Patterns of maternal gestational weight gain in association with allergic diseases in offspring: A prospective cohort study.

OBJECTIVE: To evaluate the association between patterns of gestational weight gain (GWG) and allergic diseases in offspring. DESIGN: Prospective cohort study. SETTING: Prenatal clinics in Wuhan, China. POPULATION: A cohort of 2546 mother and offspring pairs were enrolled before 16 weeks of gestation and followed up to 24 months postpartum. METHODS: Maternal body weights were measured regularly during pregnancy, and their GWG patterns were estimated using the growth mixture model. Robust Poisson models were used to evaluate relative risk (RR) and 95% CI after multivariable adjustment. MAIN OUTCOME MEASURES: Offspring atopic allergy and allergic contact dermatitis were defined according to a physician's diagnosis reported by the mother, and food allergy was reported by the mother. RESULTS: Three GWG patterns were identified: 18.1% (461) of the women were described as pattern 1, characterised by rapid GWG earlier in pregnancy; 56.6% (1442) of the women were described as pattern 2, with steady GWG throughout pregnancy; and 25.3% (643) of the women was described as pattern 3, with rapid GWG later in pregnancy. By the age of 24 months, 360 (14.1%), 109 (4.3%) and 757 (29.7%) offspring had atopic allergy, allergic contact dermatitis or food allergy, respectively. Compared with women in GWG pattern 2, the RRs (95% CIs) among women in pattern 1 were 0.74 (0.55-0.99) for atopic allergy, 0.64 (0.36-1.15) for allergic contact dermatitis and 0.95 (0.81-1.12) for food allergy. CONCLUSIONS: Maternal GWG pattern characterised by rapid GWG earlier in pregnancy was associated with a lower risk of atopic allergy in offspring.

A comparative study of the efficacy of intra-articular injection of different drugs in the treatment of mild to moderate knee osteoarthritis: A network meta-analysis.

BACKGROUND: Knee osteoarthritis (KOA) has a high clinical prevalence and frequently interferes with patients normal lives. In KOA patients, evidence suggests that intra-articular (IA) injection improves joint function and decreases discomfort. Several IA injection treatments are used in daily practice to improve symptomatic control of knee osteoarthritis, but their efficacy is frequently disputed. METHODS: This network meta-analysis compares the efficacy of different IA injections for mild to moderate knee osteoarthritis. Seven databases (PubMed, EMBASE, Web of Science, Cochrane Library, China Biology Medicine disc, WanFang, and China National Knowledge Infrastructure) were searched for randomized controlled trials published up to and including December 20, 2021, and final follow up indicators were used. Visual analogue scale (VAS) score and The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (WOMAC) score change from baseline were the primary outcomes. We used the Cochrane risk of bias tool to assess the quality and risks of biases of papers. We calculated the weighted mean difference (WMD) and 95% confidence interval (CI) for each outcome. State (Version 15.1, Texas, USA) and SPSS (Version 20, Chicago, USA) was used in all statistical analyses, and Review Manager (version 5.4) was used in assessing the risks of biases. RESULTS: Our study included 16 randomized controlled trials with a total of 1652 patients. platelet-rich plasma (PRP) IA injection therapy had the highest likelihood of being the best intervention in reducing WOMAC pain (surface under the cumulative ranking area [SUCRA] 84.7%), stiffness (SUCRA 95.1%), and function (SUCRA 98.5%) scores, according to the SUCRA. The best measures for lowering the WOMAC total and VAS scores were IA injection platelet-rich plasma-derived growth factor (SUCRA 84.9%) and hyaluronic acid and platelet-rich plasma (SUCRA 84.9%). In the VAS score group, PRP outperformed hyaluronic acid (HA) (WMD 1.3, 95% CI 0.55-2.55) and corticosteroids (CS) (WMD 4.85, 95% CI 4.02-5.08), according to the forest map results. PRP also outperformed CS (WMD 14.76, 95% CI 12.11-17.41), ozone (WMD 9.16, 95% CI 6.89-11.43), and PRP + HA (WMD 2.18, 95% CI 0.55-3.81) in the WOMAC total score group. Furthermore, PRP outperforms other drugs in terms of reducing WOMAC function, stiffness, and function score. CONCLUSION: In patients with mild to moderate KOA, IA injection PRP outperformed IA injection ozone, HA, CS, platelet-rich plasma-derived growth factor, and hyaluronic acid and platelet-rich plasma in terms of pain, stiffness, and dysfunction.

[Effect of Erjing Pills on alleviating neuroinflammation of AD rats based on TLR4/NF-κB/NLRP3 pathway and its mechanism].

This paper aimed to study the effect of Erjing Pills on the improvement of neuroinflammation of rats with Alzheimer's di-sease(AD) induced by the combination of D-galactose and Aß_(25-35) and its mechanism. SD rats were randomly divided into a sham group, a model control group, a positive drug group(donepezil, 1 mg·kg~(-1)), an Erjing Pills high-dose group(9.0 g·kg~(-1)), and an Erjing Pills low-dose group(4.5 g·kg~(-1)), with 14 rats each group. To establish the rat model of AD, Erjing Pills were intragastrically administrated to rats for 5 weeks after 2 weeks of D-galactose injection. D-galactose was intraperitoneally injected into rats for 3 weeks, and then Aß_(25-35) was injected into the bilateral hippocampus. The new object recognition test was used to evaluate the learning and memory ability of rats after 4 weeks of intragastric administration. Tissues were acquired 24 h after the last administration. The immunofluorescence method was used to detect the activation of microglia in the brain tissue of rats. The positive expressions of Aß_(1-42) and phosphory protein Tau~(404)(p-Tau~(404)) in the CA1 area of the hippocampus were detected by immunohistochemistry. The levels of inflammatory factors interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6) in the brain tissue were determined by enzyme-linked immunosorbent assay(ELISA). Toll-like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)/nucleotide-binding oligomerization domain-like receptors 3(NLRP3) pathway-associated proteins in the brain tissue were determined by Western blot. The results showed that as compared with the sham group, the new object recognition index of rats in the model control group decreased significantly, the deposition of Aß_(1-42) and p-Tau~(404) positive protein in the hippocampus increased significantly, and the levels of microglia activation increased significantly in the dentate gyrus. The levels of IL-1ß, TNF-α, and IL-6 in the hippocampus of the model control group increased significantly, and the expression levels of TLR4, p-NF-κB p65/NF-κB p65, p-IκBα/IκBα, and NLRP3 proteins in the hippocampus increased significantly. Compared with the model control group, the Erjing Pill groups enhanced the new object recognition index of rats, decreased the deposition of Aß_(1-42) and the expression of p-Tau~(404) positive protein in the hippocampus, inhibited the activation of microglia in the dentate gyrus, reduced the levels of inflammatory factors IL-1ß, TNF-α, and IL-6 in the hippocampus, and down-regulated the expression levels of TLR4, p-NF-κB P65/NF-κB P65, p-IκBα/IκBα, and NLRP3 proteins in the hippocampus. In conclusion, Erjing Pills can improve the learning and memory ability of the rat model of AD presumably by improving the activation of microglia, reducing the expression levels of neuroinflammatory factors IL-1ß, TNF-α, and IL-6, inhibiting the TLR4/NF-κB/NLRP3 neuroinflammation pathway, and decreasing hippocampal deposition of Aß and expression of p-Tau, thereby restoring the hippocampal morphological structure.

Clinical efficacy of tetrandrine in artificial stone-associated silicosis: A retrospective cohort study.

Background: Outbreaks of silicosis have occurred among workers in the artificial stone (AS) industry, and there is currently no effective antifibrosis treatment for silicosis. Design: A retrospective cohort study. Methods: We retrospectively analyzed the clinical data of 89 artificial stone-associated silicosis patients treated in Shanghai Pulmonary Hospital (China). Patients who agreed to be administered tetrandrine entered the observation group and those who disagreed entered the control group. Changes in chest HRCT, pulmonary function, and clinical symptoms of patients in two groups were compared pre- and post-treatment. Results: After treatment for 3-12 months, 56.5%-65.4% of patients in the observation group showed improvements in HRCT imaging, while there was no improvement in the control group (p < 0.05). Disease progression occurred in 0%-17.4% of patients in the observation group after 3-12 months of treatment compared with 44.4%-92.0% of patients in the control group (p < 0.05). After 3 months of treatment, the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and diffusing capacity of the lung for carbon monoxide (DLco) in the observation group increased by 136.7 ± 189.2 mL (p < 0.05), 124.2 ± 169.9 mL (p < 0.05), and 1.4 ± 2.3 mL/min/mmHg (p > 0.05), respectively, while those in the control group decreased (145.8 ± 356.5; 107.5 ± 272.1; 1.9 ± 3.8). After 6 months of treatment, FVC, FEV1, and DLco in the observation group increased by 207.8 ± 372.2 mL (p > 0.05), 107.8 ± 295.2 mL (p > 0.05) and 0.7 ± 6.0 mL/min/mmHg (p > 0.05), respectively, while those of the control group decreased (383.3 ± 536.7; 215.6 ± 228.9; 1.4 ± 1.7). The incidences of clinical symptoms such as cough, expectoration, dyspnea, chest tightness, and chest pain in the observation group were decreased-after treatment (all p < 0.05), while the incidences of these symptoms increased in the control group, although the change was not statistically significant (all p > 0.05). Conclusion: Tetrandrine can control and delay the progression of AS-associated silicosis fibrosis, with improved chest HRCT imaging and pulmonary function.

Modelling chloroform in indoor swimming pool air and water: the influences of internal air circulation and occupants.

The release of chloroform from water to air in an indoor swimming pool (ISP) exhibits complex physicochemical interactions among many variables, including environmental conditions, occupant activities, and geometry of the ISP. By combining the relevant variables, a structured mathematical model, the double-layer air compartment (DLAC) model, was developed to predict the level of chloroform in ISP air. A physical parameter, the indoor airflow recycle ratio (R), was incorporated into the DLAC model due to internal airflow circulation resulting in the ISP structural configuration. The theoretical R-value for a specific indoor airflow rate (vy) can be found by fitting the predicted residence time distribution (RTD) to the simulated RTD from computational fluid dynamics (CFD), showing a positive linear relationship with vy. The mechanical energies induced by occupant activities were converted into a lumped overall mass-transfer coefficient to account for the enhanced mass transfer of chloroform from the water into the air and mixing in ISP air. The DLAC model predicted that chloroform air concentrations were statistically less accurate without considering the influence of R compared with the online open-path Fourier transform infrared measurements. A novel index, the magnitude of emission (MOE) from swimmers, was linked to the level of chloroform in ISP water. The capability of the DLAC model associated with the MOE concept may facilitate upgrading the hygiene management of ISPs, including the ability to administer necessary chlorine additives in pool water and monitor the chloroform in ISP air.

Cognitive distortions mediate relationships between early maladaptive schemas and aggression in women and men.

Difficult childhood experiences can lead to the development of early maladaptive schemas (EMS) that cause emotional and behavioral problems later in life. The present study examined the role of cognitive distortions in mediating relationships between EMS and aggression in adults as a function of sex. Participants were 59 women (Mage = 34.7 years, standard deviation [SD] = 8.0) and 86 men (Mage = 39.3 years, SD = 13.2) who completed the Young Schema Questionnaire-Short Form-V3, the How I Think Questionnaire of cognitive distortions, and the Buss-Warren Aggression Questionnaire. Multiple mediation analysis identified EMS domain impaired limits to be uniquely and directly related to aggression, and the domain impaired autonomy to be indirectly related via a range of cognitive distortions. Multigroup analyses revealed no sex differences in these relationships, and analysis of covariance with age as a covariate revealed no sex differences in levels of EMS, cognitive distortion, or aggression. The results suggest that impaired limits and impaired autonomy are EMS domains of relevance to aggression regardless of sex. Furthermore, in the case of impaired autonomy, self-serving, proaggression cognitive distortions appear to be involved. Interventions for aggression may thus benefit by focusing on clients with entitlement/grandiosity traits indicative of impaired limits, and vulnerability/dependence traits indicative of impaired autonomy, and in the latter case consider addressing the self-serving cognitions that enable the expression of aggression in these clients.

Incidence, prognostic factors and survival outcomes in patients with blastic plasmacytoid dendritic cell neoplasm: a retrospective study in the SEER database.

There are few large-scale epidemiological and prognostic studies on blastic plasmacytoid dendritic cell neoplasm (BPDCN) due to its rarity. We used the Surveillance, Epidemiology, and End Results (SEER) database to investigate the incidence, clinical characteristics, prognostic factors, and survival trends of BPDCN. The age-adjusted incidence of BPDCN had a bimodal pattern with peaks in those under 20 and above 60 years. Of 697 patients, the median age at diagnosis was 31 years. The most common primary sites were lymph nodes (59.4%), followed by bone marrow (17.1%) and skin (11.6%). Extranodal involvement (59.7%) was more common in patients aged 60 years and above, while lymph node involvement was predominant in other age groups. The 1-year, 3-year, and 5-year OS rates were 90.7%, 83.7%, and 82.3% in patients aged under 20, but dropped to 53.1%, 27.7%, and 20.0% in patients aged 60 and above. Multivariate Cox regression analysis revealed that age, sex, and first malignancy were independent prognostic factors for OS. Based on this regression model, a nomogram was built with high discrimination and calibration. The incidence, clinical characteristics, and prognosis of BPDCN patients vary by age group. Moreover, using the nomogram to predict OS can help guide individualized evaluations and clinical decisions.

Stellate ganglion block ameliorated central post-stroke pain with comorbid anxiety and depression through inhibiting HIF-1α/NLRP3 signaling following thalamic hemorrhagic stroke.

BACKGROUND: Central post-stroke pain (CPSP) is an intractable and disabling central neuropathic pain that severely affects patients' lives, well-being, and socialization abilities. However, CPSP has been poorly studied mechanistically and its treatment remains challenging. Here, we used a rat model of CPSP induced by thalamic hemorrhage to investigate its underlying mechanisms and the effect of stellate ganglion block (SGB) on CPSP and emotional comorbidities. METHODS: Thalamic hemorrhage was produced by injecting collagenase IV into the ventral-posterolateral nucleus (VPL) of the right thalamus. The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Behavioral tests were carried out to examine depressive and anxiety-like behaviors including the open field test (OFT), elevated plus maze test (EPMT), novelty-suppressed feeding test (NSFT), and forced swim test (FST). The peri-thalamic lesion tissues were collected for immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA). Genetic knockdown of thalamic hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) with microinjection of HIF-1α siRNA and NLRP3 siRNA into the VPL of thalamus were performed 3 days before collagenase injection into the same regions. Microinjection of lificiguat (YC-1) and MCC950 into the VPL of thalamus were administrated 30 min before the collagenase injection in order to inhibited HIF-1α and NLRP3 pharmacologically. Repetitive right SGB was performed daily for 5 days and laser speckle contrast imaging (LSCI) was conducted to examine cerebral blood flow. RESULTS: Thalamic hemorrhage caused persistent mechanical allodynia and anxiety- and depression-like behaviors. Accompanying the persistent mechanical allodynia, the expression of HIF-1α and NLRP3, as well as the activities of microglia and astrocytes in the peri-thalamic lesion sites, were significantly increased. Genetic knockdown of thalamic HIF-1α and NLRP3 significantly attenuated mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. Further studies revealed that intra-thalamic injection of YC-1, or MCC950 significantly suppressed the activation of microglia and astrocytes, the release of pro-inflammatory cytokines, the upregulation of malondialdehyde (MDA), and the downregulation of superoxide dismutase (SOD), as well as mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. In addition, repetitive ipsilateral SGB significantly restored the upregulated HIF-1α/NLRP3 signaling and the hyperactivated microglia and astrocytes following thalamic hemorrhage. The enhanced expression of pro-inflammatory cytokines and the oxidative stress in the peri-thalamic lesion sites were also reversed by SGB. Moreover, LSCI showed that repetitive SGB significantly increased cerebral blood flow following thalamic hemorrhage. Most strikingly, SGB not only prevented, but also reversed the development of mechanical allodynia and anxiety- and depression-like behaviors induced by thalamic hemorrhage. However, pharmacological activation of thalamic HIF-1α and NLRP3 with specific agonists significantly eliminated the therapeutic effects of SGB on mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. CONCLUSION: This study demonstrated for the first time that SGB could improve CPSP with comorbid anxiety and depression by increasing cerebral blood flow and inhibiting HIF-1α/NLRP3 inflammatory signaling.

Value of neutrophil-to-lymphocyte ratio for diagnosing sarcopenia in patients undergoing maintenance hemodialysis and efficacy of Baduanjin exercise combined with nutritional support.

Objective: To investigate the value of neutrophil-to-lymphocyte ratio (NLR) for diagnosing sarcopenia in patients undergoing maintenance hemodialysis (MHD) and efficacy of Baduanjin exercise combined with nutritional support on MHD patients with sarcopenia. Methods: A total of 220 patients undergoing MHD in MHD centers were selected, among which 84 had occurred with sarcopenia confirmed by measurements from the Asian Working Group for Sarcopenia. Data were collected for analyzing the influencing factors that lead to the onset of sarcopenia in MHD patients with the use of one-way analysis of variance and multivariate logistic regression. The role of NLR in the diagnosis of sarcopenia was explored, and its correlation with relevant diagnostic measurement performance such as grip strength, gait speed and skeletal muscle mass index was analyzed. In the end, some 74 patients with sarcopenia that qualify for further intervention and observation standards were divided into observation group (Baduanjin exercise plus nutritional support) and control group (nutritional support only), which were both intervened for 12 weeks. A total of 68 patients finished all interventions, with 33 patients in the observation group and 35 in the control group. The grip strength, gait speed, skeletal muscle mass index as well as the NLR were compared between the two groups. Results: With the employment of multivariate logistic regression analysis, it was found that age, hemodialysis duration and NLR were risk factors for the onset of sarcopenia in MHD patients (P < 0.05). The area under ROC curve for NLR of MHD patients with sarcopenia was 0.695, and NLR was negatively correlated with a biochemical indicator-human blood albumin (P < 0.05). NLR was also negatively correlated with patient's grip strength, gait speed and skeletal muscle mass index, with the same correlation found in sarcopenia patients (all P < 0.05). After intervention, patient's grip strength and gait speed were both higher, and the NLR lower in the observation group than those in the control group (P < 0.05). Conclusion: The occurrence of sarcopenia in MHD patients is associated with patient's age, hemodialysis duration and NLR. Therefore, it has been concluded that NLR has certain values in the diagnosis of sarcopenia in patients undergoing MHD. Moreover, the muscular strength can be enhanced and inflammation decreased in sarcopenia patients through nutritional support and physical exercise, i.e., Bajinduan exercise.

Pseudorabies Virus Infection Activates the TLR-NF-κB Axis and AIM2 Inflammasome To Enhance Inflammatory Responses in Mice.

Pseudorabies virus (PRV) infection activates inflammatory responses to release robust proinflammatory cytokines, which are critical for controlling viral infection and clearance of PRV. However, the innate sensors and inflammasomes involved in the production and secretion of proinflammatory cytokines during PRV infection remain poorly studied. In this study, we report that the transcription and expression levels of some proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α), are upregulated in primary peritoneal macrophages and in mice during PRV infection. Mechanistically, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR5 were induced by the PRV infection to enhance the transcription levels of pro-IL-1ß, pro-IL-18, and gasdermin D (GSDMD). Additionally, we found that PRV infection and transfection of its genomic DNA triggered AIM2 inflammasome activation, apoptosis-related speckle-like protein (ASC) oligomerization, and caspase-1 activation to enhance the secretion of IL-1ß and IL-18, which was mainly dependent on GSDMD, but not GSDME, in vitro and in vivo. Taken together, our findings reveal that the activation of the TLR2-TLR3-TRL4-TLR5-NF-κB axis and AIM2 inflammasome, as well as GSDMD, is required for proinflammatory cytokine release, which resists the PRV replication and plays a critical role in host defense against PRV infection. Our findings provide novel clues to prevent and control PRV infection. IMPORTANCE PRV can infect several mammals, including pigs, other livestock, rodents, and wild animals, causing huge economic losses. As an emerging and reemerging infectious disease, the emergence of PRV virulent isolates and increasing human PRV infection cases indicate that PRV is still a high risk to public health. It has been reported that PRV infection leads to robust release of proinflammatory cytokines through activating inflammatory responses. However, the innate sensor that activates IL-1ß expression and the inflammasome involved in the maturation and secretion of proinflammatory cytokines during PRV infection remain poorly studied. In this study, our findings reveal that, in mice, activation of the TLR2-TLR3-TRL4-TLR5-NF-κB axis and AIM2 inflammasome, as well as GSDMD, is required for proinflammatory cytokine release during PRV infection, and it resists PRV replication and plays a critical role in host defense against PRV infection. Our findings provide novel clues to prevent and control PRV infection.

Vincristine and dexamethasone pulses in addition to maintenance therapy among pediatric acute lymphoblastic leukemia (GD-ALL-2008): An open-label, multicentre, randomized, phase III clinical trial.

The efficacy and safety on the addition of vincristine (VCR) and dexamethasone (DEX) pulses to maintenance therapy among childhood acute lymphoblastic leukemia (ALL) remain uncertain. Herein, we perform an open-label, multicentre, randomized, phase III clinical trial that was conducted at nine major medical centers in Guangdong Province, China. Patients were randomly assigned either the conventional maintenance therapy (control group, n = 384) or the VCR/DEX pulse (treatment group, n = 375). When limited to the SR cohort, 10-year EFS was 82.6% (95% CI: 75.9-89.9) in the control group and 80.7% (95% CI: 74-88.1) in the treatment group (pnon-inferiority  = .0002). Similarly, patients with IR also demonstrated non-inferiority of the treatment group to the control group in terms of 10-year EFS (73.6% [95% CI: 67.6-80] vs. 77.6% [95% CI: 71.8-83.9]; pnon-inferiority  = .005). Among the HR cohort, compared with the control group, patients in the treatment group experienced a significant benefit in terms of 10-year EFS (61.1% [95% CI: 47.7-78.2] vs. 72.6% [95% CI: 55.6-94.7], p = .026) and a trend toward higher 10-year OS (73.8% [95% CI: 61.6-88.4] vs. 87.9% [95% CI: 579.2-97.5], p = .068). In the HR cohort, the total rate of drug-induced liver injury and Grade 3 chemotherapy-induced anemia were both lower for patients in the treatment group than in the control group (55.6% vs. 100%, p = .033; 37.5% vs. 60%, p = .036). Conversely, the total prevalence of chemotherapy-induced thrombocytopenia was higher for patients in the treatment group than in the control group (88.9% vs. 40%, p = .027). Pediatric acute lymphoblastic leukemia with high risk is suitable to VCR/DEX pulse during maintenance phase for the excellent outcome, while the standard-to-intermediate-risk patients could eliminate the pulses.

Comparative Treatment Outcomes for Idiopathic Subglottic Stenosis: 5-Year Update.

The North American Airway Collaborative (NoAAC) previously published a 3-year multi-institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re-enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision-making. Level of evidence: 2-prospective cohort study.

Bacterial outer membrane vesicle based versatile nanosystem boosts the efferocytosis blockade triggered tumor-specific immunity.

Efferocytosis inhibition is emerging as an attractive strategy for antitumor immune therapy because of the subsequent leak of abundant immunogenic contents. However, the practical efficacy is seriously impeded by the immunosuppressive tumor microenvironments. Here, we construct a versatile nanosystem that can not only inhibit the efferocytosis but also boost the following antitumor immunity. MerTK inhibitor UNC2025 is loaded into the bacterial outer membrane vesicles (OMVs), which are then modified with maleimide (mU@OMVs). The prepared mU@OMVs effectively inhibits the efferocytosis by promoting the uptake while preventing the MerTK phosphorylation of tumor associated macrophages, and then captures the released antigens through forming universal thioether bonds. The obtained in situ vaccine effectively transfers to lymph nodes by virtue of the intrinsic features of OMVs, and then provokes intense immune responses that can efficiently prevent the growth, metastasis and recurrence of tumors in mice, providing a generalizable strategy for cancer immunotherapy.

Augmenter of Liver Regeneration Monoclonal Antibody Promotes Apoptosis of Hepatocellular Carcinoma Cells.

Background and Aims: Hepatocellular carcinoma (HCC) is one of the most common types of cancer, often resulting in death. Augmenter of liver regeneration (ALR), a widely expressed multifunctional protein, has roles in liver disease. In our previous study, we reported that ALR knockdown inhibited cell proliferation and promoted cell death. However, there is no study on the roles of ALR in HCC. Methods: We used in vitro and in vivo models to investigate the effects of ALR in HCC as well as its mechanism of action. We produced and characterized a human ALR-specific monoclonal antibody (mAb) and investigated the effects of the mAb in HCC cells. Results: The purified ALR-specific mAb matched the predicted molecular weight of IgG heavy and light chains. Thereafter, we used the ALR-specific mAb as a therapeutic strategy to suppress tumor growth in nude mice. Additionally, we assessed the proliferation and viability of three HCC cell lines, Hep G2, Huh-7, and MHC97-H, treated with the ALR-specific mAb. Compared with controls, tumor growth was inhibited in mice treated with the ALR-specific mAb at 5 mg/kg, as shown by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling. Simultaneous treatment with the ALR-specific mAb and adriamycin promoted apoptosis, whereas treatment with the ALR-specific mAb alone inhibited cell proliferation. Conclusions: The ALR-specific mAb might be a novel therapy for HCC by blocking extracellular ALR.

African Swine Fever Virus HLJ/18 CD2v Suppresses Type I IFN Production and IFN-Stimulated Genes Expression through Negatively Regulating cGMP-AMP Synthase-STING and IFN Signaling Pathways.

African swine fever is a fatal infectious disease caused by African swine fever virus (ASFV). The high mortality caused by this infectious disease is a significant challenge to the swine industry worldwide. ASFV virulence is related to its ability to antagonize IFN response, yet the mechanism of antagonism is not understood. Recently, a less virulent recombinant virus has emerged that has a EP402R gene deletion within the parental ASFV HLJ/18 (ASFV-ΔEP402R) strain. EP402R gene encodes CD2v. Hence we hypothesized that ASFV uses CD2v protein to evade type I IFN-mediated innate immune response. We found that ASFV-ΔEP402R infection induced higher type I IFN response and increased the expression of IFN-stimulated genes in porcine alveolar macrophages when compared with parental ASFV HLJ/18. Consistent with these results, CD2v overexpression inhibited type I IFN production and IFN-stimulated gene expression. Mechanistically, CD2v, by interacting with the transmembrane domain of stimulator of IFN genes (STING), prevented the transport of STING to the Golgi apparatus, and thereby inhibited the cGMP-AMP synthase-STING signaling pathway. Furthermore, ASFV CD2v disrupted IFNAR1-TYK2 and IFNAR2-JAK1 interactions, and thereby inhibited JAK-STAT activation by IFN-α. In vivo, specific pathogen-free pigs infected with the mutant ASFV-ΔEP402R strain survived better than animals infected with the parental ASFV HLJ/18 strain. Consistent with this finding, IFN-ß protein levels in the peripheral blood of ASFV-ΔEP402R-challenged pigs were significantly higher than in the blood of ASFV HLJ/18-challenged pigs. Taken together, our findings suggest a molecular mechanism in which CD2v inhibits cGMP-AMP synthase-STING and IFN signaling pathways to evade the innate immune response rendering ASFV infection fatal in pigs.

Mechanosensitive channel MscL induces non-apoptotic cell death and its suppression of tumor growth by ultrasound.

Mechanosensitive channel of large conductance (MscL) is the most thoroughly studied mechanosensitive channel in prokaryotes. Owing to its small molecular weight, clear mechanical gating mechanism, and nanopore forming ability upon opening, accumulating studies are implemented in regulating cell function by activating mechanosensitive channel of large conductance in mammalian cells. This study aimed to investigate the potentials of mechanosensitive channel of large conductance as a nanomedicine and a mechano-inducer in non-small cell lung cancer (NSCLC) A549 cells from the view of molecular pathways and acoustics. The stable cytoplasmic vacuolization model about NSCLC A549 cells was established via the targeted expression of modified mechanosensitive channel of large conductance channels in different subcellular organelles. Subsequent morphological changes in cellular component and expression levels of cell death markers are analyzed by confocal imaging and western blots. The permeability of mitochondrial inner membrane (MIM) exhibited a vital role in cytoplasmic vacuolization formation. Furthermore, mechanosensitive channel of large conductance channel can be activated by low intensity focused ultrasound (LIFU) in A549 cells, and the suppression of A549 tumors in vivo was achieved by LIFU with sound pressure as low as 0.053 MPa. These findings provide insights into the mechanisms underlying non-apoptotic cell death, and validate the nanochannel-based non-invasive ultrasonic strategy for cancer therapy.

Red fluorescence protein (DsRed2) promotes the screening efficiency in peanut genetic transformation.

Peanut (Arachis hypogaea L.), one of the leading oilseed crops worldwide, is an important source of vegetable oil, protein, minerals and vitamins. Peanut is widely cultivated in Asia, Africa and America, and China is the largest producer and consumer of peanut. Genetic engineering has shown great potential to alter the DNA makeup of an organism which is largely hindered by the low transformation and screening efficiency including in peanut. DsRed2 is a reporter gene widely utilized in genetic transformation to facilitate the screening of transformants, but never used in peanut genetic transformation. In this study, we have demonstrated the potential of the red fluorescence protein DsRed2 as a visual reporter to improve screening efficiency in peanut. DsRed2 was firstly expressed in protoplasts isolated from peanut cultivar Zhonhua 12 by PEG, and red fluorescence was successfully detected. Then, DsRed2 was expressed in peanut plants Zhonghua 12 driven by 35S promoter via Agrobacterium tumefaciens-mediated transformation. Red fluorescence was visually observed in calli and regenerated shoots, as well as in roots, leaves, flowers, fresh pod shells and mature seeds, suggesting that transgenic screening could be initiated at the early stage of transformation, and continued to the progeny. Upon screening with DsRed2, the positive plant rate was increased from 56.9% to 100%. The transgenic line was then used as the male parent to be crossed with Zhonghua 24, and the hybrid seeds showed red fluorescence as well, indicating that DsRed2 could be applied to hybrid plant identification very efficiently. DsRed2 was also expressed in hairy roots of Huayu 23 via Agrobacterium rhizogenes-mediated transformation, and the transgenic roots were easily selected by red fluorescence. In summary, the DsRed2 is an ideal reporter to achieve maximum screening efficiency and accuracy in peanut genetic transformation.

Association of Breastfeeding Practices During the First 3 Months with Infant Sleep Trajectories: A Prospective Cohort Study.

BACKGROUND: Breastfeeding has numerous effects on maternal and child health. The effect of breastfeeding on infant sleep remains inconclusive. OBJECTIVES: We aimed to examine whether full breastfeeding (FBF) during the first 3 mo is associated with longitudinal infant sleep trajectories in their first 2 y of life. METHODS: The study was embedded in the Tongji Maternal and Child Health Cohort study. Information on infant feeding practices was collected at 3 mo of age, and maternal/child pairs were assigned to the FBF or the non-FBF group (including partially breastfeeding and exclusive formula feeding) on the basis of feeding practices during the first 3 mo of life. Sleep data of infants were obtained at 3, 6, 12, and 24 mo. Total, night, and day sleep trajectories across 3 to 24 mo were estimated with group-based models. Each sleep trajectory was differentiated on the basis of sleep duration at 3 mo (long/moderate/short) and the interval from 6 to 24 mo (moderate/short). Multinomial logistic regression was used to investigate the association of breastfeeding practices with infant sleep trajectories. RESULTS: Among the 4056 infants studied, 2558 (63.1%) received FBF for 3 mo. When compared with FBF infants, non-FBF infants had shorter sleep duration at 3, 6, and 12 mo (P < 0.01). Non-FBF infants were more likely to experience Moderate-Short (OR: 1.31; 95% CI: 1.06, 1.61) and Short-Short (OR: 1.56; 95% CI: 1.12, 2.16) total sleep trajectories and more likely to experience Moderate-Short (OR: 1.84; 95% CI: 1.22, 2.77), and Short-Moderate (OR: 1.40; 95% CI: 1.06, 1.85) night sleep trajectories than FBF infants. CONCLUSIONS: Full breastfeeding for ≥3 mo were positively associated with longer infant sleep duration. Infants fully breastfed were more likely to experience better sleep trajectories characterized by longer duration in their first 2 y of life. Full breastfeeding may benefit infants through healthy sleep.