Strengthening through adversity: The hormesis model in developmental psychopathology.

BACKGROUND: Employing a developmental psychopathology framework, we tested the utility of the hormesis model in examining the strengthening of children and youth through limited levels of adversity in relation to internalizing and externalizing outcomes within a brain-by-development context. METHODS: Analyzing data from the Adolescent Brain and Cognitive Development study (N = 11,878), we formed latent factors of threat, deprivation, and unpredictability. We examined linear and nonlinear associations between adversity dimensions and youth psychopathology symptoms and how change of resting-state functional connectivity (rsFC) in the default mode network (DMN) from Time 1 to Time 5 moderates these associations. RESULTS: A cubic association was found between threat and youth internalizing problems; low-to-moderate family conflict levels reduced these problems. Deprivation also displayed a cubic relation with youth externalizing problems, with moderate deprivation levels associated with fewer problems. Unpredictability linearly increased both problem types. Change in DMN rsFC significantly moderated the cubic link between threat levels and internalizing problems, with declining DMN rsFC levels from Time 1 to Time 5 facilitating hormesis. Hormetic effects peaked earlier, emphasizing the importance of sensitive periods and developmental timing of outcomes related to earlier experiences. CONCLUSIONS: Strengthening through limited environmental adversity is crucial for developing human resilience. Understanding this process requires considering both linear and nonlinear adversity-psychopathology associations. Testing individual differences by brain and developmental context will inform preventive intervention programming.

Near-Infrared Fluorescence Probe for Monoamine Oxidase A with a Large Stokes Shift for Intraoperative Navigation.

Monoamine oxidase A (MAO-A) is a dimeric flavoprotein that is found in the mitochondrial membrane. Currently, there is a lack of near-infrared fluorescent probes (NIR-FPs) with good specificity and high sensitivity for detecting MAO-A, making it difficult to accurately recognize and image cells in vitro and in vivo. In this study, the NIR-FP DDM-NH2 was designed and synthesized in order to detect MAO-A specifically in live biological systems. The probe comprised two functional components: dicyanoisophosphone as an NIR dye precursor and alanine as a recognition moiety. After identifying MAO-A, the probe exhibited an NIR emission peak at 770 nm with a significant Stokes shift (180 nm), 11-fold response factor, low detection limit of 99.7 nM, and considerably higher affinity toward MAO-A than that toward MAO-B, indicating high sensitivity. In addition, DDM-NH2 was effective when applied to the image-based assessment of MAO-A activity in HeLa cells, zebrafish, and tumor-bearing mice, demonstrating great potential for visualization-based research and MAO-A application in vivo.

Latent Profiles of Sleep Patterns in Early Adolescence: Associations With Behavioral Health Risk.

PURPOSE: The present study characterized sleep profiles in a national longitudinal sample of early adolescents and examined whether profiles predicted later behavioral problems. METHODS: Three waves of data (2016-2021) were obtained from the Adolescent Behavior and Cognitive Development study, including 3,326 participants with both weekday and weekend sleep data measured by Fitbit wearables (age range 10.58-13.67 years; 49.3% female). Latent profile analysis was utilized to identify sleep profiles using multiple sleep indicators (duration, latency, efficiency, wake minutes, wake counts, and midpoint). We then explored whether demographic predictors predicted profile membership and tested the latent sleep profiles' predictive utility of internalizing and externalizing symptoms. RESULTS: Four profiles were identified: average sleep (40.39%), high duration & high wakefulness (28.58%), high efficiency, low duration &low wakefulness (16.86%), and low duration & low efficiency (14.17%). Participants with older age, males, higher body mass index, and advanced pubertal status were more likely to be classified in the low duration & low efficiency profile than the average group. Participants with lower income, minority identification, older age, and higher body mass index were more likely to be classified in the high efficiency, low duration &low wakefulness than the average group. Participants with lower parental education and males were more likely to be in the high sleep duration & high wakefulness than the average group. The low duration & low efficiency group had the highest attention problems, social problems, and rule-breaking behaviors. DISCUSSION: Our findings highlight unique sleep patterns in early adolescence and their prospective links with internalizing and externalizing problems.

COVID-19-related stress exacerbates the effect of child maltreatment on negative affect via increased identity confusion during adolescence.

INTRODUCTION: Exposure to childhood maltreatment may undermine the crucial developmental task of identity formation in adolescence, placing them at risk for developing negative affect. The current study investigated whether COVID-19-related stress intensified the indirect link between child maltreatment and adolescents' negative affect through identity confusion. METHOD: Using multidimensional assessments of child maltreatment (threat vs. deprivation), the study included a sample of 124 adolescents (Mage = 12.89, SD = 0.79; 52% female) assessed before (January 2018 to March 2020) and during the pandemic (May to October 2020) in Georgia, United States. The majority of the participants were European American (78.8%), followed by African American (11.5%), Hispanic (3.8%), Asian/Pacific Islander (1.0%), and other (4.8%). We used structural equation modeling to test (a) the mediating role of identity confusion in the link between childhood maltreatment and negative affect and (b) whether COVID-19-related stress moderated these indirect effects. Simple slopes and Johnson-Neyman plots were generated to probe regions of significant interaction effects. RESULTS: Threat and deprivation predicted an increase in adolescent identity confusion. Additionally, childhood threat and deprivation were indirectly linked to adolescents' negative affect through increased levels of identity confusion. COVID-19-related stress significantly exacerbated the link between identity confusion and negative affect. CONCLUSION: Identity confusion is a mechanism underlying the link between child maltreatment and the development of negative affect in adolescence. Our results inform prevention and intervention programs that aim to reduce negative affect among adolescents who experience threatening and depriving rearing environments.

The Influence of Pubertal Development on Early Adolescent Sleep and Changes in Family Functioning.

Pubertal development has been separately linked to adolescents' sleep problems and larger family functioning, but research connecting these inter-related processes remains sparse. This study aimed to examine how pubertal status and tempo were related to early adolescents' sleep and their family functioning. Using longitudinal data from the Adolescent Brain and Cognitive Development study, the study's sample (N = 4682) was 49.2% female, was an average of 9.94 years old at baseline, and was 60.1% white. Analyses in the current study modeled the indirect associations between pubertal change and changes in family conflict via adolescent sleep duration and variability of duration. The results suggested that pubertal status and tempo predicted shorter adolescent sleep durations and greater variability in those durations, which predicted residual increases in family conflict. The findings highlight the role of adolescents' pubertal changes in their sleep and how such changes can negatively affect family functioning.

Non-linear association of triglyceride-glucose index with prevalence of prediabetes and diabetes: a cross-sectional study.

Background: The Triglyceride-glucose (TyG) index has been acknowledged as a convenient, cost-effective, and relatively simple marker for insulin resistance (IR). Meanwhile, prediabetes, described as an asymptomatic, moderately hyperglycemic state, tends to be more prevalent than diabetes. Thus, the objective of this study was to explore the relationship between the TyG index and the prevalence of both prediabetes and diabetes within the U.S. population. Methods: This study utilized a cross-sectional dataset derived from the National Health and Nutrition Survey (NHANES) spanning 1999 to 2018. The subjects were individuals aged 18 years and above, who had available fasting glucose and fasting triglyceride information, permitting a diagnosis of prediabetes or diabetes. The TyG index was computed using laboratory data, and participants were subsequently categorized into quartiles based on this information. The relationship between the TyG index and the prevalence of prediabetes and diabetes was investigated using logistic regression analysis. Results: Out of the 25,159 participants, 23.88% were found to have prediabetes, while 16.22% were diagnosed with diabetes. After adjusting for confounding factors, a linear increase in relative odds was observed in Q2 (OR: 1.69; 95% CI: 1.52, 1.89), Q3 (OR: 2.57; 95% CI: 2.30, 2.88), and Q4 (OR: 4.88; 95% CI: 4.33, 5.49) groups in comparison to the reference group, Q1. In addition, a non-linear relationship was observed between the TyG index and the prevalence of prediabetes and diabetes. Specifically, patients with a TyG index greater than 8.00 overall exhibited a significantly higher risk of prediabetes and diabetes, confirming that an increase in the TyG index is associated with a corresponding increase in risk. However, this shift showed gender-specific variations; the threshold was observed at 8.00 in males but shifted to 9.00 in females. Conclusion: The TyG index demonstrated a non-linear positive correlation with both prediabetes and diabetes. This suggests that maintaining the TyG index at a certain, reduced level could potentially aid in preventing the onset of prediabetes and diabetes.

Disruption of cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis alleviates liver fibrosis.

B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-ß signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-ß or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.

Recent progress of self-immobilizing and self-precipitating molecular fluorescent probes for higher-spatial-resolution imaging.

Flourished in the past two decades, fluorescent probe technology provides researchers with accurate and efficient tools for in situ imaging of biomarkers in living cells and tissues and may play a significant role in clinical diagnosis and treatment such as biomarker detection, fluorescence imaging-guided surgery, and photothermal/photodynamic therapy. In situ imaging of biomarkers depends on the spatial resolution of molecular probes. Nevertheless, the majority of currently available molecular fluorescent probes suffer from the drawback of diffusing from the target region. This leads to a rapid attenuation of the fluorescent signal over time and a reduction in spatial resolution. Consequently, the diffused fluorescent signal cannot accurately reflect the in situ information of the target. Self-immobilizing and self-precipitating molecular fluorescent probes can be used to overcome this problem. These probes ensure that the fluorescent signal remains at the location where the signal is generated for a long time. In this review, we introduce the development history of the two types of probes and classify them in detail according to different design strategies. In addition, we compare their advantages and disadvantages, summarize some representative studies conducted in recent years, and propose prospects for this field.

Atypical cholangiocytes derived from hepatocyte-cholangiocyte transdifferentiation mediated by COX-2: a kind of misguided liver regeneration.

BACKGROUND: Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism. METHODS: A thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. The biliary tract was injected with ink and visualized by whole liver optical clearing. Serum and liver bile acid (BA) concentrations were measured. Either a COX-2 selective inhibitor or a ß-catenin pathway inhibitor was administered in vitro. RESULTS: Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-ß/ß-catenin signaling pathway. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-ß-TGFBR1-ß-catenin pathway in vitro. CONCLUSIONS: Atypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-ß-TGFBR1-ß-catenin pathway and improve liver function.

Sleep mediates the effect of stressful environments on youth development of impulsivity: The moderating role of within default mode network resting-state functional connectivity.

OBJECTIVES: Youth raised in stressful environments are at increased risk for developing impulsive traits, which are a robust precursor of problem behaviors. Sleep may mediate the link between stress and problem behaviors as it is both sensitive to stress and essential for neurocognitive development underlying behavioral control during adolescence. The default mode network (DMN) is a brain network implicated in stress regulation and sleep. Yet, it is poorly understood how individual differences in resting-state DMN moderate the effect of stressful environments on impulsivity via sleep problems. METHODS: Three waves of data spanning 2 years were obtained from the Adolescent Brain and Cognitive Development Study, a national longitudinal sample of 11,878 children (Mage at baseline = 10.1; 47.8% female). Structural equation modeling was used to test (a) the mediating role of sleep at T3 in the link between stressful environments at baseline and impulsivity at T5 and (b) the moderation of this indirect association by baseline levels of within-DMN resting-state functional connectivity. RESULTS: Sleep problems, shorter sleep duration, and longer sleep latency significantly mediated the link between stressful environments and youth impulsivity. Youth with elevated within-DMN resting-state functional connectivity showed intensified associations between stressful environments and impulsivity via shorter sleep duration. CONCLUSION: Our findings suggest that sleep health can be a target for preventive intervention and thereby mitigate the link between stressful environments and increased levels of youth impulsivity.

CH02 peptide promotes ex vivo expansion of umbilical cord blood-derived CD34 + hematopoietic stem/progenitor cells.

Umbilical cord blood (UCB) is an advantageous source for hematopoietic stem/progenitor cell (HSPC) transplantation, yet the current strategies for large-scale and cost-effective UCB-HSPC preparation are still unavailable. To overcome these obstacles, we systematically evaluate the feasibility of our newly identified CH02 peptide for ex vivo expansion of CD34 + UCB-HSPCs. We herein report that the CH02 peptide is specifically enriched in HSPC proliferation via activating the FLT3 signaling. Notably, the CH02-based cocktails are adequate for boosting 12-fold ex vivo expansion of UCB-HSPCs. Meanwhile, CH02-preconditioned UCB-HSPCs manifest preferable efficacy upon wound healing in diabetic mice via bidirectional orchestration of proinflammatory and anti-inflammatory factors. Together, our data indicate the advantages of the CH02-based strategy for ex vivo expansion of CD34 + UCB-HSPCs, which will provide new strategies for further development of large-scale HSPC preparation for clinical purposes.

Sample Size Effects on Petrophysical Characterization and Fluid-to-Pore Accessibility of Natural Rocks.

Laboratory-scale analysis of natural rocks provides petrophysical properties such as density, porosity, pore diameter/pore-throat diameter distribution, and fluid accessibility, in addition to the size and shape of framework grains and their contact relationship with the rock matrix. Different types of laboratory approaches for petrophysical characterization involve the use of a range of sample sizes. While the sample sizes selected should aim to be representative of the rock body, there are inherent limitations imposed by the analytical principles and holding capacities of the different experimental apparatuses, with many instruments only able to accept samples at the µm-mm scale. Therefore, a total of nine (three limestones, three shales, two sandstones, and one dolomite) samples were collected from Texas to fill the knowledge gap of the sample size effect on the resultant petrophysical characteristics. The sample sizes ranged from 3 cm cubes to <75 µm particles. Using a combination of petrographic microscopy, helium expansion pycnometry, water immersion porosimetry, mercury intrusion porosimetry, and (ultra-) small-angle X-ray scattering, the impact of sample size on the petrophysical properties of these samples was systematically investigated here. The results suggest that the sample size effect is influenced by both pore structure changes during crushing and sample size-dependent fluid-to-pore connectivity.

FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, but current treatment options remain limited and cause serious life-threatening side effects. Aberrant FGFR4 signaling has been validated as an oncogenic driver of HCC, and EZH2, the catalytic subunit of the PRC2 complex, is a potential factor that contributes to acquired drug resistance in many tumors, including HCC. However, the functional relationship between these two carcinogenic factors, especially their significance for HCC treatment, remains unclear. In this study, we systematically evaluated the feasibility of a combination therapy targeting FGFR4 and EZH2 for HCC. METHODS: RNA sequencing data of patients with Liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA) were analyzed to determine FGFR4 and EZH2 expression and their interaction with prognosis. Moreover, the HCC cell lines, zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors were treated with FGFR4 inhibitor (Roblitinib) and/or EZH2 inhibitor (CPI-169) and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for HCC both in vitro and in vivo. Furthermore, RNA-Seq was performed in combination with ChIP-Seq data analysis to investigate the critical mechanism underlying the combination treatment with Roblitinib and CPI-169. RESULTS: EZH2 accumulated through the non-canonical NF-kB signaling in response to FGFR4 inhibitor treatment, and the elevated EZH2 levels led to the antagonism of HCC against Roblitinib (FGFR4 inhibitor). Notably, knockdown of EZH2 sensitized HCC cells to Roblitinib, while the combination treatment of Roblitinib and CPI-169 (EZH2 inhibitor) synergistically induced the HCC cell apoptosis in vitro and suppressed the zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors development in vivo. Moreover, Roblitinib and CPI-169 synergistically inhibited HCC development via repressing YAP signaling. CONCLUSIONS: Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC.

Pretreatment of Dienogest for Women with Endometriosis in in vitro Fertilization: A Systematic Review and Meta-Analysis.

INTRODUCTION: Dienogest (DNG) was demonstrated to be comparable to gonadotropin-releasing hormone agonist (GnRH-a) in controlling symptoms of endometriosis. GnRH-a is used before in vitro fertilization (IVF) in women with endometriosis to improve pregnancy outcomes. We aimed to determine the effect of DNG pretreatment on IVF outcomes, including number of mature oocytes, rate of clinical pregnancies, and rate of live births in women with endometriosis. METHODS: All studies involving DNG, IVF, and endometriosis were searched from the PubMed; Ovid/MEDLINE, Wanfang, CQVIP, China National Knowledge Infrastructure databases; and ClinicalTrials.gov. The study population was women with endometriosis in IVF. Randomized controlled trials and cohort studies were included. All included studies comprised a DNG group and a control group. The outcomes were number of mature oocytes, rate of clinical pregnancies, and rate of live births. We calculated the odds ratio or mean difference and 95% confidence interval for each study and used a random-effects model to estimate the results. RESULTS: Five articles were screened by the search strategy. One article without a control group was excluded. Finally, four articles with 422 patients were included. No significant differences in number of mature oocytes (MD = -1.27, 95% CI: -3.63 to 1.09, I2 = 91%), the rate of clinical pregnancies (odds ratio = 1.07, 95% CI: 0.33-3.47, I2 = 84%), or the rate of live births (odds ratio = 1.09, 95% CI: 0.34-3.46, I2 = 84%) were found between the DNG group and the control group. CONCLUSION: Pretreatment with DNG for women with endometriosis who underwent IVF could not improve the number of mature oocytes, the rate of clinical pregnancies, or the rate of live births.

Effects of gonadotropin-releasing hormone agonist pretreatment on frozen embryo transfer outcomes in artificial cycles: a meta-analysis.

PURPOSE: Gonadotropin-releasing hormone agonist (GnRHa) before artificial cycle (AC) is expected to improve pregnancy outcomes in frozen-thawed embryo transfer (FET). Many studies have explored the impact of GnRHa pretreatment of AC in FET, but the results were inconsistent. This meta-analysis was performed to systematically evaluate the effect of GnRHa pretreatment on AC in FET. METHODS: The last search was January 31, 2022. Randomized controlled trials and cohort studies aiming to assess the effect of GnRHa as the pretreatment of AC for endometrial preparation in FET were included. GnRHa was used before AC in the treatment group. In the control group, no pretreatment was used before AC. The eligible studies included at least one of the following outcomes: implantation, clinical pregnancy, and live birth. We calculated the odds ratio (OR) or mean difference (MD) and 95% confidence interval (CI) for each study and used a random-effects or fixed model to estimate the results. RESULTS: 27 articles (10 RCTs and 17 non-RCTs) and 14152 patients were included. AC + GnRHa improved the implantation rate (OR = 1.31, 95% CI 1.03-1.66, I2 = 79%), clinical pregnancy rate (OR = 1.27, 95% CI 1.10-1.45, I2 = 53%), and live birth rate (OR = 1.16, 95% CI 1.05-1.29, I2 = 39%). We also found that AC + GnRHa increased the implantation rate (OR = 1.35, 95% CI 1.07-1.69, I2 = 53%) and clinical pregnancy rate (OR = 1.50, 95% CI 1.12-2.01, I2 = 50%) in repeated implantation failure. In addition, AC + GnRHa was positively associated with preterm birth (OR = 1.5, 95% CI 1.15-1.94, I2 = 0%). CONCLUSIONS: GnRHa pretreatment in FET can improve implantation, clinical pregnancy, and live birth rates, especially in patients with repeated implantation failure. GnRHa pretreatment seems to improve FET outcomes, though with a higher preterm birth rate.

Treatment of refractory hepatic encephalopathy induced by spontaneous portosystemic shunt: Selective splenic vein embolization versus shunt embolization.

BACKGROUND AND AIMS: Spontaneous portosystemic shunt (SPSS) can cause refractory hepatic encephalopathy (HE) in cirrhotic patients. The embolization of the shunt (ES) can resolve the HE, while the selective embolization of the splenic vein (SESV) can treat splenorenal shunts related HE. The aim of this study was to compare the clinical outcomes of ES and SESV when applied for the treatment of SPSS-induced refractory HE in cirrhotic patients. METHODS: Patients with refractory HE who were treated with ES or SESV were retrospectively identified. The clinical outcomes were compared and analyzed. RESULTS: The 6-month mortality after the ES procedure was significantly higher than that after the SESV procedure. During the 6-month follow-up, both the white blood cell and the platelet counts were significantly lower after the ES procedure than after the SESV procedure. There was a significant increase in aspartate aminotransferase levels after ES. However, the albumin levels as well as the Child-Pugh score and grade were found to be significantly improved at 6 months after the undertaking of an SESV (as compared with baseline). CONCLUSION: The 6-month mortality was improved after SESV (as compared with ES) in the treatment of SPSS-induced refractory HE. A prospective multicenter study for validation is warranted.

Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives.

(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound 6d exhibited the most promising inhibitory activity (IC50 = 3.81 µM) and did not show any significant cytotoxicity against the tested cell lines. Investigation of the mechanism of action indicated that 6d down-regulated NF-κB expression, possibly by suppressing TNF-α-induced expression of the p65 protein. Most of the compounds exhibited potent anti-inflammatory activity. Compound 4f was the most potent compound with 83.08% inhibition of inflammation after intraperitoneal administration, which was more potent than mollugin and the reference drugs (ibuprofen and mesalazine). ADMET prediction analysis indicated that compounds 6d and 4f had good pharmacokinetics and drug-like behavior; (4) Conclusions: Several series of mollugin derivatives were designed, synthesized, and evaluated for NF-κB inhibitory activity and toxicity. These results provide an initial basis for the development of 4f and 6d as potential anti-inflammatory agents.

Inhibition of Transketolase Improves the Prognosis of Colorectal Cancer.

Colorectal cancer (CRC) remains a heavy health burden worldwide. Transketolase (TKT) is a crucial enzyme in the non-oxidative phase of the Pentose Phosphate Pathway (PPP), and is up-regulated in multiple cancer types. However, the role of TKT in the prognosis of CRC remains unclear. We aimed to explore whether TKT expression is altered in CRC, how TKT is associated with the prognosis of CRC, and whether the regulation of TKT might have an impact on CRC. Differentially expressed genes (DEGs) were identified using bioinformatics analysis. TKT expression was examined in the human colon adenocarcinoma tissue microarray and xenografts. Cell viability, proliferation, migration, and apoptosis assays in vitro were applied to evaluate the protumoral effects of TKT on CRC. TKT was found to be a risk factor for the poor prognosis of CRC by bioinformatics analysis among the DEGs. TKT was significantly up-regulated in colon adenocarcinoma tissues compared with normal colon tissues in patients. Moreover, similar results were found in HCT116 and RKO human colon adenocarcinoma xenografts in nude mice. TKT expression was positively associated with advanced TNM stage, positive lymph nodes, and poor 5 or 10-year overall survival of CRC patients. In vitro, inhibition of TKT reduced cell viability, proliferation, and migration, and induced cell apoptosis. In addition, inhibition of TKT decreased the protein levels of NICD and Hes1. In conclusion, high TKT expression was associated with the poor prognosis of CRC patients. The protumoral effects of downregulating TKT may be realized by suppressing the Notch signaling pathway. TKT may be a new prognostic biomarker and therapeutic target for CRC.

Family stress during the pandemic worsens the effect of adverse parenting on adolescent sleep quality.

BACKGROUND: Adverse parenting is consistently associated with increased sleep problems among adolescents. Shelter-in-Place restrictions and the uncertainty linked to the Covid-19 pandemic have introduced new stressors on parents and families, adding to the risk for youth's sleep problems. OBJECTIVE: Using multidimensional assessments of child maltreatment (CM; threat vs. deprivation), the present study examined whether parent-report and child-report of Covid-19 related stress potentiated the effect of CM on sleep problems among boys and girls. PARTICIPANTS AND SETTING: The study focused on a sample of 124 dyads of adolescents (Mage = 12.89, SD = 0.79; 52% female) and their primary caregivers (93% mothers) assessed before and during the pandemic (May to October 2020). METHOD: Data were obtained from both youth and their parents. Structural equation modeling (SEM) was used to test all study hypotheses. Simple slopes and Johnson-Neyman plots were generated to probe significant interaction effects. RESULTS: Deprivation, but not threat, directly predicted increased sleep problems among boys during the pandemic. Additionally, elevation in Covid-19 stress (both parent and child report) intensified the link between CM (threat and deprivation) and sleep problems among boys. CONCLUSION: Our findings inform prevention and intervention efforts that aim to reduce sleep problems among boys during stressful contexts, such as the Covid-19 pandemic.