NRF1-mediated mitochondrial biogenesis antagonizes innate antiviral immunity.

Mitochondrial biogenesis is the process of generating new mitochondria to maintain cellular homeostasis. Here, we report that viruses exploit mitochondrial biogenesis to antagonize innate antiviral immunity. We found that nuclear respiratory factor-1 (NRF1), a vital transcriptional factor involved in nuclear-mitochondrial interactions, is essential for RNA (VSV) or DNA (HSV-1) virus-induced mitochondrial biogenesis. NRF1 deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in mice. Mechanistically, the inhibition of NRF1-mediated mitochondrial biogenesis aggravated virus-induced mitochondrial damage, promoted the release of mitochondrial DNA (mtDNA), increased the production of mitochondrial reactive oxygen species (mtROS), and activated the innate immune response. Notably, virus-activated kinase TBK1 phosphorylated NRF1 at Ser318 and thereby triggered the inactivation of the NRF1-TFAM axis during HSV-1 infection. A knock-in (KI) strategy that mimicked TBK1-NRF1 signaling revealed that interrupting the TBK1-NRF1 connection ablated mtDNA release and thereby attenuated the HSV-1-induced innate antiviral response. Our study reveals a previously unidentified antiviral mechanism that utilizes a NRF1-mediated negative feedback loop to modulate mitochondrial biogenesis and antagonize innate immune response.

Association of Helicobacter pylori infection with complications of diabetes: a single-center retrospective study.

BACKGROUND: Previous studies examined the association of Helicobacter pylori infection (H. pylori) with complications of diabetes, but the results have been inconsistent. The aim of this study of patients with type-2 diabetes (T2D) was to determine the association of H. pylori infection with the major complications of diabetes. METHODS: This single-center retrospective study examined patients with T2D who received H. pylori testing between January 2016 and December 2021. Logistic regression analyses were used to evaluate the association of H. pylori infection with four major complications of diabetes. RESULTS: We examined 960 patients with T2D, and 481 of them (50.1%) were positive for H. pylori. H. pylori infection was significantly associated with diabetic nephropathy (odds ratio [OR] = 1.462; 95% confidence interval [CI]: 1.006,2.126; P = 0.046). In addition, the co-occurrence of H. pylori positivity with hypertension (OR = 4.451; 95% CI: 2.351,8.427; P < 0.001), with glycated hemoglobin A1c (HbA1c) of at least 8% (OR = 2.925; 95% CI: 1.544,5.541; P = 0.001), and with diabetes duration of at least 9 years (OR = 3.305; 95% CI:1.823,5.993; P < 0.001) further increased the risk of diabetic nephropathy. There was no evidence of an association of H. pylori infection with retinopathy, neuropathy, or peripheral vascular disease. CONCLUSIONS: Our study of T2D patients indicated that those with H. pylori infections had an increased risk of nephropathy, and this risk was greater in patients who also had hypertension, an HbA1c level of 8% or more, and diabetes duration of 9 years or more.

[Integrin and N-cadherin Co-Regulate the Polarity of Mesenchymal Stem Cells via Mechanobiological Mechanisms]. / æ•´åˆç´ å’ŒN-é’™é»ç´ ååŒè°ƒæŽ§é—´å è´¨å¹²ç»†èƒžæžæ€§çš„åŠ›å­¦ç”Ÿç‰©å­¦æœºåˆ¶ç ”ç©¶.

Objective: To investigate the synergistic regulation of the polarization of mesenchymal stem cells by integrin and N-cadherin-mediated mechanical adhesion and the underlying mechanobiological mechanisms. Methods: Bilayer polyethylene glyeol (PEG) hydrogels were formulated and modified with RGD and HAVDI peptides, respectively, to achieve mechanical adhesion to integrin and N-cadherin and to replicate the integrin-mediated mechanical interaction between cells and the extracellular matrix and the N-cadherin-mediated cell-cell mechanical interaction. The polar proteins, phosphatidylinositol 3-kinase (PI3K) and phosphorylated myosin light chain (pMLC), were characterized through immunofluorescence staining in individual cells with or without contact with HAVDI peptides under integrin-mediated adhesion, N-cadherin-mediated adhesion, and different intracellular forces. Their expression levels and polar distribution were analyzed using Image J. Results: Integrin-mediated adhesion induced significantly higher polar strengths of PI3K and pMLC in the contact group than in those in the no contact group, resulting in the concentration of the polar angle of PI3K to ß-catenin in the range of 135° to 180° and the concentration of the polar angle of pMLC to ß-catenin in the range of 0° to 45° in the contact group. Inhibition of integrin function led to inhibition of the polarity distribution of PI3K in the contact group, but did not change the polarity distribution of pMLC protein. The effect of N-cadherin on the polarity distributions of PI3K and pMLC was similar to that of integrin. However, inhibition of the mechanical adhesion of N-cadherin led to inhibition of the polarity intensity and polarity angle distribution of PI3K and pMLC proteins in the contact group. Furthermore, inhibition of the mechanical adhesion of N-cadherin caused weakened polarity intensity of integrin ß1, reducing the proportion of cells with polarity angles between integrin ß1 and ß-catenin concentrating in the range of 135° to 180°. Additionally, intracellular forces influenced the polar distribution of PI3K and pMLC proteins. Reducing intracellular forces weakened the polarity intensity of PI3K and pMLC proteins and their polarity distribution, while increasing intracellular forces enhanced the polarity intensity of PI3K and pMLC proteins and their polarity distribution. Conclusion: Integrin and N-cadherin co-regulate the polarity distribution of cell proteins and N-cadherin can play an important role in the polarity regulation of stem cells through local inhibition of integrin.

Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2.

Tumor necrosis factor-alpha (TNF-α) plays an important pathogenic role in cardiac hypertrophy and heart failure (HF); however, anti-TNF is paradoxically negative in clinical trials and even worsens HF, indicating a possible protective role of TNF-α in HF. TNF-α exists in transmembrane (tmTNF-α) and soluble (sTNF-α) forms. Herein, we found that TNF receptor 1 (TNFR1) knockout (KO) or knockdown (KD) by short hairpin RNA or small interfering RNA (siRNA) significantly alleviated cardiac hypertrophy, heart dysfunction, fibrosis, and inflammation with increased tmTNF-α expression, whereas TNFR2 KO or KD exacerbated the pathological phenomena with increased sTNF-α secretion in transverse aortic constriction (TAC)- and isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro, respectively, indicating the beneficial effects of TNFR2 associated with tmTNF-α. Suppressing TNF-α converting enzyme by TNF-α Protease Inhibitor-1 (TAPI-1) to increase endogenous tmTNF-α expression significantly alleviated TAC-induced cardiac hypertrophy. Importantly, direct addition of exogenous tmTNF-α into cardiomyocytes in vitro significantly reduced ISO-induced cardiac hypertrophy and transcription of the pro-inflammatory cytokines and induced proliferation. The beneficial effects of tmTNF-α were completely blocked by TNFR2 KD in H9C2 cells and TNFR2 KO in primary myocardial cells. Furthermore, we demonstrated that tmTNF-α displayed antihypertrophic and anti-inflammatory effects by activating the AKT pathway and inhibiting the nuclear factor (NF)-κB pathway via TNFR2. Our data suggest that tmTNF-α exerts cardioprotective effects via TNFR2. Specific targeting of tmTNF-α processing, rather than anti-TNF therapy, may be more useful for the treatment of hypertrophy and HF.

Establishment and application of a screening method for 354 organic toxicants in blood and urine with high-performance liquid chromatography-high-resolution orbitrap mass spectrometry.

A rapid and sensitive high-performance liquid chromatography-high-resolution orbitrap mass spectrometry method was developed for the simultaneous screening of 354 organic poisons and metabolites in blood and urine, including drugs, medications, pesticides, rodenticides, veterinary drugs, alkaloids, and mycotoxins with a multi-toxicant chromatography-mass spectrometry information library. The method and library showed good prospects in clinical poisoning screening and forensic toxicological identification. Blood and urine samples were extracted successively with ethyl acetate in acidic and alkaline conditions; then, the extract was blown to nearly dry by nitrogen gas and redissolved with methanol-aqueous solution (v:v, 50:50), and the dissolved solution was analyzed by LC-MS/MS after filtering. Precursor ions' m/z was set for identification, retention time, fragment ions, and isotopic pattern which were used for confirmation. No interference peaks were found in the blank samples, showing good specificity. The LODs of toxicants in urine and blood were 1.00×10-3-50.0 ng/mL and 2.07×10-3-50.0 ng/mL, respectively, while the LOQs were 3.30×10-3-1.67×102 ng/mL and 6.91×10-3-1.67×102 ng/mL. The intra-day precision and inter-day precision of urine samples were 2.31-9.13% and 4.75-12.3%, respectively, which were 1.92-10.8% and 2.01-12.1% in blood samples. The established method was applied to analyze 9 cases of clinical poisoning patients, and bromadiolone, carbofuran, and amanitins were detected, respectively. A total of 382 biospecimens from drug abusers were analyzed with the proposed method, which indicated that some drugs were detected in 62 cases, mainly including methamphetamine, heroin, and MDMA. The results were consistent with the information from traditional liquid chromatography-triple quadrupole mass spectrometry.

Research progress in human biological monitoring of aromatic hydrocarbon with emphasis on the analytical technology of biomarkers.

Aromatic hydrocarbons are unsaturated compounds containing carbon and hydrogen that form single aromatic ring, or double, triple, or multiple fused rings. This review focuses on the research progress of aromatic hydrocarbons represented by polycyclic aromatic hydrocarbons (including halogenated polycyclic aromatic hydrocarbons), benzene and its derivatives including toluene, ethylbenzene, xylenes (o-, m- and p-), styrene, nitrobenzene, and aniline. Due to the toxicity, widespread coexistence, and persistence of aromatic hydrocarbons in the environment, accurate assessment of exposure to aromatic hydrocarbons is essential to protect human health. The effects of aromatic hydrocarbons on human health are mainly derived from three aspects: different routes of exposure, the duration and relative toxicity of aromatic hydrocarbons, and the concentration of aromatic hydrocarbons which should be below the biological exposure limit. Therefore, this review discusses the primary exposure routes, toxic effects on humans, and key populations, in particular. This review briefly summarizes the different biomarker indicators of main aromatic hydrocarbons in urine, since most aromatic hydrocarbon metabolites are excreted via urine, which is more feasible, convenient, and non-invasive. In this review, the pretreatment and analytical techniques are compiled systematically for the qualitative and quantitative assessments of aromatic hydrocarbons metabolites such as gas chromatography and high-performance liquid chromatography with multiple detectors. This review aims to identify and monitor the co-exposure of aromatic hydrocarbons that provides a basis for the formulation of corresponding health risk control measures and guide the adjustment of the exposure dose of pollutants to the population.

Cardioprotective Role of Myeloid-Derived Suppressor Cells in Heart Failure.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand in cancer, inflammation, and infection and negatively regulate inflammation and the immune response. Heart failure (HF) is a complex clinical syndrome wherein inflammation induction and incomplete resolution can potentially contribute to HF development and progression. However, the role of MDSCs in HF remains unclear. METHODS: The percentage of MDSCs in patients with HF and in mice with pressure overload-induced HF using isoproterenol infusion or transverse aortic constriction (TAC) was detected by flow cytometry. The effects of MDSCs on isoproterenol- or TAC-induced HF were observed on depleting MDSCs with 5-fluorouracil (50 mg/kg) or gemcitabine (120 mg/kg), transferring purified MDSCs, or enhancing endogenous MDSCs with rapamycin (2 mg·kg-1·d-1). Hypertrophic markers and inflammatory factors were detected by ELISA, real-time polymerase chain reaction, or Western blot. Cardiac functions were determined by echocardiography and hemodynamic analysis. RESULTS: The percentage of human leukocyte antigen-D-related (HLA-DR)-CD33+CD11b+ MDSCs in the blood of patients with HF was significantly increased and positively correlated with disease severity and increased plasma levels of cytokines, including interleukin-6, interleukin-10, and transforming growth factor-ß. Furthermore, MDSCs derived from patients with HF inhibited T-cell proliferation and interferon-γ secretion. Similar results were observed in TAC- and isoproterenol-induced HF in mice. Pharmaceutical depletion of MDSCs significantly exacerbated isoproterenol- and TAC-induced pathological cardiac remodeling and inflammation, whereas adoptive transfer of MDSCs prominently rescued isoproterenol- and TAC-induced HF. Consistently, administration of rapamycin significantly increased endogenous MDSCs by suppressing their differentiation and improved isoproterenol- and TAC-induced HF, but MDSC depletion mostly blocked beneficial rapamycin-mediated effects. Mechanistically, MDSC-secreted molecules suppressed isoproterenol-induced hypertrophy and proinflammatory gene expression in cardiomyocytes in a coculture system. Neutralization of interleukin-10 blunted both monocytic MDSC- and granulocytic MDSC-mediated anti-inflammatory and antihypertrophic effects, but treatment with a nitric oxide inhibitor only partially blocked the antihypertrophic effect of monocytic MDSCs. CONCLUSIONS: Our findings revealed a cardioprotective role of MDSCs in HF by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin-10 and nitric oxide. Pharmacological targeting of MDSCs by rapamycin constitutes a promising therapeutic strategy for HF.

Transmembrane TNF-α preferentially expressed by leukemia stem cells and blasts is a potent target for antibody therapy.

To design an effective antibody therapy to improve clinical outcomes in leukemia, the identification of novel cell surface antigens is needed. Herein, we demonstrate a role for transmembrane tumor necrosis factor-α (tmTNF-α) in leukemia. To characterize tmTNF-α expression in acute leukemia (AL), normal hematopoietic cells, and nonhematopoietic tissues, we used a monoclonal antibody, termed C1, which specifically recognizes the tmTNF-α domain. We found that tmTNF-α was preferentially expressed by AL and leukemia stem cells (LSCs). More abundant expression correlated with poor risk stratification, extramedullary infiltration, and adverse clinical parameters. Moreover, knockdown of tmTNF-α(+) expression rendered leukemia cells more sensitive to chemotherapy in vitro and delayed regeneration of leukemia in NOD-SCID mice. Targeting tmTNF-α by C1 resulted in leukemia cell killing via antibody-dependent cell-mediated and complement-dependent cytotoxicity in vitro and inhibited leukemia cell growth in vivo while simultaneously sparing normal hematopoietic cells. Notably, C1 administration impaired the regeneration of leukemia in secondary serial transplantation into NOD-SCID mice. In conclusion, tmTNF-α has a favorable AL- and LSC-associated expression profile and is important for the survival and proliferation of these cells. C1-mediated targeting shows potent anti-LSC activity, indicating that tmTNF-α represents a novel target antigen in AL.

Kupffer-cell-expressed transmembrane TNF-α is a major contributor to lipopolysaccharide and D-galactosamine-induced liver injury.

Tumor necrosis factor (TNF)-α exists in two bioactive forms, a 26-kDa transmembrane form (tmTNF-α) and a 17-kDa soluble form (sTNF-α). sTNF-α has been recognized as a key regulator of hepatitis; however, serum sTNF-α disappears in mice during the development of severe liver injury, and high levels of serum sTNF-α do not necessarily result in liver damage. Interestingly, in a mouse model of acute hepatitis, we have found that tmTNF-α expression on Kupffer cells (KCs) significantly increases when mice develop severe liver injury caused by lipopolysaccharide (LPS)/D-galactosamine (D-gal), and the level of tmTNF-α expression is positively related to the activity of serum transaminases. Therefore, we hypothesized that KC-expressed tmTNF-α constitutes a pathomechanism in hepatitis and have explored the role of tmTNF-α in this disease model. Here, we have compared the impact of KCs(tmTNFlow) and KCs(tmTNFhigh) on acute hepatitis in vivo and ex vivo and have further demonstrated that KCs(tmTNFhigh), rather than KCs(tmTNFlow), not only exhibit an imbalance in secretion of pro- and anti-inflammatory cytokines, favoring inflammatory response and exacerbating liver injury, but also induce hepatocellular apoptosis via tmTNF-α and the expression of another pro-apoptotic factor, Fas ligand. Our data suggest that KC(tmTNFhigh) is a major contributor to liver injury in LPS/D-gal-induced hepatitis.

Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2.

It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF-α (tmTNF-α) is the primary ligand for TNFR2, we hypothesized that tmTNF-α is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-ß, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α-induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α-mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-α mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-ß, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-α mutant by 4T1 cells that only released sTNF-α without expression of surface tmTNF-α markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-α acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.

A field survey for Wolbchia and phage WO infections of Aedes albopictus in Guangzhou City, China.

Wolbachia are maternal endosymbiotic bacterium, which infect a diverse range of arthropods, ranging from 20 to 76% in nature. They are capable of inducing a wide range of reproductive abnormalities to their hosts, such as cytoplasmic incompatibility (CI), which has been proposed to be used as a tool to modify mosquitoes that are resistant to the development of pathogen, as an alternative vector control strategy. Here, we evaluated the prevalence of Wolbachia and phage WO infections in the field population of Aedes albopictus in Guangzhou City via polymerase chain reaction (PCR) assay using the Wolbachia specific Wolbachia surface protein (wsp) and phage WO orf7 gene primers. Based on the results of PCR and phylogeny analysis, we found that A. albopictus in Guangzhou City were infected with two Wolbachia strains, wAlbA and wAlbB. Phage WO, the virus-infected Wolbachia, was also detected in A. albopictus. One hundred and ten female individuals were screened via PCR, with 109 super-infected with Wolbachia and one sample single-infected with wAlbB strain. And 104 of 113 male individuals were both infected with wAlbA and wAlbB, and nine male samples were found to be infected with wAlbA strain only. The infection rates of phage WO in female and male individuals were 82.73 and 46.02%, respectively. These results showed that the natural Wolbachia and phage WO infections in A. albopictus population in Guangzhou were at a higher frequency at present, indicating that Wolbachia appear to be a better candidate nature resource for biological control insect vectors to reduce vector-borne diseases.

The formation pattern, causes, and governance of network public opinion on university emergencies.

Background: University emergencies, garnering significant public attention and shaping network opinions, pose a crucial challenge to universities' management and societal stability. Hence, network public opinion on university emergencies is a vital issue. Nevertheless, the underlying mechanism has not been fully explored and cannot be efficiently controlled. This study aimed to explore the formation pattern of network public opinion on university emergencies, analyze its causes, and provide scientific governance strategies for coping with this issue. Methods: Based on a sample set of 204 cases from the Zhiwei Data Sharing Platform, this study classifies network public opinion on university emergencies into six types and visually analyzes their characteristics: time distribution, subject, duration, and emotion. By integrating the theory of the network public opinion field, this study develops a network public opinion field model of university emergencies to reveal its formation pattern. Furthermore, it analyzes the causes of network public opinion on university emergencies from the perspective of the public opinion lifecycle and proposes corresponding governance strategies. Results: The sample consisted of 304 cases of real-life public opinion, and the visualization results show that public opinion on mental health and teacher-student safety constitutes the predominant types, accounting for 83.3%. High-occurrence subjects are public universities (88.24%) and students (48%). The most frequent months are July and December. 90.20% of the public opinions have a lifespan of less than 19 days, with an impact index ranging from 40 to 80. The public's emotional response to different types of public opinion varies, with negative emotions dominating. Conclusion: This study provides novel insights for understanding their formation and dissemination. It also provides practical implications for relevant departments to govern network public opinion on university emergencies.

Laccase2 is required for sclerotization and pigmentation of Aedes albopictus eggshell.

Laccase (EC 1.10.3.2) is a member of multicopper oxidases that have been found in higher plants, fungus, bacterium, and insects. Two types of laccase genes have been detected in many species of insects: laccase1 and laccase2. It has been identified that laccase2 enzyme may play a key role in sclerotization and pigmentation of insect cuticle. But few attentions were given to the biological role of laccase2 in the synthesizing of similar structures, such as oothecae, eggshell, or silk cocoons. We cloned laccase2 gene from Aedes albopictus, one main mosquito vector of dengue virus in China. An upregulation of laccase2 gene was observed after a blood meal in female adult mosquitoes, suggesting that laccase2 gene may have an involvement in the development of ovary. RNA interference experiment was performed by using adult female mosquitoes. Female mosquitoes were injected with 20 ng of double-strain RNA into the thorax. Pigmentation of mosquito eggshell was blocked that these eggs never became dark. And the incomplete sclerotization of eggshell weakened the stability and flexibility of the eggs. These eggs without enough protection were deformed and died in water. These results demonstrate that laccase2 plays a critical role in the development of eggs of A. albopictus. Laccase2 may provide a novel target for mosquito control and management.

Molecular cloning, expression, and characterization of a putative activation-associated secreted protein from Angiostrongylus cantonensis.

Activation-associated secreted protein (ASP) had been found in many helminthes, which was associated with pathogenesis and stage transition. A complementary DNA (cDNA) sequence encoding a putative two-domain ASP was obtained from an Angiostrongylus cantonensis fourth-stage larvae cDNA library, which we designated as AgASP. The cDNA of AgASP contains an open reading frame encoding 424 amino acids, the first 19 residues being a putative secretion signal. The expression pattern of this protein was investigated by real-time polymerase chain reaction and Western blot. We found that this protein expressed most highly in the brain-stage larvae (Lbr) of this parasite and existed in the excretory/secretory products of this stage. Immunofluorescence showed it existed in the lumen of the Lbr. The recombinant protein can be recognized by the infection sera from mice (nonpermissive host), while it cannot be recognized by infection sera from rats (permissive host). The infiltration of neutrophils in infected nonpermissive host can be lessened by immunizing this host with this protein (immunized vs control group, 13.7 ± 10.2 vs 65.5 ± 19.2). These findings suggest that this protein plays a role in the pathogenesis of human angiostrongyliasis and is worthy of further study.

Comparison of cataract patients with regular corneal astigmatism after implantation of extended range-of-vision and bifocal toric intraocular lenses.

Purpose: To compare the postoperative visual acuity and visual quality between extended range-of-vision and multifocal toric intraocular lens (IOLs) after implantation in cataract patients with regular corneal astigmatism. Setting: Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, Jilin Province, China. Design: Retrospective and single-center study. Methods: The study involved implanting the Tecnis Symphony (ZXR00IOL) or the bifocal toric (ZMTIOL) in patients undergoing cataract surgery. Three months after surgery, lens performance was evaluated using distance, intermediate, and near visual acuity tests, defocus curves, the modulation transfer function (MTF), a visual function index questionnaire (VF-14), and the adverse optical interference phenomena. Results: The 3-month postoperative follow-up found that both groups had good corrected distance vision. The ZMT group had better-uncorrected distance visual acuity and near visual acuity (p < 0.05). However, the ZXR group showed better uncorrected intermediate visual acuity (p < 0.05) and visual continuity. Overall astigmatism in the postoperative ZMT group was significantly lower than that in the pre-operative group (p < 0.05). The ZMT group had lower total high-order aberrations (tHOs), higher MTF values, and higher VF-14 scores (p < 0.05). Finally, the ZXR group exhibited reduced halo and glare phenomena (p < 0.05). Conclusion: We found that ZMT can effectively correct a corneal astigmatism of 1.0-1.5 D and ZXR can improve patient outcomes regarding subjective optical quality and range of vision. These findings have the potential to improve future astigmatism treatment options.

Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers.

BACKGROUND: Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies. METHODS: We generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo. RESULTS: Our tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy. CONCLUSION: Our findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC.

Assessment of an exhaled breath test using ultraviolet photoionization time-of-flight mass spectrometry for the monitoring of kidney transplant recipients.

Continuous monitoring for immunosuppressive status, infection and complications are a must for kidney transplantation (KTx) recipients. Traditional monitoring including blood sampling and kidney biopsy, which caused tremendous medical cost and trauma. Therefore, a cheaper and less invasive approach was urgently needed. We thought that a breath test has the potential to become a feasible tool for KTx monitoring. A prospective-specimen collection, retrospective-blinded assessment strategy was used in this study. Exhaled breath samples from 175 KTx recipients were collected in West China Hospital and tested by online ultraviolet photoionization time-of-flight mass spectrometry (UVP-TOF-MS). The classification models based on breath test performed well in classifying normal and abnormal values of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN) and tacrolimus, with AUC values of 0.889, 0.850, 0.849 and 0.889, respectively. Regression analysis also demonstrated the predictive ability of breath test for clinical creatinine, eGFR, BUN, tacrolimus level, as the predicted values obtained from the regression model correlated well with the clinical true values (p < 0.05). The findings of this investigation implied that a breath test by using UVP-TOF-MS for KTx recipient monitoring is possible and accurate, which might be useful for future clinical screenings.

Translation of TRAF1 is regulated by IRES-dependent mechanism and stimulated by vincristine.

TRAF1 is a member of the TRAF family, which plays important roles in signal transduction that mediate cell life and death in the immune response, inflammatory and malignant diseases. It is known that TRAF1 transcription is inducible by various cytokines, but little is known about the regulation of its mRNA translation. In the present study, we demonstrated that the human TRAF1 mRNA has an unusually long 5'-UTR that contains internal ribosome entry segment (IRES) regulating its translation. By performing gene transfection and reporter assays, we revealed that this IRES sequence is located within the 572 nt upstream from the AUG start codon. An element between nt -392 and -322 was essential for the IRES activity. Interestingly, we found that the TRAF1 expression is induced in cancer cells by chemotherapeutic drug vincristine that regulates cytoplasmic localization of polypyrimidine tract binding protein, which may contribute to the IRES-dependent translation of TRAF1 during vincristine treatment. These results indicate that TRAF1 translation is initiated via the IRES and regulated by vincristine, and suggest that regulation of the IRES-dependent translation of TRAF1 may be involved in effecting the cancer cell response to vincristine treatment.