Diagnostic capacity of miRNAs in neonatal sepsis: a systematic review and meta-analysis.

BACKGROUND: Neonatal sepsis is the third leading cause of mortality during the neonatal period, with manifestations atypical and obscure. But the gold standard-blood culture test, requiring 3-5 days, makes it difficult to unveil the final pathogen and leads to the increasing ratio of false-negative results. The empirical method is consulting traditional biomarkers, such as procalcitonin (PCT), C-reactive protein (CRP), and white blood cell count. However, they are not specific for neonate in diagnostic capacity, especially for infants within three days after delivery, so more novel biomarkers are urgently needed to assist diagnosing neonatal sepsis. microRNAs (miRNAs) have been widely studied in recent years for their diagnostic and prognostic values in different diseases and we conducted a meta-analysis of miRNAs on the topic that whether they are potentially novel biomarkers in early detection of neonatal sepsis. OBJECTIVES: The purpose of the study was to assess whether circulating miRNAs could be used as potential biomarkers for neonatal sepsis, including early and late-onset neonatal sepsis, then calculate their overall accuracy (OA) via meta-analysis. METHODS: PubMed, Cochrane Library, Embase, Web of Science, Scopus, and Ovid databases were retrieved; data cutoff for this analysis was 15 January 2023. Methodological quality assessment of included studies was performed through the Quality in Prognostic Studies tool. Corresponding 95% confidence interval (95%CI) was calculated to present miRNAs' diagnostic value including the pooled sensitivity (Sen), specificity (Spe), positive or negative likelihood ratios (PLR or NLR), diagnostic odds ratio (DOR), and area under the curve (AUC). Differences in OA between the septic group and non-septic group were compared using Chi-square test. RESULTS: After identification, 16 records out of 11 selected articles were eligible for systematic review of miRNAs and four records for PCT; the case group for miRNAs included 945 neonatal sepsis cases; contrast group included 190 respiratory tract infections or pneumonia cases, 60 systemic inflammatory response syndrome (SIRS) cases and 559 healthy neonates. The pooled Sen, Spe, and DOR of miRNAs were 0.87 (95%CI 0.81-0.91), 0.79 (95%CI 0.71-0.85), and 24 (95%CI 12-50), respectively. The pooled Sen, Spe, and DOR of PCT were 0.92 (95%CI 0.83-0.96), 0.64 (95%CI 0.56-0.70), and 20 (95%CI, 7-56), respectively. The OA value of miRNAs was 80.38% and that of PCT was 77.36%, which were not statistically significant difference (p = .13) after the Chi-square test. In addition, no significant publication bias was indicated (p = .92). CONCLUSIONS: Circulating miRNA levels could be applied as diagnostic biomarkers in neonatal sepsis.

Screen time, sleep, brain structural neurobiology, and sequential associations with child and adolescent psychopathology: Insights from the ABCD study.

Background and Aims: The precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation. Methods: This study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined. Results: Participants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (ß = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (ß = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (ß = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (ß = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (ß = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable. Conclusion: We found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.

[ADAMTS13-Mediated Proteolytic Cleavage of Unusually Large von Willebrand Factor Polymers on Endothelial Cells in the Absence of Fluid Shear Stress].

OBJECTIVE: To investigate the molecular mechanism of proteolytic cleavage of unusually large von Willebrand Factor(ULVWF) on endothelial cells by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) in the absence of fluid shear stress, so as to provide a theoretical basis for the pathogenesis of thrombotic thrombocytopenic purpura (TTP) and other thrombotic disorders. METHODS: The ADAMTS13-mediated proteolysis of ULVWF on the surface of endothelial cells in the absence of fluid shear stress was observed through immunofluorescence microscopy. The variation in VWF antigen levels in the conditioned media were determined by ELISA assay. The levels of VWF and the proteolytic fragments released into the conditioned media were determined by ELISA assay and Western blot in the absence and presence of fluid shear stress or FVIII. The effect of ADAMTS13-mediated ULVWF cleavage on the normal distribution of plasma VWF multimers was evaluated by multimer analysis. Histamine stimulated human umbilical vein endothelial cells (HUVECs) were incubated with ADAMTS13 and various N- and C-terminally truncated mutants. Then the ULVWF that maintained binding to the cells were observed through immunofluorescence microscopy and the soluble ULVWF released from endothelial cells was determined by ELISA, so as to demonstrate the domains of ADAMTS13 required for proteolysis of ULVWF on endothelial cells. RESULTS: The ULVWF strings on the endothelial cell surface were rapidly proteolyzed by recombinant and plasma ADAMTS13 in the absence of fluid shear stress. This proteolytic processing of ULVWF depended on incubation time and ADAMTS13 concentration, but not shear stress and FVIII. The distribution of VWF releaseded by ADAMTS13-mediated proteolysis was quite similar to that secreted by endothelial cells under histamine stimulation, suggesting the ULVWF cleavage occured at the cell surface. The proteolysis of the ULVWF on endothelial cells required the Cys-rich(CysR) and spacer domains, but not the TSP1 2-8 and CUB domains of ADAMTS13. CONCLUSION: The ULVWF polymers on endothelial cells are sensitive to ADAMTS13-mediated cleavage even in the absence of fluid shear stress. The findings provide novel insight into the molecular mechanism of ADAMTS13-mediated ULVWF cleavage at the cellular level and may contribute to understanding of the pathogenesis of TTP and other thrombotic disorders.

Associations between individual and structural level racism and gestational age at birth in the Nulliparous Pregnancy Outcomes Study: Monitoring mothers-to-be.

The purpose of this study was to investigate the associations between multilevel racism and gestational age at birth among nulliparous non-Hispanic Black, non-Hispanic White and Hispanic women. We conducted a secondary analysis of data of the nuMoM2b Study (2010-2013) to examine the associations between individual and structural-level experiences of racism and discrimination and gestational age at birth among nulliparous women (n=7,732) at eight sites across the U.S. Measures included the individual Experiences of Discrimination (EOD) scale and the Index of Concentration (ICE) at the Extremes to measure structural racism. After adjustment,we observed a significant individual and structural racism interaction on gestational length (p=0.03). In subgroup analyses, we found that among these with high EOD scores, women who were from households concentrated in the more privileged group had significantly longer gestations (ß = 1.07, 95% CI: 0.24, 1.90). Women who reported higher EOD scores and more economic privilege had longer gestations, demonstrating the moderating effect of ICE as a measure of structural racism. In conclusion, ICE may represent a modifiable factor in the prevention of adverse birth outcomes in nulliparas.

Relative brain age is associated with socioeconomic status and anxiety/depression problems in youth.

Brain age, a measure of biological aging in the brain, has been linked to psychiatric illness, principally in adult populations. Components of socioeconomic status (SES) associate with differences in brain structure and psychiatric risk across the lifespan. This study aimed to investigate the influence of SES on brain aging in childhood and adolescence, a period of rapid neurodevelopment and peak onset for many psychiatric disorders. We reanalyzed data from the Healthy Brain Network to examine the influence of SES components (occupational prestige, public assistance enrollment, parent education, and household income-to-needs ratio [INR]) on relative brain age (RBA). Analyses included 470 youth (5-17 years; 61.3% men), self-identifying as White (55%), African American (15%), Hispanic (9%), or multiracial (17.2%). Household income was 3.95 ± 2.33 (mean ± SD) times the federal poverty threshold. RBA quantified differences between chronological age and brain age using covariation patterns of morphological features and total volumes. We also examined associations between RBA and psychiatric symptoms (Child Behavior Checklist [CBCL]). Models covaried for sex, scan location, and parent psychiatric diagnoses. In a linear regression, lower RBA is associated with lower parent occupational prestige (p = .01), lower public assistance enrollment (p = .03), and more parent psychiatric diagnoses (p = .01), but not parent education or INR. Lower parent occupational prestige (p = .02) and lower RBA (p = .04) are associated with higher CBCL anxious/depressed scores. Our findings underscore the importance of including SES components in developmental brain research. Delayed brain aging may represent a potential biological pathway from SES to psychiatric risk. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Hexadecanamide alleviates Staphylococcus aureus-induced mastitis in mice by inhibiting inflammatory responses and restoring blood-milk barrier integrity.

Subacute ruminal acidosis (SARA) has been demonstrated to promote the development of mastitis, one of the most serious diseases in dairy farming worldwide, but the underlying mechanism is unclear. Using untargeted metabolomics, we found hexadecanamide (HEX) was significantly reduced in rumen fluid and milk from cows with SARA-associated mastitis. Herein, we aimed to assess the protective role of HEX in Staphylococcus aureus (S. aureus)- and SARA-induced mastitis and the underlying mechanism. We showed that HEX ameliorated S. aureus-induced mastitis in mice, which was related to the suppression of mammary inflammatory responses and repair of the blood-milk barrier. In vitro, HEX depressed S. aureus-induced activation of the NF-κB pathway and improved barrier integrity in mouse mammary epithelial cells (MMECs). In detail, HEX activated PPARα, which upregulated SIRT1 and subsequently inhibited NF-κB activation and inflammatory responses. In addition, ruminal microbiota transplantation from SARA cows (S-RMT) caused mastitis and aggravated S. aureus-induced mastitis, while these changes were reversed by HEX. Our findings indicate that HEX effectively attenuates S. aureus- and SARA-induced mastitis by limiting inflammation and repairing barrier integrity, ultimately highlighting the important role of host or microbiota metabolism in the pathogenesis of mastitis and providing a potential strategy for mastitis prevention.

Study on identification of a three-microRNA panel in serum for diagnosing neonatal early onset sepsis.

BACKGROUND: Comparing with other diseases, early onset sepsis (EOS) is a global health concern in neonatal period for its high morbidity and mortality rates. In recent years, many studies have contributed to the figure out the expression patterns of circulating micro-RNAs (miRNAs) in different diseases and progressions, which could function as diagnostic biomarkers for EOS. The purpose of this study was to analyze the expression patterns of selected miRNAs and evaluate their diagnostic value for early detection and treatment. METHODS: This was a prospective cross-sectional study conducted from 1 July 2021 to 30 June 2022. We collected surplus peripheral blood and demographic statistics of septic neonates and non-infected neonates during the first 24 h after delivery and obtained 11 candidate miRNAs by literature screening. First, we extracted the candidate miRNAs from the serum of selected neonates and analyzed their expression levels, and then the receiver operating characteristic (ROC) curve was used to select the differentially expressed miRNAs. We analyzed their sensitivity and specificity and obtained the best diagnostic panel. Finally, with the help of differentially expressed miRNAs, we performed gene ontology (GO) enrichment and protein-protein interaction (PPI) analyses by their target genes. RESULTS: In patients with EOS, three miRNAs (mir-223-3p, mir-15a-5p, and mir-17-5p) in serum were significantly downregulated, and mir-146a-5p, mir-1-3p, and mir-16-5p were upregulated. The diagnostic value of these miRNAs (miR-15a-5p, AUC = 0.67; miR-223-3p, AUC = 0.72; miR-16-5p, AUC = 0.68; miR-17-5p, AUC = 0.70; miR-1-3p, AUC = 0.69; miR-146a-5p, AUC = 0.72) was moderate, and the diagnostic panel constructed by miR-15a-5p, miR-223-3p, and miR-16-5p possessed a comparatively higher diagnostic value (AUC = 0.85, sensitivity: 74.6%, specificity: 86%), indicating that their combined application may be a promising biomarker for clinical diagnosis of EOS. According to GO enrichment analysis, most proteins encoded by target genes were located in the cytosol as for cellular component (CC), for molecular function (MF), most proteins acted as regulators in protein binding, and for biological process (BP). Most genes function in positive or negative regulation of transcription from RNA polymerase II promoter, and the top 10 hub genes were CDKN1A, YAP1, CCNE1, CCND1, CKK6, ERBB4, CHEK1, DICER1, VEGFA, and APP by rank degree after PPI construction. CONCLUSIONS: The three-miRNA panels (miR-15a-5p, miR-223-3p, and miR-16-5p) may be a novel noninvasive biological marker for EOS screening.

Neural correlates of negative life events and their relationships with alcohol and cannabis use initiation.

OBJECTIVE: Negative life events (NLEs), e.g., poor academic performance (controllable) or being the victim of a crime (uncontrollable), can profoundly affect the trajectory of one's life. Yet, their impact on how the brain develops is still not well understood. This investigation examined the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) dataset for the impact of NLEs on the initiation of alcohol and cannabis use, as well as underlying neural mechanisms. METHODS: This study evaluated the impact of controllable and uncontrollable NLEs on substance use initiation in 207 youth who initiated alcohol use, 168 who initiated cannabis use, and compared it to 128 youth who remained substance-naïve, using generalised linear regression models. Mediation analyses were conducted to determine neural pathways of NLE impacting substance use trajectories. RESULTS: Dose-response relationships between controllable NLEs and substance use initiation were observed. Having one controllable NLE increased the odds of alcohol initiation by 50% (95%CI [1.18, 1.93]) and cannabis initiation by 73% (95%CI [1.36, 2.24]), respectively. Greater cortical thickness in left banks of the superior temporal sulcus mediated effects of controllable NLEs on alcohol and cannabis initiations. Greater left caudate gray-matter volumes mediated effects of controllable NLEs on cannabis initiation. CONCLUSIONS: Controllable but not uncontrollable NLEs increased the odds of alcohol and cannabis initiation. Moreover, those individuals with less mature brain structures at the time of the NLEs experienced a greater impact of NLEs on subsequent initiation of alcohol or cannabis use. Targeting youth experiencing controllable NLEs may help mitigate alcohol and cannabis initiation.

Screen media activity in youth: A critical review of mental health and neuroscience findings.

This review has two primary objectives: (1) to offer a balanced examination of recent findings on the relationship between screen media activity (SMA) in young individuals and outcomes such as sleep patterns, mood disturbances, anxiety-related concerns, and cognitive processes; and (2) to introduce a novel multi-level system model that integrates these findings, resolves contradictions in the literature, and guides future studies in examining key covariates affecting the SMA-mental health relationship. Key findings include: (1) Several meta-analyses reveal a significant association between SMA and mental health issues, particularly anxiety and depression, including specific negative effects linked to prolonged screen time; (2) substantial evidence indicates that SMA has both immediate and long-term impacts on sleep duration and quality; (3) the relationship between SMA and cognitive functioning is complex, with mixed findings showing both positive and negative associations; and (4) the multifaceted relationship between SMA and various aspects of adolescent life is influenced by a wide range of environmental and contextual factors. SMA in youth is best understood within a complex system encompassing individual, caregiver, school, peer, and environmental factors, as framed by Bronfenbrenner's ecological systems theory, which identifies five interrelated systems (microsystem, mesosystem, exosystem, macrosystem, and chronosystem) that influence development across both proximal and distal levels of the environment. This model provides a framework for future research to examine these interactions, considering moderating factors, and to develop targeted interventions that can mitigate potential adverse effects of SMA on mental well-being.

Retinoic acid ameliorates low-grade endotoxemia-induced mastitis by limiting inflammatory responses in mice.

Mastitis is a serious disease for humans and animals, which causes huge economic losses in the dairy industry and is hard to prevent due to the complex and unclear pathogenesis. Subacute ruminal acidosis (SARA) has contributed to the development of mastitis by inducing ruminal dysbiosis and subsequent low-grade endotoxemia (LGE), however, how ruminal metabolic changes regulate this progress is still unclear. Our previous study revealed that cows with SARA had increased ruminal retinoic acid (RA) levels, a metabolic intermediate of vitamin A that plays an essential role in mucosal immune responses. Hence, the aim of this study was to investigate the protective effect of RA on LGE-induced mastitis and the underlying mechanisms in mice. The results showed that RA alleviated LGE-induced mastitis, as evidenced by RA significantly reduced the increase in mammary proinflammatory cytokines and improved blood-milk barrier injury caused by LGE. In addition, RA increased the expression of tight junction proteins, including ZO-1, occludin and claudin-3. Furthermore, we found that RA limited the mammary inflammatory responses by inhibiting the activation of NF-κB and NLRP3 signaling pathways. These findings suggest that RA effectively alleviates LGE-induced mastitis and implies a potential strategy for the treatment and prevention of mastitis and other diseases.

Analysis of the brain transcriptome for substance-associated genes: An update on large-scale genome-wide association studies.

Substance use disorder (SUD) arises from the initiation to subsequent regular, irregular and harmful use of substances such as alcohol, tobacco/nicotine and cannabis. While thousands of genetic variants have been identified from recent large-scale genome-wide association studies (GWAS), understanding their functions in substance involvement and investigating the mechanisms by which they act in the addiction circuits remains challenging. In this study, we re-analysed the brain regional transcriptome data from the most comprehensive postmortem transcriptomic study, with a focus on up- or down-regulation of substance-associated protein-coding genes in the addiction circuit-related brain regions (AddictRegions), including six cortical and 11 subcortical regions. We found that substance-associated genes were overrepresented in AddictRegions. Interestingly, we observed a greater degree of genetic overlap between initiation and use and between use and SUD than between initiation and SUD. Moreover, substance initiation, use and SUD-associated genes tend to shift their enriched AddictRegions from the cortical for initiation and, to a lesser extent, substance use to subcortical regions for SUD (e.g., thalamus, substantia nigra and ventral tegmental area). We also uncovered a pattern of coordinated cortical up-regulation and subcortical down-regulation for the genes associated with tobacco initiation and alcohol use. Moreover, the Gene Ontology terms of glutamate receptor activity and neurotransmitter binding were most significantly overrepresented in AddictRegion-upregulated, substance-associated genes, with the strongest enrichment for those involved in common substance use behaviours. Overall, our analysis provides a resource of AddictRegion-related transcriptomes for studying substance-associated genes and generates intriguing insights into the genetic control of substance initiation, use and SUD.

Characterising symptom clusters in patients with atrial fibrillation undergoing catheter ablation.

OBJECTIVE: This study aims to leverage natural language processing (NLP) and machine learning clustering analyses to (1) identify co-occurring symptoms of patients undergoing catheter ablation for atrial fibrillation (AF) and (2) describe clinical and sociodemographic correlates of symptom clusters. METHODS: We conducted a cross-sectional retrospective analysis using electronic health records data. Adults who underwent AF ablation between 2010 and 2020 were included. Demographic, comorbidity and medication information was extracted using structured queries. Ten AF symptoms were extracted from unstructured clinical notes (n=13 416) using a validated NLP pipeline (F-score=0.81). We used the unsupervised machine learning approach known as Ward's hierarchical agglomerative clustering to characterise and identify subgroups of patients representing different clusters. Fisher's exact tests were used to investigate subgroup differences based on age, gender, race and heart failure (HF) status. RESULTS: A total of 1293 patients were included in our analysis (mean age 65.5 years, 35.2% female, 58% white). The most frequently documented symptoms were dyspnoea (64%), oedema (62%) and palpitations (57%). We identified six symptom clusters: generally symptomatic, dyspnoea and oedema, chest pain, anxiety, fatigue and palpitations, and asymptomatic (reference). The asymptomatic cluster had a significantly higher prevalence of male, white and comorbid HF patients. CONCLUSIONS: We applied NLP and machine learning to a large dataset to identify symptom clusters, which may signify latent biological underpinnings of symptom experiences and generate implications for clinical care. AF patients' symptom experiences vary widely. Given prior work showing that AF symptoms predict adverse outcomes, future work should investigate associations between symptom clusters and postablation outcomes.

Association between Sexual Activity during Pregnancy, Pre- and Early-Term Birth, and Vaginal Cytokine Inflammation: A Prospective Study of Black Women.

This study aimed to investigate the association between sexual activity during pregnancy and adverse birth outcomes among Black women, and to explore whether vaginal cytokine inflammation mediates this association. Data from 397 Black pregnant women through questionnaires on sexual activity and vaginal biosamples during early (8-14 weeks) and late (24-30 weeks) pregnancy, and birth outcomes were analyzed. Using a data-driven approach, the study found that vaginal sex during late pregnancy was associated with spontaneous early-term birth (sETB, 38-39 completed weeks' gestation) (OR = 0.39, 95% CI: [0.21, 0.72], p-value = 0.003) but not with spontaneous preterm birth (sPTB) (OR = 1.08, p-value = 0.86) compared to full-term birth. Overall, despite vaginal sex in late pregnancy showing an overall positive effect on sETB (total effect = -0.1580, p-value = 0.015), we observed a negative effect of vaginal sex on sETB (indirect effect = 0.0313, p-value = 0.026) due to the fact that having vaginal sex could lead to elevated IL6 levels, which in turn increased the odds of sETB. In conclusion, the study found an overall positive association between sexual activity on ETB and a negative partial mediation effect via increased vaginal cytokine inflammation induced by vaginal sexual activity. This inconsistent mediation model suggested that vaginal sexual activity is a complex behavior that could have both positive and negative effects on the birth outcome.

Phytosphingosine alleviates Staphylococcus aureus-induced mastitis by inhibiting inflammatory responses and improving the blood-milk barrier in mice.

Mastitis is one of the common diseases in dairy cows which threatens the health of cows and impacts on economic benefits seriously. Recent studies have been showed that Subacute Ruminal Acidosis (SARA) increased the susceptibility of cow mastitis. SARA leads the disturbance of the rumen microbiota, and the rumen bacterial disordered community is an important endogenous factor of cow mastitis. That is to say, cows which suffer from SARA have a disordered rumen microbiota, a prolonged decline in ruminal PH and a high level of lipopolysaccharide (LPS) in the rumen, blood. Therefore, ruminal metabolism is closely related to the rumen microbiota. However, the specific mechanism of SARA and mastitis still not clear. We found an intestinal metabolite according to the metabonomics, which is correlated to inflammation. Phytophingosine (PS), a product from rumen fluid and milk of the cows which suffer from SARA and mastitis. It has the effect of killing bacteria and anti-inflammatory. Emerging evidences indicate that PS can alleviate inflammatory diseases. However, how PS affects mastitis is largely unknown. In this study, we explored the concrete role of PS on Staphylococcus aureus (S. aureus) -induced mastitis in mice. We found that PS obviously decreased the level of the proinflammatory cytokines. Meanwhile, PS also significantly relieved the mammary gland inflammation caused by S. aureus and restored the function of the blood-milk barrier. Here, we showed that PS increased the expression of the classic Tight-junctions (TJs) proteins including ZO-1, Occludin and Claudin-3. Moreover, PS improves S. aureus-induced mastitis by inhibiting the activation of the NF-κB and NLRP3 signaling pathways. These data indicated that PS relieved S. aureus-induced mastitis effectively. This also provides a reference for exploring the correlation between the intestinal metabolism and inflammation.

Epigenetic Implications of Neighborhood Disorder and Psychological Distress among Pregnant Black Women.

Background: In the United States, Black women experience preterm birth (PTB; <37 weeks gestation) at more than 1.5 times the rate of non-Hispanic White women. Social determinants of health including the neighborhood environment have been recognized as contributing to the risk of PTB. Due to historical segregation, Black women are more likely to live in neighborhoods with higher levels of neighborhood disorder compared with White women. Perceived neighborhood disorder appears to be a risk factor for maternal psychological distress in Black women and psychological distress has mediated the association between neighborhood disorder and the risk for PTB. However, the biological pathways underpinning these associations are not clear. Objective: We examined the associations among neighborhood disorder; psychological distress; DNA methylation of six stress-related, glucocorticoid candidate genes (AVP, CRH, CRHBP, FKBP5, HSD11B2, NR3C1); and gestational age at birth among 44 Black pregnant women. Methods: Women who were 18-45 years old and 8-18 weeks gestation had blood drawn and completed questionnaires measuring perceived neighborhood disorder, neighborhood crime, and psychological distress. Results: Three CpG sites were associated with neighborhood disorder (cg03405789 [CRH], cg14939152 and cg15910486 [NR3C1]). One CpG site, cg03098337 (FKBP5) was associated with psychological distress. Three of the identified CpG sites were located within gene CpG islands or shores-areas at which DNA methylation is known to affect gene transcription. Conclusion: These findings warrant further research to clarify intermediate biological pathways and potential biomarkers to identify women at risk for PTB. Identification of PTB risk early in pregnancy would allow for interventions to prevent PTB.

Expanding the "Magic Triangle" of Reinforced Rubber Using a Supramolecular Filler Strategy.

A strategy for optimizing the rolling resistance, wet skid and cut resistance of reinforced rubber simultaneously using a supramolecular filler is demonstrated. A ß-alanine trimer-grafted Styrene Butadiene Rubber (A3-SBR) pristine polymer was designed and mechanically mixed with commercially available styrene butadiene rubber to help the dispersion of a ß-alanine trimer (A3) supramolecular filler in the rubber matrix. To increase the miscibility of A3-SBR with other rubber components during mechanical mixing, the pristine polymer was saturated with ethanol before mixing. The mixture was vulcanized using a conventional rubber processing method. The morphology of the assembles of the A3 supramolecular filler in the rubber matrix was studied by Differential Scanning Calorimetry (DSC) and Transmission Electron Microscopy (TEM). The Differential Scanning Calorimetry study showed that the melting temperature of ß-sheet crystals in the vulcanizates was around 179 °C and was broad. The melting temperature was similar to that of the pristine polymer, and the broad melting peak likely suggests that the size of the crystals is not uniform. The Transmission Electron Microscopy study revealed that after mixing the pristine polymer with SBR, some ß-sheet crystals were rod-like with several tens of nanometers and some ß-sheet crystals were particulate with low aspect ratios. Tensile testing with pre-cut specimens showed that the vulcanizate containing A3-SBR was more cut-resistant than the one that did not contain A3-SBR, especially at a large cut size. The rolling resistance and wet skid were predicted by dynamic mechanical analysis (DMA). DMA tests showed that the vulcanizates containing A3-SBR were significantly less hysteretic at 60 °C and more hysteretic at 0 °C based on loss factor. Overall, the "magic triangle" was expanded by optimizing the rolling resistance, wet-skid, and cut resistance simultaneously using a ß-alanine trimer supramolecular filler. The Payne effect also became less severe after introducing the ß-alanine trimer supramolecular filler into the system.

From comfort zone to mortality: Sequence of physiological stress thresholds in Robinia pseudoacacia seedlings during progressive drought.

Introduction: Parameterizing the process of trees from the comfort zone to mortality during progressive drought is important for, but is not well represented in, vegetation models, given the lack of appropriate indices to gauge the response of trees to droughts. The objective of this study was to determine reliable and readily available tree drought stressindices and the thresholds at which droughts activate important physiological responses. Methods: We analyzed the changes in the transpiration (T), stomatal conductance, xylem conductance, and leaf health status due to a decrease in soil water availability (SWA), predawn xylem water potential (ψpd), and midday xylem water potential (ψmd) in Robinia pseudoacacia seedlings during progressive drought. Results: The results showed that ψmd was a better indicator of drought stress than SWA and ψpd, because ψmd was more closely related to the physiological response (defoliation and xylem embolization) during severe drought and could be measured more conveniently. We derived the following five stress levels from the observed responses to decreasing ψmd: comfort zone (ψmd > -0.9 MPa), wherein transpiration and stomatal conductance are not limited by SWA; moderate drought stress (-0.9 to -1.75 MPa), wherein transpiration and stomatal conductance are limited by drought; high drought stress (-1.75 to -2.59 MPa), wherein transpiration decreases significantly (T< 10%) and stomata closes completely; severe drought stress (-2.59 to -4.02 MPa), wherein transpiration ceases (T< 0.1%) and leaf shedding orwilting is > 50%; and extreme drought stress (< -4.02 MPa), leading to tree mortality due to xylem hydraulic failure. Discussion: To our knowledge, our scheme is the first to outline the quantitative thresholds for the downregulation of physiological processes in R. pseudoacacia during drought, therefore, can be used to synthesize valuable information for process-based vegetation models.

Sialic acid exacerbates gut dysbiosis-associated mastitis through the microbiota-gut-mammary axis by fueling gut microbiota disruption.

BACKGROUND: Mastitis is one of the most severe diseases in humans and animals, especially on dairy farms. Mounting evidence indicates that gastrointestinal dysbiosis caused by induction of subacute ruminal acidosis (SARA) by high-grain diet consumption and low in dietary fiber is associated with mastitis initiation and development, however, the underlying mechanism remains unknown. RESULTS: In the present study, we found that cows with SARA-associated mastitis have altered metabolic profiles in the rumen, with increased sialic acids level in particular. Consumption of sialic acid (SA) in antibiotic-treated mice, but not healthy mice, induced marked mastitis. SA treatment of antibiotic-treated mice also induced mucosal and systemic inflammatory responses, as evidenced by increased colon and liver injuries and several inflammatory markers. In addition, gut dysbiosis caused by antibiotic impaired gut barrier integrity, which was aggravated by SA treatment. SA potentiated serum LPS level caused by antibiotic treatment, leading to increased activation of the TLR4-NF-κB/NLRP3 pathways in the mammary gland and colon. Moreover, SA facilitated gut dysbiosis caused by antibiotic, and especially enhanced Enterobacteriaceae and Akkermansiaceae, which correlated with mastitis parameters. Fecal microbiota transplantation from SA-antibiotic-treated mice mimicked mastitis in recipient mice. In vitro experiments showed that SA prompted Escherichia coli growth and virulence gene expression, leading to higher proinflammatory cytokine production in macrophages. Targeting the inhibition of Enterobacteriaceae by sodium tungstate or treating with the commensal Lactobacillus reuteri alleviated SA-facilitated mastitis. In addition, SARA cows had distinct ruminal microbial structure by the enrichment of SA-utilizing opportunistic pathogenic Moraxellaceae and the depletion of SA-utilizing commensal Prevotellaceae. Treating mice with the specific sialidase inhibitor zanamivir reduced SA production and Moraxellaceae abundance, and improved mastitis in mice caused by ruminal microbiota transplantation from cows with SARA-associated mastitis. CONCLUSIONS: This study, for the first time, indicates that SA aggravates gut dysbiosis-induced mastitis by promoting gut microbiota disturbance and is regulated by commensal bacteria, indicating the important role of the microbiota-gut-mammary axis in mastitis pathogenesis and suggesting a potential strategy for mastitis intervention based on gut metabolism regulation. Video Abstract.

Youth Screen Media Activity Patterns and Associations With Behavioral Developmental Measures and Resting-state Brain Functional Connectivity.

OBJECTIVE: Screen media activity (SMA) consumes considerable time in youth's lives, raising concerns about the effects it may have on youth development. Disentangling mixed associations between SMA of youth and developmental measures should move beyond overall screen time and consider types and patterns of SMA. This study aimed to identify reliable and generalizable SMA patterns among youth and examine their associations with behavioral developmental measures and developing brain functional connectivity. METHOD: Three waves of Adolescent Brain and Cognitive Development (ABCD) data were examined. The Lifespan Human Connectome Project in Development (HCP-D) was interrogated as an independent sample. ABCD participants included 11,876 children at baseline. HCP-D participants included 652 children and adolescents. Youth-reported SMA and behavioral developmental measures (neurocognitive performance, behavioral problems, psychotic-like experiences, impulsivity, and sensitivities to punishment/reward) were assessed with validated instruments. We identified SMA patterns in the ABCD baseline data using K-means clustering and sensitivity analyses. Generalizability and stability of the identified SMA patterns were examined in HCP-D data and ABCD follow-up waves, respectively. Relations between SMA patterns and behavioral and brain (resting-state brain functional connectivity) measures were examined using linear mixed effects modeling with false discovery rate (FDR) correction. RESULTS: SMA data from 11,815 children (mean [SD] age = 119.0 [7.5] months; 6,159 [52.1%] boys) were examined; 3,151 (26.7%) demonstrated a video-centric higher-frequency SMA pattern, and 8,664 (73.3%) demonstrated a lower-frequency pattern. SMA patterns were validated in similarly aged HCP-D youth. Compared with the lower-frequency SMA pattern group, the video-centric higher-frequency SMA pattern group showed poorer neurocognitive performance (ß = -.12, 95% CI [-0.08, -0.16], FDR-corrected p < .001), more total behavioral problems (ß = .13, 95% CI [0.09, 0.18], FDR-corrected p < .001), and more psychotic-like experiences (ß = .31, 95% CI [0.27, 0.36], FDR-corrected p < .001). The video-centric higher-frequency SMA pattern group demonstrated higher impulsivity, more sensitivity to punishment/reward, and altered resting-state brain functional connectivity among brain areas implicated previously in cognitive processes. Most of the associations persisted with age in the ABCD data, with more participants (n = 3,378, 30.4%) in the video-centric higher-frequency SMA group at 1-year follow-up. A social communication-centric SMA pattern was observed in HCP-D adolescents. CONCLUSION: Video-centric SMA patterns are reliable and generalizable during late childhood. A higher-frequency video entertainment SMA pattern group showed altered resting-state brain functional connectivity and poorer developmental measures that persisted longitudinally. The findings suggest that public health strategies to decrease excessive time spent by children on video entertainment-related SMA are needed. Further studies are needed to examine potential video-centric/social communication-centric SMA bifurcation to understand dynamic changes and trajectories of SMA patterns and related outcomes developmentally. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Brain structural co-development is associated with internalizing symptoms two years later in the ABCD cohort.

Background and aims: About 1/3 of youth spend more than four hours/day engaged in screen media activity (SMA). This investigation utilized longitudinal brain imaging and mediation analyses to examine relationships among SMA, brain patterns, and internalizing problems. Methods: Data from Adolescent Brain Cognitive Development (ABCD) participants with baseline and two-year follow-up structural imaging data that passed quality control (N = 5,166; 2,385 girls) were analyzed. Joint and Individual Variation Explained (JIVE) identified a brain co-development pattern among 221 brain features (i.e., differences in surface area, thickness, or cortical and subcortical gray-matter volume between baseline and two-year-follow-up data). Generalized linear mixed-effect models investigated associations between baseline SMA, structural co-development and internalizing and externalizing psychopathology at two-year follow-up. Results: SMA at baseline was related to internalizing psychopathology at year 2 (ß=0.020,SE=0.008,P=0.014) and a structural co-development pattern (ß=0.015,SE=0.007,P=0.029), where the co-development pattern suggested that rates of change in gray-matter volumes of the brainstem, gray-matter volumes and/or cortical thickness measures of bilateral superior frontal, rostral middle frontal, inferior parietal, and inferior temporal regions were more similar than those in other regions. This component partially mediated the relationship between baseline SMA and future internalizing problems (indirect effect = 0.020, P-value = 0.043, proportion mediated: 2.24%). Discussion and conclusions: Greater youth engagement in SMA at ages 9-10 years statistically predicted higher levels of internalizing two years later. This association was mediated by cortical-brainstem circuitry, albeit with relatively small effect sizes. The findings may help delineate processes contributing to internalizing behaviors and assist in identifying individuals at greater risk for such problems.