A combination weighting method for debris flow risk assessment based on t-distribution and linear programming optimization algorithm.

Debris flow risk assessment can provide some reference for debris flow prevention and control projects. In risk assessment, researchers often only focus on the impact of objective or subjective indicators. For this purpose, this paper proposed a weight calculation method based on t-distribution and linear programming optimization algorithm (LPOA). Taking 72 mudslides in Beichuan County as an example, this paper used analytic hierarchy process (AHP), entropy weight method (EWM) and variation coefficient method (VCM) to obtain the initial weights. Based on the initial weights, weight intervals with different confidence levels were obtained by t-distribution. Subsequently, the final weights were obtained by LOPA in the 90% confidence interval. Finally, the final weights were used to calculate the risk score for each debris flow, thus delineating the level of risk for each debris flow. The results showed that this paper's method can avoid overemphasizing the importance of a particular indicator compared to EWM and VCM. In contrast, EWM and VCM ignored the effect of debris flow frequency on debris flow risk. The assessment results showed that the 72 debris flows in Beichuan County were mainly dominated by moderate and light risks. Of these, there were 8 high risk debris flows, 24 medium risk debris flows, and 40 light risk debris flows. The excellent triggering conditions provide favorable conditions for the formation of high-risk debris flows. Slightly and moderate risk debris flows are mainly located on both sides of highways and rivers, still posing a minor threat to Beichuan County. The proposed fusion weighting method effectively avoids the limitations of single weight calculating method. Through comparison and data analysis, the rationality of the proposed method is verified, which can provide some reference for combination weighting method and debris flow risk assessment.

CARDS, a Novel Prognostic Index for Risk Stratification and In-Hospital Monitoring.

Background: Sodium fluctuation is independently associated with clinical deterioration. We developed and validated a prognostic index based on sodium fluctuation for risk stratification and in-hospital monitoring. Methods: This study included 33,323 adult patients hospitalized at a tertiary care hospital in 2014. The first 28,279 hospitalizations were analyzed to develop the model and then the validity of the model was tested using data from 5044 subsequent hospitalizations. We predict in-hospital mortality using age, comorbidity, range of sodium fluctuation, and duration of sodium fluctuation, abbreviated as CARDS. Results: In-hospital mortality was similar in the derivation (0.6%) and validation (0.4%) cohorts. In the derivation cohort, four independent risk factors for mortality were identified using logistic regression: age (66-75, 2 points; >75, 3 points); Charlson comorbidity index (>2, 5 points); range of sodium fluctuation (7-10, 4 points; >10, 10 points); and duration of fluctuation (≤3, 3 points). The AUC was 0.907 (95% CI: 0.885-0.928) in the derivation cohort and 0.932 (95% CI: 0.895-0.970) in the validation cohort. In the derivation cohort, in-hospital mortality was 0.106% in the low-risk group (0-7 points), 1.076% in the intermediate-risk group (8-14 points), and 8.463% in the high-risk group (15-21 points). In the validation cohort, in-hospital mortality was 0.049% in the low-risk group, 1.064% in the intermediate-risk group, and 8.403% in the high-risk group. Conclusions: These results suggest that patients at low, intermediate, and high risk for in-hospital mortality may be identified by CARDS mainly based on sodium fluctuation.

Synergistic oxidation of humic acid treated by H2O2/O3 activated by CuCo/C with high efficiency and wide pH range.

Combination of oxidation processes are one of the most promising humic acid treatment technologies. Single oxidant or even two oxidants in advance oxidation process can hardly achieve satisfactory removal efficiency of refractory organic matter, mainly humic acid, in the treatment process of reverse osmosis concentrates from landfill leachate. To solve this problem, this study investigated the synergistic degradation of Humic acid (HA) using a Cu and Co supported on carbon catalyst (CuCo/C) in a Hydrogen peroxide (H2O2) with ozone (O3) system. The catalyst was characterized by performing SEM, XRD, BET, XPS and FTIR technologies. UV-vis spectra, 3D Excitation Emission Matrix Spectra (3D-EEM) and gas chromatography-mass spectrometry (GC-MS) were applied for exploring degradation mechanism of HA. To further understand the oxidation mechanism, electron paramagnetic resonance (EPR) was used to evaluate the generation of hydroxyl (·OH) and superoxide radicals (O2·-). As a result, CuCo/C catalyst possessed stable catalytic performance for HA degradation with a wide pH range from 5 to 8, while T = 40 °C，catalyst dosage of 2.4 g/L，O3 intake rate of 0.15 g/min and H2O2 dosage of 1.92 mL/L, the degradation rate of total organic carbon (TOC) achieved 40-46.5 mg·L-1min-1. As affirmed by the EPR, ·OH and O2·- were effectively generated with addition of the CuCo/C catalyst. Degradation performance of UV254 proved that the catalytic activity can still be maintained above 95% with removal rate of 82% after 5 cycles reuse. GC-MS shows that the oxidation products mainly consist of amide, benzoheterocyclic ring and carboxylic acid. This work promotes an effective method for degrading HA, which has the potential for satisfactory application in landfill leachate.

Stability analysis of rainfall-induced landslide considering air resistance delay effect and lateral seepage.

Accumulation landslides are prone to occur during the continuous infiltration of heavy rainfall, which seriously threatens the lives and property safety of local residents. In this paper, based on the Green-Ampt (GA) infiltration model, a new slope rainfall infiltration function is derived by combining the effect of air resistance and lateral seepage of saturated zone. Considering that when the soil layer continues to infiltrate after the saturation zone is formed, the air involvement cannot be discharged in time, which delays the infiltration process. Therefore, the influence of air resistance factor in soil pores is added. According to the infiltration characteristics of finite long slope, the lateral seepage of saturated zone is introduced, which makes up for the deficiency that GA model is only applicable to infinite long slope. Finally, based on the seepage characteristics of the previous analysis, the overall shear strength criterion is used to evaluate the stability of the slope. The results show that the safety factor decreases slowly with the increase of size and is inversely correlated with the slope angle and initial moisture content. The time of infiltration at the same depth increases with the increase of size and slope angle, and is inversely correlated with the initial moisture content, but is less affected by rainfall intensity. By comparing with the results of experimental data and other methods, the results of the proposed method are more consistent with the experimental results than other methods.

Comparison of Aroma Compounds and Sensory Characteristics between Two Different Types of Rice-Based Baijiu.

Rice-based Baijiu has gained popularity in the Chinese market. Qingya-flavored Baijiu, a variant of Xiaoqu-fermented Baijiu, employs rice as its primary raw material, with an improved production process compared to traditional rice-flavored Baijiu. We comprehensively characterized and compared the aroma profiles of these two rice-based Baijiu types using static sensory experiments (QDA, quantitative descriptive analysis) and dynamic sensory experiments (TDS, temporal dominance of sensations). Qingya-flavored Baijiu exhibited pronounced plant, oily, and roasted aromas, while traditional rice-flavored Baijiu displayed more prominent fruity, floral, and sour notes. Utilizing GC-O-MS (gas chromatography-olfactometry-mass spectrometry) and multi-method quantification, we qualitatively and quantitatively analyzed 61 key aroma compounds, identifying 22 compounds with significant aroma contributions based on odor activity values (OAVs). Statistical analyses, combining sensory and chemical results, were conducted to predict important aroma compounds responsible for the aroma differences between the two Baijiu types. Aroma Recombination and Omission experiments showed that seven compounds play key roles in the aroma of Qingya-flavored Baijiu, including (2E,4E)-Deca-2,4-dienal, linalool, apricolin, ethyl acetate, ethyl isobutyrate, ethyl caprylate, and ethyl isovalerate.

Iron-Catalyzed Denitrogenative Annulation Reactions between α-Azido Acetamides and Cyclic Ketones.

We report an FeCl2-catalyzed annulation reaction between α-azido acetamides and cyclic ketones. Two types of α,ß-unsaturated γ-lactam products can be obtained, depending on the reaction conditions. When α-azido acetamides were reacted with cyclohexanone, 8-amino-5,6,7,8-tetrahydro-1H-indol-2(4H)-ones were obtained when a primary amine was present in the reaction system; conducting the reaction in the presence of 2-aminobenzenesulfonic acid, on the contrary, resulted in the formation of 5,6-dihydro-1H-indol-2(4H)-ones. Cycloheptanone and cyclooctanone reacted in the same way as cyclohexanone. The reactions proceed via the intermediacy of 2-iminoacetamides, which are formed by FeCl2-facilitated dinitrogenation of α-azido acetamides. These reactions constitute a new strategy for expanding the synthetic dimensions of organic azides.

Antihyperlipidemic drug rosuvastatin suppressed tumor progression and potentiated chemosensitivity by downregulating CCNA2 in lung adenocarcinoma.

Rosuvastatin (RSV) is widely used to treat hyperlipidemia and hypercholesterolemia and is recommended for the primary and secondary prevention of cardiovascular diseases (CVD). In this study, we aimed to explore its action and mechanism in lung adenocarcinoma (LUAD) therapy. Lewis and CMT64 cell-based murine subcutaneous LUAD models were employed to explore the effects of RSV monotherapy combined with cisplatin and gemcitabine. Human lung fibroblasts and human LUAD cell lines were used to assess the effects of RSV on normal and LUAD cells. Bioinformatics and RNA interference were used to observe the contribution of cyclin A2 (CCNA2) knockdown to RSV inhibition and to improve chemosensitivity in LUAD. RSV significantly suppressed grafted tumor growth in a murine subcutaneous LUAD model and exhibited synergistic anti-tumor activity with cisplatin and gemcitabine. In vitro and in vivo experiments demonstrated that RSV impaired the proliferation and migration of cancer cells while showing little inhibition of normal lung cells. RNA interference and CCK8 detection preliminarily indicated that RSV inhibited tumor growth and enhanced the chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2. RSV suppressed LUAD progression and enhanced chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2, which should be prior consideration for the treatment of LUAD, especially for patients co-diagnosed with hyperlipidemia and hypercholesterolemia.

Comparison of moving bed biofilm reactor and bio-contact oxidation reactor start-up with heterotrophic nitrification-aerobic denitrification bacteria and activated sludge inoculation under high ammonia nitrogen conditions.

To overcome poor ammonia tolerance and removal performance of bio-contact oxidation (BCO) reactor inoculated with activated sludge for high-ammonia nitrogen (NH4+-N) chemical wastewater treatment, this study compared inoculating heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria in moving bed biofilm reactor (MBBR) with activated sludge inoculation in BCO reactor under simulated high NH4+-N conditions. Results revealed that MBBR achieved faster biofilm formation (20 days vs. 100 days for BCO) with notable advantages: 27.6 % higher total nitrogen (TN) and 29.9 % higher NH4+-N removal efficiency than BCO. Microbial analysis indicated optimal enrichment of the key nitrogen removal (NR) bacterium Alcaligenes, leading to increased expression of NR enzymes hydroxylamine reductase, ensuring the superior NR efficiency of the MBBR. Additionally, functional enzymes and genes analysis speculated that the NR pathway in MBBR was: NH4+-N â†’ NH2OH â†’ NO3--N â†’ NO2--N â†’ NO â†’ N2O â†’ N2. This research offers a practical and theoretical foundation for extending HN-AD bacteria-inoculated MBBR processes.

Bacteriophage endolysin Ply113 as a potent antibacterial agent against polymicrobial biofilms formed by enterococci and Staphylococcus aureus.

Antibiotic resistance in Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus remains a major public health concern worldwide. Furthermore, these microbes frequently co-exist in biofilm-associated infections, largely nullifying antibiotic-based therapy. Therefore, it is imperative to develop an efficient therapeutic strategy for combating infections caused by polymicrobial biofilms. In this study, we investigated the antibacterial and antibiofilm activity of the bacteriophage endolysin Ply113 in vitro. Ply113 exhibited high and rapid lytic activity against E. faecium, E. faecalis, and S. aureus, including vancomycin-resistant Enterococcus and methicillin-resistant S. aureus isolates. Transmission electron microscopy revealed that Ply113 treatment led to the detachment of bacterial cell walls and considerable cell lysis. Ply113 maintained stable lytic activity over a temperature range of 4-45°C, over a pH range of 5.0-8.0, and in the presence of 0-400 mM NaCl. Ply113 treatment effectively eliminated the mono-species biofilms formed by E. faecium, E. faecalis, and S. aureus in a dose-dependent manner. Ply113 was also able to eliminate the dual-species biofilms of E. faecium-S. aureus and E. faecalis-S. aureus. Additionally, Ply113 exerted potent antibacterial efficacy in vivo, distinctly decreasing the bacterial loads in a murine peritoneal septicemia model. Our findings suggest that the bacteriophage endolysin Ply113 is a promising antimicrobial agent for the treatment of polymicrobial infections.

Endopeptidase O promotes Streptococcus suis immune evasion by cleaving the host- defence peptide cathelicidins.

Streptococcus suis is a zoonotic Gram-positive bacterium that causes invasive infections such as sepsis and meningitis, threatening public health worldwide. For successful establishment of infection, the bacterium should subvert the innate effectors of immune defence, including the cathelicidin family of host-defence peptides that combat pathogenic bacteria by directly disrupting cell membranes and coordinating immune responses. Here, our study shows that an extracellular endopeptidase O (PepO) of S. suis contributes to assisting the bacterium to resist cathelicidin-mediated killing, as the deletion of the pepO gene makes S. suis more sensitive to the human cathelicidin LL-37, as well as its mouse equivalent, mCRAMP. This protease targets and cleaves both LL-37 and mCRAMP, degrading them into shorter peptides with only a few amino acids, thereby abrogating their ability to kill S. suis. By cleaving LL-37 and mCRAMP, PepO impairs their chemotactic properties for neutrophil migration and undermines their anti-apoptosis activity, which is required for prolonging neutrophil lifespan. Also, PepO inhibits the ability of LL-37 and mCRAMP to promote lysosome development in macrophages. Moreover, the loss of PepO attenuates organ injury and decreases bacterial burdens in a murine model of S. suis bacteraemia. Taken together, these data provide novel insights into the role of the intrinsic proteolytic characteristics of PepO in S. suis-host interaction. Our findings demonstrate that S. suis utilizes the PepO protease to cleave cathelicidins, which is an immunosuppressive strategy adopted by this bacterium to facilitate pathogenesis.

[An examination of the carbon metabolic pathways in Acinetobacter sp. TAC-1 in the context of poly (3-hydroxybutyrate-co-3-hydroxyvalerate) utilization].

The present study aimed to unravel the carbon metabolism pathway of Acinetobacter sp. TAC-1, a heterotrophic nitrification-aerobic denitrification (HN-AD) strain that utilizes poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) as a carbon source. Sodium acetate was employed as a control to assess the gene expression of carbon metabolic pathways in the TAC-1 strain. The results of genome sequencing demonstrated that the TAC-1 strain possessed various genes encoding carbon metabolic enzymes, such as gltA, icd, sucAB, acs, and pckA. KEGG pathway database analysis further verified the presence of carbon metabolism pathways, including the glycolytic pathway (EMP), pentose phosphate pathway (PPP), glyoxylate cycle (GAC), and tricarboxylic acid (TCA) cycle in the TAC-1 strain. The differential expression of metabolites derived from distinct carbon sources provided further evidence that the carbon metabolism pathway of TAC-1 utilizing PHBV follows the sequential process of PHBV (via the PPP pathway)→gluconate (via the EMP pathway)→acetyl-CoA (entering the TCA cycle)→CO2+H2O (generating electron donors and releasing energy). This study is expected to furnish a theoretical foundation for the advancement and implementation of novel denitrification processes based on HN-AD and solid carbon sources.

Tacrolimus and Diabetes in Kidney Transplantation: The Impact of Cyp3a5 Gene Polymorphism.

BACKGROUND: To explore the correlation between single nucleotide polymorphisms (SNPs) of CYP3A4 rs2740574 and CYP3A5 rs776746 and post-transplant diabetes mellitus (PTDM) in Chinese renal allograft recipients treated with tacrolimus. METHODS: A total of 244 patients treated with tacrolimus were included in this study, wherein DNA sequencing was detected through fluorescence in situ hybridization, and SNP genotyping was performed. RESULTS: Among the 244 patients, 44 (18%) developed PTDM. The PTDM group exhibited higher preoperative body mass index and fasting plasma glucose levels, with higher creatinine values one year after surgery. The CYP3A4 rs2740574 genotype was found to be unique in its homozygous AA form. For CYP3A5 rs776746, the genotypes were distributed as follows: 28 (11.5%) cases with AA, 101 (41.4%) cases with AG, and 115 (47.1%) cases with GG, respectively (P = .042). The AA genotype showed a statistically significant difference from both AG and GG genotypes. Furthermore, the A allele of CYP3A5 rs776746 was found to be associated with an increased risk for PTDM development. CONCLUSIONS: The occurrence of tacrolimus-related PTDM is associated with body mass index, fasting plasma glucose levels, and CYP3A5 genotype before renal transplantation. Post-transplant diabetes mellitus is correlated with unfavorable long-term renal graft function, whereas the expression of the CYP3A5 rs776746 gene is linked to an elevated risk of PTDM.

The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC.

This study aimed to explore the role and mechanism of felodipine in lung cancer therapy. Murine subcutaneous lung squamous cancer (LUSC) models constructed by KLN-205 cells were utilized to assess the effect of felodipine monotherapy and in combination with the programmed cell death protein 1 antibody (PD1ab) and cytotoxic T lymphocyte-associated antigen-4 (CTLA4ab). Immunohistochemistry analysis was subsequently applied to detect the number of CD8+ T cells and Ki67+ cells. Lastly, a series of in vitro and in vivo experiments were performed to evaluate the effects of felodipine on human LUSC cells and explore the preliminary mechanism underlying felodipine inhibition. The results revealed that felodipine monotherapy exerted a significant inhibitory effect on LUSC growth and synergistic antitumoral activity with PD1ab and CTLA4ab. Meanwhile, immunohistochemistry analysis displayed that felodipine promoted CD8+ T-cell infiltration and downregulated Ki67 expression in tumor cells. Moreover, in vitro and in vivo experiments utilizing human LUSC cells determined that felodipine impaired the proliferative and migratory abilities of cancer cells. In addition, TCGA data analysis uncovered that nuclear factor of activated T cell (NFAT1) expression was positively correlated with overall survival and disease-free survival. Finally, the cell counting kit-8 assay signaled that felodipine might suppress tumor growth by modulating NFAT1.

Transdermal drug delivery via microneedles for musculoskeletal systems.

As the population is ageing and lifestyle is changing, the prevalence of musculoskeletal (MSK) disorders is gradually increasing with each passing year, posing a serious threat to the health and quality of the public, especially the elderly. However, currently prevalent treatments for MSK disorders, mainly administered orally and by injection, are not targeted to the specific lesion, resulting in low efficacy along with a series of local and systemic adverse effects. Microneedle (MN) patches loaded with micron-sized needle array, combining the advantages of oral administration and local injection, have become a potentially novel strategy for the administration and treatment of MSK diseases. In this review, we briefly introduce the basics of MNs and focus on the main characteristics of the MSK systems and various types of MN-based transdermal drug delivery (TDD) systems. We emphasize the progress and broad applications of MN-based transdermal drug delivery (TDD) for MSK systems, including osteoporosis, nutritional rickets and some other typical types of arthritis and muscular damage, and in closing summarize the future prospects and challenges of MNs application.

Bactericidal synergism between phage endolysin Ply2660 and cathelicidin LL-37 against vancomycin-resistant Enterococcus faecalis biofilms.

Antibiotic resistance and the ability to form biofilms of Enterococcus faecalis have compromised the choice of therapeutic options, which triggered the search for new therapeutic strategies, such as the use of phage endolysins and antimicrobial peptides. However, few studies have addressed the synergistic relationship between these two promising options. Here, we investigated the combination of the phage endolysin Ply2660 and the antimicrobial peptide LL-37 to target drug-resistant biofilm-producing E. faecalis. In vitro bactericidal assays were used to demonstrate the efficacy of the Ply2660-LL-37 combination against E. faecalis. Larger reductions in viable cell counts were observed when Ply2660 and LL-37 were applied together than after individual treatment with either substance. Transmission electron microscopy revealed that the Ply2660-LL-37 combination could lead to severe cell lysis of E. faecalis. The mode of action of the Ply2660-LL-37 combination against E. faecalis was that Ply2660 degrades cell wall peptidoglycan, and subsequently, LL-37 destroys the cytoplasmic membrane. Furthermore, Ply2660 and LL-37 act synergistically to inhibit the biofilm formation of E. faecalis. The Ply2660-LL-37 combination also showed a synergistic effect for the treatment of established biofilm, as biofilm killing with this combination was superior to each substance alone. In a murine peritoneal septicemia model, the Ply2660-LL-37 combination distinctly suppressed the dissemination of E. faecalis isolates and attenuated organ injury, being more effective than each treatment alone. Altogether, our findings indicate that the combination of a phage endolysin and an antimicrobial peptide may be a potential antimicrobial strategy for combating E. faecalis.

Molecular imaging of fibroblast activity in pressure overload heart failure using [68 Ga]Ga-FAPI-04 PET/CT.

PURPOSE: We aimed to evaluate whether [68 Ga]Ga-FAPI-04 PET/CT could characterize the early stages of cardiac fibrosis in pressure overload heart failure. METHODS: Sprague-Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with [68 Ga]Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. The expression of fibroblast activation protein (FAP) in the myocardium was detected by immunohistochemistry. [68 Ga]Ga-FAPI-04 PET signal and FAP expression were compared between two groups. RESULTS: Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p < 0.01). The AAC group showed higher [68 Ga]Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, and FAPI increased significantly from 2 to 8 weeks (all p < 0.001). Immunohistochemistry confirmed the higher density of the FAP+ area in the AAC group. The intensity of the [68 Ga]Ga-FAPI-04 correlated with the density of the FAP+ area (p < 0.001). The expression of the [68 Ga]Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = - 0.87; FS: R = - 0.72; LVIDd: R = 0.77; LVIDs: R = 0.79; all p < 0.001). The AAC group also showed an increased [68 Ga]Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010), suggesting an early fibrotic link between organs. A combination of the [68 Ga]Ga-FAPI-04 intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks. CONCLUSIONS: The activated fibroblasts in the heart and liver after pressure overload can be monitored by [68 Ga]Ga-FAPI-04 PET/CT, which reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis.

Alkaloid binding to opium poppy major latex proteins triggers structural modification and functional aggregation.

Opium poppy accumulates copious amounts of several benzylisoquinoline alkaloids including morphine, noscapine, and papaverine, in the specialized cytoplasm of laticifers, which compose an internal secretory system associated with phloem throughout the plant. The contiguous latex includes an abundance of related proteins belonging to the pathogenesis-related (PR)10 family known collectively as major latex proteins (MLPs) and representing at least 35% of the total cellular protein content. Two latex MLP/PR10 proteins, thebaine synthase and neopione isomerase, have recently been shown to catalyze late steps in morphine biosynthesis previously assigned as spontaneous reactions. Using a combination of sucrose density-gradient fractionation-coupled proteomics, differential scanning fluorimetry, isothermal titration calorimetry, and X-ray crystallography, we show that the major latex proteins are a family of alkaloid-binding proteins that display altered conformation in the presence of certain ligands. Addition of MLP/PR10 proteins to yeast strains engineered with morphine biosynthetic genes from the plant significantly enhanced the conversion of salutaridine to morphinan alkaloids.

A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as a major liver disease increasingly in association with non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). However, there are currently no approved therapies for treating NAFLD and NASH. Fibroblast growth factor 4 (FGF4) has recently been shown as a promising drug candidate for several metabolic diseases. METHODS: Mice fed a high-fat diet with high fructose/glucose drinking water (HF/HFG, Western-like diet) for 21 weeks were intraperitoneally injected with non-mitogenic recombinant FGF4△NT (rFGF4△NT, 1.0 mg/kg body weight) every other day for 8 weeks. Primary mouse hepatocytes cultured in medium containing high glucose/palmitic acid (HG/PA) or TNFα/cyclohexane (TNFα/CHX) were treated with 1.0 µg/ml rFGF4△NT. Changes in parameters for histopathology, lipid metabolism, inflammation, hepatocellular apoptosis and fibrosis were determined. The Caspase6 activity and AMPK pathway were assessed. RESULTS: Administration of rFGF4△NT significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4△NT treatment reduced fatty acid-induced lipid accumulation and lipotoxicity-induced hepatocyte apoptosis, which were associated with inhibition of Caspase6 cleavage and activation. Inhibition of AMP-activated protein kinase (AMPK) by Compound C or deficiency of Ampk abrogated rFGF4△NT-induced hepatoprotection in primary hepatocytes and in mice with NASH. CONCLUSION: rFGF4△NT exerts significant protective effects on NASH via an AMPK-dependent signaling pathway. Our study indicates that FGF4 analogs may have therapeutic potential for the Western-like diet induced NASH.

The polarization of politics and public opinion and their effects on racial inequality in COVID mortality.

Evidence from the early months of the COVID-19 pandemic in the U.S. indicated that the virus had vastly different effects across races, with black Americans faring worse on dimensions including illness, hospitalization and death. New data suggests that our understanding of the pandemic's racial inequities must be revised given the closing of the gap between black and white COVID-related mortality. Initial explanations for inequality in COVID-related outcomes concentrated on static factors-e.g., geography, urbanicity, segregation or age-structures-that are insufficient on their own to explain observed time-varying patterns in inequality. Drawing from a literature suggesting the relevance of political factors in explaining pandemic outcomes, we highlight the importance of political polarization-the partisan divide in pandemic-related policies and beliefs-that varies over time and across geographic units. Specifically, we investigate the role of polarization through two political factors, public opinion and state-level public health policies, using fine-grained data on disparities in public concern over COVID and in state containment/health policies to understand the changing pattern of inequality in mortality. We show that (1) apparent decreases in inequality are driven by increasing total deaths-mostly among white Americans-rather than decreasing mortality among black Americans (2) containment policies are associated with decreasing inequality, likely resulting from lower relative mortality among Blacks (3) as the partisan disparity in Americans who were "unconcerned" about COVID increased, racial inequality in COVID mortality decreased, generating the appearance of greater equality consistent with a "race to the bottom'' explanation as overall deaths increased and substantively swamping the effects of containment policies.

Cross-sectional and prospective association between internet addiction and risk of fatigue among Chinese college students.

Severe internet addiction (IA) is associated with a higher risk of musculoskeletal pain, but whether there is a significant prospective association between IA and fatigue is unclear. This study aimed to examine the association between IA and fatigue level among Chinese college students. A cross-sectional (n = 1011) and prospective study (n = 653) was conducted to examine the association between IA and risk of fatigue. IA was measured using Young internet addiction test. Fatigue level was evaluated using the Chalder fatigue scale. Multivariate logistic regression analyses showed a cross-sectional association between IA and the risk of fatigue. The odds ratios (95% CIs) of fatigue for normal, mild, and moderate to severe groups were 1.00 (reference), 1.88 (1.20, 2.95), and 5.60 (3.33, 9.42), respectively (P for trend: <0.001). Similarly, multivariate logistic regression analyses also revealed a significant prospective relationship between IA and the risk of fatigue during the 1-year follow-up period. The odds ratios (95% CIs) of fatigue for normal, mild, and moderate to severe groups were 1.00 (reference), 1.56 (0.67, 3.67), and 3.29 (1.08, 10.04), respectively (P for trend: 0.046). Our findings indicate that IA is positively related to risk of fatigue among Chinese college students. Further interventional studies are needed to explore the causality underlying the effects of IA on fatigue.