A strategy of vascular-targeted therapy for liver fibrosis.

BACKGROUND AND AIMS: No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling. APPROACH AND RESULTS: The CCl4 -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects. CONCLUSIONS: Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.

RNA methyltransferase BmMettl3 and BmMettl14 in silkworm (Bombyx mori) and the regulation of silkworm embryonic development.

N6-methyladenosine (m6A) is a ubiquitous reversible epigenetic RNA modification that plays an important role in regulating many biological processes, especially embryonic development. However, regulation of m6A methylation during silkworm embryonic development and diapause remains to be investigated. In this study, we analyzed the phylogeny of subunits of methyltransferases BmMettl3 and BmMettl14, and detected the expression patterns of BmMettl3 and BmMettl14 in different tissues and at different developmental stages in silkworm. To investigate the function of m6A on the development of silkworm embryo, we analyzed the m6A/A ratio in diapause and diapause termination eggs. The results showed that BmMettl3 and BmMettl14 were highly expressed in gonads and eggs. Moreover, the expression of BmMettl3 and BmMettl14 and the m6A/A ratio were significantly increased in diapause termination eggs compared with diapause eggs in the early stage of silkworm embryonic development. Furthermore, in BmN cell cycle experiments, the percentage of cells in the S phase increased when lacking BmMettl3 or BmMettl14. This work contributes to understanding the role of m6A methylation during insect embryogenesis and gametogenesis. It also provides a research orientation to further analyze the role of m6A methylation in diapause initiation and termination during insect embryonic development.

Cesium Lead Bromide Nanocrystals: Synthesis, Modification, and Application to O2 Sensing.

The fluorescence intensity of inorganic CsPbBr3 (CPB) perovskite nanocrystals (NCs) decreases in the presence of O2. In this study, we synthesized CPB NCs with various shapes and sizes for use as optical gas sensing materials. We fabricated O2 gas sensors from the various CPB NCs on several porous and nonporous substrates and examined the effects of the NC shapes and aggregate sizes and the substrate pore size on the device response. Our sensor fabricated from CPB nanocrystals on a porous substrate exhibited the highest response; the porous substrate allowed the rapid diffusion of O2 such that the NC surface was exposed effectively to the gas. Thus, the interfacial interaction between NC surfaces and substrates is a critical factor for consideration when preparing gas sensors with a high response.

Assessment of anti-PD-(L)1 for patients with coexisting malignant tumor and tuberculosis classified by active, latent, and obsolete stage.

BACKGROUND: It is not a rare clinical scenario to have patients presenting with coexisting malignant tumor and tuberculosis. Whether it is feasible to conduct programmed death-(ligand) 1 [PD-(L)1] inhibitors to these patients, especially those with active tuberculosis treated with concurrent anti-tuberculosis, is still unknown. METHODS: This study enrolled patients with coexisting malignancy and tuberculosis and treated with anti-PD-(L)1 from Jan 2018 to July 2021 in 2 institutions. The progression-free survival (PFS), objective response rate (ORR), and safety of anti-PD-(L)1 therapy, as well as response to anti-tuberculosis treatment, were evaluated. RESULTS: A total of 98 patients were screened from this cohort study, with 45 (45.9%), 21 (21.4%), and 32 (32.7%) patients diagnosed with active, latent, and obsolete tuberculosis, respectively. The overall ORR was 36.0% for anti-PD-(L)1 therapy, with 34.2%, 35.5%, and 41.2% for each subgroup. Median PFS was 8.0 vs 6.0 vs 6.0 months (P=0.685) for each subgroup at the time of this analysis. For patients with active tuberculosis treated with concurrent anti-tuberculosis, median duration of anti-tuberculosis therapy was 10.0 (95% CI, 8.01-11.99) months. There were 83.3% (20/24) and 93.3% (42/45) patients showing sputum conversion and radiographic response, respectively, after anti-tuberculosis therapy, and two patients experienced tuberculosis relapse. Notably, none of the patients in latent and only one patient in obsolete subgroups showed tuberculosis induction or relapse after anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 33 patients (73.3%) when treated with concurrent anti-PD-(L)1 and anti-tuberculosis. Grade 3 or higher TRAEs were hematotoxicity (n = 5, 11.1%), and one patient suffered grade 3 pneumonitis leading to the discontinuation of immunotherapy. CONCLUSIONS: This study demonstrated that patients with coexisting malignant tumor and tuberculosis benefited equally from anti-PD-(L)1 therapy, and anti-tuberculosis response was unimpaired for those with active tuberculosis. Notably, the combination of anti-PD-(L)1 and anti-tuberculosis therapy was well-tolerated without significant unexpected toxic effects.

Fe3O4/PVDF catalytic membrane treatment organic wastewater with simultaneously improved permeability, catalytic property and anti-fouling.

Fe3O4/Polyvinylidene fluoride (PVDF) three-channel hollow fiber catalytic membrane was successfully fabricated via non-solvent induced phase inversion and used for organic wastewater degradation in this work. The effects of Fe3O4 nanoparticles addition on the surface and cross-section morphologies, hydrophilicity and thermal properties of the catalytic membrane were characterized by the field emission scanning electron microscopy (SEM), water contact angle and thermogravimetric analysis (TGA), respectively. The obtained catalytic membrane exhibited good hydrophilicity, a high pure water flux of 175.8 L m-2 h-1 and a high removal of methylene blue (up to 97.6%) with Fenton catalytic reaction. Meanwhile, the catalytic membrane shows excellent anti-fouling property due to the presence of Fenton reaction. Our results show that Fe3O4/PVDF three-channel hollow fiber catalytic membrane was a promising alternative for the degradation of organic contaminants.

Dynamic quantitative proteomics characterization of TNF-α-induced necroptosis.

Emerging evidence suggested that necroptosis has essential functions in many human inflammatory diseases, but the molecular mechanisms of necroptosis remain unclear. Here, we employed SILAC quantitatively dynamic proteomics to compare the protein changes during TNF-α-induced necroptosis at different time points in murine fibrosarcoma L929 cells with caspase-8 deficiency, and then performed the systematical analysis on the signaling networks involved in the progress using bioinformatics methods. Our results showed that a total of 329, 421 and 378 differentially expressed proteins were detected at three stages of necroptosis, respectively. Gene ontology and ingenuity pathway analysis (IPA) revealed that the proteins regulated at early stages of necroptosis (2, 6 h) were mainly involved in mitochondria dysfunction, oxidative phosphorylation and Nrf-2 signaling, while the expression levels of the proteins related to ubiquitin, Nrf-2, and NF-κB pathways were found to have changes at last stages of necroptosis (6, 18 h). Taken together, we demonstrated for the first time that dysfunction of mitochondria and ubiquitin-proteasome signaling contributed to the initiation and execution of necroptosis. These findings may provide clues for the identification of important regulators in necroptosis and the development of novel therapeutic strategies for the related diseases.

Resveratrol Treatment Inhibits Proliferation of and Induces Apoptosis in Human Colon Cancer Cells.

BACKGROUND: Resveratrol, a natural isolate from plant sources, has a long and important history in traditional Chinese medicine. In the present study we investigated the effect of resveratrol on human colon cancer cell lines. MATERIAL/METHODS: We used the Cell Counting kit-8 (CCK-8) for determination of colon cancer cell viability. Apoptosis induction was analyzed using the DeadEnd™ Colorimetric TUNEL System (Promega, Madison, WI, USA). The siRNA Transfection Reagent kit (Santa Cruz Biotechnology, Inc.) was used for the administration of COX-2 silencer RNA (siRNA) into the colon cancer cells. Primer Express® software for Real-Time PCR ver. 3.0 (Applied Biosystems, Foster City, CA, USA) was used to prepare the primers for RT-PCR. RESULTS: The results revealed that exposure of colon cancer cells to resveratrol inhibited cell viability. Resveratrol exhibited a significant inhibitory effect on cell viability at 30 µM concentration after 48 h of exposure. We observed that 30-µM doses of resveratrol for 72 h led to 18, 29, and 34% reduction in the viability of HCA-17, SW480, and HT29 cells, respectively. It also significantly induced apoptosis in both of the tested carcinoma cell lines. The population of apoptotic cells in HCA-17 and SW480 cell lines after 48 h of resveratrol treatment was 59.8±4 and 67.2±4%, respectively, compared to 2.3±1% in the control cells. The colon cancer cells exposed to resveratrol showed significantly lower cyclooxygenase-2 and prostaglandin receptor expression. Treatment of colon cancer cells with the inhibitor of cyclooxygenase-2, indomethacin, and administration of silencer RNA for cyclooxygenase-2 also produced similar results. CONCLUSIONS: These findings suggest that resveratrol treatment can be a promising strategy for the treatment of colon cancer.

Advancing Detectivity and Stability of Near-Infrared Organic Photodetectors via a Facile and Efficient Cathode Interlayer.

Near-infrared (NIR) organic photodetectors (OPDs) are pivotal in numerous technological applications due to their excellent responsivity within the NIR region. Polyethylenimine ethoxylated (PEIE) has conventionally been employed as an electron transport layer (hole-blocking layer) to suppress dark current (JD) and enhance charge transport. However, the limitations of PEIE in chemical stability, processing conditions, environmental impact, and absorption range have spurred the development of alternative materials. In this study, we introduced a novel solution: a hybrid of sol-gel zinc oxide (ZnO) and N,N'-bis(N,N-dimethylpropan-1-amine oxide)perylene-3,4,9,10-tetracarboxylic diimide (PDINO) as the electron transport layer for NIR-OPDs. Our fabricated OPD exhibited significantly improved responsivity, reduced internal traps, and enhanced charge transfer efficiency. The detectivity, spanning from 400 to 1100 nm, surpassed ∼5 × 1012 Jones, reaching ∼1.1 × 1012 Jones at 1000 nm, accompanied by an increased responsivity of 0.47 A/W. Also, the unpackaged OPD remarkedly demonstrated stable JD and external quantum efficiency (EQE) over 1000 h under dark storage conditions. This innovative approach not only addresses the drawbacks of conventional PEIE-based OPDs but also offers promising avenues for the development of high-performance OPDs in the future.

Effects of baculovirus infection on intestinal microflora of BmNPV resistant and susceptible strain silkworm.

Bombyx mori L. (Lepidoptera: Bombycidae) nucleopolyhedrovirus (BmNPV) is a serious pathogen causing huge economic losses to sericulture. There is growing evidence that the gut microbiota of silkworms plays a critical role in shaping host responses and interactions with viral infection. However, little is known about the differences in the composition and diversity of intestinal microflora, especially with respect to silkworm strain differences and BmNPV infection-induced changes. Here, we aim to explore the differences between BmNPV-resistant strain A35 and susceptible strain P50 silkworm and the impact of BmNPV infection on intestinal microflora in different strains. The 16S rDNA sequencing analysis revealed that the fecal microbial populations were distinct between A35 and P50 and were significantly changed post BmNPV infection in both strains. Further analysis showed that the BmNPV-resistant strain silkworm possessed higher bacterial diversity than the susceptible strain, and BmNPV infection reduced the diversity of intestinal flora assessed by feces in both silkworm strains. In response to BmNPV infection, the abundance of Muribaculaceae increased in P50 and decreased in A35, while the abundance of Enterobacteriaceae decreased in P50 and increased in A35. These results indicated that BmNPV infection had various effects on the abundance of fecal microflora in different silkworm strains. Our findings not only broadened the understanding of host-pathogen interactions but also provided theoretical help for the breeding of resistant strains and healthy rearing of silkworms based on symbiotic bacteria.

BmNPV p35 regulates apoptosis in Bombyx mori via a novel target of interaction with the BmVDAC2-BmRACK1 complex.

Voltage-dependent anion channel 2 (VDAC2) is an important channel protein that plays a crucial role in the host response to viral infection. The receptor for activated C kinase 1 (RACK1) is also a key host factor involved in viral replication. Our previous research revealed that Bombyx mori VDAC2 (BmVDAC2) and B. mori RACK1 (BmRACK1) may interact with Bombyx mori nucleopolyhedrovirus (BmNPV), though the specific molecular mechanism remains unclear. In this study, the interaction between BmVDAC2 and BmRACK1 in the mitochondria was determined by various methods. We found that BmNPV p35 interacts directly with BmVDAC2 rather than BmRACK1. BmNPV infection significantly reduced the expression of BmVDAC2, and activated the mitochondrial apoptosis pathway. Overexpression of BmVDAC2 in BmN cells inhibited BmNPV-induced cytochrome c (cyto c) release, decrease in mitochondrial membrane potential as well as apoptosis. Additionally, the inhibition of cyto c release by BmVDAC2 requires the involvement of BmRACK1 and protein kinase C. Interestingly, overexpression of p35 inhibited cyto c release during mitochondrial apoptosis in a RACK1 and VDAC2-dependent manner. Even the mutant p35, which loses Caspase inhibitory activity, could still bind to VDAC2 and inhibit cyto c release. In summary, our results indicated that BmNPV p35 interacts with the VDAC2-RACK1 complex to regulate apoptosis by inhibiting cyto c release. These findings confirm the interaction between BmVDAC2 and BmRACK1, the interaction between p35 and the VDAC2-RACK1 complex, and a novel target that BmNPV p35 regulates apoptosis in Bombyx mori via interaction with the BmVDAC2-BmRACK1 complex. The result provide an initial exploration of the function of this interaction in the BmNPV-induced mitochondrial apoptosis pathway.

Alistipes indistinctus-derived hippuric acid promotes intestinal urate excretion to alleviate hyperuricemia.

Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.

Enhanced interactions among gut mycobiomes with the deterioration of glycemic control.

BACKGROUND: The gut mycobiome is closely linked to health and disease; however, its role in the progression of type 2 diabetes mellitus (T2DM) remains obscure. Here, a multi-omics approach was employed to explore the role of intestinal fungi in the deterioration of glycemic control. METHODS: 350 participants without hypoglycemic therapies were invited for a standard oral glucose tolerance test to determine their status of glycemic control. The gut mycobiome was identified through internal transcribed spacer sequencing, host genetics were determined by genotyping array, and plasma metabolites were measured with untargeted liquid chromatography mass spectrometry. FINDINGS: The richness of fungi was higher, whereas its dissimilarity was markedly lower, in participants with T2DM. Moreover, the diversity and composition of fungi were closely associated with insulin sensitivity and pancreatic ß-cell functions. With the exacerbation of glycemic control, the co-occurrence network among fungus taxa became increasingly complex, and the complexity of the interaction network was inversely associated with insulin sensitivity. Mendelian randomization analysis further demonstrated that the Archaeorhizomycetes class, Fusarium genus, and Neoascochyta genus were causally linked to impaired glucose metabolism. Furthermore, integrative analysis with metabolomics showed that increased 4-hydroxy-2-oxoglutaric acid, ketoleucine, lysophosphatidylcholine (20:3/0:0), and N-lactoyl-phenylalanine, but decreased lysophosphatidylcholine (O-18:2), functioned as key molecules linking the adverse effect of Fusarium genus on insulin sensitivity. CONCLUSIONS: Our study uncovers a strong association between disturbance in gut fungi and the progression of T2DM and highlights the potential of targeting the gut mycobiome for the management of T2DM. FUNDINGS: This study was supported by MOST and NSFC of China.

Which Criterion for Wound Drain Removal is Better Following Posterior 1-Level or 2-Level Lumbar Fusion With Instrumentation: Time Driven or Output Driven?

STUDY DESIGN: Case-control study. OBJECTIVES: To compare the outcomes of 2 different criteria (time driven and output driven) for wound drain removal and identify which one is better. METHODS: 743 patients who underwent posterior lumbar fusion with instrumentation involving 1 or 2 motion segments were enrolled in this study. Based on the different criteria for drain removal, the patients were divided into 2 groups. The drains were discontinued by time driven (postoperative day 2) in group I and output driven (<50 ml per day) in group II. Demographic characteristics, perioperative parameters and clinical outcomes were compared between the 2 groups. RESULTS: The demographic characteristics in both groups were comparable. The postoperative drain output, total blood loss, postoperative timing of ambulation, and postoperative duration of hospital stay in group I were lower than those in group II (P < 0.001). There was a higher proportion of patients requiring postoperative blood transfusion in group II, but not to a level of statistical significance (P = 0.054). There was no statistical significant difference in the incidence of surgical site infection (SSI) or symptomatic spinal epidural hematoma (SEH) between the 2 groups (P > 0.05). CONCLUSIONS: This study reveals that there are more benefits of wound drain removal by time driven than that by output driven for patients undergoing posterior 1-level or 2-level lumbar fusion with instrumentation, including less postoperative drain output, less total blood loss, earlier postoperative timing of ambulation and less postoperative duration of hospital stay without increasing the incidence of postoperative SSI or symptomatic SEH.

Rapid Synthesis of Diesel Precursors from Biomass-Derived Furanics Over Aluminum-Doped Mesoporous Silica Sphere Catalysts.

The condensation of biomass-derived molecules has been increasingly utilized as a sustainable strategy for the preparation of high-carbon precursors for high-density fuels, thus stimulating the demand for more efficient catalysts. This study concerns the synthesis of an aluminum-doped mesoporous silica sphere (Al-MSS) catalyst for the conversion of biobased furfural and 2-methylfuran into a C15 diesel precursor through a hydroxyalkylation/alkylation (HAA) reaction. A series of Al-MSS catalysts with different Si/Al ratios and calcination temperatures is prepared and extensively characterized, among which Al-MSS20-450 (Si/Al=20 : 1, calcined at 450 °C) exhibits unprecedentedly high reaction efficiency in catalyzing HAA reaction, offering a 94 % product yield at 140 °C in 20 min. The catalyst also gives high product yields across a broad temperature range from 80 °C to 140 °C with varied reaction time. Reaction kinetics reveal that both competitive substrate adsorption and temperature-dependent system viscosity affect the reaction efficiencies. Correlations between the catalytic activity and surface acid sites disclose that moderate and strong acid sites are primarily responsible for catalysis. Brønsted and Lewis acid sites are found by poisoning assays to work synergistically to catalyze the reaction, with the former being the primary sites. Finally, the catalyst displays good recycling performance, which further highlights its potential for industrial application.

Regulation of Bombyx mori ferritin heavy-chain homolog on ROS induces multiple effects on BmNPV replication.

Ferritin is an iron-binding protein composed of light-chain and heavy-chain homologs with a molecular weight of about 500 kDa. Free iron ions significantly affect reactive oxygen species (ROS) accumulation. Previous research has shown that Bombyx mori nucleopolyhedrosis virus (BmNPV) can increase ROS accumulation, activate autophagy, induce apoptosis, and upregulate the expression of B. mori ferritin heavy-chain homolog (BmFerHCH). However, the mechanism of mutual regulation between BmFerHCH and ROS-mediated autophagy and apoptosis induced by BmNPV remains unclear. In this study, we found that BmNPV induced the time-dependent accumulation of ROS in BmN cells, thereby promoting BmFerHCH expression. Interestingly, in BmFerHCH-overexpressed cells, BmNPV replication was inhibited in the first 18 h after infection but stimulated after 24 h. Further research on H2O2 or antioxidant-treated cells indicated that ROS-induced autophagy slightly increased in the early infection stage and increased BmNPV replication, while in the late stage, a large accumulation of ROS induced apoptosis and inhibited BmNPV replication. In this process, BmFerHCH inhibits BmNPV-induced ROS accumulation by chelating Fe2+. Taken together, BmFerHCH regulates ROS-mediated autophagy and apoptosis to achieve its various effects on BmNPV replication. These findings will help elucidate BmNPV-induced autophagy and apoptosis mediated by ROS and BmFerHCH, as well as the mutually fighting relationship between viruses and hosts.

Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.

c-Jun N-terminal kinase (JNK) phosphorylation is widely observed during virus infection, modulating various aspects of the virus-host interaction. In our previous research, we have proved that B. mori ferritin heavy-chain homolog (BmFerHCH), an inhibitor of reactive oxygen species (ROS), facilitates B. mori nucleopolyhedrovirus (BmNPV) proliferation. However, one question remains: Which downstream signaling pathways does BmFerHCH regulate by inhibiting ROS? Here, we first determined that silencing BmFerHCH inhibits BmNPV proliferation, and this inhibition depends on ROS. Then, we substantiated that BmNPV infection activates the JNK signaling pathway. Interestingly, the JNK phosphorylation during BmNPV infection is activated by ROS. Further, we found that the enhanced nuclear translocation of phospho-JNK induced by BmNPV infection was dramatically reduced by pretreatment with the antioxidant N-acetylcysteine (NAC), whereas there was more detectable phospho-JNK in the cytoplasm. Next, we investigated how changes in BmFerHCH expression affect JNK phosphorylation. BmFerHCH overexpression suppressed the phosphorylation of JNK and nuclear translocation of phospho-JNK during BmNPV infection, whereas BmFerHCH knockdown facilitated phosphorylation of JNK and nuclear translocation of phospho-JNK. By measuring the viral load, we found the inhibitory effect of BmFerHCH knockdown on BmNPV infection depends on phosphorylated JNK. In addition, the JNK signaling pathway was involved in BmNPV-triggered apoptosis. Hence, we hypothesize that ROS-mediated JNK phosphorylation is involved in the regulation of BmFerHCH on BmNPV proliferation. These results elucidate the molecular mechanisms and signaling pathways of BmFerHCH-mediated response to BmNPV infection.

Trehalose hydrolysis and transport-related genes promote Bombyx mori nucleopolyhedrovirus proliferation through the phosphoinositide 3-kinase-Akt signalling pathway in BmN cell.

The reprogramming of host physiology has been considered an essential process for baculovirus propagation. Trehalose, the main sugar in insect blood, plays a crucial role as an instant energy source. Although the trehalose level is modulated following infection with Bombyx mori nucleopolyhedrovirus (BmNPV), the mechanism of trehalose metabolism in response to BmNPV infection is still unclear. In this study, we demonstrated that the trehalose level tended to be lower in BmNPV-infected hemolymph and higher in the midgut. The omics analysis revealed that two trehalose transporters, BmTret1-1 and BmTret1-2, and trehalase, BmTRE1 and BmTRE2, were differentially expressed in the midgut after BmNPV infection. BmTret1-1 and BmTret1-2 had the ability to transport trehalose into the cell and promoted cellular absorption of trehalose. Furthermore, the functions of BmTret1-1, BmTret1-2, BmTRE1 and BmTRE2 in BmNPV infection were analyzed. These genes were upregulated in the midgut after BmNPV infection. Virus amplification analysis revealed that these genes could promote BmNPV proliferation in BmN cells. In addition, these genes could promote the expression of BmPI3K, BmPDK1 and BmAkt and inhibit the expression of BmFoxO in the phosphoinositide 3-kinase (PI3K)-Akt signalling pathway. Similarly, the increased trehalose level in BmN cells could promote the expression of BmPI3K, BmPDK1 and BmAkt and inhibit the expression of BmFoxO. Taken together, BmNPV infection promote the expression of trehalose hydrolysis and transport-related genes. These changes affect the PI3K-Akt signalling pathway to facilitate BmNPV proliferation. These findings help clarify the relationship between trehalose metabolism and BmNPV infection.

Short-term effect of meteorological factors and extreme weather events on daily outpatient visits for dry eye disease between 2013 and 2020: a time-series study in Urumqi, China.

Dry eye disease (DED) is a common disorder of tear secretion on the ocular surface caused by multiple factors with dry eyes as the main symptom, but until now studies focusing on relationship between local meteorological factors and ocular surface diseases in Urumqi are very limited. Besides, the effects of long-term and extreme meteorological factors on DED and the lag effect have not been fully evaluated. Electronic case information of 9970 DED outpatients from the Ophthalmology Department of the First Affiliated Hospital of Xinjiang Medical University (Urumqi, Xinjiang, China) between January 1, 2013, and December 31, 2020, was screened and analyzed. We used a time-series analysis design and a quasi-Poisson generalized linear regression model combined with a distributed lagged nonlinear model (DLNM) to fit the effects of exposure to different meteorological factors and extreme weather on DED outpatient visits. Subgroup analyses were further performed for gender, age, and season. The results showed that exposure to extremely low mean temperature (P1:RR = 1.18), atmospheric pressure (P1:RR = 1.11), and extremely high relative humidity (P99:RR = 1.35) were the risk factors, while extremely high atmospheric pressure (P90:RR = 0.883) and extremely low humidity (P10:RR = 0.856) appeared to have a positive effect on reduced risk of DED. Relative humidity exhibited a 1-day lag effect (RR = 1.06). Increased mean temperature positively affected female DED patients (RR = 0.761) with similar effects in the cold season (RR = 0.926). However, elevated relative humidity had a negative effect on female patients (RR = 1.14). We conducted the first large sample size time-series analysis study in this major city at the farthest distance from the ocean in the world and in northwest China, confirming the association of DED outpatient visits with the remaining three meteorological factors except wind speed in Urumqi, and a larger sample size multi-center epidemiological study with a longer duration is still needed.

Nanoscale coordination polymer Fe-DMY downregulating Poldip2-Nox4-H2O2 pathway and alleviating diabetic retinopathy.

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults. The high levels of glucose trigger multiple intracellular oxidative stress pathways, such as POLDIP2, resulting in excessive reactive oxygen species (ROS) production and increased expression of vascular cell adhesion molecule-1 (VCAM-1), hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF), causing microvascular dysfunction. Dihydromyricetin (DMY) is a natural flavonoid small molecule antioxidant. However, it exhibits poor solubility in physiological environments, has a short half-life in vivo, and has low oral bioavailability. In this study, we present, for the first time, the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles (Fe-DMY NCPs), formed by combining DMY with low-toxicity iron ions. In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose, scavenge excess ROS, and improve pathological features of DR, such as retinal vascular leakage and neovascularization. Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H2O2 signaling pathway and downregulate vital vascular function indicators such as VCAM-1, HIF-1α, and VEGF. These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent, with the potential as a novel multimeric drug for DR therapy.

Association of retinopathy with risk of all-cause and specific-cause mortality in the National Health and Nutrition Examination Survey, 2005 to 2008.

Objective: This study aimed to elucidate the relationship between retinopathy status or severity and the all-cause and specific-cause mortality risk based on the updated National Health and Nutrition Examination Survey (NHANES) database and 2019 Public Access Link mortality file. Methods: In this prospective cohort study, a total of 6,797 participants aged over 40 years based on NHANES 2005-2008 were analyzed. The severity of retinopathy was classified into 4 grades-no retinopathy, mild non-proliferative retinopathy (NPR), moderate to severe NPR, and proliferative retinopathy (PR). Multiple covariate-adjusted Cox proportional hazards regression models and Fine and Gray competing risk regression models were used to assess the all-cause and cause-specific mortality risks, respectively. The propensity score matching (PSM) approach was also applied additionally to adequately balance between-group covariates to validate our findings. Results: A final total of 4,808 participants representing 18,282,772 United States (US) non-hospitalized participants were included for analysis, 50.27% were male (n = 2,417), 55.32% were non-hispanic white (n = 2,660), and mean [SE] age, 56.10 [0.40] years. After a median follow-up of 12.24 years (interquartile range, 11.16-13.49 years), 1,164 participants died of all-cause mortality, of which 941 (80.84%) died without retinopathy and 223 (19.16%) died with retinopathy at baseline. The presence of retinopathy was associated with increased all-cause mortality, cardiovascular disease (CVD), and diabetes mellitus (DM)-specific mortality, and the results remain consistent after PSM. Severity analysis showed that only mild NPR was associated with an increased all-cause mortality risk (hazard ratio (HR) = 2.01; 95% confidence interval (CI), 1.00-4.03), while increased CVD and DM-specific mortality risk were associated with all grades of retinopathy and were exponentially greater with increasing retinopathy severity, and the trend test was also significant (P for trend 0.004 and 0.04, respectively). Discussion: Our findings suggest that the diagnosis of retinopathy is an independent risk factor for all-cause mortality in people over 40 years old. Retinopathy grading is significantly associated with the survival risk of patients with CVD or DM, it can be a valuable predictor in the stratified management and risk warning of CVD or DM patients, as well as in the monitoring of systemic vasculopathy status.