affects the mortality rate among hospitalised patients in Taiwan. IMPLICATIONS FOR NURSING MANAGEMENT: According to the results, we suggested the government and managers in Taiwan double the nursing hours per patient day so that the inpatient mortality rate will decline by 1.1%. This might be the optimal nurse configuration that could provide a balance between cost-effectiveness and patient safety.

Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles.

BACKGROUND & AIMS: The mechanisms by which hepatocyte exposure to alcohol activates inflammatory cells such as macrophages in alcoholic liver disease (ALD) are unclear. The role of released nano-sized membrane vesicles, termed extracellular vesicles (EV), in cell-to-cell communication has become increasingly recognized. We tested the hypothesis that hepatocytes exposed to alcohol may increase EV release to elicit macrophage activation. METHODS: Primary hepatocytes or HepG2 hepatocyte cell lines overexpressing ethanol-metabolizing enzymes alcohol dehydrogenase (HepG2(ADH)) or cytochrome P450 2E1 (HepG2(Cyp2E1)) were treated with ethanol and EV release was quantified with nanoparticle tracking analysis. EV mediated macrophage activation was monitored by analysing inflammatory cytokines and macrophage associated mRNA expression, immunohistochemistry, biochemical serum alanine aminotransferase and triglycerides analysis in our in vitro macrophage activation and in vivo murine ethanol feeding studies. RESULTS: Ethanol significantly increased EV release by 3.3-fold from HepG2(Cyp2E1) cells and was associated with activation of caspase-3. Blockade of caspase activation with pharmacological or genetic approaches abrogated alcohol-induced EV release. EV stimulated macrophage activation and inflammatory cytokine induction. An unbiased microarray-based approach and antibody neutralization experiments demonstrated a critical role of CD40 ligand (CD40L) in EV mediated macrophage activation. In vivo, wild-type mice receiving a pan-caspase, Rho kinase inhibitor or with genetic deletion of CD40 (CD40(-/-)) or the caspase-activating TRAIL receptor (TR(-/-)), were protected from alcohol-induced injury and associated macrophage infiltration. Moreover, serum from patients with alcoholic hepatitis showed increased levels of CD40L enriched EV. CONCLUSION: In conclusion, hepatocytes release CD40L containing EV in a caspase-dependent manner in response to alcohol exposure which promotes macrophage activation, contributing to inflammation in ALD.

Phonon and thermal expansion properties in Weyl semimetals MX (M = Nb, Ta; X = P, As): ab initio studies.

Weyl semimetal (WSM) is a new type of topological quantum material for future spintronic devices. Using the first-principles density functional theory, we systematically investigated the thermal expansion properties, and the temperature dependence of isovolume heat capacity and bulk modulus in WSMs MX (M = Nb, Ta; X = P, As). We also presented the phonon dispersion curves and its variation under stress in MX and the anisotropic thermal expansion properties due to the anisotropic crystal structure in WSMs have been predicted in our calculations. Intriguing, we found that the heat capacities increase more rapidly with increasing temperature in the low temperature region for all MX. Furthermore, our results showed that the thermal expansion properties are determined mainly by the isovolume heat capacity at low temperatures, while the bulk modulus has the major effect at high temperatures. These results are useful for applications of WSMs in electronic and spintronic devices.