Identifying individual brain development using multimodality brain network.

The cortical development of our brains is in a hierarchical manner and promotes the emergence of large-scale functional hierarchy. However, under interindividual heterogenicity, how the spatiotemporal features of brain networks reflect brain development and mental health remains unclear. Here we collect both resting-state electroencephalography and functional magnetic resonance imaging data from the Child Mind Institute Biobank to demonstrate that during brain growth, the global dynamic patterns of brain states become more active and the dominant networks shift from sensory to higher-level networks; the individual functional network patterns become more similar to that of adults and their spatial coupling tends to be invariable. Furthermore, the properties of multimodality brain networks are sufficiently robust to identify healthy brain age and mental disorders at specific ages. Therefore, multimodality brain networks provide new insights into the functional development of the brain and a more reliable and reasonable approach for age prediction and individual diagnosis.

Old concepts, new tricks: How peptide vaccines are reshaping cancer immunotherapy?

Over the past few decades, research on cancer immunotherapy has firmly established immune cells as key players in effective cancer treatment. Peptide vaccines directly targeting immune cells have demonstrated immense potential due to their specificity and applicability. However, developing peptide vaccines to generate tumor-reactive T cells remains challenging, primarily due to suboptimal immunogenicity and overcoming the immunosuppressive tumor microenvironment (TME). In this review, we discuss various elements of effective peptide vaccines, including antigen selection, peptide epitope optimization, vaccine adjuvants, and the combination of multiple immunotherapies, in addition to recent advances in tumor neoantigens as well as epitopes bound by non-classical human leukocyte antigen (HLA) molecules, to increase the understanding of cancer peptide vaccines and provide multiple references for the design of subsequent T cell-based peptide vaccines.

Durable response to pembrolizumab in hepatic metastasis from colonic carcinoma with Lynch syndrome: a case report.

Pembrolizumab and other immunotherapies have become central in treating metastatic colon cancer, particularly effective in patients with mismatch repair deficiencies. We report a case involving a man who initially underwent radical surgery for sigmoid colon cancer on April 27, 2011, followed by hepatic tumor resection on September 21, 2017. Post-surgery, he received eight cycles of adjuvant chemotherapy with the CAPEOX regimen and was regularly monitored through CT and MRI scans. On August 24, 2022, liver metastases were detected, and he was diagnosed with Lynch syndrome (LS) due to germline mutation in the MSH2 and EPCAM genes. He commenced treatment with 200mg of pembrolizumab intravenously every three weeks on September 2, 2022, and demonstrated a sustained response. However, after 17 cycles, he developed a treatment related adverse event (TRAE) of pancreatic endocrine dysfunction, leading to type 1 diabetes, managed with subcutaneous insulin injections. After 30 cycles of treatment, no evidence of disease was observed. This case underscores the significant clinical benefits of first-line pembrolizumab in managing hepatic metastasis in colonic carcinoma associated with LS, despite the occurrence of TRAEs. It raises critical questions regarding the optimal duration of immunotherapy following a complete or partial response and whether treatment should be discontinued upon the emergency of TRAEs. Continued research and forthcoming clinical trials with checkpoint inhibitors are expected to refine treatment protocols for LS-associated carcinoma.

Understanding the link between intimate partner violence exposure and children's self-regulation: The mediating role of parenting stress and warmth.

Intimate partner violence (IPV), affecting approximately 16.3% of U.S. households annually, has detrimental effects on children who witness it, leading to psychological distress, developmental delays, and behavioral issues. Self-regulation, a critical skill in managing attention, emotions, and behaviors essential for cognitive and social development, may be significantly impacted. The negative associations between mothers' experience of IPV and child self-regulation necessitate the examination of the underlying mechanisms, particularly during the sensitive period of early childhood. This study utilized longitudinal data from the Future of Families and Child Wellbeing Study (N = 4338) to investigate the mediating pathways linking mothers' experience of IPV (maternal victimization experiences) during infancy with children's self-regulation at age five. Results suggested that IPV exposure during infancy was longitudinally and negatively associated with children's behavioral and attentional regulation. This association was mediated by elevated parenting stress and decreased maternal warmth. These findings highlight the importance of programs aimed at reducing IPV and supporting mothers affected by IPV, considering their vital roles in nurturing healthy child self-regulation skills.

Exoticin as a selective agonist of 6TM µ opioid receptors identifies endogenous chaperones essential for its activity.

BACKGROUND: Classical opioids are effective analgesics but carry various side effects, necessitating safer alternatives. Truncated six-transmembrane mu opioid receptors (6TM-µORs) mediate potent analgesia with fewer side effects and are a promising therapeutic target. However, few ligands known selectively target 6TM-µORs. Moreover, endogenous chaperones are believed essential for 6TM-µOR ligand binding and function. PURPOSE: To identify a 6TM-µOR selective agonist and elucidate requisite endogenous chaperones. METHODS: Virtual screening was used to identify promising selective 6TM-µOR agonists from traditional Chinese medicines. The role of 6TM-µOR in Exoticin analgesia was validated in loss- and gain-of-function models. APEX2 proteomics profiled proximal proteins under Exoticin or IBNtxA. Interactions were further characterized in vivo and in vitro. RESULTS: Exoticin was shortlisted for its selective binding to 6TM-µOR and ability to induce 6TM-µOR-dependent signal transduction. Exoticin analgesia was sensitive to ß-FNA and absent in E11 KO mice, but restored in mice infected with AAV-µOR1G. Slc3a2, Lrrc59, and Ppp1cb co-interacted with 6TM-µOR1G and were equally essential for Exoticin binding and 6TM-µOR1G activity. CONCLUSION: Exoticin is a promising selective agonist of 6TM µ opioid receptors with broad-spectrum analgesic efficacy but few side effects. Slc3a2, Lrrc59, Ppp1cb are endogenous chaperones essential for 6TM-µOR ligand binding and function.

Sinomenine Alleviates Rheumatoid Arthritis by Suppressing the PI3K-Akt Signaling Pathway, as Demonstrated Through Network Pharmacology, Molecular Docking, and Experimental Validation.

Purpose: Sinomenine (SIN) is commonly used in Traditional Chinese Medicine (TCM) as a respected remedy for rheumatoid arthritis (RA). Nevertheless, the therapeutic mechanism of SIN in RA remains incompletely understood. This study aimed to delve into the molecular mechanism of SIN in the treatment of RA. Methods: The potential targets of SIN were predicted using the TCMSP server, STITCH database, and SwissTarget Prediction. Differentially expressed genes (DEGs) in RA were obtained from the GEO database. Enrichment analyses and molecular docking were conducted to explore the potential mechanism of SIN in the treatment of RA. In vitro and in vivo studies were conducted to validate the intervention effects of SIN on rheumatoid arthritis, as determined through network pharmacology analyses. Results: A total of 39 potential targets associated with the therapeutic effects of SIN in RA were identified. Enrichment analysis revealed that these potential targets are primarily enriched in PI3K-Akt signaling pathway, and the molecular docking suggests that SIN may act on specific proteins in the pathway. Experimental results have shown that exposure to SIN inhibits cytokine secretion, promotes apoptosis, reduces metastasis and invasion, and blocks the activation of the PI3K-Akt signaling pathway in RA fibroblast-like synoviocytes (RA-FLS). Moreover, SIN treatment alleviated arthritis-related symptoms and regulated the differentiation of CD4+ T cells in the spleen of collagen-induced arthritis (CIA) mice. Conclusion: By utilizing network pharmacology, molecular modeling, and in vitro/in vivo validation, this study demonstrates that SIN can alleviate RA by inhibiting the PI3K-Akt signaling pathway. These findings enhance the understanding of the therapeutic mechanisms of SIN in RA, offering a stronger theoretical foundation for its future clinical application.

Critical role of thrombospondin-1 in promoting intestinal mucosal wound repair.

Thrombospondin-1 (TSP1) is a matricellular protein associated with the regulation of cell migration through direct binding interactions with integrin proteins and by associating with other receptors known to regulate integrin function, including CD47 and CD36. We previously demonstrated that deletion of an epithelial TSP1 receptor, CD47, attenuates epithelial wound repair following intestinal mucosal injury. However, the mechanisms by which TSP1 contributes to intestinal mucosal repair remain poorly understood. Our results show upregulated TSP1 expression in colonic mucosal wounds and impaired intestinal mucosal wound healing in vivo upon intestinal epithelium-specific loss of TSP1 (VillinCre/+ Thbs1fl/fl or Thbs1ΔIEC mice). We report that exposure to exogenous TSP1 enhanced migration of intestinal epithelial cells in a CD47- and TGF-ß1-dependent manner and that deficiency of TSP1 in primary murine colonic epithelial cells resulted in impaired wound healing. Mechanistically, TSP1 modulated epithelial actin cytoskeletal dynamics through suppression of RhoA activity, activation of Rho family small GTPase (Rac1), and changes in filamentous-actin bundling. Overall, TSP1 was found to regulate intestinal mucosal wound healing via CD47 and TGF-ß1, coordinate integrin-containing cell-matrix adhesion dynamics, and remodel the actin cytoskeleton in migrating epithelial cells to enhance cell motility and promote wound repair.

Sorption of Iodine on Biochar Derived from the Processing of Urban Sludge and Garden Waste at Different Pyrolysis Temperatures.

The United Nations proposed the Sustainable Development Goals with the aim to make human settlements in cities resilient and sustainable. The excessive discharge of urban waste including sludge and garden waste can pollute groundwater and lead to the emission of greenhouse gases (e.g., CH4). The proper recycling of urban waste is essential for responsible consumption and production, reducing environmental pollution and addressing climate change issues. This study aimed to prepare biochar with high adsorption amounts of iodine using urban sludge and peach wood from garden waste. The study was conducted to examine the variations in the mass ratio between urban sludge and peach wood (2/1, 1/1, and 1/2) as well as pyrolysis temperatures (300 °C, 500 °C, and 700 °C) on the carbon yield and adsorption capacities of biochar. Scanning electron microscopy, Brunauer-Emmett-Teller analysis, Fourier transform infrared spectrometry, powder X-ray diffraction, and elemental analysis were used to characterize the biochar produced at different pyrolysis temperatures and mass ratios. The results indicate that the carbon yield of biochar was found to be the highest (>60%) at a pyrolysis temperature of 300 °C across different pyrolysis temperatures. The absorbed amounts of iodine in the aqueous solution ranged from 86 to 223 mg g-1 at a mass ratio of 1:1 between urban sludge and peach wood, which were comparably higher than those observed in other mass ratios. This study advances water treatment by offering a cost-effective method by using biochar derived from the processing of urban sludge and garden waste.

Three steps toward dose optimization for oncology dose finding.

Background: Traditional dose selection for oncology registration trials typically employs a one- or two-step single maximum tolerated dose (MTD) approach. However, this approach may not be appropriate for molecularly targeted therapy, which tends to have toxicity profiles that are markedly different than cytotoxic agents. The US Food and Drug Administration launched Project Optimus to reform dose optimization in oncology drug development and has recently released a related guidance for industry. Methods: We propose a "three steps toward dose optimization" procedure, in response to these initiatives, and discuss the details in dose-optimization designs and analyses. The first step is dose escalation to identify the MTD or maximum administered dose with an efficient hybrid design, which can offer good overdose control and increases the likelihood of the recommended MTD being close to the true MTD. The second step is the selection of appropriate recommended doses for expansion (RDEs), based on all available data, including emerging safety, pharmacokinetics, pharmacodynamics, and other biomarker information. The third step is dose optimization, which uses data from a randomized fractional factorial design with multiple RDEs explored in multiple tumor cohorts during the expansion phase to ensure a feasible dose is selected for registration trials, and that the tumor type most sensitive to the investigative treatment is identified. Conclusion: We believe using this three-step approach can increase the likelihood of selecting an optimal dose for a registration trial that demonstrates a balanced safety profile while retaining much of the efficacy observed at the MTD.

Structural basis of promoter recognition by Staphylococcus aureus RNA polymerase.

Bacterial RNAP needs to form holoenzyme with σ factors to initiate transcription. While Staphylococcus aureus σA controls housekeeping functions, S. aureus σB regulates virulence, biofilm formation, persistence, cell internalization, membrane transport, and antimicrobial resistance. Besides the sequence difference, the spacers between the -35 element and -10 element of σB regulated promoters are shorter than those of σA regulated promoters. Therefore, how σB recognizes and initiates transcription from target promoters can not be inferred from that of the well studied σ. Here, we report the cryo-EM structures of S. aureus RNAP-promoter open complexes comprising σA and σB, respectively. Structural analyses, in combination with biochemical experiments, reveal the structural basis for the promoter specificity of S. aureus transcription. Although the -10 element of σA regulated promoters is recognized by domain σA2 as single-stranded DNA, the -10 element of σB regulated promoters is co-recognized by domains σB2 and σB3 as double-stranded DNA, accounting for the short spacers of σB regulated promoters. S. aureus RNAP is a validated target of antibiotics, and our structures pave the way for rational drug design targeting S. aureus RNAP.

Circadian-clock-controlled endocrine and cytokine signals regulate multipotential innate lymphoid cell progenitors in the bone marrow.

Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely mobilization of multipotential progenitors from the bone marrow. It remains unknown what triggers the mobilization of bone marrow ILC progenitors (ILCPs). We report that ILCPs are regulated by the circadian clock to emigrate and generate mature ILCs in the periphery. We found that circadian-clock-defective ILCPs fail to normally emigrate and generate ILCs. We identified circadian-clock-controlled endocrine and cytokine cues that, respectively, regulate the retention and emigration of ILCPs at distinct times of each day. Activation of the stress-hormone-sensing glucocorticoid receptor upregulates CXCR4 on ILCPs for their retention in the bone marrow, while the interleukin-18 (IL-18) and RORα signals upregulate S1PR1 on ILCPs for their mobilization to the periphery. Our findings establish important roles of circadian signals for the homeostatic efflux of bone marrow ILCPs.

Association between hemoglobin levels and diabetic foot ulcer in patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: Anemia is prevalent among patients with T2DM with DFU. However, there is limited research on the relationship between Hb level and DFU. OBJECTIVE: To investigate the characteristics and relationship between Hb level and prognosis in patients with DFU. MATERIALS AND METHODS: A total of 212 patients with T2DM were included and grouped according to the presence (n = 105) or absence (n = 107) of DFU. The independent t test and multiple logistic regression analysis were used to analyze the effect of different factors on the occurrence of anemia in patients with DFU and whether Hb level could be used to predict prognosis. RESULTS: There were significant differences in clinical indicators that directly or indirectly contributed to anemia in patients with DFU (P < .05). Hb level was independently associated with DFU (OR, 0.899; P < .05). Hb levels were significantly decreased in patients aged 65 years or older (P < .05). Mild anemia was prevalent among most patients with DFU (59.62%). Hb level decreased with the severity of foot ulcer (P < .05) and was correlated with the duration of diabetes (R2 = 0.653; P < .05). The AUC value was 0.82, with a cutoff value of 122.5 g/L to identify patients with DFU at high risk of adverse outcomes. CONCLUSION: Anemia is common in patients with DFU. Anemia is a marker of DFU severity, and Hb level can predict poor prognosis in patients with DFU.

Intermittent fasting improves the oocyte quality of obese mice through the regulation of maternal mRNA storage and translation by LSM14B.

Obesity has significant repercussions for female reproductive health, including adverse effects on oocyte quality, fertility, embryo development and offspring health. Here, we showed that intermittent fasting (IF) has several notable effects on follicular development, oocyte development and maturation and offspring health in obese mice. IF treatment prevents obesity-associated germline-soma communication defects, mitochondrial dysfunction, oxidative damage, apoptosis, and spindle/chromosomal disruption. RNA-sequencing analysis of oocytes from normal diet (ND), high-fat diet (HFD), and HFD + IF mice indicated that IF treatment improved mitochondrial oxidative phosphorylation function and mRNA storage and translation, which was potentially mediated by the Smith-like family member 14 B (LSM14B). Knockdown of LSM14B by siRNA injection in oocytes from ND mice recapitulates all the translation, mitochondrial dysfunction and meiotic defect phenotypes of oocytes from HFD mice. Remarkably, the injection of Lsm14b mRNA into oocytes from HFD mice rescued the translation, mitochondrial dysfunction and meiotic defect phenotypes. These results demonstrated that dysfunction in the oocyte translation program is associated with obesity-induced meiotic defects, while IF treatment increased LSM14B expression and maternal mRNA translation and restored oocyte quality. This research has important implications for understanding the effects of obesity on female reproductive health and offers a potential nonpharmacological intervention to improve oocyte quality and fertility in obese individuals.

Expression and prognosis analysis of TBX2 subfamily in human lung carcinoma.

PURPOSE: Lung cancer has a high morbidity and mortality rate of all cancers worldwide. Therefore, there is an urgent need for reliable cancer markers for diagnosis and prognosis of patients with lung cancer. METHODS: In this study, we used the bioinformatics database to compare the expression of the TBX2 subfamily at the transcriptional and protein levels in non-small cell lung cancer. Then, to confirm our bioinformatics analysis above, we used western bloting to determine the expression of TBX2, TBX3, TBX4 and TBX5 in human lung squamous carcinoma cell lines. Besides, low expression of TBX2 subfamily predicted a poor prognosis of patients with lung cancer. Finally, The methylation database was used to explore the relationship between the low expression of TBX2 subfamily and methylation of gene promoter region. RESULTS: Our data showed a significant decrease of TBX2 subfamily expression in lung cancer tissues of several histological subtypes. Finally, the methylation of TBX2 subfamily members in the promoter region of NSCLC was significantly higher than that in normal tissues. CONCLUSION: Our research provided sufficient evidence that TBX2 subfamily might play an inhibitory role in malignancy progression of lung cancer, which is promising to shed light on discovering a novel reliable cancer marker for prognosis of lung cancer patients.

Early adverse childhood experiences and preschoolers' attentional regulation: A latent class analysis.

BACKGROUND: Adverse childhood experiences (ACEs) profoundly disrupt preschoolers' attentional regulation development. Different patterns of ACEs may be associated with different attentional regulation outcomes. OBJECTIVE: Drawing from developmental systems theory and attachment theory, this study aimed to identify distinct patterns of early ACEs at age three and examined the associations of these patterns with preschoolers' attentional regulation at age five. PARTICIPANTS AND SETTING: This study used the two waves of longitudinal data from the Future of Families and Child Wellbeing Study (N = 4457). METHODS: First, this study applied latent class analysis (LCA) across nine indicators of ACEs at age three. Second, class membership was examined for associations with preschoolers' attentional regulation at age five. RESULTS: LCA identified four latent classes of ACEs: separation (41.2 %), parental incarceration (33 %), family dysfunction (20.8 %), and child abuse (5 %). Children in the child abuse class exhibited lower levels of attentional regulation than those in the family dysfunction class (0.33 standard deviation difference, p < .01) or separation class (0.48 standard deviation difference, p < .001). Children in the parental incarceration class demonstrated lower levels of attentional regulation than those in the separation class (0.63 standard deviation difference, p < .001). CONCLUSIONS: Findings provide implications for the need to prevent early child abuse and incorporate trauma-informed intervention programs to support preschoolers' attentional regulation during school-entry age.

Satellite microwave measurements complementary to fire weather improve the assessment of fires among different biomes in Southeast Asia.

Microwaves have the advantage of penetrating vegetation and exhibit sensitivity to properties such as vegetation water content (VWC); yet, their potential utility in the fire domain is infrequently investigated. This study elucidates the different impacts of the microwave VWC index EDVI on fire radiative energy (FRE) across various biome types and the significant predictive power for high-severity fires (defined based on FRE) in mainland Southeast Asia. While EDVI exhibits lower predictive power for high severe fires compared to the commonly used fire weather indices (e.g., FWI), an enhancement is observed when these predictors are used in combination. Either by employing EDVI or fire weather indices, the predictability of fires is found to be highest over forests and lowest over croplands. Factors such as increasing human influence and fuel limitation in croplands are likely reducing the roles of VWC and weather on fires, contributing to the lower prediction skill of EDVI and fire weather. These results indicate the usefulness of microwave VWC index in fire studies. Although fire weather presents more considerable impacts on fires, the microwave VWC index seem to still provide some complementary information in fire danger assessment.

Factors That Influence the Tenure of Direct Support Professionals in New York State Provider Agencies.

The New York State Office for People With Developmental Disabilities seeks to better understand the direct support professional (DSP) workforce and offer data-informed strategies for DSP retention. We used the 2018 NCI-IDD Staff Stability Survey (now called State of the Workforce Survey) to investigate agency-level factors influencing DSP tenure. A total 303 provider agencies completed the survey in New York State, representing 72,252 DSPs. Multiple linear regression analysis revealed that selected agency-level variables explained 12.6% of the variance in DSP tenure, R2 = .16, Radj2 = .126, F (11, 260) = 4.54, p < .05. This study yielded strong empirical evidence consistent with existing national reports and research on the role that wages, benefits, and supervisory support play on DSP tenure.

Parametric modal regression with error in covariates.

An inference procedure is proposed to provide consistent estimators of parameters in a modal regression model with a covariate prone to measurement error. A score-based diagnostic tool exploiting parametric bootstrap is developed to assess adequacy of parametric assumptions imposed on the regression model. The proposed estimation method and diagnostic tool are applied to synthetic data generated from simulation experiments and data from real-world applications to demonstrate their implementation and performance. These empirical examples illustrate the importance of adequately accounting for measurement error in the error-prone covariate when inferring the association between a response and covariates based on a modal regression model that is especially suitable for skewed and heavy-tailed response data.

High loadings of carbonaceous aerosols from wood smoke in the atmosphere of Beijing from 2015 to 2017: Implications for energy transition policy.

Recently, biomass has been regarded as a promising option for solid energy in China, which is promoted in the residential sector and firing power plants. We collected 200 PM2.5 samples (particulate matter with a aerodynamic diameter smaller than 2.5 µm) at multi-sites across Beijing from three individual sampling cases from 2015 to 2017. The levels of OC, OC fractions, EC, EC fractions, as well as K+ were measured. Then, we adopted the Positive Matrix Factorization 5.0 to apportion the sources of carbonaceous aerosols. The source apportionment results were compared with the estimates of source contribution using the bottom-up technical method with the latest emission inventories after the Action Plan was put into effect in 2013. Our results demonstrate that high pollution of carbonaceous aerosols originated from wood smoking based on the receptor modeling and bottom-up technical method in Beijing from 2015 to 2017. Future energy transition policy should focus on the technologies and regulations for reducing emissions from renewable biomass fuel combustion. This study highlights the importance of regulations that address emissions controls on fuels replacing coal combustion to meet the needs to mitigate air pollution from primary energy use.

Possible molecular exploration of herbal pair Haizao-Kunbu in the treatment of Graves' disease by network pharmacology, molecular docking, and molecular dynamic analysis.

Objective: To promote the development and therapeutic application of new medications, it is crucial to conduct a thorough investigation into the mechanism by which the traditional Chinese herb pair of Haizao-Kunbu (HK) treats Graves' disease (GD). Materials and methods: Chemical ingredients of HK, putative target genes, and GD-associated genes were retrieved from online public databases. Using Cytoscape 3.9.1, a compound-gene target network was established to explore the association between prosperous ingredients and targets. STRING, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses visualized core targets and disease pathways. Additionally, we conducted a refined analysis of the binding interactions between active ingredients and their respective targets. To visualize these findings, we employed precise molecular docking techniques. Furthermore, we carried out molecular dynamics simulations to gain insights into the formation of more tightly bound complexes. Results: We found that there were nine key active ingredients in HK, which mainly acted on 21 targets. These targets primarily regulated several biological processes such as cell population proliferation, protein phosphorylation, and regulation of kinase activity, and acted on PI3K-AKT and MAPK pathways to treat GD. Analysis of the molecular interaction simulation under computer technology revealed that the key targets exhibited strong binding activity to active ingredients, and Fucosterol-AKT1 and Isofucosterol-AKT1 complexes were highly stable in humans. Conclusion: This study demonstrates that HK exerts therapeutic effects on GD in a multi-component, multi-target, and multi-pathway manner by regulating cell proliferation, differentiation, inflammation, and immunomodulatory-related targets. This study provides a theoretical foundation for further investigation into GD.