Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review).

Hepatocellular carcinoma (HCC), one of the leading causes of cancer­related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi­tyrosine kinase inhibitors approved for first­line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non­apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.

Prediction of the Effects of Pulsating Hydraulic Fracturing on the Porous Structure and Permeability of Coal Based on NMR and AE Spectra.

Pulsating hydraulic fracturing has been an environmentally friendly method to improve the permeability of rock formations to stimulate gas production and reduce hazard risks. It has the advantage of fracturing the reservoir with lower cracking pressure and less water volume, as the mechanical strength of rock materials has been reduced by the hydraulic pulse pressure. Many researchers have found significant changes in hard rocks after cyclic loading. However, the existing work still cannot clearly explain the mechanism of the rock damage by pulsating hydraulic fracturing within a short-time experiment. To solve the issue, an investigation of the effects of pulsating hydraulic fracturing on CBM production has been carried out in lab and field applications. Results indicate that the long-term hydraulic pulse pressure can cause a linear decline in cracking pressure directly measured in the lab. It plays an essential role in the permeability enhancement by generating more flow channels for CBM production. The low-field NMR quantitatively evaluates the increase in porosity, which reveals significant incremental ratios of over 20% in the porosity of macropores, mesopores, and micropores of coal caused by fatigue damage. It is first proven that hydraulic pulse pressure has a significant influence on the porosity components of macropores, mesopores, and micropores. To validate the effectiveness of the technique on the field scale, a field application of pulsating hydraulic fracturing has been carried out in a coal mine. It shows that gas production has been largely enhanced with a long and stable production stage and higher gas flux after the applied pulsating load. The gas concentration and gas flux of the fractured boreholes are about 2 times that of the nonfractured boreholes. This work provides an investigation of the effects of pulsating hydraulic fracturing on CBM production, which gives a better understanding of the mechanism for the engineers in the field.

Red emissive fluorescent carbon dots based on ternary carbon source for imaging α-synuclein fibrils.

The misfolding and aggregation of α-synuclein monomers usually cause the occurrence and development of Parkinson's disease (PD). It is important to develop effective methods for detection of α-synuclein aggregates. Carbon dots (CDs) could be the potential fluorescence probe for this purpose owing to their appreciated optical properties. However, undefined structure of CDs and complicated three-dimensional structure of protein severely hindered the design of fluorescence probe towards protein aggregates. Herein, a red emissive fluorescent amphiphilic CD, named as CL-9, was designed with a high sensitivity to α-synuclein fibrils by a one-step heating process, using the ternary carbon source, including Congo red, l-tryptophan and urea. The CL-9 exhibited turn-on red emissive fluorescence towards α-synuclein fibril, but remained no change towards its monomer. Compared with the original Congo red dye, CL-9 exhibited stronger turn-on red fluorescence towards α-synuclein fibrils with better anti-photobleaching resistance, biocompatibility and signal-to-noise ratio. The CL-9 was successful as a fluorescent probe to image α-synuclein fibrils in NL-5901 C. elegans. The present study provided a feasible approach using the multiple carbon sources to construct the CDs based fluorescence probe targeting amyloid proteins.

Mitochondrial genomes of four slug moths (Lepidoptera, Limacodidae): Genome description and phylogenetic implications.

The family Limacodidae belongs to the superfamily Zygaenoidea, which includes 1672 species commonly referred to as slug moths. Limacodidae larvae are major pests for many economically important plant species and can cause human dermatitis. At present, the structure of the mitochondrial genome (mitogenome), phylogenetic position, and adaptive evolution of slug moths are poorly understood. Herein, the mitogenomes of Parasa lepida, Phlossa conjuncta, Thosea sinensis, and Setora sinensis were sequenced and compared with other available mitogenome sequences to better characterize the mitogenomic diversity and evolution of this moth family. The mitogenomes of P. lepida, P. conjuncta, T. sinensis, and S. sinensis were confirmed to be circular in structure with lengths of 15,575 bp, 15,553 bp, 15,535 bp, and 15,529 bp, respectively. The Limacodidae mitogenomes exhibited similar nucleotide composition, codon usage, RNA structure, and control region patterns, indicating the conservation of the mitogenome in the family Limacodidae. A sliding window, Ka/Ks, and genetic distance analyses revealed that the atp8 and nad6 genes exhibited the highest levels of variability and the most rapid evolutionary rates among the 13 protein-coding genes (PCGs) encoded in these Limacodidae mitogenomes, suggesting that they may offer value as candidate DNA markers. The phylogenetic analysis recovered the overall relationship as Tortricoidea + (Sesiidae + (Zygaenoidea + (Cossoidea/+Choreutoidea + (others)))). Within Zygaenoidea, Limacodidae was recovered as monophyletic, and the phylogenetic relationships were recovered as (Phaudidae + Zyganidae) + Limacodidae in all six phylogenetic trees. The analysis indicated that P. lepida, P. conjuncta, T. sinensis, and S. sinensis are members of the Limacodidae.

Deformation and Failure Characteristics of Strong-Weak Coupling Structures with Different Height Ratios Under Cyclic Loading and Unloading.

Strong-weak coupling outburst prevention technology can reduce the hazard of coal and gas outburst in mines based on hydraulic punching and grouting reinforcement. In this study, the mechanism of outburst hazards in the strong-weak coupling structure under mining disturbance was explored, and then cyclic loading and unloading experiments were performed on samples with different strong-weak height ratios (HRs) using the noncontact full-field strain testing (DIC) system and the acoustic emission (AE) system. The results show that the failure strength of the sample gradually increases with the increase in HR. The residual strain of the strong and weak structures undergoes three stages, i.e., the decelerated deformation, the constant-velocity deformation, and the accelerated deformation. Deformation mainly occurs in the weak structure and starts at the strong-weak interface. The AE signals present strong regional distribution characteristics and the Felicity effect, and the damage is concentrated near 70% of each stage in the cyclic loading process. As the HR rises, the weak structure transitions from brittle damage to ductile damage and from shear damage to tensile damage. In addition, due to the difference in Poisson effects of strong and weak structures, the strong structure transitions from a unidirectional stress state to a triaxial tensile-compressive stress state. When the HR increases to 85:15, the strong structure undergoes tensile damage.

Core-Shell CoS2@MoS2 with Hollow Heterostructure as an Efficient Electrocatalyst for Boosting Oxygen Evolution Reaction.

It is imperative to develop an efficient catalyst to reduce the energy barrier of electrochemical water decomposition. In this study, a well-designed electrocatalyst featuring a core-shell structure was synthesized with cobalt sulfides as the core and molybdenum disulfide nanosheets as the shell. The core-shell structure can prevent the agglomeration of MoS2, expose more active sites, and facilitate electrolyte ion diffusion. A CoS2/MoS2 heterostructure is formed between CoS2 and MoS2 through the chemical interaction, and the surface chemistry is adjusted. Due to the morphological merits and the formation of the CoS2/MoS2 heterostructure, CoS2@MoS2 exhibits excellent electrocatalytic performance during the oxygen evolution reaction (OER) process in an alkaline electrolyte. To reach the current density of 10 mA cm-2, only 254 mV of overpotential is required for CoS2@MoS2, which is smaller than that of pristine CoS2 and MoS2. Meanwhile, the small Tafel slope (86.9 mV dec-1) and low charge transfer resistance (47 Ω) imply the fast dynamic mechanism of CoS2@MoS2. As further confirmed by cyclic voltammetry curves for 1000 cycles and the CA test for 10 h, CoS2@MoS2 shows exceptional catalytic stability. This work gives a guideline for constructing the core-shell heterostructure as an efficient catalyst for oxygen evolution reaction.

Hierarchically Structured Graphene Aerogel Supported Nickel-Cobalt Oxide Nanowires as an Efficient Electrocatalyst for Oxygen Evolution Reaction.

The rational design of a heterostructure electrocatalyst is an attractive strategy to produce hydrogen energy by electrochemical water splitting. Herein, we have constructed hierarchically structured architectures by immobilizing nickel-cobalt oxide nanowires on/beneath the surface of reduced graphene aerogels (NiCoO2/rGAs) through solvent-thermal and activation treatments. The morphological structure of NiCoO2/rGAs was characterized by microscopic analysis, and the porous structure not only accelerates the electrolyte ion diffusion but also prevents the agglomeration of NiCoO2 nanowires, which is favorable to expose the large surface area and active sites. As further confirmed by the spectroscopic analysis, the tuned surface chemical state can boost the catalytic active sites to show the improved oxygen evolution reaction performance in alkaline electrolytes. Due to the synergistic effect of morphology and composition effect, NiCoO2/rGAs show the overpotential of 258 mV at the current density of 10 mA cm-2. Meanwhile, the small values of the Tafel slope and charge transfer resistance imply that NiCoO2/rGAs own fast kinetic behavior during the OER test. The overlap of CV curves at the initial and 1001st cycles and almost no change in current density after the chronoamperometric (CA) test for 10 h confirm that NiCoO2/rGAs own exceptional catalytic stability in a 1 M KOH electrolyte. This work provides a promising way to fabricate the hierarchically structured nanomaterials as efficient electrocatalysts for hydrogen production.

Ovary metabolome and cecal microbiota changes in aged laying hens supplemented with vitamin E.

This study was aimed to evaluate the effect of vitamin E (VE) on laying performance, VE deposition, antioxidant capacity, immunity, follicle development, estrogen secretion, ovary metabolome, and cecal microbiota of laying hens. One hundred and twenty XinYang Black-Feathered laying hens (70 wk old) were randomly assigned to 2 groups (6 replicates of 20 birds), and fed a basal diet (containing 20 mg/kg VE, control (CON) group) and a basal diet supplemented with 20 mg/kg VE (VE group). The experiment lasted for 10 wk. Results showed that VE supplementation increased laying performance, antioxidant capacity, and immunity, as evidenced by increased (P < 0.05) performance (laying rate), antioxidant (glutathione peroxidase, total superoxide dismutase, total antioxidant capacity, and catalase) and immune (immunoglobulins) parameters, and decreased (P < 0.05) feed/egg ratio and malondialdehyde. Meanwhile, VE group had higher (P < 0.05) pregrade follicles, ovary index and serum estrogen levels than CON group. 16S rRNA sequencing showed that VE supplementation altered the cecal microbiota composition by increasing Bacteroides, Rikenellaceae_RC9_gut_group, Prevotellaceae_UCG-001 and Megamonas abundances and reducing Christensenellaceae_R-7_group abundance (at genus level), which are mainly associated with the production of short-chain fatty acids. Metabolomic profiling of the ovary revealed that the major metabolites altered by VE supplementation were mainly related to follicle development, estrogen secretion, anti-inflammatory, antioxidant, phototransduction, bile acid synthesis, and nutrient transport. Furthermore, changes in cecal microbiota (at genus level) and ovary metabolites were highly correlated with laying performance, antioxidant, and immune parameters. In summary, VE contributed to the laying performance of aged laying hens by enhancing antioxidant, immune, and ovarian functions, promoting follicle development and estrogen secretion, and regulating gut microbiota and ovary metabolites. These findings will provide a new perspective on the mechanisms of egg production in aged poultry ovaries.

Effect of an Airbag-selective Portal Vein Blood Arrester on the Liver after Hepatectomy: A New Technique for Selective Clamping of the Portal Vein.

OBJECTIVE: A novel technique was explored using an airbag-selective portal vein blood arrester that circumvents the need for an intraoperative assessment of anatomical variations in patients with complex intrahepatic space-occupying lesions. METHODS: Rabbits undergoing hepatectomy were randomly assigned to 4 groups: intermittent portal triad clamping (PTC), intermittent portal vein clamping (PVC), intermittent portal vein blocker with an airbag-selective portal vein blood arrester (APC), and without portal blood occlusion (control). Hepatic ischemia and reperfusion injury were assessed by measuring the 7-day survival rate, blood loss, liver function, hepatic pathology, hepatic inflammatory cytokine infiltration, hepatic malondialdehyde levels, and proliferating cell nuclear antigen levels. RESULTS: Liver damage was substantially reduced in the APC and PVC groups. The APC animals exhibited transaminase levels similar to or less oxidative stress damage and inflammatory hepatocellular injury compared to those exhibited by the PVC animals. Bleeding was significantly higher in the control group than in the other groups. The APC group had less bleeding than the PVC group because of the avoidance of portal vein skeletonization during hepatectomy. Thus, more operative time was saved in the APC group than in the PVC group. Moreover, the total 7-day survival rate in the APC group was higher than that in the PTC group. CONCLUSION: Airbag-selective portal vein blood arresters may help protect against hepatic ischemia and reperfusion injury in rabbits undergoing partial hepatectomy. This technique may also help prevent liver damage in patients requiring hepatectomy.

Interfacial Design of Ti3C2Tx MXene/Graphene Heterostructures Boosted Ru Nanoclusters with High Activity Toward Hydrogen Evolution Reaction.

The development of a cost-competitive and efficient electrocatalyst is both attractive and challenging for hydrogen production by hydrogen evolution reaction (HER). Herein, a facile glycol reduction method to construct Ru nanoclusters coupled with hierarchical exfoliated-MXene/reduced graphene oxide architectures (Ru-E-MXene/rGA) is reported. The hierarchical structure, formed by the self-assembly of graphene oxides, can effectively prohibit the self-stacking of MXene nanosheets. Meanwhile, the formation of the MXene/rGA interface can strongly trap the Ru3+ ions, resulting in the uniform distribution of Ru nanoclusters within Ru-E-MXene/rGA. The boosted catalytic activity and underlying catalytic mechanism during the HER process are proved by density functional theory. Ru-E-MXene/rGA exhibits overpotentials of 42 and 62 mV at 10 mA cm-2 in alkaline and acidic electrolytes, respectively. The small Tafel slope and charge transfer resistance (Rct) values elucidate its fast dynamic behavior. The cyclic voltammetry (CV) curves and chronoamperometry test confirm the high stability of Ru-E-MXene/rGA. These results demonstrate that coupling Ru nanoclusters with the MXene/rGA heterostructure represents an efficient strategy for constructing MXene-based catalysts with enhanced HER activity.

Apparent differences in prostate zones: susceptibility to prostate cancer, benign prostatic hyperplasia and prostatitis.

Men are inevitably plagued by prostate disease throughout their lives. However, the understanding of the pathogenesis of prostate diseases is still limited. In the 1960s, McNeal proposed the theory of prostate zones: the prostate was divided into three main zones: transition zone, central zone, and peripheral zone. Over the past 50 years, significant differences between different prostate zones have been gradually revealed. We summarized the most significant differences in different zones of the prostate. For the first time, we proposed the "apparent difference in prostate zones" concept. This new concept has been proposed to understand the different zones of the prostate better. It also provided new ideas for exploring the susceptibility of lesions in different prostate zones. Despite the reported differences between zones, the treatment of prostate-related diseases remains partition agnostic. Therefore, we also discussed the clinical significance of the "apparent difference in the prostate zone" and emphasized the necessity of prostate zones.

HIV coinfection exacerbates HBV-induced liver fibrogenesis through a HIF-1α- and TGF-ß1-dependent pathway.

BACKGROUND & AIMS: Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-ß1 signaling. METHODS: The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice. RESULTS: We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-ß1 (TGF-ß1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-ß1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-ß1-induced fibrogenesis. CONCLUSIONS: Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-ß1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection. IMPACT AND IMPLICATIONS: HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-ß1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection.

Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a.

CD4+ T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.

Application of Amorphous-Crystalline Coupling Materials in Electrocatalysis.

Interface engineering has proven to be a highly efficient strategy for modulating the physicochemical properties of electrocatalysts and further enhancing their electrochemical performance in related energy applications. In this context, the newly proposed crystalline-amorphous (c-a) heterostructures with unusual atomic arrangements at interfaces show strong competitiveness. Nonetheless, few efforts have been made to reveal and summarize the structure-activity relationship at the two-phase interface and the corresponding electrocatalytic mechanism. This concept is devoted to comprehensively discussing the fundamental characteristics of crystalline-amorphous electrocatalysts and their application in the field of energy conversion with typical examples. In addition, the development prospects and opportunities of crystalline-amorphous heterostructure are summarized to provide potential development directions for other types of clean energy development.

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.

Immune targeting of HIV-1 reservoir cells: a path to elimination strategies and cure.

Successful approaches for eradication or cure of HIV-1 infection are likely to include immunological mechanisms, but remarkably little is known about how human immune responses can recognize and interact with the few HIV-1-infected cells that harbour genome-intact viral DNA, persist long term despite antiretroviral therapy and represent the main barrier to a cure. For a long time regarded as being completely shielded from host immune responses due to viral latency, these cells do, on closer examination with single-cell analytic techniques, display discrete footprints of immune selection, implying that human immune responses may be able to effectively engage and target at least some of these cells. The failure to eliminate rebound-competent virally infected cells in the majority of persons likely reflects the evolution of a highly selected pool of reservoir cells that are effectively camouflaged from immune recognition or rely on sophisticated approaches for resisting immune-mediated killing. Understanding the fine-tuned interplay between host immune responses and viral reservoir cells will help to design improved interventions that exploit the immunological vulnerabilities of HIV-1 reservoir cells.

Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway.

BACKGROUND: Development of end-stage renal disease is predominantly attributed to diabetic nephropathy (DN). Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue. Nevertheless, the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain. AIM: To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism. METHODS: Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk. Subsequently, blood and urine indexes were assessed, along with examination of renal tissue pathology. Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin, periodic acid-Schiff, Masson's trichrome, and Sirius-red. Additionally, high-glucose culturing was conducted on the RAW 264.7 cell line, treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h. In both in vivo and in vitro settings, quantification of inflammation factor levels was conducted using western blotting, real-time qPCR and ELISA. RESULTS: In db/db mice, administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis. Notably, we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin, along with a decrease in expressions of inflammatory cytokine-related factors. Furthermore, myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha, interleukin-6, and interluekin-1ß induced by high glucose in RAW 264.7 cells. Additionally, myricetin modulated the M1-type polarization of the RAW 264.7 cells. Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin. The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002. CONCLUSION: This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Characteristics of aerosol aminiums over a coastal city in North China: Insights from the divergent impacts of marine and terrestrial influences.

Aminium ions, as crucial alkaline components within fine atmospheric particles, have a notable influence on new particle formation and haze occurrence. Their concentrations within coastal atmosphere depict considerable variation due to the interplay of distinctive marine and terrestrial sources, further complicated by dynamic meteorological conditions. This study conducted a comprehensive examination of aminiums ions concentrations, with a particular focus on methylaminium (MMAH+), dimethylaminium (DMAH+), trimethylaminium (TMAH+), and triethylaminium (TEAH+) within PM2.5, over varying seasons (summer, autumn, and winter of 2019 and summer of 2021), at an urban site in the coastal megacity of Qingdao, Northern China. The investigations revealed that the total concentration of particulate aminium ions (∑Aminium) was 21.6 ± 23.6 ng/m3, exhibiting higher values in the autumn and winter compared to the two summer periods. Considering diurnal variations during autumn and winter, concentrations of particulate aminium ions (excluding TEAH+) exhibited a slight increase during the day compared to night, with a notable peak during the morning hours. However, it was not the case for TEAH+, which was argued to be readily oxidized by ambient oxidants in the afternoon. Additionally, the ∑Aminium within the summer demonstrated markedly elevated levels during the day compared to night, potentially attributed to daytime sea fog associated with sea-land breeze interactions. Positive matrix factorization results indicate terrestrial anthropogenic emissions, including vehicle emission mixed with road dust and primary pollution, as the primary sources of MMAH+ and DMAH+. Conversely, TMAH+ was predominantly emitted from agricultural and marine sources. With the dominance of sea breeze in summer, TMAH+ was identified as a primary marine emission correlated with sea salt, while MMAH+, DMAH+, and TEAH+ were postulated to undergo secondary formation. Furthermore, a notable inverse correlation was observed between TMAH+ and methanesulfonate in PM2.5, consistent with dynamic emissions of sulfur-content and nitrogen-content gases reported in the literature.

SARS-CoV-2 infection elucidates unique features of pregnancy-specific immunity.

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 + T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

ML-FGAT: Identification of multi-label protein subcellular localization by interpretable graph attention networks and feature-generative adversarial networks.

The prediction of multi-label protein subcellular localization (SCL) is a pivotal area in bioinformatics research. Recent advancements in protein structure research have facilitated the application of graph neural networks. This paper introduces a novel approach termed ML-FGAT. The approach begins by extracting node information of proteins from sequence data, physical-chemical properties, evolutionary insights, and structural details. Subsequently, various evolutionary techniques are integrated to consolidate multi-view information. A linear discriminant analysis framework, grounded on entropy weight, is then employed to reduce the dimensionality of the merged features. To enhance the robustness of the model, the training dataset is augmented using feature-generative adversarial networks. For the primary prediction step, graph attention networks are employed to determine multi-label protein SCL, leveraging both node and neighboring information. The interpretability is enhanced by analyzing the attention weight parameters. The training is based on the Gram-positive bacteria dataset, while validation employs newly constructed datasets: human, virus, Gram-negative bacteria, plant, and SARS-CoV-2. Following a leave-one-out cross-validation procedure, ML-FGAT demonstrates noteworthy superiority in this domain.