Pongamol Alleviates Neuroinflammation and Promotes Autophagy in Alzheimer's Disease by Regulating the Akt/mTOR Signaling Pathway.

Alzheimer's disease (AD), one of the neurodegenerative disorders, is highly correlated with the abnormal hyperphosphorylation of Tau and aggregation of ß-amyloid (Aß). Oxidative stress, neuroinflammation, and abnormal autophagy are key drivers of AD and how they contribute to neuropathology remains largely unknown. The flavonoid compound pongamol is reported to possess a variety of pharmacological activities, such as antioxidant, antibacterial, and anti-inflammatory. This study investigated the neuroprotective effect and its mechanisms of pongamol in lipopolysaccharide (LPS)-induced BV2 cells, d-galactose/sodium nitrite/aluminum chloride (d-gal/NaNO2/AlCl3)-induced AD mice, and Caenorhabditis elegans models. Our research revealed that pongamol reduced the release of inflammatory factors IL-1ß, TNF-α, COX-2, and iNOS in LPS-induced BV2 cells. Pongamol also protected neurons and significantly restored memory function, inhibited Tau phosphorylation, downregulated Aß aggregation, and increased oxidoreductase activity in the hippocampus of AD mice. In addition, pongamol reversed the nuclear transfer of NF-κB and increased the levels of Beclin 1 and LC3 II/LC3 I. Most importantly, the anti-inflammatory and promoter autophagy effects of pongamol may be related to the regulation of the Akt/mTOR signaling pathway. In summary, these results showed that pongamol has a potential neuroprotective effect, which greatly enriched the research on the pharmacological activity of pongamol for improving AD.

Synergistic effects of inhaled aztreonam plus tobramycin on hypermutable cystic fibrosis Pseudomonas aeruginosa isolates in a dynamic biofilm model evaluated by mechanism-based modelling and whole genome sequencing.

OBJECTIVE: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P. aeruginosa strains using the CDC dynamic in vitro biofilm reactor (CBR), mechanism-based mathematical modelling (MBM) and genomic studies. METHODS: Two CF multidrug-resistant strains were investigated in a 168 h CBR (n = 2 biological replicates). Regimens were inhaled aztreonam (75 mg 8-hourly) and tobramycin (300 mg 12-hourly) in monotherapies and combination. The simulated pharmacokinetic profiles of aztreonam and tobramycin (t1/2 = 3 h) were based on published lung fluid concentrations in patients with CF. Total viable and resistant counts were determined for planktonic and biofilm bacteria. MBM of total and resistant bacterial counts and whole genome sequencing were completed. RESULTS: Both isolates showed reproducible bacterial regrowth and resistance amplification for the monotherapies by 168 h. The combination performed synergistically, with minimal resistant subpopulations compared to the respective monotherapies at 168 h. Mechanistic synergy appropriately described the antibacterial effects of the combination regimen in the MBM. Genomic analysis of colonies recovered from monotherapy regimens indicated noncanonical resistance mechanisms were likely responsible for treatment failure. CONCLUSION: The combination of aztreonam and tobramycin was required to suppress the regrowth and resistance of planktonic and biofilm bacteria in all biological replicates of both hypermutable multidrug-resistant P. aeruginosa CF isolates. The developed MBM could be utilised for future investigations of this promising inhaled combination.

Evolutionary trajectory of diverse SARS-CoV-2 variants at the beginning of COVID-19 outbreak.

Despite extensive scientific efforts directed toward the evolutionary trajectory of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans at the beginning of the COVID-19 epidemic, it remains unclear how the virus jumped into and evolved in humans so far. Herein, we recruited almost all adult coronavirus disease 2019 (COVID-19) cases appeared locally or imported from abroad during the first 8 months of the outbreak in Shanghai. From these patients, SARS-CoV-2 genomes occupying the important phylogenetic positions in the virus phylogeny were recovered. Phylogenetic and mutational landscape analyses of viral genomes recovered here and those collected in and outside of China revealed that all known SARS-CoV-2 variants exhibited the evolutionary continuity despite the co-circulation of multiple lineages during the early period of the epidemic. Various mutations have driven the rapid SARS-CoV-2 diversification, and some of them favor its better adaptation and circulation in humans, which may have determined the waxing and waning of various lineages.

Design and tribological performance of graphene nanofluids dispersed by dragging effect of bicomponent gelator.

Nanofluids have excellent lubrication and high thermal conductivity. However, the agglomeration and sedimentation produced by the large surface energy of nanoparticles in base liquid threaten the long-term dispersion stability and impact the wide application of nanofluid. In this work, based on the self-assemble behavior and continuous network structure formed by low molecular weight organic gelator, the uniform clusters were formed through regulating the kinetics behavior in the gelling process. The dragging effect was demonstrated by oleic acid - sodium dodecyl sulfate (OA-SDS) bicomponent gelator and graphene oxide (GO) nanosheets. The results showed that GO nanofluids dispersed by OA-SDS were stable for more than 12 months. The well-dispersed GO nanofluid exhibited better anti-friction and anti-wear properties under both immersion and electrostatic minimum quantity lubrication conditions. Moreover, the lower contact angle, surface tension and droplet size of nanofluids after charging improved the wettability on the frictional interface. The GO adsorption film formed on the friction interface protected the tribochemical reaction film of iron oxide and prevented the occurrence of sintering of base oil.

Comprehensive stability analysis of 13 ß-lactams and ß-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation.

Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain ß-lactams (e.g., imipenem) and ß-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 ß-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at -20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on ß-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of ß-lactamase-related degradation.

Formation of Corrugated Damage on Bearing Race under Different AC Shaft Voltages.

Corrugated damage to bearings is a common fault in electrical facilities such as new energy vehicles, wind power, and high-speed railways. The aim of this article is to reveal the microscopic characteristics and formation mechanism of such damages. The corrugation with alternating "light" and "dark" shape was produced on GCr15 bearing races in the experimental conditions. Compared to the light area, the dark area (in the images generated by optical microscope) has more severe electrical erosion, lower hardness, more concave morphology, and lower oxidation. As the voltage increases, the width of the corrugation, the height difference between corrugation, and surface roughness all increase. It is believed that the formation of corrugated damage requires a sufficiently high voltage to induce the periodic destruction and reconstruction of the lubrication film. When the bearing is in a metal-lubrication film-metal contact state, the high voltage causes the lubrication film to break down and induce electrical erosion. Then, the contact area is in metal-metal contact, and the surface is mainly damaged by mechanical rolling. After the reconstruction of lubrication film, the next round of electrical erosion begins. The results are helpful for a deeper understanding of the mechanism of bearing erosion in electrical application.

Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure.

BACKGROUND: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF. METHODS: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on ß-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF. RESULTS: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the ß-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF. CONCLUSIONS: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.

Improved characterization of aminoglycoside penetration into human lung epithelial lining fluid via population pharmacokinetics.

Aminoglycosides are important treatment options for serious lung infections, but modeling analyses to quantify their human lung epithelial lining fluid (ELF) penetration are lacking. We estimated the extent and rate of penetration for five aminoglycosides via population pharmacokinetics from eight published studies. The area under the curve in ELF vs plasma ranged from 50% to 100% and equilibration half-lives from 0.61 to 5.80 h, indicating extensive system hysteresis. Aminoglycoside ELF peak concentrations were blunted, but overall exposures were moderately high.

Aureusidin ameliorates 6-OHDA-induced neurotoxicity via activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway in SH-SY5Y cells and Caenorhabditis elegans.

Movement disorder Parkinson's disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer's disease, which severely affects the quality of patients' lives and imposes an increasingly heavy socioeconomic burden. Aureusidin is a kind of natural flavonoid compound with anti-inflammatory and anti-oxidant activities, while its pharmacological action and mechanism are rarely reported in PD. This study aimed to explore the neuroprotective effects and potential mechanisms of Aureusidin in PD. The present study demonstrated that Aureusidin protected SH-SY5Y cells from cell damage induced by 6-hydroxydopamine (6-OHDA) via inhibiting the mitochondria-dependent apoptosis and activating the Nrf2/HO-1 antioxidant signaling pathway. Additionally, Aureusidin diminished dopaminergic (DA) neuron degeneration induced by 6-OHDA and reduced the aggregation toxicity of α-synuclein (α-Syn) in Caenorhabditis elegans (C. elegans.) In conclusion, Aureusidin showed a neuroprotective effect in the 6-OHDA-induced PD model via activating Nrf2/HO-1 signaling pathway and prevented mitochondria-dependent apoptosis pathway, and these findings suggested that Aureusidin may be an effective drug for the treatment of PD.

ICTV Virus Taxonomy Profile: Discoviridae 2023.

Discoviridae is a family of negative-sense RNA viruses with genomes of 6.2-9.7 kb that have been associated with fungi and stramenopiles. The discovirid genome consists of three monocistronic RNA segments with open reading frames (ORFs) that encode a nucleoprotein (NP), a nonstructural protein (Ns), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Discoviridae, which is available at ictv.global/report/discoviridae.

ICTV Virus Taxonomy Profile: Mypoviridae 2023.

Mypoviridae is a family of negative-sense RNA viruses with genomes of about 16.0 kb that have been found in myriapods. The mypovirid genome consists of three monocistronic RNA segments that encode a nucleoprotein (NP), a glycoprotein (GP), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Mypoviridae, which is available at: ictv.global/report/mypoviridae.

ICTV Virus Taxonomy Profile: Tulasviridae 2023.

Tulasviridae is a family of ambisense RNA viruses with genomes of about 12.2 kb that have been found in fungi. The tulasvirid genome is nonsegmented and contains three open reading frames (ORFs) that encode a nucleoprotein (NP), a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain, and a protein of unknown function (X). This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Tulasviridae, which is available at ictv.global/report/tulasviridae.

ICTV Virus Taxonomy Profile: Wupedeviridae 2023.

Wupedeviridae is a family of negative-sense RNA viruses with genomes of about 20.5 kb that have been found in myriapods. The wupedevirid genome consists of three monocistronic RNA segments with open reading frames (ORFs) that encode a nucleoprotein (NP), a glycoprotein (GP), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Wupedeviridae, which is available at ictv.global/report/wupedeviridae.

ICTV Virus Taxonomy Profile: Cruliviridae 2023.

Cruliviridae is a family of negative-sense RNA viruses with genomes of 10.8-11.5 kb that have been found in crustaceans. The crulivirid genome consists of three RNA segments with ORFs that encode a nucleoprotein (NP), a glycoprotein (GP), a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain, and in some family members, a zinc-finger (Z) protein of unknown function. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Cruliviridae, which is available at ictv.global/report/cruliviridae.

Prognostic significance of inflammation in patients with coronary artery disease at low residual inflammatory risk.

Patients with coronary artery disease (CAD) at low residual inflammatory risk are often overlooked in research and practice. This study examined the associations between fourteen inflammatory indicators and all-cause mortality in 5,339 CAD patients with baseline high-sensitivity C-reactive protein (hsCRP) <2 mg/L who received percutaneous coronary intervention and statin and aspirin therapy. The median follow-up time was 2.1 years. Neutrophil-derived systemic inflammatory response index (SIRI) yielded the strongest and most robust association with all-cause mortality among all indicators. Lower hsCRP remained to be associated with a lower risk of all-cause mortality. A newly developed comprehensive inflammation score (CIS) showed better predictive performance than other indicators, which was validated by an independent external cohort. In conclusion, neutrophil-derived indicators, particularly SIRI, strongly predicted all-cause mortality independent of hsCRP in CAD patients at low residual inflammatory risk. CIS may help identify individuals with inflammation burdens that cannot be explained by hsCRP alone.

Application of arterial infusion ports in hepatic arterial infusion chemotherapy and embolization for advanced hepatocellular carcinoma.

OBJECTIVES: To investigate the safety and feasibility of subcutaneous implantable infusion ports in repeated hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) in China. METHODS: A total of 237 patients who were clinically diagnosed with advanced HCC (CNLC III a/III b) in our hospitals from December 2020 to October 2022 were retrospectively analyzed. The approaches of HAIC were divided into 2 groups: arterial infusion port implantation (group A) and one-time femoral artery catheterization (group B) based on the physicians' suggestion and the patients' intention. The comfort level (evaluated with the General Comfort Questionnaire), complications and average inpatient expenditure were compared between the 2 groups. RESULTS: 116 patients were finally enrolled in the study (group A: 69; group B: 47) and completed HAIC (FOLFOX-4 regimen) according to the dosing schedules (mean: 6±1 cycles). The comfort level of group A was greater than that of group B (p<0.05). The average inpatient expenditure of group A was lower than that of group B (5.4±2.4 vs 10.4±1.9 thousand yuan RMB/cycle, p<0.05). No patients developed port incision infection, hematoma or catheter-related thrombosis in group A, whereas four patients had groin hematomas, one had femoral artery dissection and four had deep vein thrombosis in group B. CONCLUSION: Hepatic arterial infusion chemotherapy via arterial infusion ports for advanced HCC decreased complications and medical expenditures and improved patient comfort levels compared with indwelling catheters.

Host traits shape virome composition and virus transmission in wild small mammals.

Bats, rodents, and shrews are the most important animal sources of human infectious diseases. However, the evolution and transmission of viruses among them remain largely unexplored. Through the meta-transcriptomic sequencing of internal organ and fecal samples from 2,443 wild bats, rodents, and shrews sampled from four Chinese habitats, we identified 669 viruses, including 534 novel viruses, thereby greatly expanding the mammalian virome. Our analysis revealed high levels of phylogenetic diversity, identified cross-species virus transmission events, elucidated virus origins, and identified cases of invertebrate viruses in mammalian hosts. Host order and sample size were the most important factors impacting virome composition and patterns of virus spillover. Shrews harbored a high richness of viruses, including many invertebrate-associated viruses with multi-organ distributions, whereas rodents carried viruses with a greater capacity for host jumping. These data highlight the remarkable diversity of mammalian viruses in local habitats and their ability to emerge in new hosts.

Association Between Free Fatty Acids and Cardiometabolic Risk in Coronary Artery Disease: Results From the PROMISE Study.

CONTEXT: The association between free fatty acids (FFAs) and unfavorable clinical outcomes has been reported in the general population. However, evidence in the secondary prevention population is relatively scarce. OBJECTIVE: We aimed to examine the relationship between FFA and cardiovascular risk in patients with coronary artery disease (CAD). METHODS: This study was based on a multicenter cohort of patients with CAD enrolled from January 2015 to May 2019. The primary outcome was all-cause death. Secondary outcomes included cardiac death and major adverse cardiovascular events (MACE), a composite of death, myocardial infarction, and unplanned revascularization. RESULTS: During a follow-up of 2 years, there were 468 (3.0%) all-cause deaths, 335 (2.1%) cardiac deaths, and 1279 (8.1%) MACE. Elevated FFA levels were independently associated with increased risks of all-cause death, cardiac death, and MACE (all P < .05). Moreover, When FFA were combined with an original model derived from the Cox regression, there were significant improvements in discrimination and reclassification for prediction of all-cause death (net reclassification improvement [NRI] 0.245, P < .001; integrated discrimination improvement [IDI] 0.004, P = .004), cardiac death (NRI 0.269, P < .001; IDI 0.003, P = .006), and MACE (NRI 0.268, P < .001; IDI 0.004, P < .001). Notably, when stratified by age, we found that the association between FFA with MACE risk appeared to be stronger in patients aged ≥60 years compared with those aged <60 years. CONCLUSION: In patients with CAD, FFAs are associated with all-cause death, cardiac death, and MACE. Combined evaluation of FFAs with other traditional risk factors could help identify high-risk individuals who may require closer monitoring and aggressive treatment.

Association of cigarette smoking with risk of colorectal cancer subtypes classified by gut microbiota.

INTRODUCTION: Both cigarette smoking and gut microbiota play important roles in colorectal carcinogenesis. We explored whether the association between smoking and colorectal cancer (CRC) risk varies by gut microbial enterotypes and how smoking-related enterotypes promote colorectal carcinogenesis. METHODS: A case-control study was conducted. Fecal microbiota was determined by 16S rDNA sequencing. The cases with CRC or adenoma were subclassified by gut microbiota enterotypes. Multivariate analyses were used to test associations between smoking and the odds of colorectal neoplasm subtypes. Mann-Whitney U tests were used to find differential genera, genes, and pathways between the subtypes. RESULTS: Included in the study were 130 CRC patients (type I: n=77; type II: n=53), 120 adenoma patients (type I: n=66; type II: n=54), and 130 healthy participants. Smoking increased the odds for type II tumors significantly (all p for trend <0.05) but not for type I tumors. The associations of smoking with increased odds of colorectal neoplasm significantly differed by gut microbiota enterotypes (p<0.05 for heterogeneity). An increase in carcinogenic bacteria (genus Escherichia shigella) and a decrease in probiotics (family Lachnospiraceae and Ruminococcaceae) in type II tumors may drive disease progression by upregulating oncogenic signaling pathways and inflammatory/oxidative stress response pathways, as well as protein phospholipase D1/2, cytochrome C, and prostaglandin-endoperoxide synthase 2 expression. CONCLUSIONS: Smoking was associated with a higher odds of type II colorectal neoplasms but not type I tumors, supporting a potential role for the gut microbiota in mediating the association between smoking and colorectal neoplasms.

Inverse Association of Lipoprotein(a) on Long-Term Bleeding Risk in Patients with Coronary Heart Disease: Insight from a Multicenter Cohort in Asia.

BACKGROUND: Lipoprotein(a), or Lp(a), has been recognized as a strong risk factor for atherosclerotic cardiovascular disease. However, the relationship between Lp(a) and bleeding remains indistinct, especially in the secondary prevention population of coronary artery disease (CAD). This investigation aimed to evaluate the association of Lp(a) with long-term bleeding among patients with CAD. METHODS: Based on a prospective multicenter cohort of patients with CAD consecutively enrolled from January 2015 to May 2019 in China, the current analysis included 16,150 participants. Thus, according to Lp(a) quintiles, all subjects were divided into five groups. The primary endpoint was bleeding at 2-year follow-up, and the secondary endpoint was major bleeding at 2-year follow-up. RESULTS: A total of 2,747 (17.0%) bleeding and 525 (3.3%) major bleeding were recorded during a median follow-up of 2.0 years. Kaplan-Meier survival analysis showed the highest bleeding incidence in Lp(a) quintile 1, compared with patients in Lp(a) quintiles 2 to 5 (p < 0.001), while the incidence of major bleeding seemed similar between the two groups. Moreover, restricted cubic spline analysis suggested that there was an L-shaped association between Lp(a) and 2-year bleeding after adjustment for potential confounding factors, whereas there was no significant association between Lp(a) and 2-year major bleeding. CONCLUSION: There was an inverse and L-shaped association of Lp(a) with bleeding at 2-year follow-up in patients with CAD. More attention and effort should be made to increase the clinician awareness of Lp(a)'s role, as a novel marker for bleeding risk to better guide shared-decision making in clinical practice.