The association between problematic short video use and suicidal ideation and self-injurious behaviors: the mediating roles of sleep disturbance and depression.

BACKGROUND: Prior work suggests that problematic short video use was associated with adverse psychological, physiological, and educational outcomes. With the prevailing of short video platforms, the potential relationships between this problematic behavior and suicidal ideation and self-injurious behaviors have yet to be thoroughly examined. Besides, considering the potential dual nature of problematic short video use, particularly its positive aspects, a potential mechanism may exist linking such problematic behavior to SI and SIBs, ultimately driving individuals towards extreme outcomes. Nevertheless, such mediation paths have not been rigorously examined. Thus, the current study aimed to investigate their relationships and delve into the underlying mechanism, specifically identifying potential mediators between sleep disturbance and depression. METHODS: A quantitative cross-sectional study design was employed to model data derived from a large sample of first- and second-year university students residing in mainland China (N = 1,099; Mage = 19.80 years; 51.7% male). RESULTS: Results showed that problematic short video use has a dual impact on SI and SIBs. On the one hand, problematic short video use was directly related to the decreased risk of suicidal ideation, attempts, and NSSI. On the other hand, such problematic behavior was indirectly associated with the increased risk of NSSI through sleep disturbance, and it indirectly related to the elevated risk of suicidal ideation, attempts, and NSSI through depression. Besides, on the whole, problematic short video use was positively associated with NSSI but not suicidal ideation and attempts. CONCLUSIONS: These findings indicated that problematic short video use had a dual impact on SI and SIBs. Consequently, it is paramount to comprehend the genuine magnitude of the influence that such problematic behavior holds over these intricate psychological conditions.

Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.

The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 µg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.

Discovery of an Imine Reductase for Reductive Amination of Carbonyl Compounds with Sterically Challenging Amines.

The synthesis of structurally diverse amines is of fundamental significance in the pharmaceutical industry due to the ubiquitous presence of amine motifs in biologically active molecules. Biocatalytic reductive amination for amine production has attracted great interest owing to its synthetic advantages. Herein, we report the direct synthesis of a wide range of sterically demanding secondary amines, including several important active pharmaceutical ingredients and pharmaceutical intermediates, via reductive amination of carbonyl substrates and bulky amine nucleophiles employing imine reductases. Key to success for this route is the identification of an imine reductase from Penicillium camemberti with unusual substrate specificity and its further engineering, which empowered the accommodation of a broad range of sterically demanding amine nucleophiles encompassing linear alkyl and (hetero)aromatic (oxy)alkyl substituents and the formation of final amine products with up to >99% conversion. The practical utility of the biocatalytic route has been demonstrated by its application in the preparative synthesis of the anti-hyperparathyroidism drug cinacalcet.

Phylotranscriptomics Resolves the Phylogeny of Pooideae and Uncovers Factors for Their Adaptive Evolution.

Adaptation to cool climates has occurred several times in different angiosperm groups. Among them, Pooideae, the largest grass subfamily with ∼3,900 species including wheat and barley, have successfully occupied many temperate regions and play a prominent role in temperate ecosystems. To investigate possible factors contributing to Pooideae adaptive evolution to cooling climates, we performed phylogenetic reconstruction using five gene sets (with 1,234 nuclear genes and their subsets) from 157 transcriptomes/genomes representing all 15 tribes and 24 of 26 subtribes. Our phylogeny supports the monophyly of all tribes (except Diarrheneae) and all subtribes with at least two species, with strongly supported resolution of their relationships. Molecular dating suggests that Pooideae originated in the late Cretaceous, with subsequent divergences under cooling conditions first among many tribes from the early middle to late Eocene and again among genera in the middle Miocene and later periods. We identified a cluster of gene duplications (CGD5) shared by the core Pooideae (with 80% Pooideae species) near the Eocene-Oligocene transition, coinciding with the transition from closed to open habitat and an upshift of diversification rate. Molecular evolutionary analyses homologs of CBF for cold resistance uncovered tandem duplications during the core Pooideae history, dramatically increasing their copy number and possibly promoting adaptation to cold habitats. Moreover, duplication of AP1/FUL-like genes before the Pooideae origin might have facilitated the regulation of the vernalization pathway under cold environments. These and other results provide new insights into factors that likely have contributed to the successful adaptation of Pooideae members to temperate regions.

A Dynamically Stable Sulfide Electrolyte Architecture for High-Performance All-Solid-State Lithium Metal Batteries.

All-solid-state batteries employing sulfide solid electrolyte and Li metal anode are promising because of their high safety and energy densities. However, the interface between Li metal and sulfides suffers from catastrophic instability which stems the practical use. Here, a dynamically stable sulfide electrolyte architecture to construct the hierarchy of interface stability is reported. By rationally designing the multilayer structures of sulfide electrolytes, the dynamic decomposing-alloying process from MS4 (M = Ge or Sn) unit in sulfide interlayer can significantly prohibit Li dendrite penetration is revealed. The abundance of highly electronic insulating decompositions, such as Li2 S, at the sulfide interlayer interface helps to well constrain the dynamic decomposition process and preserve the long-term polarization stability is also highlighted. By using Li6 PS5 Cl||Li10 SnP2 S12 ||Li6 PS5 Cl electrolyte architecture, Li metal anode shows an unprecedented critical current density over 3 mA cm-2 and achieves the steady over-potential for ≈900 hours. Based upon the merits, the Li||LiNi0.8 Co0.1 Mn0.1 O2 battery delivers a remarkable 75.3% retention even after 600 cycles at 1 C (1C-0.95 mA cm-2 ) under a low stack pressure of 15 MPa.

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.

Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased in the cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Pparafl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (PparaΔCM), and myeloid-specific Ppara-deficient (PparaΔMac) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara△CM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease.

Predicting Participation Willingness in Ecological Momentary Assessment of General Population Health and Behavior: Machine Learning Study.

BACKGROUND: Ecological momentary assessment (EMA) is widely used in health research to capture individuals' experiences in the flow of daily life. The majority of EMA studies, however, rely on nonprobability sampling approaches, leaving open the possibility of nonrandom participation concerning the individual characteristics of interest in EMA research. Knowledge of the factors that predict participation in EMA research is required to evaluate this possibility and can also inform optimal recruitment strategies. OBJECTIVE: This study aimed to examine the extent to which being willing to participate in EMA research is related to respondent characteristics and to identify the most critical predictors of participation. METHODS: We leveraged the availability of comprehensive data on a general young adult population pool of potential EMA participants and used and compared logistic regression, classification and regression trees, and random forest approaches to evaluate respondents' characteristic predictors of willingness to participate in the Decades-to-Minutes EMA study. RESULTS: In unadjusted logistic regression models, gender, migration background, anxiety, attention deficit hyperactivity disorder symptoms, stress, and prosociality were significant predictors of participation willingness; in logistic regression models, mutually adjusting for all predictors, migration background, tobacco use, and social exclusion were significant predictors. Tree-based approaches also identified migration status, tobacco use, and prosociality as prominent predictors. However, overall, willingness to participate in the Decades-to-Minutes EMA study was only weakly predictable from respondent characteristics. Cross-validation areas under the curve for the best models were only in the range of 0.56 to 0.57. CONCLUSIONS: Results suggest that migration background is the single most promising target for improving EMA participation and sample representativeness; however, more research is needed to improve prediction of participation in EMA studies in health.

1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway.

Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.

PSTPIP2 is associated with disease severity in patients with pressure ulcer sepsis and has anti-inflammatory effects.

BACKGROUND: One of the common adverse reactions in patients with pressure ulcers (PU) is sepsis, which is mainly related to microbial infections caused by pathogenic organisms. The activation of nuclear factor kappa-B (NF-κB) frequently occurs in conjunction with pathogenic microbial infections. Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) is closely related to inflammatory disorders. The role and mechanism of PSTPIP2 in sepsis because of pressure ulcers is unclear. In this study, we discovered that PSTPIP2 was lowly expressed in peripheral blood of patients with sepsis induced by pressure ulcers. METHODS: Peripheral blood was collected from 20 patients with sepsis due to pressure ulcers and 10 healthy controls, and the expression of PSTPIP2 in peripheral blood was discovered by polymerase chain reaction and Western blot analysis. Information on the clinical characteristics of patients was summarized, and the expression data of PSTPIP2 were correlated with the patients' acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and C-reactive protein (CRP) and procalcitonin (PCT) scores by Spearman's correlation analysis. One of the main mediators of Gram-negative sepsis is lipopolysaccharide (LPS). In order to establish an in vitro sepsis model, THP-1 cells were treated with LPS, and the cells were transfected with PSTPIP2. Contents of interleukin 6 (IL-6), interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) in each group of cells were detected by enzyme-linked--immunosorbent serologic assay, and NF-κB-related proteins were detected by Western blot analysis. RESULTS: When compared to healthy controls, the peripheral blood of patients with pressure sepsis had lower PSTPIP2 expression, which had a negative correlation with the APACHE II, SOFA, CRP, and PCT scores. LPS-induced THP-1 cells expressed less PSTPIP2 than the untreated control cells, and PSTPIP2 transfection decreased IL-6, IL-1ß, and TNF-α levels and inhibited the activation of NF-κB pathway. CONCLUSION: PSTPIP2 is associated with disease severity in patients with pressure ulcer sepsis and has anti-inflammatory effects.

Recent Advances in the Synthesis of 3,n-Fused Tricyclic Indole Skeletons via Palladium-Catalyzed Domino Reactions.

3,n-fused (n = 4-7) tricyclic indoles are pervasive motifs, embedded in a variety of biologically active molecules and natural products. Thus, numerous catalytic methods have been developed for the synthesis of these skeletons over the past few decades. In particular, palladium-catalyzed transformations have received much attention in recent years. This review summarizes recent developments in the synthesis of these tricyclic indoles with palladium-catalyzed domino reactions and their applications in the total synthesis of representative natural products.

Correlation of plasma adipokines with endometrial atypical hyperplasia and type I/II endometrial cancer.

The aim of the study was to systematically explore the relationships between various adipokines and risks of endometrial atypical hyperplasia (EAH), type I endometrial cancer (EC), and type II EC. We enrolled 219 patients in this study, including 39 EAH, 87 type I EC, 38 type II EC and 55 control individuals. We subsequently explored the association of adipokine levels and the leptin-to-adiponectin (L/A) ratio with EAH, type I EC, and type II EC. The plasma leptin level and L/A ratio were significantly higher in the EAH group than in the control group (p = 0.012). Leptin, resistin, vaspin, and visfatin levels were significantly higher in the type I EC group; however, the adiponectin level was lower in the type I EC, which resulted in a higher L/A ratio. Notably, the L/A ratio and visfatin level in the type II EC group were significantly higher. Multiple logistic regression analysis revealed that a higher leptin level was significantly associated with a higher EAH risk (p = 0.012). Higher leptin level (p = 0.042) and L/A ratio (p = 0.027) were significantly associated with an increased type I EC risk. By contrast, higher leptin (p = 0.059) and visfatin (p = 0.003) levels, higher L/A ratio (p = 0.033), and lower adiponectin level (p = 0.042) were associated with an increased type II EC risk. We suggested that adipokines are potentially correlated with EAH and EC risks.

What is already known on this subject? EAH and EC are considered significantly correlated with obesity and the related insulin resistance. Studies reported that some of the adipokines mediate obesity-related EC risk.What do the results of this study add? We systematically explored whether the adipokines produced from adipose tissue, including leptin, adiponectin, resistin, vaspin, and visfatin as well as the L/A ratio were associated with increased EAH, type I EC, and type II EC risks; whether they are independent risk factors for EAH and EC. Moreover, we analysed the underlying roles of these adipokines in EC tumorigenesis and development.What are the implications of these findings for clinical practice and/or further research? This study aimed to systematically explore the relationships between various adipokines and risks of EAH, type I EC, and type II EC, to suggest that adipokine levels correlated with EAH and EC risks, and to analyse the underlying molecular mechanisms linking adipokines with endometrial carcinogenesis. It is helpful to improve our understanding of EC tumorigenesis and development.

Trajectories of Screen Time across Adolescence and Their Associations with Adulthood Mental Health and Behavioral Outcomes.

Excessive screen time among adolescents is discussed as a significant public health concern. Identifying adolescent longitudinal patterns of time spent on regularly-used media screens and understanding their young adulthood mental health and behavioral issue correlates may help inform strategies for improving these outcomes. This study aimed to characterize joint developmental patterns of time spent on videogames, surfing/chatting the Internet, and TV/DVDs during adolescence (at ages 11, 13, 15, 17) and their associations with mental health (i.e., depression, anxiety, suicidal ideation, and self-injury) and behavioral issues (i.e., substance use, delinquency, aggression) in early adulthood (at age 20). A parallel-process latent class growth analysis was used to model data from a diverse community-ascertained sample of youth in Zurich, Switzerland (n = 1521; 51.7% males). Results suggested that a five-class model best fitted the data: (1) low-screen use, 37.6%; (2) increasing chatting/surfing, 24.0%; (3) moderate-screen use, 18.6%; (4) early-adolescence screen use, 9.9%; and (5) increasing videogame and chatting/surfing, 9.9%. After adjusting for baseline levels of outcomes (primarily at age 11), the trajectory groups differed in their associations with adulthood outcomes of mental health and behavioral problems, indicating the importance of problematic screen usage patterns in predicting these outcomes. Future research to test the directionality of these associations will be important. These findings suggest which patterns of screen use may be a marker for later mental health and behavioral issues in different domains.

[The role of inflammation in heart failure with preserved ejection fraction].

Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterized by left ventricular diastolic dysfunction with preserved ejection fraction. With the aging of the population and the increasing prevalence of metabolic diseases, such as hypertension, obesity and diabetes, the prevalence of HFpEF is increasing. Compared with heart failure with reduced ejection fraction (HFrEF), conventional anti-heart failure drugs failed to reduce the mortality in HFpEF due to the complex pathophysiological mechanism and multiple comorbidities of HFpEF. It is known that the main changes of cardiac structure of in HFpEF are cardiac hypertrophy, myocardial fibrosis and left ventricular hypertrophy, and HFpEF is commonly associated with obesity, diabetes, hypertension, renal dysfunction and other diseases, but how these comorbidities cause structural and functional damage to the heart is not completely clear. Recent studies have shown that immune inflammatory response plays a vital role in the progression of HFpEF. This review focuses on the latest research progress in the role of inflammation in the process of HFpEF and the potential application of anti-inflammatory therapy in HFpEF, hoping to provide new research ideas and theoretical basis for the clinical prevention and treatment in HFpEF.

Developmental associations between bullying victimization and suicidal ideation and direct self-injurious behavior in adolescence and emerging adulthood.

BACKGROUND: Bullying, suicide, and self-injury are significant issues among young people. Extensive research has documented bullying victimization associations with suicidal ideation and self-injury; however, the modeling approaches used have mostly not addressed the relations between these constructs at the within-person level, and it is these links that are critical for testing developmental theories and guiding intervention efforts. This examined the within-person, bidirectional relations between these constructs in adolescence and emerging adulthood. METHODS: Participants were from the Zurich Project on Social Development from Childhood to Adulthood (z-proso). Random intercept cross-lagged panel models (RI-CLPMs) were fit to general and sexual bullying victimization and suicidal ideation data at ages 15, 17, and 20 (n = 1465), and general and sexual victimization and direct self-injurious behavior data at ages 13, 15, 17, and 20 (n = 1482). RESULTS: There was a positive within-person effect of age 15 general bullying victimization on age 17 suicidal ideation (ß = .10) and age 17 suicidal ideation on age 20 general bullying victimization (ß = .14). CONCLUSIONS: General bullying victimization and suicidal ideation may have detrimental effects on each other over development but at different stages.

Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling.

Peroxisome proliferator-activated receptor α (PPARα), a ligand-activated nuclear receptor critical for systemic lipid homeostasis, has been shown closely related to cardiac remodeling. However, the roles of cardiomyocyte PPARα in pressure overload-induced cardiac remodeling remains unclear because of lacking a cardiomyocyte-specific Ppara-deficient (PparaΔCM) mouse model. This study aimed to determine the specific role of cardiomyocyte PPARα in transverse aortic constriction (TAC)-induced cardiac remodeling using an inducible PparaΔCM mouse model. PparaΔCM and Pparafl/fl mice were randomly subjected to sham or TAC for 2 weeks. Cardiomyocyte PPARα deficiency accelerated TAC-induced cardiac hypertrophy and fibrosis. Transcriptome analysis showed that genes related to fatty acid metabolism were dramatically downregulated, but genes critical for glycolysis were markedly upregulated in PparaΔCM hearts. Moreover, the hypertrophy-related genes, including genes involved in extracellular matrix (ECM) remodeling, cell adhesion, and cell migration, were upregulated in hypertrophic PparaΔCM hearts. Western blot analyses demonstrated an increased HIF1α protein level in hypertrophic PparaΔCM hearts. PET/CT analyses showed an enhanced glucose uptake in hypertrophic PparaΔCM hearts. Bioenergetic analyses further revealed that both basal and maximal oxygen consumption rates and ATP production were significantly increased in hypertrophic Pparafl/fl hearts; however, these increases were markedly blunted in PparaΔCM hearts. In contrast, hypertrophic PparaΔCM hearts exhibited enhanced extracellular acidification rate (ECAR) capacity, as reflected by increased basal ECAR and glycolysis but decreased glycolytic reserve. These results suggest that cardiomyocyte PPARα is crucial for the homeostasis of both energy metabolism and ECM during TAC-induced cardiac remodeling, thus providing new insights into potential therapeutics of cardiac remodeling-related diseases.

Comparative Transcriptome Analysis Identifies Key Defense Genes and Mechanisms in Mulberry (Morus alba) Leaves against Silkworms (Bombyx mori).

As a consequence of long-term coevolution and natural selection, the leaves of mulberry (Morus alba) trees have become the best food source for silkworms (Bombyx mori). Nevertheless, the molecular and genomic basis of defense response remains largely unexplored. In the present study, we assessed changes in the transcriptome changes of mulberry in response to silkworm larval feeding at 0, 3, and 6 h. A total of 4709 (up = 2971, down = 1738) and 3009 (up = 1868, down = 1141) unigenes were identified after 3 and 6 h of silkworm infestation, respectively. MapMan enrichment analysis results show structural traits such as leaf surface wax, cell wall thickness and lignification form the first physical barrier to feeding by the silkworms. Cluster analysis revealed six unique temporal patterns of transcriptome changes. We predicted that mulberry promoted rapid changes in signaling and other regulatory processes to deal with mechanical damage, photosynthesis impairment, and other injury caused by herbivores within 3-6 h. LRR-RK coding genes (THE1, FER) was predicted participated in perception of cell wall perturbation in mulberry responding to silkworm feeding. Ca2+ signal sensors (CMLs), ROS (OST1, SOS3), RBOHD/F, CDPKs, and ABA were part of the regulatory network after silkworm feeding. Jasmonic acid (JA) signal transduction was predicted to act in silkworm feeding response, 10 JA signaling genes (such as OPR3, JAR1, and JAZ1) and 21 JA synthesis genes (such as LOX2, AOS, and ACX1) were upregulated after silkworm feeding for 3 h. Besides, genes of "alpha-Linolenic acid metabolism" and "phenylpropanoid biosynthesis" were activated in 3 h to reprogram secondary metabolism. Collectively, these findings provided valuable insights into silkworm herbivory-induced regulatory and metabolic processes in mulberry, which might help improve the coevolution of silkworm and mulberry.

Developmental Relations Between Bullying Victimization and Suicidal Ideation in Middle Adolescence and Emerging Adulthood: Do Internalizing Problems and Substance Use Mediate Their Links?

Previous research has suggested that bullying victimization is associated with higher suicidal risk among young people; however, the mechanisms underlying this relation have not been well examined. The current study aimed to illuminate the developmental links between bullying victimization and suicidal ideation by examining the mediating roles of depressive symptoms, anxiety symptoms, and substance use. The study sample consisted of n = 1465 participants (51.7% male) from the normative z-proso study. Using random intercept cross-lagged panel models and three waves of longitudinal data (ages 15, 17, and 20), the hypothesized mediation effects at the within-person level were tested while partialling out between-person confounds. The results suggested that, at the within-person level, bullying victimization did not predict subsequent suicidal ideation via depressive symptoms, anxiety symptoms, or substance use. However, age 15 bullying victimization predicted within-person increases in age 17 depressive symptoms and suicidal ideation. In addition, depressive symptoms at age 15 and tobacco and cannabis use at age 17 were associated with within-person increases in bullying victimization at ages 17 and 20, respectively. The results also indicated that cannabis use and suicidal ideation were positively and reciprocally related over time. Future studies collecting data at multiple timescales are needed to understand proximal and longer-term mechanisms underlying the relation between bullying victimization and suicidality.

Human endometrial perivascular stem cells exhibit a limited potential to regenerate endometrium after xenotransplantation.

STUDY QUESTION: What are the localization, characteristics and potential for tissue regeneration of two perivascular stem cells, namely CD34+ adventitial cells and CD146+ pericytes, in human endometrium? SUMMARY ANSWER: Human endometrial CD34+ adventitial cells (located in the outermost layer of blood vessels and mainly in the basal layer) and CD146+ pericytes showed mesenchymal stem cell (MSC) phenotypes in in vitro culture, but presented limited potential to regenerate endometrium. WHAT IS KNOWN ALREADY: Periodic endometrial regeneration is considered to be maintained by MSCs. Blood vessel wall, regarded as stem cell niche, harbors a large reserve of progenitor cells that may be integral to the origin of MSCs. However, a lack of validated markers has hampered the isolation of putative endometrial MSCs. Currently, CD146+ pericytes and Sushi Domain Containing 2 (SUSD2) positive cells have been identified in the endometrial perivascular region as sharing MSCs characteristics. STUDY DESIGN, SIZE, DURATION: The locations of adventitial cells and pericytes in the human endometrium were identified by immunofluorescence staining (n = 4). After CD34+CD146-CD45-CD56-CD144- adventitial cells and CD146+CD34-CD45-CD56-CD144- pericytes were isolated from the endometrium of normal women (n = 6) by fluorescence-activated cell sorting, their characteristics were investigated in culture. Adventitial cells and pericytes were induced to differentiate, respectively, into vascular endothelial-like cells or endometrial stromal-like cells in vitro, with their potential explored by in vivo xenotransplantation (n = 2 in each group) and eutopic transplantation (n = 2 in each group). PARTICIPANTS/MATERIALS, SETTING, METHODS: CD34+ adventitial cells and CD146+ pericytes were cultured in the inducing medium to differentiate into endothelial-like cells in vitro, and then analyzed for CD31, von Willebrand factor immunofluorescent staining and tube formation. They were also cultured to differentiate into endometrial stromal cells in vitro, with the expression of vimentin and CD13 being detected by western blot before and after induction, and the expression of prolactin and insulin-like growth factor-binding protein 1 being determined as well. Single dispersed CD34+ adventitial cells and CD146+ pericytes were respectively transplanted under the kidney capsule of NOG mice to investigate their differentiation potential in vivo. A eutopic transplantation model was constructed by grafting recellularized uterine matrix loaded up with CM-Dil labeled adventitial cells or pericytes into the injury region of nude rat's uterus. MAIN RESULTS AND THE ROLE OF CHANCE: CD34+ adventitial cells were mainly located at the outmost layer of endometrial large vessels, while CD146+ pericytes were found surrounding the inner endothelial cells of microvessels. A small proportion of CD34+ adventitial cells expressed SUSD2. The number of adventitial cells was ∼40 times higher than that of pericytes in the endometrium. Both adventitial cells and pericytes showed MSC phenotypes after in vitro culture. After in vitro induction into endometrial endothelial-like cells and stromal-like cells, adventitial cells showed higher plasticity than pericytes and a closer correlation with stromal-like cells. In the mouse xenotransplantation model, vimentin+ cells, CD31+ endothelial-like cells and CD146+ pericyte-like cells could be observed after adventitial cells were transplanted. CM-Dil-labeled adventitial cells or pericytes could survive in the immunocompromised nude rats after eutopic transplantation, and vimentin+ cells were detected. In addition, CM-Dil-labeled adventitial cells or pericytes did not express α-smooth muscle actin or E-cadherin after transplantation. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: CD34 was chosen as a novel marker to isolate adventitial cells from human endometrium according to previous literature. The association of endometrial CD34+ adventitial cells and SUSD2+ MSCs should be further investigated. WIDER IMPLICATIONS OF THE FINDINGS: The decellularized uterine matrix model might be useful in endometrial stem cell therapy. STUDY FUNDING/COMPETING INTEREST(S): L.D. is supported by grants from National Key Research and Development Program of China (2018YFC1004700), Nature Science Foundation of China (81871128, 81571391) and Nanjing Medical Science Development Project (ZKX16042). H.S. is supported by a grant from Jiangsu Province Social Development Project (BE2018602). X.Z. was supported by grants from the Postgraduate Innovative Project of Jiangsu Province (KYCX19-1177). The authors declare no conflict of interest.

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis.

BACKGROUND: Aim to establish the inhibitors of programmed cell death protein 1 (PD-1) as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC). METHODS: Published clinical trials in the PubMed, Medline, Embase databases on PD-1 inhibitors for the treatment of ESCC were searched, along with an additional search on abstracts from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) from inception to September 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were synthesized using STATA. RESULTS: A total of 1970 patients (PD-1 inhibitors: 987; chemotherapy: 983) were enrolled in five randomized controlled trials. Compared with conventional chemotherapy, second-line PD-1 inhibitors significantly improved the OS (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.66-0.81; P < 0.001) and ORR (relative risk [RR] = 1.89, 95% CI: 1.16-3.05; P = 0.01) of advanced ESCC patients, especially significantly prolonged the OS in the patients with positive programmed death-ligand 1 (PD-L1) status (HR = 0.64, 95% CI: 0.53-0.77; P < 0.001); but did not better PFS (HR = 0.88, 95% CI: 0.68-1.14; P = 0.330) and DCR (RR = 0.89, 95% CI: 0.59-1.37; P = 0.603). Moreover, PD-1 inhibitors were associated with statistically lower incidences of grade 3-5 TRAEs. CONCLUSION: Second line PD-1 inhibitors significantly improved the OS and ORR of patients with advanced ESCC, especially the OS of those with positive PD-L1 expression, and did not result in significant improvement in PFS and DCR. Compared to chemotherapy, second-line PD-1 inhibitors had superior safety profiles for the treatment of advanced ESCC.

Formylation and Bromination of Pyrrolo[2,1-a]isoquinoline Derivatives with Bromoisobutyrate and Dimethyl Sulfoxide.

We have developed an efficient formylation of pyrroloisoquinolines using bromoisobutyrate and dimethyl sulfoxide as carbonyl reagent. Various formylated pyrroloisoquinolines could be prepared in good yields (up to 94%). This formylation process can be easily scaled up to gram scale with good yield. In most cases of pyrroloisoquinolines without methoxy groups, the combination of bromoisobutyrate and dimethyl sulfoxide could act as a bromination reagent, delivering brominated pyrroloisoquinolines in acceptable to good yields (up to 82%).