Association between red cell distribution width-and-albumin ratio and the risk of peripheral artery disease in patients with diabetes.

Aim: The aim of this study is to explore the association between red blood cell distribution width-to-albumin ratio (RAR) and the risk of peripheral artery disease (PAD) in patients with diabetes. Methods: This cross-sectional study extracted the data of 1,125 participants with diabetes from the National Health and Nutrition Examination Survey database. A weighted univariable logistic regression model was used to explore variables associated with PAD. With PAD as the outcome variable, a weighted logistic regression model was established. The odds ratio (OR) and 95% confidence interval (CI) were effect size. Results: After adjusting for covariates, the risk of PAD in patients with diabetes was observed in those with higher RAR (OR = 1.83; 95% CI: 1.06-3.15). In addition, RAR ≥3.25 was related to increased risk of PAD in patients with diabetes (OR = 2.04; 95% CI: 1.05-3.95). In people with diabetes aged ≥65, RAR was a risk factor for PAD with an OR value of 2.67 (95% CI: 1.30-5.46). RAR ≥3.25 was associated with increased risk of PAD (OR = 3.06; 95% CI: 1.15-8.11) relative to RAR <2.80. In people with diabetes who smoked, the risk of PAD was elevated in those with RAR ≥3.25 (OR = 2.85; 95% CI: 1.28-6.32). As for patients with cardiovascular disease, the risk of PAD was elevated as the increase of RAR (OR = 2.31; 95% CI: 1.05-5.10). RAR ≥3.25 was correlated with increased risk of PAD (OR = 3.75; 95% CI: 1.42-9.87). The area under the curve of RAR for the risk of PAD in patients with diabetes was 0.631 (95% CI: 0.588-0.675). Conclusion: A higher RAR was related to increased risk of PAD in patients with diabetes. The findings might offer a reference for the management of PAD in patients with diabetes.

Identification of autophagy-related genes in diabetic foot ulcer based on bioinformatic analysis.

Diabetic foot ulcer (DFU) complications involve autophagy dysregulation. This study aimed to identify autophagy-related bioindicators in DFU. Differentially expressed genes (DEGs) between DFU and healthy samples were analysed from the Gene Expression Omnibus (GEO) datasets, GSE7014 and GSE29221. The roles of autophagy-related DEGs were investigated using protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Gene Ontology (GO) enrichment, and Gene Set Enrichment Analysis (GSEA). Immune cell infiltration's correlation with these DEGs was also assessed. From the Human Autophagy Database (HADB), 232 autophagy-related genes (ARGs) were identified, with an intersection of 17 key DEGs between GSE7014 and GSE29221. These genes are involved in pathways like autophagy-animal, NOD-like receptor signalling, and apoptosis. In the protein network, epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN) showed significant interactions with ARGs. Survival analysis indicated the prognostic importance of calpain 2 (CAPN2), integrin subunit beta 1 (ITGB1), and vesicle-associated membrane protein 3 (VAMP3). Lower immune scores were observed in the type 2 diabetes mellitus (DM2) group than in controls. Autophagy and ARGs significantly influence DFU pathophysiology.

Moral resilience in registered nurses: Cultural adaption and validation study.

BACKGROUND: Healthcare professionals, especially professional nurses, experience various types of moral suffering due to inevitable ethical conflicts. Moral resilience is recently proposed as a resource to address moral suffering. However, there is no tool to measure moral resilience in Chinese professional nurses. AIM: This study aimed to translate the Rushton Moral Resilience Scale (RMRS) into Chinese and evaluate the psychometric properties of the Chinese version of RMRS (Chi-RMRS). RESEARCH DESIGN: A methodological and descriptive research design. PARTICIPANTS AND RESEARCH CONTEXT: A convenience sample of 411 Chinese professional nurses was recruited through an online survey platform between February and March 2023. ETHICAL CONSIDERATIONS: This study was approved by the Research Ethics Committees of the University and hospitals involved. RESULTS: The RMRS was translated and culturally adapted into a Chinese version. Neither floor nor ceiling effects were observed. The scale-level content validity index (CVI) was 0.922 with the item-level CVIs ranging from 0.833 to 1.000. The explanatory factor analysis (EFA) generated a three-factor structure for the Chi-RMRS, and the confirmatory factor analysis (CFA) demonstrated the three-factor structure with factor loadings for each item ranging from 0.42 to 0.80. The scale-level Cronbach's α coefficient was 0.811 with each dimension ranging from 0.717 to 0.821, and composite reliability (CR) coefficient for the overall scale was 0.920, with each dimension varying from 0.739 to 0.824. The standard error of measurement (SEM) and smallest detectable change (SDC) were 3.522 and 9.763, respectively. DISCUSSION: The Chi-RMRS is able to measure moral resilience of Chinese professional nurses, and has good validity and reliability. It can be used in research and practice to determine the level of moral resilience, thus helping nursing managers to monitor the status of Chinese professional nurses, then develop interventions to maintain the well-being of professional nurses and to ensure quality of care.

Changes in the Microbiota and their Roles in Patients with Type 2 Diabetes Mellitus.

An association between type 2 diabetes mellitus (T2DM) and gut microbiota is well established, but the results of related studies are inconsistent. The purpose of this investigation is to elucidate the characteristics of the gut microbiota in T2DM and non-diabetic subjects. Forty-five subjects were recruited for this study, including 29 T2DM patients and 16 non-diabetic subjects. Biochemical parameters, including body mass index (BMI), fasting plasma glucose (FPG), serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), and hemoglobin A1c (HbA1c), were analyzed and correlated with the gut microbiota. Bacterial community composition and diversity were detected in fecal samples using direct smear, sequencing, and real-time polymerase chain reaction (PCR). In this study, it was observed that indicators such as BMI, FPG, HbA1c, TC, and TG in T2DM patients were on the rise, concurrent with dysbiosis of the microbiota. We observed an increase in Enterococci and a decrease in Bacteroides, Bifidobacteria, and Lactobacilli in patients with T2DM. Meanwhile, total short-chain fatty acids (SCFAs) and D-lactate concentrations were decreased in the T2DM group. In addition, FPG was positively correlated with Enterococcus and negatively correlated with Bifidobacteria, Bacteroides, and Lactobacilli. This study reveals that microbiota dysbiosis is associated with disease severity in patients with T2DM. The limitation of this study is that only common bacteria were noted in this study, and more in-depth related studies are urgently needed.

An experimental study on grammatical sensitivity and production competence in Chinese and Spanish EFL learners and its implications on EFL teaching methods.

Implicit knowledge acquired by L2 learners determines their language competence; however, it remains an issue to what extent advanced EFL learners can acquire implicit language knowledge. This study aims at finding out whether advanced EFL learners from two different L1s could acquire a level of implicit knowledge of English questions by using the modified Elicited Oral Imitation Task. A quantitative, experimental study with the Elicited Oral Imitation Task experimental tool was designed. A total number of 91 participants were recruited via the online experimental platform from October to November, 2021, distributed into a native speaker group, a Chinese EFL learner group, and a Spanish EFL group. The study evaluated participants' implicit language knowledge by assessing two indicators: the grammatical sensitivity index and the production index. Independent-sample t-test and one-way analysis of variance (ANOVA) were applied to examine the differences in the two indices among different groups. Results revealed that both EFL groups displayed a significant difference with the native speaker group in their degree of implicit knowledge of English questions in general. A further comparison of the two indicators showed that while both EFL groups displayed a relatively high grammatical sensitivity to morpho-syntactic errors in English questions, their corrective production rate of ungrammatical sentences was notably lower. These results indicate that advanced EFL learners had difficulty in acquiring implicit knowledge of English questions at native speaker' level. These findings also imply a gap between EFL learners' language knowledge level and corresponding language production competence. Targeting this gap within the Interaction-based production-oriented approach pedagogical implications based on were suggested for enhancing EFL learners' language production competence in EFL contexts.

Implicit Knowledge Acquisition and Potential Challenges for Advanced Chinese and Spanish EFL Learners: A Word Monitoring Test on English Questions.

This study aims to explore whether advanced EFL learners can acquire implicit knowledge of basic sentence structures, such as English questions. We ran a reaction-time experiment, a word monitoring test experiment to test learners' implicit knowledge by checking advanced EFL learners' grammatical sensitivity to English questions with five types of grammatical errors. The study recruited three groups of participants: native English speakers (n = 12), advanced Chinese EFL learners (n = 32), and advanced Spanish EFL learners (n = 37). Our results revealed that advanced EFL learners had not yet attained native-equivalent implicit grammar knowledge in English questions, despite their English proficiency level. The results also indicated that the learners' different L1 languages do not impact advanced learners' overall implicit knowledge acquisition but constitute influential factors for particular morphosyntactic inflections in English question formation.

Heterospecific eavesdropping on disturbance cues of a treefrog.

Alarm signals and cues are crucial to animal survival and vary greatly across species. Eavesdropping on heterospecific alarm signals and cues can provide eavesdroppers with information about potential threats. In addition to acoustic alarm signals, evidence has accumulated that chemical alarm cues and disturbance cues can also play a role in alerting conspecifics to potential danger in adult anurans (frogs and toads). However, there is very little known about whether disturbance cues are exploited by heterospecifics. In the present study, we conducted a binary choice experiment and a prey chemical discrimination experiment, respectively, to test the responses of a sympatric anuran species (red webbed treefrogs, Rhacophorus rhodopus) and a sympatric predator species (Chinese green tree vipers, Trimeresurus stejnegeri) to disturbance odors emitted by serrate-legged small treefrogs (Kurixalus odontotarsus). In the binary choice experiment, we found that the presence of disturbance odors did not significantly trigger the avoidance behavior of R. rhodopus. In the prey chemical discrimination experiment, compared with odors from undisturbed K. odontotarsus (control odors) and odorless control, T. stejnegeri showed a significantly higher tongue-flick rate in response to disturbance odors. This result implies that disturbance odor cues of K. odontotarsus can be exploited by eavesdropping predators to detect prey. Our study provides partial evidence for heterospecific eavesdropping on disturbance cues and has an important implication for understanding heterospecific eavesdropping on chemical cues of adult anurans.

Learners' perceived advantages and social-affective dispositions toward online peer feedback in academic writing.

Peer feedback is widely acknowledged for its advantages and benefits in improving students' learning in writing classes. Although the integration of online platforms has been found to impact peer feedback, research on second language learners' perceived advantages of social affective disposition to using multiple platforms for delivering peer feedback is limited. To address the aforementioned research gap, we conducted this 12-week action research to explore how 12 doctoral students at a university in Macau perceived their experience of using multiple online feedbacks in an academic writing course. To integrate the various advantages of different online platforms, we adopted three tools including Moodle, Rain Classroom, and WeChat for the delivery of peer feedback. The results demonstrated learners' perceived advantages and disadvantages of online peer feedback and how the different online peer feedback can be combined to magnify their benefits for academic writing. It also revealed that the use of emojis, memes, and one-to-one conversation window on WeChat can foster students' positive emotions. However, the ubiquitous connection by WeChat Moments increased their emotional load and undermined peer trust.

Noise affects mate choice based on visual information via cross-sensory interference.

Animal communication is often hampered by noise interference. Noise masking has primarily been studied in terms of its unimodal effect on sound information provision and use, while little is known about its cross-modal effect and how animals weigh unimodal and multimodal courtship cues in noisy environments. Here, we examined the cross-modal effects of background noise on female visual perception of mate choice and female preference for multimodal displays (sound + vocal sac) in a species of treefrog. We tested female mate choices using audio/video playbacks in the presence and absence of noise (white noise band-filtered to match or mismatch female sensitive hearing range, heterospecific chorus). Surprisingly, multimodal displays do not improve receiver performance in noise. The heterospecific chorus and white noise band-filtered to match female sensitive hearing ranges, significantly reduced female responses to the attractive visual stimuli in addition to directly impairing auditory information use. Meanwhile, the cross-modal impacts of background noise are influenced to some extent by whether the noise band matches female sensitive hearing range and the difficulty of distinguishing tasks. Our results add to the evidence for cross-modal effects of noise and are the first to demonstrate that background noise can disrupt female responses to visual information related to mate choice, which may reduce the communication efficiency of audiovisual signals in noisy environments and impose fitness consequences. This study has key ecological and evolutionary implications because it illustrates how noise influences mate choice in wildlife via cross-sensory interference, which is crucial in revealing the function and evolution of multimodal signals in noisy environments as well as informing evidence-based conservation strategies for forecasting and mitigating the multimodal impacts of noise interference on wildlife.

Combination of sodium butyrate and probiotics ameliorates severe burn-induced intestinal injury by inhibiting oxidative stress and inflammatory response.

Burns are a common traumatic injuries with considerable morbidity and mortality rates. Post-burn intestinal injuries are closely related to oxidative stress and inflammatory response. The aim of the current study was to investigate the combined effect of sodium butyrate (NaB) and probiotics (PROB) on severe burn-induced oxidative stress and inflammatory response and the underlying mechanism of action. Sprague-Dawley rats with severe burns were treated with NaB with or without PROB. Pathomorphology of skin and small intestine tissue was observed using hematoxylin and eosin staining and severe burn-induced apoptosis in small intestine tissue was examined via terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The release of factors related to inflammation was quantified using ELISA kits and qRT-PCR and levels of oxidative stress markers were evaluated using biochemical assays. Furthermore, mitochondrial morphological changes in small intestinal epithelial cells were observed using transmission electron microscopy. In addition, the underlying mechanism associated with the combined effect of NaB and PROB on severe burn-induced oxidative stress and inflammatory response was investigated using western blotting. The combination of NaB and PROB exerted protective effects against severe burn-induced intestinal barrier injury by reducing the levels of diamine oxidase and intestinal fatty acid binding protein. Combined NaB and PROB treatment inhibited severe burn-induced oxidative stress by increasing superoxide dismutase levels and decreasing those of malondialdehyde and myeloperoxidase levels. Severe burn-induced inflammation was suppressed by combined NaB and PROB administration, as demonstrated by the decreased mRNA expression of tumor necrosis factor-α, interleukin-6, interleukin-1ß, and high mobility group box-1 in the small intestine. In addition, this study showed that combined NaB and PROB administration increased nuclear factor-erythroid 2-related factor 2 (Nrf2) protein expression and decreased the phosphorylation of nuclear factor (NF)-κB and extracellular signal-regulated kinase 1/2 (ERK 1/2). In conclusion, our findings indicate that combined NaB and PROB treatment may inhibit severe burn-induced inflammation and oxidative stress in the small intestine by regulating HMGB1/NF-κB and ERK1/2/Nrf2 signaling, thereby providing a new therapeutic strategy for intestinal injury induced by severe burn.

TSSK4 upregulation in alveolar epithelial type-II cells facilitates pulmonary fibrosis through HSP90-AKT signaling restriction and AT-II apoptosis.

Alveolar epithelial injury is one of the important pathological changes in idiopathic pulmonary interstitial fibrosis (IPF), but the regulatory mechanism remains unclear. Here, we reported that alveolar epithelial type-II cells (AT II) play important roles in pathological process of pulmonary fibrosis. Through iTRAQ (isobaric tagging for relative and absolute quantification) quantitative proteomics, TSSK4 was identified to be upregulated in bleomycin-induced fibrotic mice model, which was further confirmed in clinical IPF patients' tissue specimens. TSSK4 is a germ-related protein, but its expression in other tissues and the association with other diseases are not reported. Immunofluorescence staining showed that TSSK4 selectively expressed in AT-II cells, which are essential for inflammation-induced AT-II loss during fibrosis. Luciferase assay and other molecular biological experiments proved that TSSK4 expression is regulated by TNF-α-mediated NF-κB signaling. The TSSK4 kinase activity is found to be closely related to the function of HSP90-AKT pathway that TSSK4 can phosphorylate its substrate HSP90ß on serine 255, to inhibit the ATPase activity of HSP90ß and reduce its molecular chaperone function on AKT. Under this condition, kinase activity of AKT is diminished to interfere its survival function, subsequently facilitating AT-II cellular apoptosis through the mitochondrial death machinery. Our findings highlight the importance of TSSK4 in regulating pulmonary fibrosis by facilitating AT-II loss through HSP90-AKT signaling, all of which suggest TSSK4 and the regulating mechanism as attractive targets for the clinical intervention of pulmonary injury and fibrosis.

HSP70 promotes tumor progression by stabilizing Skp2 expression in gastric cancer cells.

Gastric cancer (GC) has one of the highest tumor incidences worldwide. Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To explore the regulatory role of HSP70 in GC, we performed cell counting kit-8 (CCK-8) and EdU staining assays to assess cell proliferation; immunohistochemistry and western blot analyses to assess protein expression; coimmunoprecipitation (Co-IP) assays to assess interactions between two proteins; and immunofluorescence to assess protein expression and localization. HSP70 was highly expressed in clinical samples from patients with GC and indicated a poor prognosis. HSP70 inhibition enhanced the sensitivity of GC cells to thermochemotherapy. Furthermore, we found that S phase kinase-associated protein 2 (Skp2) was highly expressed in GC and correlated with HSP70 in array data from The Cancer Genome Atlas (TCGA). Importantly, HSP70 inhibition promoted Skp2 degradation. Skp2 overexpression abrogated HSP70 inhibition-induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy.

Females and males respond differently to calls impaired by noise in a tree frog.

Both human and nonhuman animals communicating acoustically face the problem of noise interference, especially anurans during mating activities. Previous studies concentrated on the effect of continuous noise on signal recognition, but it is still unknown whether different notes in advertisement calls impaired by noise affect female choice and male-male competition or not. In this study, we tested female preferences and male-evoked vocal responses in serrate-legged small tree frog (Kurixalus odontotarsus), by broadcasting the five-note advertisement call and the advertisement call with the second, third, or fourth note replaced by noise, respectively. In phonotaxis experiments, females significantly discriminated against the advertisement call with the fourth note impaired by noise, although they did not discriminate against other two calls impaired by noise, which indicates that the negative effect of noise on female preference is related to the order of impaired notes in the advertisement call. In playback experiments, males increased the total number of notes in response to noise-impaired calls compared with spontaneous calls. More interestingly, the vocal responses evoked by noise-impaired calls were generally similar to those evoked by complete advertisement calls, suggesting that males may recognize the noise-impaired calls as complete advertisement calls. Taken together, our study shows that different notes in advertisement calls replaced by noise have distinct effects on female choice and male-male competition.

Conspecific odor cues induce different vocal responses in serrate-legged small treefrogs, but only in the absence of acoustic signals.

BACKGROUND: Signal detection is crucial to survival and successful reproduction, and animals often modify behavioral decisions based on information they obtained from the social context. Undeniably, the decision-making in male-male competition and female choice of anurans (frogs and toads) depends heavily on acoustic signals. However, increasing empirical evidence suggests that additional or alternative types of cue (e.g., visual, chemical, and vibratory) can be used to detect, discriminate and locate conspecifics in many anuran species. Nevertheless, few studies have investigated whether conspecific odor cues affect male's calling behavior. In this study, we conducted an experiment to investigate whether and how different chemical cues (male odors, female odors, and stress odors) from conspecifics affect male's calling strategies in serrate-legged small treefrogs (Kurixalus odontotarsus), and whether the combined chemical and acoustic stimuli have additive effects on calling behavior or not. RESULTS: We found that compared with female odors, male K. odontotarsus reduced calling investment in response to male odors or stress odors, in the absence of rival's advertisement calls. When odor stimuli and advertisement calls were presented simultaneously, however, there were no differences in the vocal response of focal males among odor groups. CONCLUSIONS: These results provide evidence that male treefrogs switch calling investment according to different odor cues from conspecifics, and further demonstrate that calling behavior can be affected by chemical cues in anuran species. Our study highlights the potential role of airborne chemical cues in sex identification and contributes to increase our understanding of anuran communication.

Immunoglobulin D-λ/λ biclonal multiple myeloma: A case report.

BACKGROUND: Immunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of MM and commonly occurs in younger subjects but at a later stage of the International Staging System (ISS) when admitted. As a special type of IgD myeloma, IgD-λ/λ biclonal MM is rarer. Its serum protein electrophoresis and serum immuno-fixation electrophoresis (IFE) might find no anomalies even if the bone marrow (BM) examination is performed. Thus, it is easy to miss the diagnosis. CASE SUMMARY: A 62-year-old man diagnosed as IgD-λ/λ myeloma (ISS stage III) was admitted with fatigue and weight loss. The physical examination suggested an anemic face, a few moist rales at the left lung base, and mild concave edema in both lower extremities. Laboratory examinations showed the elevated creatinine levels, ß2-microglobulin, lactic dehydrogenase, and erythrocyte sedimentation rate, while the decreased neutrophils, granulocytes, and hemoglobin. In the serum protein electrophoresis, there appeared two inconspicuous M-spikes. Serum IFE indicated an over-representation of lambda light chain and yielded two monoclonal bands in λ region, but only one corresponding heavy chain band in the antisera to IgD region. The BM histology and BM cytology both supported the diagnosis of IgD-λ/λ myeloma. CONCLUSION: This case highlights the differential clinical manifestations and laboratory findings of IgD-λ/λ myeloma to help minimize the chance of misdiagnosis.

Fibrinogen/AKT/Microfilament Axis Promotes Colitis by Enhancing Vascular Permeability.

BACKGROUND & AIMS: Increased vascular permeability (VP) has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). However, the pathological causes of increased intestinal VP in IBD remain largely unknown. METHOD: Fibrinogen level was measured in dextran sulphate sodium (DSS)-induced colitis and patients with ulcerative colitis. Gly-Pro-Arg-Pro acetate (GPRP), an Fg inhibitor, was used to detect the effect of Fg inhibition on the pathogenesis of DSS-induced colitis, as indicated by tissue damage, cytokine release and inflammatory cell infiltration. Miles assay was used to detect vascular permeability. RESULTS: Through tandem mass tag-based quantitative proteomics, fibrinogen (Fg) was found to be upregulated in the colon of DSS-treated mice, which was consistent with increased Fg level in colon sample of patients with ulcerative colitis. Gly-Pro-Arg-Pro acetate (GPRP), an Fg inhibitor, significantly alleviated DSS-induced colitis as indicated by improvement of body weight loss and mortality. GPRP decreased colonic inflammation and VP in DSS-treated mice. In vivo, Fg enhanced VP as indicated by Miles assay, which was significantly inhibited by GRPR, AKT (serine/threonine kinase 1) inhibitors and low doses of Jasplakinolide which induced actin polymerization, while was dramatically enhanced by Cytochalasin D (an actin polymerization inhibitor). Moreover, activation of AKT was found in vessels of DSS-treated mice. In vitro, Fg induced activation of AKT and depolymerization of microfilament and promoted cell-to-cell disaggregation. Furthermore, inhibition of AKT decreased Fg-induced microfilament depolymerization. CONCLUSIONS: Our findings highlight the importance of Fg in regulating colitis by modulation of VP via activating AKT and subsequent depolymerization of microfilament and suggest Fg as an attractive target for anti-colitis treatment.

Male serrate-legged treefrogs adjust competition strategies according to visual or chemical cues from females.

There is increasing evidence that many anurans use multimodal cues to detect, discriminate and/or locate conspecifics and thus modify their behaviors. To date, however, most studies have focused on the roles of multimodal cues in female choice or male-male interactions. In the present study, we conducted an experiment to investigate whether male serrate-legged small treefrogs (Kurixalus odontotarsus) used visual or chemical cues to detect females and thus altered their competition strategies in different calling contexts. Three acoustic stimuli (advertisement calls, aggressive calls and compound calls) were broadcast in a randomized order after a spontaneous period to focal males in one of four treatment groups: combined visual and chemical cues of a female, only chemical cues, only visual cues and a control (with no females). We recorded the vocal responses of the focal males during each 3 min period. Our results demonstrate that males reduce the total number of calls in response to the presence of females, regardless of how they perceived the females. In response to advertisement calls and compound calls, males that perceived females through chemical cues produced relatively fewer advertisement calls but more aggressive calls. In addition, they produced relatively more aggressive calls during the playback of aggressive calls. Taken together, our study suggests that male Kodontotarsus adjust their competition strategies according to the visual or chemical cues of potential mates and highlights the important role of multisensory cues in male frogs' perception of females.

Toll-like Receptor 4 Deficiency Aggravates Airway Hyperresponsiveness and Inflammation by Impairing Neutrophil Apoptosis in a Toluene Diisocyanate-Induced Murine Asthma Model.

PURPOSE: Accumulating evidence has suggested that toll-like receptor 4 (TLR4) is critically involved in the pathogenesis of asthma. The aim of this study was to investigate the role of TLR4 in toluene diisocyanate (TDI)-induced allergic airway inflammation. METHODS: TLR4-/- and wild-type (WT) C57BL/10J mice were sensitized and challenged with TDI to generate a TDI-induced asthma model. B-cell lymphoma 2 (Bcl-2) inhibitors, ABT-199 (4 mg/kg) and ABT-737 (4 mg/kg), were intranasally given to TDI-exposed TLR4-/- mice after each challenge. RESULTS: TDI exposure led to increased airway hyperresponsiveness (AHR), granulocyte flux, bronchial epithelial shedding and extensive submucosal collagen deposition, which were unexpectedly aggravated by TLR4 deficiency. Following TDI challenge, TLR4-/- mice exhibited down-regulated interleukin-17A and increased colony-stimulating factor 3 in bronchoalveolar lavage fluid (BALF), while WT mice did not. In addition, TLR4 deficiency robustly suppressed the expression of NOD-like receptor family pyrin domain containing 3 and NLR family CARD domain containing 4, decreased caspase-1 activity in TDI-exposed mice, but had no effect on the level of high mobility group box 1 in BALF. Flow cytometry revealed that TDI hampered both neutrophil and eosinophil apoptosis, of which neutrophil apoptosis was further inhibited in TDI-exposed TLR4-/- mice, with marked up-regulation of Bcl-2. Moreover, inhibition of Bcl-2 with either ABT-199 or ABT-737 significantly alleviated neutrophil recruitment by promoting apoptosis. CONCLUSIONS: These data indicated that TLR4 deficiency promoted neutrophil infiltration by impairing its apoptosis via up-regulation of Bcl-2, thereby resulting in deteriorated AHR and airway inflammation, which suggests that TLR4 could be a negative regulator of TDI-induced neutrophilic inflammation.

Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model.

Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1ß signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased TH2/TH17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased TH2 response and lower levels of IL-18 and IL-1ß. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1ß, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed TH2/TH17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.

Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells.

Necroptosis of intestinal epithelial cells has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). The identification of dysregulated proteins that can regulate necroptosis in dextran sulfate sodium (DSS)-induced colitis is the key to the rational design of therapeutic strategies for colitis. Through tandem mass tag (TMT)-based quantitative proteomics, HtrA2 was found to be downregulated in the colon of DSS-treated mice. UCF-101, a specific serine protease inhibitor of HtrA2, significantly alleviated DSS-induced colitis as indicated by prevention of body weight loss and decreased mortality. UCF-101 decreased DSS-induced colonic inflammation, prevented intestinal barrier function loss and inhibited necroptosis of intestinal epithelial cells. In vitro, UCF-101 or silencing of HtrA2 decreased necroptosis of HT-29 and L929 cells. UCF-101 decreased phosphorylation of RIPK1 and subsequent phosphorylation of RIPK3 and MLKL during necroptosis. Upon necroptotic stimulation, HtrA2 translocated from mitochondria to cytosol. HtrA2 directly interacted with RIPK1 and promoted its degradation during a specific time phase of necroptosis. Our findings highlight the importance of HtrA2 in regulating colitis by modulation of necroptosis and suggest HtrA2 as an attractive target for anti-colitis treatment.