Prognostic value of right ventricular trabecular complexity in patients with arrhythmogenic cardiomyopathy.

OBJECTIVES: The present study aimed to investigate the incremental prognostic value of the right ventricular fractal dimension (FD), a novel marker of myocardial trabecular complexity by cardiac magnetic resonance (CMR) in patients with arrhythmogenic cardiomyopathy (ACM). METHODS: Consecutive patients with ACM undergoing CMR were followed up for major cardiac events, including sudden cardiac death, aborted cardiac arrest, and appropriate implantable cardioverter defibrillator intervention. Prognosis prediction was compared by Cox regression analysis. We established a multivariable model supplemented with RV FD and evaluated its discrimination by Harrell's C-statistic. We compared the category-free, continuous net reclassification improvement (cNRI) and integrated discrimination index (IDI) before and after the addition of FD. RESULTS: A total of 105 patients were prospectively included from three centers and followed up for a median of 60 (48, 66) months; experienced 36 major cardiac events were recorded. Trabecular FD displayed a strong unadjusted association with major cardiac events (p < 0.05). In the multivariable Cox regression analysis, RV maximal apical FD maintained an independent association with major cardiac events (hazard ratio, 1.31 (1.11-1.55), p < 0.002). The Hosmer-Lemeshow goodness of fit test displayed good fit (X2 = 0.68, p = 0.99). Diagnostic performance was significantly improved after the addition of RV maximal apical FD to the multivariable baseline model, and the continuous net reclassification improvement increased 21% (p = 0.001), and the integrated discrimination index improved 16% (p = 0.045). CONCLUSIONS: In patients with ACM, CMR-assessed myocardial trabecular complexity was independently correlated with adverse cardiovascular events and provided incremental prognostic value. CLINICAL RELEVANCE STATEMENT: The application of FD values for assessing RV myocardial trabeculae may become an accessible and promising parameter in monitoring and early diagnosis of risk factors for adverse cardiovascular events in patients with ACM. KEY POINTS: • Ventricular trabecular morphology, a novel quantitative marker by CMR, has been explored for the first time to determine the severity of ACM. • Patients with higher maximal apical fractal dimension of RV displayed significantly higher cumulative incidence of major cardiac events. • RV maximal apical FD was independently associated with major cardiac events and provided incremental prognostic value in patients with ACM.

RNAi of yellow-y, required for normal cuticle pigmentation, impairs courtship behavior and oviposition in the German cockroach (Blattella germanica).

The insect cuticle plays a key role in maintaining the insect's physiological function and behavior. Herein, the yellow-y protein is required to produce black melanin, and is expressed in a pattern that correlates with the distribution of this pigment. However, yellow-y can also have other functions, for instance, in insect behavior, but not much is known. In this study, we have studied the yellow-y gene in one important model and pest species, namely the German cockroach (Blattella germanica), which is to our knowledge the first time reported. In essence, we identified the yellow-y gene (BgY-y) and characterized its function by using RNA interference (RNAi). Silencing of BgY-y gene led to different developmental abnormalities (body weight and wings) in both genders. Specifically, there was an abundant decrease in melanin, turning the body color in pale yellow and the cuticle softer and more transparent. Interestingly, we also observed that the knockdown of BgY-y impaired the male cockroaches to display a weaker response to female-emitted contact sex pheromones, and also that the oviposition ability was weakened in the RNAi females. This study comprehensively analyzed the biological functions of the yellow-y gene in German cockroaches from the perspectives of development, body color, courtship behavior and oviposition, and as a consequence, this may opens new avenues to explore it as a novel pest control gene.

Diet and lifestyle behaviours simultaneously act on frailty: it is time to move the threshold of frailty prevention and control forward.

BACKGROUND: To analyse the association among the simultaneous effects of dietary intake, daily life behavioural factors, and frailty outcomes in older Chinese women, we predicted the probability of maintaining physical robustness under a combination of different variables. METHODS: The Fried frailty criterion was used to determine the three groups of "frailty", "pre-frailty", and "robust", and a national epidemiological survey was performed. The three-classification decision tree model was fitted, and the comprehensive performance of the model was evaluated to predict the probability of occurrence of different outcomes. RESULTS: Among the 1,044 participants, 15.9% were frailty and 50.29% were pre-frailty; the overall prevalence first increased and then decreased with age, reaching a peak at 70-74 years of age. Through univariate analysis, filtering, and embedded screening, eight significant variables were identified: staple food, spices, exercise (frequency, intensity, and time), work frequency, self-feeling, and family emotions. In the three-classification decision tree, the values of each evaluation index of Model 3 were relatively average; the accuracy, recall, specificity, precision, and F1 score range were between 75% and 84%, and the AUC was also greater than 0.800, indicating excellent performance and the best interpretability of the results. Model 3 takes exercise time as the root node and contains 6 variables and 10 types, suggesting the impact of the comprehensive effect of these variables on robust and non-robust populations (the predicted probability range is 6.67-93.33%). CONCLUSION: The combined effect of these factors (no exercise or less than 0.5 h of exercise per day, occasional exercise, exercise at low intensity, feeling more tired at work, and eating too many staple foods (> 450 g per day) are more detrimental to maintaining robustness.

The melanin pigment gene black mediates body pigmentation and courtship behaviour in the German cockroach Blattella germanica.

Genes involved in melanin production directly impact insect pigmentation and can affect diverse physiology and behaviours. The role these genes have on sex behaviour, however, is unclear. In the present study, the crucial melanin pigment gene black was functionally characterised in an urban pest, the German cockroach, Blattella germanica. RNAi knockdown of B. germanica black (Bgblack) had no effect on survival, but did result in black pigmentation of the thoraxes, abdomens, heads, wings, legs, antennae, and cerci due to cuticular accumulation of melanin. Sex-specific variation in the pigmentation pattern was apparent, with females exhibiting darker coloration on the abdomen and thorax than males. Bgblack knockdown also resulted in wing deformation and negatively impacted the contact sex pheromone-based courtship behaviour of males. This study provides evidence for black function in multiple aspects of B. germanica biology and opens new avenues of exploration for novel pest control strategies.

Holographic 3D renal segments reconstruction protects renal function by promote choice of selective renal artery clamping during robot-assisted partial nephrectomy.

OBJECTIVE: To investigate the impact of selective artery clamping (SAC) and main artery clamping (MAC) during robot-assisted partial nephrectomy (RAPN) on renal function and the influence of holographic three-dimensional (3D) reconstruction of renal segments on the selection between SAC and MAC. METHODS: This retrospective observational study included patients who underwent RAPN at First Hospital Affiliated to the Army Medical University between December 2016 and July 2022. According to the clamping methods, the patients were divided into the SAC group and the MAC group. The primary outcome was renal function. RESULTS: A total of 422 patients (194 in the SAC group and 228 in the MAC group) were included. The RAPN procedures were all completed successfully. The patients in SAC group had less glomerular filtration rate (GFR) decline in the affected kidney (8.6 ± 7.0 ml/min vs. 18.7 ± 10.9 ml/min, P < 0.001) and minor estimated glomerular filtration rate (eGFR) decrease (4.3 ± 10.5 ml/min vs. 12.6 ± 12.1 ml/min, P < 0.001) than those in MAC group. Among 37 patients with baseline renal insufficiency, the GFR decline of the affected kidney in the SAC subgroup was significantly lower than in the MAC subgroup (5.5 ± 6.5 ml/min vs. 14.3 ± 9.2 ml/min, P = 0.002). The proportion of patients who underwent 3D reconstruction was significant higher in the SAC group than in the MAC group. (65.46% vs. 28.07%, P < 0.001). CONCLUSION: The SAC technique during RAPN may serve as a protective measure for renal function, while the implementation of holographic 3D renal segment reconstruction technique may facilitate optimal selection of SAC.

Myocardial extracellular volume quantified by cardiac magnetic resonance predicts left ventricular aneurysm following acute myocardial infarction.

OBJECTIVE: This study aimed to investigate the correlation between increased extracellular matrix estimated by cardiac magnetic resonance (CMR) and left ventricular aneurysm after acute myocardial infarction. METHODS: A total of 175 patients from 3 centers with an isolated left anterior descending culprit vessel underwent CMR examinations within 1 week and at a 6-month follow-up. Of these, 92 were identified to have left ventricular aneurysms (LVAs): 74 with functional aneurysm and 18 with anatomical aneurysm. The predictive significance of acute extracellular volume (ECV), left gadolinium enhancement (LGE), and other characteristics were analyzed using binary logistic regression analysis. RESULTS: Patients with LVA were more likely to present with left ventricular adverse remodeling (LVAR) than those without (p = 0.009). With optimal cutoff values of 30.90% for LGE and 33% for ECV to discriminate LVA from non-LVA, the area under the curve (AUC) by receiver operator characteristic curve (ROC) analysis was 0.92 (95% CI: 0.87-0.96; p < 0.001) and 0.93 (95% CI: 0.88-0.96; p < 0.001), respectively. ECV was significantly better than LGE at discriminating between functional and anatomical LVA (p < 0.001). Both acute LGE and ECV were predictors of LVA, with an odds ratio of 1.35 (95% CI: 1.21-1.52, p < 0.001) and 1.23 (95% CI: 1.13-1.33, p < 0.001), respectively, by multivariable logistic regression analysis. CONCLUSIONS: Acute LGE and ECV of the myocardium provided predictive significance for LVA. The discriminative significance of ECV for functional versus anatomical LVA was better than the discriminative significance of LGE. KEY POINTS: • Patients with LVA were more likely to present with LVAR. • Acute LGE and ECV of the myocardium provided the strongest predictive significance for LVA. • The discriminative significance of ECV for functional versus anatomical LVA was better than that of LGE.

A novel type II crustin in the innate immune response of the freshwater crab (Sinopotamon henanense) against infection and its expression changes by cadmium.

Antibacterial peptide (AMP), an effector of the innate immune system, is an essential component of invertebrate innate immunity. Crustin is a family of antimicrobial peptides that are widely studied in crustaceans. Here we report a novel crustin (designated Shcrustin) from the freshwater crab Sinopotamon henanense. The results revealed that the full-length cDNA of Shcrustin was 691 bp with an open reading frame (ORF) of 510 bp. Phylogenetic analysis of the Shcrustin sequence showed that it clustered with type II crustin. Shcrustin exists in different tissues, among which the highest expression level is found in the gills. After the bacterial challenge, the expression of Shcrustin increased in hemocytes or gills. However, crustin expression was suppressed in the presence of cadmium (Cd). To elucidate the biological activity of Shcrustin, we constructed a recombinant Shcrustin protein. Purified rShcrustin could bind to a variety of bacteria and inhibit the growth of different bacteria indicating that Shcrustin has inhibitory activity against gram-positive and gram-negative bacteria. In addition, the phagocytic rate of hemocytes toward bacteria decreased after the interference of Shcrustin expression by RNA interference, suggesting that Shcrustin may be involved in such a process. Therefore, we conclude that Shcrustin may be involved in the innate immunity of S. henanense by binding to bacteria and promoting hemolymph phagocytosis to clear invading pathogens. It is an important immune effector against pathogen infection. In the presence of Cd, it may alter the expression of Shcrustin and suppress its immune function.

Cloning, identification, and functional characterization of novel prophenoloxidases (ShproPO) from the freshwater crab Sinopotamon henanense in response to cadmium exposure and Aeromonas hydrophila infection.

Prophenoloxidase (proPO) is essential in the prophenoloxidase-activating system (proPO-AS) which is important for defense against foreign infection in crustaceans. However, most studies have focused on expression in the presence of a single pathogenic bacterium, and very few have addressed the presence of environmental contaminants simultaneously, such as cadmium (Cd) and Aeromonas hydrophila. Our study aimed to investigate the function of proPO in the freshwater crab Sinopotamon henanense and the changes in its expression by Cd and infection of A. hydrophila. A novel proPO from the hemocytes of S. henanense (ShproPO) was found in this research, the full-length cDNA of ShproPO was 2620 bp of encoding a protein of 678 amino acids containing three typical hemocyanin domains. The ShproPO protein could be found in both the granular (GHc) and the semi-granular hemocytes (SGHc). The ShproPO mRNA was found to be abundantly expressed in hemocytes and could be influenced by A. hydrophila infection. These results indicate that ShproPO could be involved in the antibacterial process. Further research found that low concentrations of Cd could promote its expression after infection with A. hydrophila. Therefore, it was hypothesized that Cd disrupted the response of crabs to A. hydrophila infection. Subsequently, PO enzyme activity was found to be significantly reduced through in vivo RNA interference with ShproPO, and the results suggested that ShproPO is likely to be a key enzyme in the melanization response. Finally, ShproPO was found to significantly enhance the phagocytosis of A. hydrophila-infected hemocytes by in vitro recombination, confirming that ShproPO is involved in hemocyte-mediated melanization and phagocytosis. Our findings reveal completely new insight into the immunotoxicity of Cd and the immune function of ShproPO in S. henanense.

Big data on the prevalence of injury deaths among 187 488 elderly Chinese in the past 20 years (2000-2020): a systematic review and meta-analysis.

BACKGROUND: This study systematically reviewed injury death and causes in the elderly population in China from 2000 to 2020, to prevent or reduce the occurrence of injuries and death. METHODS: The CNKI, VIP, Wan Fang, MEDLINE, Embase, SinoMed, and Web of Science databases were searched to collect epidemiological characteristics of injury death among elderly over 60 years old in China from January 2000 to December 2020. Random effects meta-analysis was performed to pool injury mortality rate and identify publication bias, with study quality assessed using the AHRQ risk of bias tool. RESULTS: (1) A total of 41 studies with 187 488 subjects were included, covering 125 million elderly. The pooled injury mortality rate was 135.58/105 [95%CI: (113.36 to 162.14)/105], ranking second in the total death cause of the elderly. (2)Subgroup analysis showed that male injury death (146.00/105) was significantly higher than that of females (127.90/105), and overall injury mortality increased exponentially with age (R2 = 0.957), especially in those over 80 years old; the spatial distribution shows that the injury death rate in the central region is higher than that in the east and west and that in the countryside is higher than that in the city; the distribution of death time shows that after entering an aging society (2000-2020) is significantly higher than before (1990-2000). (3) There are more than 12 types of injury death, and the top three are falling, traffic accidents, and suicide. CONCLUSIONS: China's elderly injury death rate is at a high level in the world, with more males than females, especially after the age of 80. There are regional differences. The main types of injury death are falling, traffic, and suicide. During the 14th Five-Year Plan period, for accidental injuries and death, a rectification list for aging and barrier-free environments was issued. PROSPERO REGISTRATION: The systematic review was registered in PROSPERO under protocol number CRD42022359992.

[Association of Geriatric Nutritional Risk Index with Adverse Events and Time to Treatment Failure in Malignant Lymphoma Patients Treated with(R-)EPOCH].

To date, there are no reports that examine the relationship between geriatric nutritional risk index(GNRI)at the start of chemotherapy for malignant lymphoma and adverse effects. In this study, we investigated the relationship between GNRI at the start of chemotherapy and the incidence of side effects and time to treatment failure(TTF)in(R-)EPOCH-treated patients with relapsed or refractory malignant lymphoma. A significant difference in the incidence of Grade 3 or higher thrombocytopenia was observed between high and low GNRI groups(p=0.043). The GNRI may be an indicator of hematologic toxicity in malignant lymphoma patients treated with(R-)EPOCH. There was a statistically significant difference in TTF between the high and low GNRI groups(p=0.025), suggesting that nutritional status at the start of(R-)EPOCH may affect treatment continuation.

A Radiomic MRI based Nomogram for Prediction of Heart Failure with Preserved Ejection Fraction in Systemic Lupus Erythematosus Patients: Insights From a Three-Center Prospective Study.

BACKGROUND: Myocardial T1 and extracellular volume (ECV) fraction values have important roles in the prognostication of heart failure with preserved ejection fraction (HFpEF). However, the traditional mean quantification of intensity levels is not sufficient. PURPOSE: To evaluate a T1 map-based radiomic nomogram as a long-term prognosticator for HFpEF in systemic lupus erythematosus (SLE) patients. STUDY TYPE: Prospective. POPULATION: A total of 115 SLE patients and 50 age- and gender-matched controls. FIELD STRENGTH/SEQUENCE: A 3.0 T scanner; cine imaging, precontrast and post-contrast T1 mapping and T2 mapping sequences. ASSESSMENT: A radiomic nomogram was developed based on precontrast T1 mapping. Three independent readers assessed and compared the ECV value and the value of the radiomic nomogram for predicting HFpEF in SLE patients. STATISTICAL TEST: Cox proportional hazard models, Youden index for determining cut-off values for high HFpEF risk vs. low HFpEF risk classification, Kaplan-Meier analysis, intraclass correlation (ICC), and Uno C statistic test. RESULTS: During a median follow-up of 27 (interquartile range, 19-37) months, 31 SLE patients developed HFpEF. Patients with elevated ECV (≥31%) and a higher output (≥42.7) from the radiomic feature "S_33_sum average" of the precontrast T1 map had a significantly higher risk of developing HFpEF than those who had lower ECV (<31%) and an output <42.7. Patients with a higher "S_33_sum average" value on precontrast T1 map had a significantly increased risk for HFpEF (hazard ratio, 1.363, 95% CI, 1.130-1.645), after adjusting for covariates including ECV and LVEF. Finally, "S_33_sum average" from precontrast T1 mapping had modest but significantly incremental prognostic value over the mean ECV value (Uno C statistic comparing models, 0.860 vs. 0.835). DATA CONCLUSION: The precontrast T1 map-based radiomic nomogram, as a measure of diffuse myocardial fibrosis was associated with HFpEF and provided modest prognostic value for predicting HFpEF in SLE patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

[Intelligent fault diagnosis expert system for multi-parameter monitor based on fault tree].

Aiming at the dilemma of expensive and difficult maintenance, lack of technical data and insufficient maintenance force for modern medical equipment, an intelligent fault diagnosis expert system of multi-parameter monitor based on fault tree was proposed in this study. Firstly, the fault tree of multi-parameter monitor was established and analyzed qualitatively and quantitatively, then based on the analysis results of fault tree, the expert system knowledge base and inference engine were constructed and the overall framework of the system was determined, finally the intelligent fault diagnosis expert system for multi-parameter monitor was developed by using the page hypertext preprocessor (PHP) language, with an accuracy rate of 80% in fault diagnosis. The results showed that technology fusion on the basis of fault tree and expert system can effectively realize intelligent fault diagnosis of multi-parameter monitors and provide troubleshooting suggestions, which can not only provide experience accumulation for fault diagnosis of multi-parameter monitors, but also provide a new idea and technical support for fault diagnosis of medical equipment.

A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening.

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.

Round ligament suspending treatment in orthotopic ileal-neobladder after radical cystectomy in women: a single-centre prospective randomised trial.

OBJECTIVES: To compare the occurrence of emptying dysfunction between surgical techniques for orthotopic neobladder suspended with round ligament (rONB) and the standard procedure (sONB). PATIENTS AND METHODS: A prospective randomised controlled trial was performed in a single centre of female patients undergoing creation of an ONB using rONB or sONB. Patients were followed for ≥24 months after ONB. The primary endpoints were significant post-void residual urine volume (sPVR) and need for clean intermittent catheterisation (CIC) at 24 months postoperatively. The secondary endpoints included early and late complications, urodynamic profile, and ONB continence. RESULTS: Between January 2011 and October 2017, the trial enrolled 85 patients, of whom 82 were randomised. A total of 41 patients had a rONB and 41 a sONB. At 24 months, 17 of the 37 patients with a sONB and nine of the 39 patients with a rONB had a sPVR. The cumulative risk of a sPVR was significantly lower in the rONB group (23.1%) vs the sONB group (45.9%) (hazard ratio [HR] 0.43, 95% confidence interval [CI], 0.19-0.96; P = 0.040). In all, 15 of the 37 patients with a sONB and four of the 39 patients with a rONB needed CIC. The cumulative risk of requiring CIC was significantly lower in the rONB group (10.3%) vs the sONB group (40.5%) (HR 0.22, 95% CI 0.07-0.67; P = 0.008) at 24 months. Multivariable Cox regression analysis also showed that the rONB type was an independently protective factor for sPVR and CIC. The rates of early (0-90 days) and late complication (>90 days) were 54.1% and 13.5% in the sONB group, and 64.1% and 10.3% in the rONB group, respectively. There were no significant differences in complications, urodynamic profile or ONB continence. A major limitation is the small sample size at a single centre. CONCLUSION: Posterior support with round ligament for an ONB significantly improved the emptying of the ONB and resulted in a reduced need for CIC. The surgical modification is a feasible and safe technique without additional complication-related surgeries.

[Intelligent fault diagnosis of medical equipment based on long short term memory network].

In order to solve the current problems in medical equipment maintenance, this study proposed an intelligent fault diagnosis method for medical equipment based on long short term memory network(LSTM). Firstly, in the case of no circuit drawings and unknown circuit board signal direction, the symptom phenomenon and port electrical signal of 7 different fault categories were collected, and the feature coding, normalization, fusion and screening were preprocessed. Then, the intelligent fault diagnosis model was built based on LSTM, and the fused and screened multi-modal features were used to carry out the fault diagnosis classification and identification experiment. The results were compared with those using port electrical signal, symptom phenomenon and the fusion of the two types. In addition, the fault diagnosis algorithm was compared with BP neural network (BPNN), recurrent neural network (RNN) and convolution neural network (CNN). The results show that based on the fused and screened multi-modal features, the average classification accuracy of LSTM algorithm model reaches 0.970 9, which is higher than that of using port electrical signal alone, symptom phenomenon alone or the fusion of the two types. It also has higher accuracy than BPNN, RNN and CNN, which provides a relatively feasible new idea for intelligent fault diagnosis of similar equipment.

Clone, identification and functional characterization of a novel toll (Shtoll1) from the freshwater crab Sinopotamon henanense in response to cadmium exposure and Aeromonas hydrophila infection.

Toll is essential in innate immune system which is important for defense against bacterial, fungal and viral infections in invertebrates. Our previous study showed that cadmium (Cd) could change the expression pattern of ShToll3 in the epithelium (gills and midgut from the freshwater crab Sinopotamon henanense) infected by Aeromonas hydrophila. To investigate the diverse innate immune roles of crustacean homolog Tolls, in this study, we cloned Shtoll1 from S. henanense. The full-length cDNA of Shtoll1 was 4746 bp, with an ORF of 3033 bp encoding a putative protein of 111 amino acids, a 5'-untranslated region of 255 bp and a 3'-untranslated region of 1713 bp. Phylogenetic analysis showed that ShToll1 was clustered into the group of DmToll1, DmToll 4 and DmToll 5. In addition, the tissue distribution results showed that Shtoll1 was expressed widely in different tissues, with the highest expression in heamocytes. Besides, Shtoll1 expressions were upregulated in heamocytes and hepatopancreas after A. hydrophila infection. At the same time, the increase of Shtoll1 expressions were examined in heamocytes in response to Cd exposure and A. hydrophila infection in combination. Through western blotting and immunohistochemical analysis, the ShToll1 expressions in heamocytes were increased in response to A. hydrophila and Cd independently as well as in combination. Moreover, the mRNA level of three antimicrobial peptides (AMPs) alf5, alf6, and c-lys, which possibly responded to Cd and A. hydrophila stimulation through Shtoll1, were analyzed. Thus, we conclude that Cd expand the susceptibility of ShToll1 to A. hydrophila infection in heamocytes. This suggest that ShToll1 may contribute to the innate immune defense of S. henanense against A. hydrophila and Cd in heamocytes.

Resveratrol attenuates diabetes-associated cell centrosome amplification via inhibiting the PKCα-p38 to c-myc/c-jun pathway.

Type 2 diabetes increases the risk for cancer. Centrosome amplification can initiate tumorigenesis. We have described that type 2 diabetes increases the centrosome amplification of peripheral blood mononuclear cells, with high glucose, insulin, and palmitic acid as the triggers, which suggests that centrosome amplification is a candidate biological mechanism linking diabetes to cancer. In this study, we aimed to further investigate the signaling pathways of the diabetes-associated centrosome amplification and to examine whether and how resveratrol inhibits the centrosome amplification. The results showed that treatment with high glucose, insulin, and palmitic acid, alone or in combination, could increase the protein levels of phospho-protein kinase C alpha (p-PKCα), phospho-p38 mitogen-activated protein kinases (p-p38), c-myc, and c-jun, as well as the mRNA levels of c-myc and c-jun. PKCα inhibitor could inhibit the treatment-induced increase in the protein levels of p-p38, c-myc, and c-jun. Inhibitor or siRNA of p38 was also able to inhibit the treatment-induced increase in the levels of p-p38, c-myc, and c-jun. Meanwhile, knockdown of c-myc or c-jun did not alter the treatment-induced increase in the phosphorylation of PKCα or p38. Importantly, inhibition of the phosphorylation of PKCα or p38 and knockdown of c-myc or c-jun could attenuate the centrosome amplification. In diabetic mice, the levels of p-PKCα, p-p38, c-myc, and c-jun were all increased in the colon tissues. Interestingly, resveratrol, but not metformin, was able to attenuate the treatment-induced increase in the levels of p-PKCα, p-p38, c-myc, and c-jun, as well as the centrosome amplification. In conclusion, our results suggest that PKCα-p38 to c-myc/c-jun is the signaling pathway of the diabetes-associated centrosome amplification, and resveratrol attenuates the centrosome amplification by inhibiting this signaling pathway.

Cadmium induces cell centrosome amplification via reactive oxygen species as well as endoplasmic reticulum stress pathway.

There is evidence that cadmium can initiate carcinogenesis. However, the underlying mechanisms remain unknown. There is also evidence that moderate centrosome amplification can initiate tumorigenesis. The present study investigated whether cadmium could trigger cell centrosome amplification, and examined the underlying molecular mechanisms. We found that cadmium was able to cause cell centrosome amplification at the subtoxic concentrations, in a dose-dependent manner. It could cause centrosome amplification via the signaling of reactive oxygen species (ROS). Proteomic analysis revealed that cadmium caused differential expressions of three proteins, which included HSPA1A which is associated with endoplasmic reticulum (ER) stress. Western blot analysis confirmed that cadmium upregulated HSPA1A. Further analyses showed that cadmium upregulated Bip and decreased the phosphorylation of ASK1 as well as increased the phosphorylation of MKK7 and c-Jun N-terminal kinases (JNK). Knockdown of JNK2 using small interfering RNA inhibited the cadmium-induced centrosome amplification but not the level of ROS. N-acetylcysteine did not inhibit the cadmium-activated ER stress pathway. In conclusion, our results suggest that cadmium can induce cell centrosome amplification via ROS as well as ER stress through the Bip-TRAF2-ASK1-MKK7-JNK signaling route, in parallel. More studies are required to clarify whether centrosome amplification underlies cadmium-induced carcinogenesis.

Nuclear localization signal peptide enhances transfection efficiency and decreases cytotoxicity of poly(agmatine/N,N'-cystamine-bis-acrylamide)/pDNA complexes.

At present, nonviral gene vectors develop rapidly, especially cationic polymers. A series of bioreducible poly(amide amine) (PAA) polymers containing guanidino groups have been synthesized by our research team. These novel polymer vectors demonstrated significantly higher transfection efficiency and lower cytotoxicity than polyethylenimine (PEI)-25kDa. However, compared with viral gene vectors, relatively low transfection efficiency, and high cytotoxicity are still critical problems confronting these polymers. In this study, poly(agmatine/N,N'-cystamine-bis-acrylamide) p(AGM-CBA) was selected as a model polymer, nuclear localization signal (NLS) peptide PV7 (PKKKRKV) with good biocompatibility and nuclear localization effect was introduced to investigate its impact on transfection efficiency and cytotoxicity. NLS peptide-mediated in vitro transfection was performed in NIH 3T3 cells by directly incorporating NLS peptide with the complexes of p(AGM-CBA)/pDNA. Meanwhile, the transfection efficiency and cytotoxicity of these complexes were evaluated. The results showed that the transfection efficiency could be increased by 5.7 times under the appropriate proportion, and the cytotoxicity brought by the polymer vector could be significantly reduced.

Indigo Naturalis Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Modulating the Intestinal Microbiota Community.

Indigo naturalis (IN) is a traditional Chinese medicine, named Qing-Dai, which is extracted from indigo plants and has been used to treat patients with inflammatory bowel disease (IBD) in China and Japan. Though there are notable effects of IN on colitis, the mechanisms remain elusive. Regarding the significance of alterations of intestinal flora related to IBD and the poor water solubility of the blue IN powder, we predicted that the protective action of IN on colitis may occur through modifying gut microbiota. To investigate the relationships of IN, colitis, and gut microbiomes, a dextran sulfate sodium (DSS)-induced mice colitis model was tested to explore the protective effects of IN on macroscopic colitis symptoms, the histopathological structure, inflammation cytokines, and gut microbiota, and their potential functions. Sulfasalazine (SASP) was used as the positive control. Firstly, because it was a mixture, the main chemical compositions of indigo and indirubin in IN were detected by ultra-performance liquid chromatography (UPLC). The clinical activity score (CAS), hematoxylin and eosin (H&E) staining results, and enzyme-linked immunosorbent assay (ELISA) results in this study showed that IN greatly improved the health conditions of the tested colitis mice, ameliorated the histopathological structure of the colon tissue, down-regulated pro-inflammatory cytokines, and up-regulated anti-inflammatory cytokines. The results of 16S rDNA sequences analysis with the Illumina MiSeq platform showed that IN could modulate the balance of gut microbiota, especially by down-regulating the relative quantity of Turicibacter and up-regulating the relative quantity of Peptococcus. The therapeutic effect of IN may be closely related to the anaerobic gram-positive bacteria of Turicibacter and Peptococcus. The inferred metagenomes from 16S data using PICRUSt demonstrated that decreased metabolic genes, such as through biosynthesis of siderophore group nonribosomal peptides, non-homologous end-joining, and glycosphingolipid biosynthesis of lacto and neolacto series, may maintain microbiota homeostasis during inflammation from IN treatment in DSS-induced colitis.