5-Hydroxytryptamine 4 Receptor Agonist Attenuates Diabetic Enteric Neuropathy through Inhibition of the Receptor-Interacting Protein Kinase 3 Pathway.

Necroptosis, considered as a form of programmed cell death, contributes to neural loss. The 5-hydroxytryptamine 4 receptor (5-HT4R) is involved in neurogenesis in the enteric nervous system. However, whether the activation of 5-HT4R can alleviate diabetic enteric neuropathy by inhibiting receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is unclear. This study aimed to explore the beneficial effects of 5-HT4R agonist on enteric neuropathy in a mouse model of diabetes and the mechanisms underlying these effects. Diabetes developed neural loss in the colon of mice. 5-HT4Rs localized in submucosal and myenteric plexuses were confirmed. Administration of 5-HT4R agonist attenuated diabetes-induced colonic hypomotility and neural loss of the colon in mice. Remarkably, RIPK3, phosphorylated RIPK3, and its downstream target mixed lineage kinase domain-like protein (MLKL), two key proteins regulating necroptosis, were significantly up-regulated in the colon of diabetic mice. Treatment with 5-HT4R agonist appeared to inhibit diabetes-induced elevation of RIPK3, phosphorylated RIPK3, and MLKL in the colon of mice. Diabetes-induced up-regulation of MLKL in both the mucosa and the muscularis of the colon was prevented by Ripk3 deletion. Moreover, diabetes-evoked neural loss and delayed colonic transit were significantly inhibited by Ripk3 removal. These findings suggest that activation of 5-HT4Rs could potentially provide a protective effect against diabetic enteric neuropathy by suppressing RIPK3-mediated necroptosis.

UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting.

Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including α-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fast-twitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer.

LncRNA AFAP1-AS1 mediates breast cancer cell proliferation and migration through the miR-21/PTEN axis.

LncRNAs play various effects, mostly by sponging with miRNAs. Based on public databases integrating bioinformatics analyses and further validation in breast cancer (BC) tissue and cell lines, the effect of lncRNA AFAP1-AS1 on breast cancer cell proliferation and migration was verified. It might work via the miR-21/PTEN axis. The expression of AFAP1-AS1, which was significantly upregulated in BC tissues and cell lines, was correlated with old age and lymph node metastasis of patients with BC. Knockdown of AFAP1-AS1 inhibited the proliferation and migration of BC cells in vitro and in vivo. And downregulated miR-21 expression and upregulated PTEN expression additionally. Mechanistically, the knockdown of lncRNA AFAP1-AS1 upregulated PTEN expression and consequently attenuated miR-21-mediated enhanced BC cell proliferation and migration. LncRNA AFAP1-AS1 is a potential prognostic biomarker for BC patients.

Transcriptome and Metabolome Analyses Provide Insight into the Glucose-Induced Adipogenesis in Porcine Adipocytes.

Glucose is a major energy substrate for porcine adipocytes and also serves as a regulatory signal for adipogenesis and lipid metabolism. In this study, we combined transcriptome and metabolome analyses to reveal the underlying regulatory mechanisms of high glucose (HG) on adipogenesis by comparing differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) identified in porcine adipocytes. Results showed that HG (20 mmol/L) significantly increased fat accumulation in porcine adipocytes compared to low glucose (LG, 5 mmol/L). A total of 843 DEGs and 365 DAMs were identified. Functional enrichment analyses of DEGs found that multiple pathways were related to adipogenesis, lipid metabolism, and immune-inflammatory responses. PPARγ, C/EBPα, ChREBP, and FOS were identified as the key hub genes through module 3 analysis, and PPARγ acted as a central regulator by linking genes involved in lipid metabolism and immune-inflammatory responses. Gene-metabolite networks found that PPARγ-13-HODE was the most important interaction relationship. These results revealed that PPARγ could mediate the cross-talk between adipogenesis and the immune-inflammatory response during adipocyte maturation. This work provides a comprehensive view of the regulatory mechanisms of glucose on adipogenesis in porcine adipocytes.

Study on the susceptibility of bovine coronavirus to BALB/c mice.

There are no other bovine coronavirus (BCoV) infection models except calves, which makes efficacy evaluation of vaccines and pathogenic mechanism research of BCoV inconvenient owing to their high value and inconvenient operation. This study aimed to establish a mouse model of BCoV infection. BCoV was used to infect 4-week-old male BALB/c mice and the optimal infection conditions were screened, including the following infection routes: gavage, intraperitoneal injection, and tail vein injection at doses of 1 × 108 TCID50, 2 × 108 TCID50 and 4 × 108 TCID50. Using the optimal infection conditions, BALB/c mice were infected with BCoV, and their body weight, blood routine, inflammatory factors, autopsy, virus distribution, and viral load were measured at 1, 3, 5, and 7 days after infection. The results showed that the optimal conditions for infecting BALB/c mice with BCoV HLJ-325 strain were continuous oral gavage for 3 days with a dose of 4 × 108 TCID50. On the 7th day after infection, there was significant extensive consolidation of the lungs and thinning of the colon wall. Significant inflammation was observed in various organs, especially in the colon and alveoli, where a large number of inflammatory cells infiltrate. Both BCoV Ag and nucleic acid are positive in visceral organs. The viral load in the colon and lungs was significantly higher than that in the other organs (p < 0.001). BCoV-infected mice showed a decreasing trend in body weight starting from day 5, and there was a significant difference compared to the control group on days 6 and 7 (p < 0.001). The total number of white blood cells and lymphocytes began to decrease and was significantly lower than that in the control group 24 h after infection (p < 0.001), and gradually returned to the control level. The cytokine TNF-α, IL-1ß, and IL-6 showed an increasing trend, significantly higher than the control group on day 5 and 7 (p < 0.001). These results indicate that the BCoV HLJ-325 strain can infect BALB/c mice and cause inflammatory reactions and tissue lesions. The most significant effect was observed on the seventh day after infection with a dose of 4 × 108 TCID50 and three consecutive gavages. This study established, for the first time, a BALB/c mouse model of BCoV infection, providing a technical means for evaluating the immune efficacy of BCoV vaccines and studying their pathogenic mechanisms.

Gut microbiota regulates chronic ethanol exposure-induced depressive-like behavior through hippocampal NLRP3-mediated neuroinflammation.

Chronic ethanol exposure (CEE), which can lead to neuroinflammation, is an increasing risk factor for depression disorder, but the underlying mechanism is not clear. Recent observations have revealed the associations among psychiatric disorders, ethanol exposure and alterations of the gut microbiota. Here, we found that CEE induced depressive-like behavior, which could be alleviated by probiotics and transferred from donor to recipient mice by fecal microbiota transplantation (FMT). Neuroinflammation and the activation of the NLRP3 inflammasome were also observed in recipient mice. The downregulation of NLRP3 in the hippocampus mitigated CEE-induced depressive-like behavior and neuroinflammation but had no significant effect on FMT recipient mice. Moreover, elevated serum inflammatory factors in recipient mice showed a significant mediation effect between the gut microbiota and depressive-like behavior. Together, our study findings indicate that the gut microbiota contributes to both hippocampal NLRP3-mediated neuroinflammation and depressive-like behavior induced by CEE, which may open avenues for potential interventions against CEE-associated psychiatric disorders.

The effects of self-esteem and parental phubbing on adolescent internet addiction and the moderating role of the classroom environment: a hierarchical linear model analysis.

BACKGROUND: With the advent of the new media era, the understanding of adolescent internet addiction needs to be enriched. It is also necessary to distinguish the related factors of adolescent internet addiction at different levels to clarify the mechanisms of this phenomenon. METHODS: This study used hierarchical linear model analysis to explore the effects of student-level factors and school-level factors on adolescent internet addiction, along with cross-level moderating effects. A total of 1,912 students between the 4th and 8th grades in China participated in the study. Participants completed the Self-Esteem Scale, Parents Phubbing Scale, Classroom Environment Scale, and the Diagnostic Questionnaire of Internet Addiction. RESULTS: Correlational analyses revealed that internet addiction was found to be negatively correlated with both self-esteem and the teacher-student relationship (p < 0.01), while father phubbing, mother phubbing, and learning burden were shown to positively correlate with internet addiction (p < 0.01). Hierarchical linear model analysis suggested that student-level variables, including self-esteem, and mother phubbing, were significant predictors of internet addiction (ß = -0.077, p < 0.001 and ß = 0.028, p < 0.01, respectively). At the school level, learning burden significantly and negatively predicted internet addiction (ß = 0.073, p < 0.05). Furthermore, the relationship between self-esteem and internet addiction was significantly moderated by learning burden (ß = -0.007, p < 0.05). Meanwhile, the teacher-student relationship also had a significant moderating effect on the association between mother phubbing and internet addiction (ß = -0.005, p < 0.01). CONCLUSIONS: This study revealed the relationships between self-esteem, parental phubbing, and classroom environment with adolescent internet addiction, and these findings could provide insights into reducing adolescent internet addiction from the perspective of individuals, families, and schools.

The mitigative role of novel aflatoxin-degrading enzymes in diverse broiler performance indicators and gut microbiota following the consumption of diets contaminated with aflatoxins.

BACKGROUND: This study aims to explore both the toxic effects of aflatoxins (AFs) and the protective effects of degrading enzymes (DE) on broilers exposed to AFs. RESULTS: The findings reveal that a diet contaminated with 69.15 µg kg-1 of aflatoxin B1 had significant adverse effects on broilers. Specifically, it led to a reduction in average daily gain, dressed yield percentage, half-eviscerated yield with giblet yield percentage, eviscerated yield percentage, as well as serum superoxide dismutase (SOD), glutathione peroxidase activity and liver SOD activity (P < 0.05). Conversely, the diet increased the feed conversion ratio, liver index, serum glutamic oxaloacetic transaminase levels and malondialdehyde levels in both serum and liver (P < 0.05). Additionally, AFs disrupted the intestinal microflora significantly (P < 0.05), altering the relative abundance of Enterococcus, Lactobacillus and Escherichia in broiler jejunum. The addition of DE to AF-contaminated feed mitigated these negative effects and reduced the residues of aflatoxin B1, aflatoxin B2 and aflatoxin M1 in the liver and duodenum (P < 0.05). We also observed that broilers fed the diet pelleted at 80 °C exhibited improved dressing percentage and water holding capacity compared to those on the 75 °C diet. CONCLUSION: In summary, DE serves as an effective feed additive for mitigating AF contamination in poultry production. © 2024 Society of Chemical Industry.

Testing the Associations Between Attachment Anxiety, Relational Aggression and Depressive Symptoms in Romantic Relationships: Actor-Partner Interdependence Model and Actor-Partner Interdependence Mediator Model.

Emerging adulthood is a pivotal period for romantic relationships, yet the specific mechanisms through which attachment anxiety influences relationship dynamics and psychological outcomes in this phase are poorly understood. Particularly, in the context of romantic dyads, understanding how partners' behaviors and emotional patterns reciprocally influence each other remains underexplored. This study utilizes the Actor-Partner Interdependence Model and Actor-Partner Interdependence Mediator Model to explore the relationship between attachment anxiety,relational aggression (both perpetration and victimization), and depressive symptoms among emerging adults. A sample of 138 mixed-sex emerging adulthood couples from China, was recruited (Mage = 21.40, SD = 2.54; 50% female, 62.6% reporting that this relationship was ongoing for more than a year). Attachment anxiety significantly predicted relational aggression in both partners, with male attachment anxiety also significantly predicted female relational aggression. Significant indirect effects of both partners' relational aggression perpetration and victimization on their own and each other's relationship between attachment anxiety and depressive symptoms. These findings contribute to understanding the intricate dynamics of attachment anxiety and relational aggression in romantic relationships during emerging adulthood, emphasizing the need for targeted interventions to mitigate these risks.

The Vicious Cycle between Loneliness and Problematic Smartphone Use among Adolescents: A Random Intercept Cross-Lagged Panel Model.

Despite extensive research on the psychological impacts of digital technology, the nuanced dynamics between adolescent loneliness and problematic smartphone use, particularly across different educational levels and genders, remain underexplored. This study aims to fill this gap by employing a Random Intercept Cross-Lagged Panel Model to dissect the bidirectional relationship between loneliness and problematic smartphone use among adolescents, with a focus on the moderating roles of educational levels and gender. Engaging 3132 students from various educational institutions in China, the research conducted a three-wave longitudinal analysis across 2022-2023. The final number of participants included 1120 adolescents (53.5% female; age in 2022: M = 14.57 years, SD = 1.57). Results reveal that loneliness significantly predicts problematic smartphone use, but not vice versa, highlighting a unidirectional influence. The study uncovers crucial differences across educational levels and gender, emphasizing the stronger effect of loneliness on problematic smartphone use among junior high students and female adolescents. These findings underscore the complexity of adolescent loneliness and its relationship with digital behavior, suggesting a need for tailored interventions considering both gender and developmental stages.

Characterizing nighttime vertical profiles of atmospheric particulate matter and ozone in a megacity of south China using unmanned aerial vehicle measurements.

Daytime atmospheric pollution has received wide attention, while the vertical structures of atmospheric pollutants at night play a crucial role in the photochemical process on the following day, which is still less reported. Focusing on Guangzhou, a megacity of South China, we established an unmanned aerial vehicle (UAV) equipped with micro detectors to collect consecutive high-resolution samples of fine particle (PM2.5), submicron particle (PM1.0), black carbon (BC) and ozone (O3) concentrations in the atmosphere, as well as the air temperature (AT) and relative humidity (RH) within a 500 m altitude during nighttime from Oct. 24th to Nov. 6th, 2018. The measurements showed that PM2.5, PM1.0, and BC decreased with altitude and were influenced by the nighttime shallow planetary boundary layer (PBL) where BC was more accumulated and fluctuated. In contrast, O3 was positively correlated with altitude. Backward trajectory clustering and Pasquill stability classification showed that advection and convection significantly influenced the vertical distribution of all pollutants, particularly particulate matter. External air masses carrying high concentrations of pollutants increased PM1.0 and PM2.5 levels by 145% and 455%, respectively, compared to unaffected periods. The ratio of BC to PM2.5 indicated that local emissions had a minor role in nighttime particulate matter. Vertical transport caused by atmospheric instability reduced the differences in pollutant concentrations at various heights. Geodetector and generalized additive model showed that RH and BC accumulation in the PBL were significant factors influencing vertical changes of the secondary aerosol intensity as indicated by the ratio of PM1.0 to PM2.5. The joint explanation of RH and atmospheric stability with other variables such as BC is essential to understand the generation of secondary aerosols. These findings provide insights into regional and local measures to prevent and control night-time particulate matter pollution.

Tuning Thermostability and Catalytic Efficiency of Aflatoxin-Degrading Enzyme by Error-prone PCR.

In our previous work, a recombinant aflatoxin-degrading enzyme derived from Myxococcus fulvus (MADE) was reported. However, the low thermal stability of the enzyme had limitations for its use in industrial applications. In this study, we obtained an improved variant of recombinant MADE (rMADE) with enhanced thermostability and catalytic activity using error-prone PCR. Firstly, we constructed a mutant library containing over 5000 individual mutants. Three mutants with T50 values higher than the wild-type rMADE by 16.5 °C (rMADE-1124), 6.5 °C (rMADE-1795), and 9.8 °C (rMADE-2848) were screened by a high-throughput screening method. Additionally, the catalytic activity of rMADE-1795 and rMADE-2848 was improved by 81.5% and 67.7%, respectively, compared to the wild-type. Moreover, structural analysis revealed that replacement of acidic amino acids with basic amino acids by a mutation (D114H) in rMADE-2848 increased the polar interactions with surrounding residues and resulted in a threefold increase in the t1/2 value of the enzyme and made it more thermaltolerate. KEY POINTS: • Mutant libraries construction of a new aflatoxins degrading enzyme by error-prone PCR. • D114H/N295D mutant improved enzyme activity and thermostability. • The first reported enhanced thermostability of aflatoxins degrading enzyme better for its application.

Prospective association between perceived stress and anxiety among nursing college students: the moderating roles of career adaptability and professional commitment.

BACKGROUND: Anxiety may stay with nursing students throughout their internship and even persist afterwards. Although many studies have explored the effects of perceived stress on anxiety, the relationship between pre-internship perceived stress and post-internship anxiety levels has not been clarified. In addition, none had focused on the moderating roles of career adaptability and professional commitment between perceived stress and anxiety. This study aims to investigate the influence of pre-internship perceived stress on the post-internship anxiety level of nursing college students, and to analyze the moderating effects of career adaptability and professional commitment on their relationships. METHODS: A longitudinal study design was employed. Full-time nursing college students from a Chinese medical university were recruited by convenient sampling. All surveys were conducted via Wen Juan Xing ( www.wjx.cn ), a widely used web-based survey platform in China. Two waves of surveys were collected in the pre-internship and post-internship periods, with an interval of one year. Among 823 nursing students recruited, 692 students completed all two waves of the survey (response rate: 84.08%). Participants completed a series of questionnaires examining general demographic characteristics, perceived stress, anxiety, career adaptability, and professional commitment both before and after the internship. The bias-corrected bootstrap technique of the Hayes PROCESS macro (Model 2) was used to test the moderation effect. RESULTS: Pre-internship perceived stress was positively associated with post-internship anxiety (ß = 0.474, p < 0.001). Career adaptability would mitigate the effect of perceived stress on anxiety (ß = -0.009, p < 0.01, 95% CI = [-0.013, -0.004]), and this influence became stronger for nursing college students with higher levels of career adaptability. Instead, the professional commitment would enhance the effect of perceived stress on anxiety (ß = 0.004, p < 0.05, 95% CI = [0.001, 0.009]). CONCLUSIONS: Adequate career adaptability was key to alleviating anxiety among nursing interns. Nursing educators and clinical nursing managers should pay attention to cultivating the career adaptability of nursing college students in order to help them successfully achieve identity transformation and career development. Meanwhile, it is crucial to guide them to develop appropriate professional commitment.

Dynamic attitude measurement taken by monocular line scan vision.

Attitude measurements are important parameters for condition monitoring of precision machines. We develop an angle measurement method based on monocular line scan vision to dynamically measure the attitude of shafts. The proposed measurement system, which consists of a single line scan camera, a parallel laser light source, and a triangular mirror, does not require fixation of a sensor on the shaft. The measurement system uses the line scan camera to capture the projection of the shaft. The light source is diffused by a cylindrical lens to yield parallel directional light. Then the parallel directional light is reflected by a fixed-angle mirror and projected onto the projection plane. The captured image can be considered a discrete time sequence. The attitude measurement principle based on linear monocular vision is derived. A double light-spot centroid algorithm is developed to obtain the centroid coordinates of the projection points. The proposed method is investigated by a simulation and experiment. The proposed method can also monitor the vibration of the shaft. The experimental results prove that the proposed method is effective and highly accurate.

Activation of the 5-hydroxytryptamine 4 receptor ameliorates tight junction barrier dysfunction in the colon of type 1 diabetic mice.

Hyperglycemia drives dysfunction of the intestinal barrier. 5-Hydroxytryptaine 4 receptor (5-HT 4R) agonists have been considered therapeutics for constipation in clnic. However, the roles of 5-HT 4R activation in mucosa should be fully realized. Here, we investigate the effects of 5-HT 4R activation on diabetes-induced disruption of the tight junction (TJ) barrier in the colon. Not surprisingly, the TJ barrier in diabetic mice with or without 5-HT 4R is tremendously destroyed, as indicated by increased serum fluorescein isothiocyanate (FITC)-dextran and decreased transepithelial electrical resistance (TER). Simultaneously, decreased expressions of TJ proteins are shown in both wild-type (WT) and 5-HT 4R knockout (KO) mice with diabetes. Notably, chronic treatment with intraperitoneal injection of a 5-HT 4R agonist in WT mice with diabetes repairs the TJ barrier and promotes TJ protein expressions, including occludin, claudin-1 and ZO-1, in the colon, whereas a 5-HT 4R agonist does not improve TJ barrier function or TJ protein expressions in 5-HT 4R KO mice with diabetes. Furthermore, stimulation of 5-HT 4R inhibits diabetes-induced upregulation of myosin light chain kinase (MLCK), Rho-associated coiled coil protein kinase 1 (ROCK1), and phosphorylated myosin light chain (p-MLC), which are key molecules that regulate TJ integrity, in the colonic mucosa of WT mice. However, such action induced by a 5-HT 4R agonist is not observed in 5-HT 4R KO mice with diabetes. These findings indicate that 5-HT 4R activation may restore TJ integrity by inhibiting the expressions of MLCK, ROCK1 and p-MLC, improving epithelial barrier function in diabetes.

Recovery of Ni matte from Ni-bearing electroplating sludge.

In this study, a novel process for the recovery of Ni from Ni-bearing electroplating sludge (ES) is proposed, which involves the carbothermic reduction stage and smelting stage. In the reduction stage, the CaSO4, Fe2O3, and NiO in the ES were reduced by carbon at 1000 °C, and the Ni3S2 and Fe4Ni5S8(Ni-rich phases) were generated. After that, the reduced ES was mixed with SiO2 and smelted at 1500 °C. During the smelting stage, Ni3S2 and Fe4Ni5S8 were melted to form liquid Ni-Fe-S matte and separated from the molten slag by gravity. Finally, 58.5%Ni-13.8%Fe-27.7%S (in weight) matte and vitrified slag were obtained. The recovery ratio of Ni (97.2%) was much higher than that of Fe (14.7%). Besides, the Ni/Fe mass ratio of the ES was 0.7, while the ratio of the prepared matte was about 4.2. Therefore, the selective recovery of Ni was achieved. The obtained Ni matte can be used as the raw material for pure Ni or Ni-bearing chemicals.

Longitudinal relationships among career adaptability, resilience, and career commitment in chinese nursing undergraduates: testing differences in career interest between cross-lagged models.

PURPOSE: Various physiological and psychological negative situations experienced by nurses as a result of COVID-19 pandemic have been shown to increase their perception of organizational difficulty and decrease their career commitment, thereby accelerating the turnover rate of nurses. Resilience and career adaptability have important influences on career commitment, so there is a need to evaluate the relationships between them and the underlying mechanisms. PATIENTS AND METHODS: Using a cross-lagged design, the Career Adaptability Scale, the Chinese version of career commitment, and Davidson's Resilience Scale as research methods, we studied 692 nursing students for two consecutive years to evaluate the relationship among career adaptability, resilience, and career commitment. RESULTS: Career adaptability at T1 substantially and positively predicts the career commitment at T2. Career adaptability and resilience are mutually predictive. No interaction is found between resilience and career commitment over time. There is a substantial difference in the cross-lagged relationship among career adaptability, resilience, and career commitment for low- and high-career interest. CONCLUSION: Our results show the importance of developing career commitment early on. Developing career adaptability, enhancing resilience, and increasing career interest in nursing students might help to increase career commitment.

A cross-lagged study of the associations among problematic smartphone use, depressive symptoms, and suicidal ideation in chinese university students.

The present study aimed to investigate the longitudinal and reciprocal relationships among problematic smartphone use (PSU), depressive symptoms (DS), and suicidal ideation (SI) in Chinese university students. Using a cross-lagged design, the Mobile Phone Addiction Inventory Scale, the Center for Epidemiologic Studies Depression Scale, and the Self-Rating Idea of Suicide Scale as research instruments, 194 university students completed a questionnaire four consecutive times. June of Year 1, December of Year 2, June of Year 2, and December of Year 3 of their college study. We refer to these as the Time 1 (T1), Time 2 (T2), Time 3 (T3), and Time 4 (T4) assessments, respectively. The levels of PSU and DS fluctuated significantly over time. DS at T1 was significantly predicted to influence SI at T2 (ß = 0.17, p < .05); DS at T3 was significantly predicted by PSU and by SI at T2 (respectively, ß = 0.30, p < .05; ß = 0.21, p < .05); DS at T2 significantly predicted PSU at T3 (ß = 0.14, p < .05); and DS at T3 significantly predicted SI at T4 (ß = 0.14, p < .05) in the cross-lagged pathway. DS at T3 fully mediated the relationship between PSU at T2 and SI at T4 (indirect effect: ß = 0.133, 95% CI = [0.063, 0.213]). The results suggest that there is a reciprocal relationship between PSU and DS and, furthermore, that DS plays an important mediating role between PSU and SI. Our results suggest the importance of early identification and treatment of SI. Timely reduction of PSU and improvement of DS among university students may help prevent SI.

G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch.

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway may play an important role in the regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G-protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER+ neurons in the RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER+ neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER+ neurons abrogated itch responses, indicating that GPER+ neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER-/- rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating µ opioid signaling.SIGNIFICANCE STATEMENT Therapeutic options for itch are limited because of an as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathologic conditions. GPER+ neurons (largely GABAergic) in the RVM are antipruritic neurons under tonic opioidergic inhibition, activation of GPER promotes phosphorylation of MOR and disinhibition of the antipruritic GPER+ neurons from inhibitory opioidergic inputs, and failure to mobilize GPER+ neurons may result in the exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain, and opioid analgesia and the paradoxical effects of morphine on pain and itch.

Vascular Endothelial Growth Factor Mediates the Sprouted Axonogenesis of Breast Cancer in Rat.

Nerve infiltration into the tumor is a common feature of the tumor microenvironment. The mechanisms of axonogenesis in breast cancer remain unclear. We hypothesized that vascular endothelial growth factor (VEGF), as well as nerve growth factor (NGF), is involved in the axonogenesis of breast cancer. A N-methyl-N-nitrosourea (MNU)-induced rat model of breast cancer was used to explore the presence of axonogenesis in breast tumor and the involvement of VEGF, as well as NGF, in the axonogenesis of breast tumor. Nerve infiltration into the tumor was found in MNU-induced rat model of breast cancer including the sensory and sympathetic nerve fibers. Nerve density was increased following the growth of tumor. The sensory neurons innervating the thoracic and abdominal mammary tumors peaked at T5 to T6 and L1 to L2 dorsal root ganglions, respectively. Either VEGF receptor inhibitor or antibody against VEGF receptor 2, as well as NGF receptor inhibitor, apparently decreased both the nerve density and vascular density of breast tumor. The reduced nerve density was correlated with the decreased vascular density induced by these treatments. In cultured dorsal root ganglion neurons, phosphatidylinositol 3 (PI3K)/Akt, extracellular signal-regulated protein kinase (ERK), and p38 inhibitors significantly attenuated VEGF-induced neurite elongation. These findings provide direct evidence that VEGF, as well as NGF, may control the axonogenesis of breast cancer.