An Improved YOLOv8 Network for Detecting Electric Pylons Based on Optical Satellite Image.

Electric pylons are crucial components of power infrastructure, requiring accurate detection and identification for effective monitoring of transmission lines. This paper proposes an innovative model, the EP-YOLOv8 network, which incorporates new modules: the DSLSK-SPPF and EMS-Head. The DSLSK-SPPF module is designed to capture the surrounding features of electric pylons more effectively, enhancing the model's adaptability to the complex shapes of these structures. The EMS-Head module enhances the model's ability to capture fine details of electric pylons while maintaining a lightweight design. The EP-YOLOv8 network optimizes traditional YOLOv8n parameters, demonstrating a significant improvement in electric pylon detection accuracy with an average mAP@0.5 value of 95.5%. The effective detection of electric pylons by the EP-YOLOv8 demonstrates its ability to overcome the inefficiencies inherent in existing optical satellite image-based models, particularly those related to the unique characteristics of electric pylons. This improvement will significantly aid in monitoring the operational status and layout of power infrastructure, providing crucial insights for infrastructure management and maintenance.

Perceived overqualification as a double-edged sword for employee creativity: The mediating role of job crafting and work withdrawal behavior.

With the continuous development of education level and the downturn of economic situation, employment competition is intensifying, more and more high-quality talents appear, and the misfit between people and posts has become a common phenomenon. However, there is no consensus on the relationship between perceived overqualification and employee creativity. Based on the conservation of resource theory, this study reveals the micro mechanism and boundary conditions of the influence of excessive qualification on employee creativity. This study analyzed 487 valid samples obtained in three stages. The results show that: (1) Job crafting has a positive mediating effect on perceived overqualification and creativity, and the path of the two halves is positive; (2) Work withdrawal behavior plays a negative mediating role between the perceived overqualification and creativity. The path in the first half is positive, and the path in the second half is negative; (3) Organizational identity moderates the effect of perceived overqualification on job crafting and work withdrawal behavior. Specifically, the higher the sense of organizational identification, the stronger the positive effect of perceived overqualification on job crafting and the weaker the positive effect on work withdrawal behavior; (4) Organizational identification moderates the mediating role of job crafting and work withdrawal behavior in the relationship between overqualification and creativity. Specifically, the higher the organizational identity, the stronger the indirect positive effect of perceived overqualification on creativity through job crafting, and the weaker the indirect negative impact of perceived overqualification on creativity through work withdrawal behavior. The study conclusion deepens the research on the mechanism of the influence of the perceived overqualification on employees' work behavior, and provides practical enlightenment for the organization and management of employees with excess qualification.

Clinical utility of digital radiography dacryocystography for preoperative assessment in nasolacrimal duct obstruction prior to endoscopic dacryocystorhinostomy.

Purpose: To evaluate the clinical usefulness of digital radiography dacryocystography in patients with primary acquired nasolacrimal duct obstruction prior to endoscopic dacryocystorhinostomy. Methods: All dacryocystography images from 129 patients with primary acquired nasolacrimal duct obstruction were analyzed. Each group was assessed for postoperative epiphora severity using Munk's score via telephone follow-up three years post-surgery. Receiver operating characteristic (ROC) curve was plotted to obtain a suitable cutoff value of the transverse diameter of the lacrimal sac (LS), used to categorize LS size into small (≤4.350 mm) and large (>4.350 mm). Results: Analysis of the transverse diameter of the LS among 129 patients showed a negative correlation between it and Munk's score (r = -0.282, p = 0.001). There was a statistical difference between the surgical outcomes and the sizes of the LS (p = 0.041). The ROC curve analysis showed that the transverse diameter of the LS at 4.350 mm was the ideal cutoff value for the outcome of endoscopic dacryocystorhinostomy, with a sensitivity of 42.2 %, and specificity of 92.3 %. After adjusting for the age and sex, the small LS was associated with an increased risk of postoperative failed outcome (adjusted odds ratio [95 % CI]: 8.628 [1.074, 69.335]). Conclusion: The small LS was independently associated with the failed surgical outcome. Furthermore, the preoperative measurement of the LS transverse diameter serves as one of the reliable predictors for postoperative epiphora severity.

Corrigendum: The influence of adolescents' internet adaptation on internet addiction: the mediating role of internet cultural adaptation.

[This corrects the article DOI: 10.3389/fpsyt.2023.1338343.].

Design of Selective PARP-1 Inhibitors and Antitumor Studies.

Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.

[In vitro and in vivo validation of cytotoxicity of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells].

Objective To evaluate the toxicology of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells and to provide a safety basis for the clinical evaluation of HER2-CAR-T cell therapy. Methods The recombinant lentiviral vector was used to generate HER2-CAR-T cells. Soft agar colony formation assay was used to observe the colony formation of HER2-CAR-T cells, and the colony formation rate was statistically analyzed. The HER2-CAR-T cell suspension was co-incubated with rabbit red blood cell suspension, and the hemolysis of red blood cells was evaluated by direct observation and microplate reader detection. The HER2-CAR-T cell preparation was injected into the ear vein of male New Zealand rabbits, and the stimulating effect of HER2-CAR-T cells on the blood vessels of the animals was observed by staining of tissue sections. The vesicular stomatitis virus envelope glycoprotein (VSV-G) gene of pMD 2.G vector was used as the target sequence, and the safety of the lentiviral vector was verified by real-time fluorescence quantitative PCR. The heart, liver, lung, and kidney of mice receiving HER2-CAR-T cell infusion were collected, and the lesions were observed by HE staining. Results The HER2-CAR-T cells were successfully prepared. These cells did not exhibit soft agar colony formation ability in vitro, and the HER2-CAR-T cell preparation did not cause hemolysis in New Zealand rabbit red blood cells. After the infusion of HER2-CAR-T cells into the ear vein of New Zealand rabbits, no obvious vascular stimulation response was found, and no specific amplification of VSV-G was detected. No obvious lesions were found in the heart, liver, lung and kidney tissues of the treatment group. Conclusion The prepared HER2-CAR-T cells have reliable safety.

Risk effects of meteorological factors on human brucellosis in Jilin province, China, 2005-2019.

Background: The impact of climate on zoonotic infectious diseases (or can be referred to as climate-sensitive zoonotic diseases) is confirmed. Yet, research on the association between brucellosis and climate is limited. We aim to understand the impact of meteorological factors on the risk of brucellosis, especially in northeastern China. Methods: Monthly incidence data for brucellosis from 2005 to 2019 in Jilin province was obtained from the China Information System for Disease Control and Prevention (CDC). Monthly meteorological data (average temperature (°C), wind velocity (m/s), relative humidity (%), sunshine hours (h), air pressure (hPa), and rainfall (mm)) in Jilin province, China, from 2005 to 2019 were collected from the China Meteorological Information Center (http://data.cma.cn/). The Spearman's correlation was used to choose among the several meteorological variables. A distributed lag non-linear model (DLNM) was used to estimate the lag and non-linearity effect of meteorological factors on the risk of brucellosis. Results: A total of 24,921 cases of human brucellosis were reported in Jilin province from 2005 to 2019, with the peak epidemic period from April to June. Low temperature and low sunshine hours were protective factors for the brucellosis, where the minimum RR values were 0.50 (95 % CI = 0.31-0.82) for -13.7 °C with 1 month lag and 0.61 (95 % CI = 0.41-0.91) for 110.5h with 2 months lag, respectively. High temperature, high sunshine hours, and low wind velocity were risk factors for brucellosis. The maximum RR values were 2.91 (95 % CI = 1.43-5.92, lag = 1, 25.7 °C), 1.85 (95 % CI = 1.23-2.80, lag = 2, 332.6h), and 1.68 (95 % CI = 1.25-2.26, lag = 2, 1.4 m/s). The trends in the impact of extreme temperature and extreme sunshine hours on the transmission of brucellosis were generally consistent. Conclusion: High temperature, high sunshine hours, and low wind velocity are more conducive to the transmission of brucellosis with an obvious lag effect. The results will deepen the understanding of the relationship between climate and brucellosis and provide a reference for formulating relevant public health policies.

Cordyceps sinensis extract protects against acute kidney injury by inhibiting perforin expression in NK cells via the STING/IRF3 pathway.

Acute kidney injury (AKI) is associated with immune cell activation and inflammation. However, the putative pathogenic mechanisms of this injury have not been thoroughly investigated. Natural killer (NK) cells play an important role in immune regulation; however, whether NK cells regulate AKI remains unclear. Cordyceps sinensis (CS), a modern Chinese patented medicine preparation, has been widely used in treating patients with chronic kidney disease (CKD) owing to its anti-inflammatory effects and maintenance of immune homeostasis. Whether 2'-deoxyadenosine, a major active component in CS, can ameliorate renal AKI by regulating immunity, particularly in NK cells, has not been reported. This study is the first to demonstrate how NK cells promote AKI by releasing perforin, interferon-gamma (IFN-γ) and other inflammatory factors in vivo and in vitro. Differential gene expression between AKI and normal tissues was assessed using bioinformatic analyses. Quantitative real-time PCR, western blotting, and immunohistochemical staining were used to detect target protein mRNA and protein expression. Levels of inflammatory factors were measured using enzyme-linked immunosorbent assay. We found the high doses of the 2'-deoxyadenosine treatment significantly alleviated FA-induced renal damage in vivo, and alleviated the NK cells of renal injury by activating the STING/IRF3 pathway to inhibit perforin release in vitro. The results showed that 2'-deoxyadenosine could mitigate AKI by downregulating the activity of NK cells (by decreasing the expressions of perforin and IFN-γ) and inhibiting the stimulator of interferon genes and phosphorylated IFN regulatory factor 3. This may provide valuable evidence supporting the clinical use of CS in treating patients with AKI.

Robust Fluorometric Aptamer Assay for Direct and Rapid Detection of Clinical Isolates of Candida spec.

Infections caused by yeasts of the genus Candida are likely to occur not only in immunocompromised patients but also in healthy individuals, leading to infections of the gastrointestinal tract, urinary tract, and respiratory tract. Due to the rapid increase in the frequency of reported Candidiasis cases in recent years, diagnostic research has become the subject of many studies, and therefore, we developed a polyclonal aptamer library-based fluorometric assay with high specificity and affinity towards Candida spec. to quantify the pathogens in clinical samples with high sensitivity. We recently obtained the specific aptamer library R10, which explicitly recognized Candida and evolved it by mimicking an early skin infection model caused by Candida using the FluCell-SELEX system. In the follow-up study presented here, we demonstrate that the aptamer library R10-based bioassay specifically recognizes invasive clinical Candida isolates, including not only C. albicans but also strains like C. tropcialis, C. krusei, or C. glabrata. The next-generation fluorometric bioassay presented here can reliably and easily detect an early Candida infection and could be used for further clinical research or could even be developed into a full in vitro diagnostic tool.

Contribution of irreversible non-180° domain to performance for multiphase coexisted potassium sodium niobate ceramics.

Despite the dominance of lead-based piezoelectric materials with ultrahigh electric-field-induced strain in actuating applications, seeking eco-friendly substitutes with an equivalent performance remains an urgent demand. Here, a strategy of regulating the irreversible non-180° domain via phase engineering is introduced to optimize the available strain (the difference between the maximum strain and the remnant strain in a unipolar strain curve) in the lead-free potassium-sodium niobate-based piezoelectric ceramics. In situ synchrotron X-ray diffraction and Rayleigh analysis reveal the contribution of the non-180° domain to available strain in the tetragonal-orthorhombic-rhombohedral phase boundary. The reducing orthorhombic phase and increasing rhombohedral/tetragonal phase accompanied by the reduced irreversible non-180° domain are obtained with increasing doping of Sb5+, resulting in an enlarged available strain due to the significantly lowered remnant strain. This optimization is mainly attributed to the reduced irreversible non-180° domain wall motion and the increased lattice distortion, which are beneficial to decrease extrinsic contribution and enhance intrinsic contribution. The mesoscopic structure of miniaturized nanosized domain with facilitated domain switching also contributes to the enhancement of available strain due to the improved random field and decreased energy barrier. The study will shed light on the design of lead-free high-performance piezoelectric ceramics for actuator applications.

Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia. Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical. Results: In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094. Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.

Small Molecule SHP2 Inhibitor LXQ-217 Affects Lung Cancer Cell Proliferation in Vitro and in Vivo.

BACKGROUND: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors. METHODS: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217. RESULTS: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs. CONCLUSIONS: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.

Association of daytime napping and nighttime sleep with all-cause mortality: A prospective cohort study of China Health and Retirement Longitudinal Study.

STUDY OBJECTIVES: The correlation of daytime napping and nighttime sleep duration on mortality was inconsistent. We aimed to explore their separate links to all-cause/premature mortality, and evaluate their combined impact on all-cause mortality risk. METHODS: All of 20617 (mean age: 56.90 ± 10.19, 52.18 % females) participants from China Health and Retirement Longitudinal Study were followed for a median of 7 years (interquartile range: 4-7) to detect death status. Baseline self-reported napping and sleep duration was categorized: napping as none, <60 min, 60-90 min, and ≥90 min, sleep as <6 h/night, 6-8 h/night, and ≥8 h/night. Death event was tracked, and premature death was defined using 2015 China's average life expectancy (73.64 years for men, and 79.43 years for women). Cox regression models analyzed the data. RESULTS: During follow-up, 1621 participants (7.86 %) died, including 985 (4.78 %) premature deaths. Compared to none nappers, napping ≥90 min associated with a higher risk of all-cause mortality (Hazard ratio, [HR] 1.23, 95 % confidence interval [CI] 1.06-1.42) and premature mortality (HR 1.23, 95 % CI 1.02-1.49), while napping <60 min correlated with a lower risk of premature mortality (HR 0.71, 95 % CI 0.54-0.95), after adjustment. Compared to sleep 6-8 h/night, nighttime sleep ≥8 h was associated with an increased risk of all-cause mortality (HR 1.20, 95 % CI 1.04-1.37) and premature mortality (HR 1.28, 95 % CI 1.08-1.52). Participants napping ≥90 min and sleeping ≥8 h had a multi-adjusted HR (95%CI) of 1.50 (95 % CI 1.17-1.92) for all-cause mortality, versus no napping and 6-8 h/night sleep. CONCLUSIONS: Prolonged napping and extended nighttime sleep linked to increased mortality risk, particularly in combination. Optimizing sleep patterns may have potential implication in mortality prevention.

Astaxanthin Inhibits H2O2-Induced Excessive Mitophagy and Apoptosis in SH-SY5Y Cells by Regulation of Akt/mTOR Activation.

Oxidative stress, which damages cellular components and causes mitochondrial dysfunction, occurs in a variety of human diseases, including neurological disorders. The clearance of damaged mitochondria via mitophagy maintains the normal function of mitochondria and facilitates cell survival. Astaxanthin is an antioxidant known to have neuroprotective effects, but the underlying mechanisms remain unclear. This study demonstrated that astaxanthin inhibited H2O2-induced apoptosis in SH-SY5Y cells by ameliorating mitochondrial damage and enhancing cell survival. H2O2 treatment significantly reduced the levels of activated Akt and mTOR and induced mitophagy, while pretreatment with astaxanthin prevented H2O2-induced inhibition of Akt and mTOR and attenuated H2O2-induced mitophagy. Moreover, the inhibition of Akt attenuated the protective effect of astaxanthin against H2O2-induced cytotoxicity. Taken together, astaxanthin might inhibit H2O2-induced apoptosis by protecting mitochondrial function and reducing mitophagy. The results also indicate that the Akt/mTOR signaling pathway was critical for the protection of astaxanthin against H2O2-induced cytotoxicity. The results from the present study suggest that astaxanthin can reduce neuronal oxidative injury and may have the potential to be used for preventing neurotoxicity associated with neurodegenerative diseases.

Effect of empowerment: how and when do high-involvement work practices influence elder employees' innovative performance?

Introduction: In today's fast-paced business environment, innovation from elder employees is increasingly vital to organizations. High-involvement work practices that emphasize engagement and empowerment have a significant impact on the innovation performance of these employees, harnessing their wealth of experience and fostering organizational growth. However, most of the current research on innovation performance focuses on the single factor of the individual or the organization, and most of them focus on the linear relationship; research on the factor of human resource practices, in particular high-involvement work practices, is inadequate. Methods: Based on social exchange theory, this paper uses structural equation modeling (SEM) to examine the impact of high-involvement work practices on elder workers' innovation performance using 278 valid samples from three time points, and the non-linear effects of exploratory and exploitative innovation on elder workers' innovation performance. Results: (1) There is no significant relationship between high-involvement work practices and elder employees' innovation performance. (2) Exploratory innovation has a significant U-shaped relationship with innovation performance, i.e., as the level of exploratory innovation increases, the innovation performance of elder employees first decreases and then increases. There is a significant inverted U-shaped relationship between exploitative innovation and innovation performance, i.e., as the level of exploitative innovation increases, innovation performance first increases and then decreases. High-involvement work practices have a U-shaped effect on elder employees' innovation performance through exploitative innovation. (3) Transformational leadership moderates the direct effects of high-involvement on exploratory innovation and elder employees' innovation performance, and transformational leadership moderates the U-shaped effect of high-involvement work practices on elder employees' innovation performance through exploratory innovation. Discussion: The conclusion is helpful for organizations to enhance elder employees' innovation performance by enriching high-involvement work practices.

Knockout of a PLD gene in Schizochytrium limacinum SR21 enhances docosahexaenoic acid accumulation by modulation of the phospholipid profile.

BACKGROUND: The hydrolysis and transphosphatidylation of phospholipase D (PLD) play important roles in the interconversion of phospholipids (PLs), which has been shown to profoundly impact lipid metabolism in plants. In this study, the effect of the PLD1 gene of Schizochytrium limacinum SR21 (S. limacinum SR21) on lipid metabolism was investigated. RESULTS: PLD1 knockout had little impact on cell growth and lipid production, but it significantly improved the percentage of polyunsaturated fatty acids in lipids, of which docosahexaenoic acid (DHA) content increased by 13.3% compared to the wild-type strain. Phospholipomics and real-time quantitative PCR analysis revealed the knockout of PLD1 reduced the interexchange and increased de novo synthesis of PLs, which altered the composition of PLs, accompanied by a final decrease in phosphatidylcholine (PC) and an increase in phosphatidylinositol, lysophosphatidylcholine, and phosphatidic acid levels. PLD1 knockout also increased DHA content in triglycerides (TAGs) and decreased it in PLs. CONCLUSIONS: These results indicate that PLD1 mainly performs the transphosphatidylation activity in S. limacinum SR21, and its knockout promotes the migration of DHA from PLs to TAGs, which is conducive to DHA accumulation and storage in TAGs via an acyl CoA-independent pathway. This study provides a novel approach for identifying the mechanism of DHA accumulation and metabolic regulation strategies for DHA production in S. limacinum SR21.

EGLN1: A Biomarker of Poor Prognosis of Cervical Cancer and a Target of Treatment.

Objective: To conduct bioinformatics analysis on the prognostic effect, mechanism of action, and drug sensitivity of Egl-9 family hypoxia-inducible factor 1 (EGLN1) expression on cervical cancer. Methods: Bioinformatics were obtained from Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), and the human cancer metastasis database (HCMDB), and the effect of EGLN1 expression level on the prognosis of cervical cancer was comprehensively analyzed. The protein-protein interaction network was constructed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the possible mechanism of EGLN1 affecting the prognosis of cervical cancer was discussed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. In addition, Gene Set Cancer Analysis (GSCALite) was used to predict sensitive drugs online. Results: The higher the expression level of EGLN1, the shorter the tumor-free survival time and overall survival time of cervical cancer. The higher the stage of cervical cancer, the higher the expression level of EGLN1. The expression of EGLN1 affects the degree of immune infiltration, the variation of somatic copy number, and the level of N6-methyladenosine (m6A) modification in cervical cancer. COX regression model suggested that EGLN1 was an independent prognostic factor of cervical cancer. Conclusions: The high expression of EGLN1 in cervical cancer is an independent risk factor for the prognosis of cervical cancer, which affects the prognosis of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) through different signal pathways. It is expected to be used to predict the sensitive anticancer drugs for the treatment of cervical cancer.

SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors.

Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF-ß promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-ß signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-ß-triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure. Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells. Mechanistically, SMAD7 downregulated TGF-ß receptor I and abrogated the interplay between the TGF-ß and NF-κB pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-ß. SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids. Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.

Two-Year Duration of Immunity of Inactivated Poliovirus Vaccine: A Follow-up Study in Pakistan in 2020.

This was a follow-up study conducted in 2020 assessing changes in levels of type 2 poliovirus-neutralizing antibodies 2 years postimmunization in children who received inactivated poliovirus vaccine (IPV) in Karachi, Pakistan. Unexpectedly, the findings revealed an increase in seroprevalence of type 2 antibodies from 73.1% to 81.6% 1 year and 2 years after IPV, respectively. The increase in type 2 immunity could result from the intensive transmission of circulating vaccine-derived poliovirus type 2 (cVDPV2) in Karachi during the second year of IPV administration. This study suggests that the cVDPV2 outbreak detected in Pakistan infected large proportions of children in Karachi. Clinical Trials Registration . NCT03286803.