Mind‑body practices, such as meditation and yoga, involve paying attention to breathing sensations. During these practices, individuals report "interoceptive lapses," moments when attention drifts away from internal bodily sensations. While lapses in attention to the external world have been widely studied, little is known about the physiological and neural mechanisms of interoceptive lapses. Interoceptive lapses may share markers with exteroceptive lapses-such as reaction time variability and default-mode network (DMN) connectivity-but may also depend on distinct brain systems and breathing physiology. We examined behavioral, physiological, and neural signals preceding lapses in a sample of 93 adolescents enriched for GAD and depression symptoms. Participants performed a 20-min breath counting task in the fMRI scanner with simultaneous breath recordings. Lapses were defined as moments when counting errors occurred. The sample was split into training and validation sets to test machine learning models predicting attentional lapses. The strongest predictors were timing and variability of button responses (AUCs > 0.75). Breathing variability and breathing-behavior synchronization showed smaller but generalizable predictive value (AUCs < 0.65). Whole-brain connectivity models also predicted lapses (AUC ≈ 0.65), incorporating the DMN, dorsal and ventral attention, and somatomotor networks. Furthermore, models that included brain connectivity marginally outperformed behavior-only models. Comparisons to previous exteroceptive findings indicate some common markers (e.g., reaction time variability) and some unique markers (e.g., selective perceptual coupling with attentional networks). Although limited by the clinical sample and lack of a control task, these results highlight brain-body markers of interoceptive attention that may inform real-time monitoring during mind-body interventions.
Cryptic differentiation poses a significant challenge to taxonomy, particularly in morphologically conserved lineages whose divergence is not immediately apparent. In eusocial insects like ants, where species boundaries are often maintained through chemical rather than morphological differentiation, integrative methodologies are essential for resolving taxonomic complexity. Here, we present compelling evidence for the recent divergence of African carpenter ants initially identified as Camponotus maculatus into two distinct sub-populations. This divergence is supported through an integrative approach combining chemical, behavioral, and genetic analyses. Most strikingly, we identify two sharply contrasting chemotypes characterized by categorically different cuticular hydrocarbon (CHC) profiles that unambiguously separate the investigated ant populations. Concordantly, behavioral assays reveal that worker ants consistently exhibit aggression toward individuals with opposing chemotypes, while displaying affiliative behaviors toward shared chemotypes irrespective of colony affiliation. Genetic barcoding further corroborates these findings, indicated by phylogenetic clusters largely corresponding with the two chemotypes. Our results highlight the primary role of chemical differentiation within morphologically indistinguishable populations to resolve cryptic sub-population structures. These findings also provide valuable insights into potential early-stage chemical differentiation mechanisms in eusocial insect populations.
Humidity levels, like light and temperature, fluctuate daily yet are less predictable; however, whether humidity can entrain circadian clocks and synchronize animal behaviors with environmental variations remains unknown. Here, we investigate the circadian humidity entrainment in various insects across multiple orders. Insect species respond to humidity cycles with distinct patterns, some active during either wet/dry periods or at the arid-humid transition. When the humidity cue is removed, most species continue to show rhythmic activity associated with the previous arid-humid (AH) cycles. Fruit flies shift their activity accordingly when humidity cycles are altered and remain in the new rhythms under the following free-running conditions (FRC; constant humidity, HH). Moreover, Drosophila clock and hygrosensation mutants have lower rhythmic activity during AH and a significant reduction in rhythms after humidity entrainment (FRC with HH), indicating that core clock components and hygrosensors are essential for humidity-dependent circadian entrainment. Our findings provide strong evidence that humidity is likely to serve as a potential zeitgeber for circadian entrainment in most, but not all, insect systems and should have broad applicability and importance across animal systems. While light and temperature act as the primary zeitgebers, understanding the mechanisms of humidity entrainment will help us better interpret the behavioral patterns of terrestrial animals, particularly small insects susceptible to dehydration.
Tobacco 21 (T21) laws effectively reduce youth tobacco use by preventing initiation. This study examines their impact on body weight among young adults aged 18-20. Using 2009-2019 Behavioral Risk Factor Surveillance System data and a two-way fixed-effects difference-in-differences (DID) design, we find limited evidence of broad weight changes in either direction across the BMI distribution. Obesity declines due to modest weight reductions concentrated near the upper BMI threshold, with no significant changes in overweight status or average BMI. Event study shows that the obesity decline emerges in the first post-T21 year and attenuates afterward. Results are robust to alternative specifications, including an imputation DID approach addressing staggered adoption. Effects are driven by "never smokers", consistent with a prevention-based pathway, and are more pronounced among males and non-White individuals, with heterogeneity observed across education levels in the upper BMI tail. Supplemental analyses using Youth Risk Behavior Survey data show reduced adverse weight outcomes among high schoolers aged 18+. T21 laws increase exercise, improve diets, and reduce sedentary behavior, underage drinking, marijuana use, and mental distress. Overall, T21 laws avoid the typical cessation-related weight gain and modestly improve weight outcomes among at-risk young adults, suggesting broader public health benefits beyond tobacco prevention.
The hippocampus exhibits marked structural, functional, and molecular heterogeneity. GluN3A, a non-classical N-methyl-D-aspartate receptor subunit enriched in hippocampal CA1, has a poorly understood role in stress-related behavior. Here, using chronic social defeat stress (CSDS), GluN3A knockout mice, and behavioral, molecular, genetic, pharmacological, and circuit analyses, we investigated the role of hippocampal GluN3A in stress coping. CSDS selectively reduced GluN3A expression in intermediate CA1 (CA1i), and both stress-induced and genetic GluN3A loss promoted passive coping, whereas CA1i-specific GluN3A overexpression reversed this phenotype. c-Fos staining, fiber photometry, and chemogenetic manipulations showed that GluN3A is required for CA1i pyramidal neuron activation during coping. In addition, local D-serine administration rapidly shifted coping from passive to active in a GluN3A-dependent manner. Circuit tracing showed that CA1i neurons project broadly, and GluN3A overexpression selectively enhanced downstream activity in CA3 and infralimbic cortex. Together, these findings identify GluN3A in CA1i as a key regulator of stress-coping behavior.
Understanding how network structure influences system dynamics is essential for advancing psychological modeling. This tutorial introduces the causalnet R package, which enables researchers to systematically enumerate candidate directed networks by orienting a user-specified undirected or partially directed adjacency template. Users can impose directional constraints-such as those derived from prior theory or time-series models (e.g., graphical vector autoregressive models)-to restrict the space of admissible directed network configurations. The package supports dynamic simulations on these networks using either a theoretically grounded nonlinear model (Park et al., 2025) or a simplified linear alternative. Researchers can simulate system behavior and compare dynamic outcomes across structural configurations, parameter sets, or modeling assumptions. The primary audience is applied psychological and behavioral scientists who wish to evaluate competing theoretical accounts of symptom and behavior dynamics when causal direction is uncertain. Importantly, causalnet is not intended to identify a unique causal network from cross-sectional data; instead, it supports theory- and evidence-constrained enumeration of candidate directed structures and simulation-based screening of their dynamic implications against empirical targets. We illustrate how this workflow can be used to adjudicate competing psychological theories by linking structural assumptions to predicted dynamic signatures such as persistence and recovery. This approach facilitates a systematic exploration of how causal architecture and interaction dynamics give rise to the emerging dynamics of psychological processes over time.
Beyond its personal importance, the health of healthcare workers (HCWs) is a critical factor influencing healthcare system performance and patient care quality due to their direct involvement in patient outcomes and the operational efficiency of healthcare services. This study investigates the association between effort-reward imbalance (ERI) and self-rated health (SRH) among HCWs, exploring the potential mediating roles of sleep quality and physical activity. This cross-sectional study used baseline data from a convenience sample of the Qazvin Employee Health Cohort Study (2021-2022, northwestern, Iran). SRH was assessed using a single-item instrument. In the cohort study, trained interviewers administered the validated Persian versions of the 22-item ERI questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the International Physical Activity Questionnaire (IPAQ). We used structural equation modeling as our main analytical approach. Analysis of 1250 medical university employees revealed that 43.39% reported suboptimal SRH. Those with suboptimal SRH were older, more likely to be female, and had a significantly higher prevalence of ERI (66.5% vs. 56.1%), poor sleep quality (63.5% vs. 37.8%), and low physical activity (33.3% vs. 26.6%) compared to those with optimal SRH (all p < 0.01). In correlation analysis, SRH was negatively associated with effort, the effort-reward ratio, and poor sleep, and positively associated with reward, and physical activity. Structural equation modeling demonstrated that ERI had a significant direct negative association with SRH (β = -0.07, p = 0.017) and a significant indirect negative association via worsened sleep quality (β = -0.08, p < 0.001) and slightly better physical activity (β = 0.01, p = 0.015). Although more than half of the participants reported optimal SRH and physical activity levels, ERI and poor sleep quality were still prevalent among HCWs. Among HCWs, the SRH of those perceiving their work effort exceeded their rewards was affected by poor sleep quality. Policymakers and health system managers must account for the complex relationship between health and behavioral constructs in occupational settings.
Gut function exhibits 24 h (circadian) rhythmicity, in part driven by intrinsic clocks within intestinal epithelial cells (IECs). The gut microbiome also demonstrates circadian rhythms in composition and function, important for maintenance of metabolic, immune and gut health. Here, we determined the influence of feeding behaviour on the 24 h colonic landscape using an interval feeding paradigm, whereby food intake was partitioned equally across the 24 h day. RNAseq analysis revealed that the IEC intrinsic clock persists in the absence of diurnal feeding rhythms; however, a subset of key transcripts loses rhythmicity, demonstrating that cell extrinsic temporal cues contribute significantly to the maintenance of the rhythmic gut transcriptome. Furthermore, interval-fed mice demonstrated a striking loss of rhythms in secretory IgA, a critical regulator of the temporal landscape of the gut microbiome. In keeping, rhythmicity within the microbiota and microbial-derived short chain fatty acids was significantly diminished. This work highlights the importance of daily rhythms in feeding behaviour for the maintenance of rhythmic processes within the gut, with implications for metabolic and immune health.
Achieving spatiotemporal control of light at subwavelength and subcycle scales is an important milestone in the development of new photonic materials for signal processing, pulse shaping and ultrafast imaging. Spatiotemporal light modulation currently relies on electronic interband and intraband transitions that yield pronounced refractive index changes but typically suffer from slow, picosecond response times due to carrier relaxation. Here we show that by leveraging resonant light-matter interactions in a high-quality factor metasurface it is possible to use the optical Kerr effect, a weaker but subfemtosecond optoelectronic polarization effect, to achieve ultrafast, reconfigurable light modulation. By the subwavelength all-optical tuning of the refractive index of the dielectric metasurface unit cells with a spatially structured pump beam, we experimentally demonstrate pulse-limited beam steering with a 74-fs response time at angles up to ±13° in the near-infrared, where the deflection angles are programmable by the pump pattern. The steering originates from the Kerr effect, with a background contribution arising from a slower two-photon-excited free carrier absorption. Additionally, we observe pump self-modulation and self-diffraction, linear frequency conversion, and demonstrate arbitrary subpicosecond spatial light modulation in two dimensions.
Accurate interpretation of pediatric elbow imaging depends on understanding the developmental relationship between the radial head and the capitellum. While the traditional sequence of pediatric elbow ossification centers provides a useful framework, it does not capture morphologic variability, asynchronous maturation, and eccentric ossification patterns that may mimic pathology. This review synthesizes current evidence on pediatric elbow ossification with particular emphasis on normal and variant radial head development. The following key questions are addressed: (1) How frequently does eccentric radial head ossification occur on MRI? (2) What is its magnitude and relationship to age and sex? (3) How should normal variants be distinguished from pathology? Recent findings reveal that the capitellum commonly ossifies eccentrically before centralizing with growth. In our cohort of 66 children, radial head ossification was eccentric in 68-71% of cases in both sagittal and coronal planes. Offsets were small (average magnitude < 3%), predominantly posterior and radial, and generally did not correlate with age except for progressive centralization in the coronal plane among males. The radiocapitellar line remained reliable on the lateral view but demonstrated expected lateral offset on AP views. Eccentric radial head ossification represents a common physiologic pattern that does not reliably centralize with age. Recognition of this variant can reduce misdiagnosis and unnecessary intervention, and has implications for fracture assessment, surgical planning, and longitudinal research. Future studies should include prospective MRI tracking across diverse populations to establish normative ranges and develop quantitative tools for clinical applications.
This paper examines sustainable development and tribological performance of fly ash reinforced AA8011 aluminium matrix composites by stir casting. Composites with 0, 4, 8 and 12 wt.% fly ash content were made and tested under dry sliding conditions using pin on disc apparatus. The Taguchi L16 orthogonal array with the aid of the multi-response optimization through the use of the Grey Relational Analysis (GRA) was used to analyze wear rate, frictional force, and coefficient of friction (COF). The experimental outcomes indicate that the wear rate was 0.00447-0.00813 mm3/m, 4.84-9.89 N frictional force, 0.228-0.711 Coefficient of Friction (COF). The best parameters were found to be 8 wt.% fly ash, 30 N load, 3 m/s sliding velocity and 3200 m sliding distance which gave a maximum Grey Relational Grade (GRG) of 0.831. The results of ANOVA showed that applied load had the greatest contribution (48.95%), and then followed by the sliding distance (23.57%), but fly ash content had a smaller but significant contribution (3.12%). The confirmatory test showed that there was a small error of 2.6% in the value of predicted and experimental GRG. SEM analysis revealed the shift towards the severe abrasive wear in the base alloy to the mild oxidative wear with the stable mechanically mixed layer in higher reinforcement level. The research confirms that the wear resistance with the use of fly ash is enhanced, and sustainable development of materials through the effective use of industrial waste is improved.
As a critical area for the ecological security barrier in the middle and lower reaches of the Yangtze River, the Jianghuai Watershed Area holds significant importance in coordinating ecological conservation and economic development through the assessment of its water ecosystem service value (ESV). This study focuses on Chuzhou, a typical city within the Jianghuai Watershed Area, to explore the spatiotemporal evolution of water ESV and analyze the spatiotemporal change of the Consistency between water Ecosystem services and Economy (CEE) from 2000 to 2022 based on remote sensing. Firstly, the water was extracted through normalized snow water index (NSWI) and Otsu threshold method (OTSU). Subsequently, the water ESV dynamic evaluation model was constructed. Using this model, the water ESV in Chuzhou was quantified, and its spatiotemporal distribution characteristics were analyzed. Finally, by calculating the coefficient of variation (CV) between ESV and GDP, the deviation between water ESV and GDP in Chuzhou was obtained. At the same time, the coordination between water ESV and economic development of Chuzhou was obtained by calculating CEE, so as to evaluate the Spatiotemporal coordination and regional differences between them. This study has found that: (1) The water ESV in Chuzhou showed a phased change of "fluctuating decline and subsequent recovery" from 2000 to 2022. (2) In terms of spatial distribution, the water ESV exhibits a gradient pattern of "high ESV in the northwest and low ESV in the southeast of the Chuzhou". (3) In terms of ecological and economic coordination, the northwest of the Chuzhou maintain a healthy CEE. However, the southeast of Chuzhou has exacerbated the imbalance in CEE due to the water space occupied by construction land. This study could provide a decision-making basis for formulating ecological priority development strategies in the Jianghuai Watershed Area.
The inferiorly based dermo-glandular sling is well described for implant coverage in post-mastectomy prosthetic reconstruction and attempted restoration of upper pole fullness in (therapeutic and aesthetic) mammaplasty procedures, to variable long-term effect. We reviewed the technique modifications by a single surgeon, over 13 years, and the aesthetic outcomes achieved, when used in the context of cosmetic breast implant removal. Breast explant patients with a Wise-pattern skin incision by a single surgeon between 2011 and 2024 were identified. implant exchange, explantation only and LeJour pattern breast lift. Demographics and perioperative data were recorded. Perioperative photographs were assessed using the established Breast Cancer Conservation Treatment. Cosmetic Results (BCCT.core) software to analyse the aesthetic result. 19 patients underwent implant removal and parenchymal re-draping with an inferiorly based dermo-glandular sling. Patients were: perimenopausal women (mean=54yrs) with raised BMI (mean=27.6kg/m2). Indications (overlapping) for explantation included: disharmony between implant and breast envelope (10/19; 52.6%), discomfort/ pain (8/19; 42.1%), concerns about BIA-ALCL (5/19; 26.3%) and symptoms of "breast implant illness" (6/19; 31.6%). Others claimed their augmented breasts were simply too large (9/19; 47.4%). Bra size decreased from pre-explant size of 36E to 36C (median). Post-operative photographs were available for 18/19 patients. BCCT.core ratings were wholly favourable, with five rated Excellent and the remainder rated as Good. An inferior, de-epithelialised dermo-glandular sling can reliably rejuvenate the female breast following breast implant removal, where there is disharmony between parenchymal volume, distribution and envelope. We illustrate a reliable technique that achieves objectively good to excellent aesthetic results, with long-term efficacy. (249 words) Most common presentations for seeking explantation in our cohort were concerns about the degree of ptosis, pain, anxiety about BIA-ALCL and symptoms of breast implant illness. This technique offers a reliable and aesthetically robust option to restore some volume and uplift and reshape the explanted breast, in patients declining re-implantation or staged surgeries. Suitable patients as determined by our cohort are middle-aged women with large, previously augmented breasts (~330cc mean, 36E median), with an above-average BMI (27.6) yielding suitable inferior pole tissue for suspension. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Most genetic variants associated with complex heritability phenotypes lie in non-coding regions and are thought to influence disease risk by regulating gene expression. However, most transcriptome-wide association approaches primarily model local (cis) genetic effects, leaving much of gene regulation unexplained. Here, we show that incorporating distal (trans) regulatory effects improves the prediction of gene expression and the identification of disease-associated genes. Using RNA sequencing data from six human post-mortem brain regions, we developed INGENE and MODULE, two models capturing the combined influence of candidate trans-acting variants within gene coexpression networks. Integrating these models with conventional cis-based predictors improved gene expression imputation (maximum likelihood estimation, α = 0.05) for 18,744 genes across regions. Applying this framework to Psychiatric Genomics Consortium wave 3 genotypes identified 766 genes associated with schizophrenia (PFDR < 0.01), including 641 not previously reported by transcriptome-wide analyses. These findings highlight the contribution of distal regulatory mechanisms and gene network interactions to schizophrenia risk.
Sex pheromones play a central role in regulating animal behavior and reproduction. In insects, these signals are perceived through specialized odorant receptors (ORs) that mediate species-specific communication and safeguard genetic integrity. However, the structural basis of sex pheromone detection remains largely unresolved. Here, we identified two ORs in the pea aphid Acyrthosiphon pisum, along with the conserved OR co-receptor (Orco), which together mediate recognition of the pheromone components nepetalactone and nepetalactol. Functional assays demonstrated that ApOR21-Orco and ApOR22-Orco specifically respond to nepetalactol and nepetalactone, respectively. Using cryo-electron microscopy, we resolved the structure of the ApOR22-Orco complex in three states - unbound closed, nepetalactone-bound closed, and nepetalactone-bound open - revealing a heterotetrameric ion channel formed by one ApOR22 and three ApOrco subunits. Ligand binding to ApOR22 triggers conformational rearrangements that induce asymmetric pore dilation, thereby enabling ion conduction. Together, these results provide a mechanistic framework for understanding sex pheromone perception in insects and establish a structural foundation for the rational development of environmentally sustainable pest-control strategies.
To investigate the expression pattern of methyltransferase-like protein 7B (METTL7B) in papillary thyroid carcinoma (PTC) and elucidate its role and molecular mechanisms in tumor metabolic reprogramming and malignant progression. Public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were analyzed to assess METTL7B expression in PTC and its association with clinicopathological features. Immunohistochemistry on tissue microarrays was performed to validate METTL7B protein expression in clinical samples. Stable METTL7B-knockdown PTC cell lines were constructed, and knockdown efficiency was confirmed by quantitative real-time PCR (qRT-PCR) and Western blotting. Cell proliferation and clonogenic potential were evaluated using MTT and colony formation assays. Transcriptome sequencing was conducted in METTL7B-overexpressing cells to identify differentially expressed genes and enriched pathways, followed by qRT-PCR and Western blotting validation of METTL7B-mediated regulation of hypoxia-inducible factor 1α (HIF-1α). Cycloheximide chase and ubiquitination assays were used to assess the effect of METTL7B on HIF-1α protein stability, and the involvement of ubiquitin-specific protease 28 (USP28) was further examined. Lactate production and glucose uptake assays were performed to assess the impact of METTL7B and HIF-1α on PTC glycolytic activity. METTL7B was significantly upregulated in PTC tissues (P<0.05) and positively correlated with lymph node metastasis (P<0.05). METTL7B knockdown markedly suppressed PTC cell proliferation and colony formation (all P<0.05). In a xenograft tumor model, METTL7B knockdown significantly slowed the growth of PTC tumors, with tumor volumes significantly lower than those in the control group (P<0.05). Bioinformatics analysis suggested a strong association between METTL7B and the HIF-1α signaling pathway. Further experiments showed that METTL7B knockdown reduced HIF-1α protein levels without affecting its mRNA expression. Mechanistically, METTL7B inhibited the ubiquitination and degradation of HIF-1α, thereby maintaining its protein stability, and this process was mediated by the deubiquitinase USP28. Functional assays demonstrated that METTL7B enhanced glycolytic activity and malignant phenotypes of PTC cells by upregulating glycolysis-related genes through the USP28/HIF-1α axis. METTL7B promotes glycolysis and malignant progression in PTC by stabilizing HIF-1α through USP28-mediated deubiquitination. 目的: 探讨甲基转移酶样蛋白7B（METTL7B）在甲状腺乳头状癌（PTC）中的表达及其在肿瘤代谢重编程及恶性进展中的作用和分子机制。方法: 基于基因表达综合（GEO）和癌症基因组图谱（TCGA）数据库分析METTL7B在PTC组织中的表达水平及其与临床特征的关系。采用免疫组织化学染色验证METTL7B在临床组织芯片样本中的表达差异;构建METTL7B稳定敲减细胞株，并通过定量逆转录聚合酶链反应（qRT-PCR）和蛋白质印迹法检测敲减效率。进一步采用MTT法检测细胞增殖能力，克隆形成实验评估克隆形成能力。通过转录组测序分析METTL7B过表达后的差异基因并进行通路富集分析，结合免疫印迹法和qRT-PCR实验验证其对低氧诱导因子1α（HIF-1α）蛋白的调控作用。采用放线菌酮处理和泛素化检测评估METTL7B对HIF-1α蛋白稳定性的影响，并进一步探讨泛素特异性蛋白酶28（USP28）在其中的作用。乳酸生成及葡萄糖吸收实验分析METTL7B及HIF-1α对PTC糖酵解的调控。结果: METTL7B在PTC组织中显著高表达（P<0.05），并与淋巴结转移呈正相关（P<0.05）。敲减METTL7B显著抑制PTC细胞增殖及克隆形成能力（均P<0.05）。体内研究显示，敲减METTL7B可显著减缓PTC 裸鼠异种移植瘤的生长速度，并且肿瘤体积显著低于对照组（P<0.05）。生物信息学分析提示METTL7B与HIF-1α信号通路密切相关。进一步研究显示，敲减METTL7B降低HIF-1α蛋白而不影响其mRNA水平。机制研究表明，METTL7B可下调HIF-1α的泛素化降解并维持其蛋白稳定性，而去泛素化酶USP28可介导该过程。功能实验表明，METTL7B通过调控USP28/HIF-1α轴上调糖酵解关键基因表达，增强细胞糖酵解活性并促进其恶性生物学行为。结论: METTL7B通过USP28介导的去泛素化作用稳定HIF-1α，从而促进PTC的糖酵解和恶性进展。.
Biodiversity loss in the present era requires new tools for studying nonmodel organisms. Elephants are both an endangered species and excellent models for studying complex phenotypes including size, social behavior and longevity. Here we report the first derivation of elephant (Elephas maximus) induced pluripotent stem (emiPS) cells. We achieved emiPS cells using two approaches: (1) a two-step process of chemical media induction and colony selection followed by over-expression of elephant transcription factors; and (2) a one-step process with transcription factors and HRAS mutant, HRASG12V. For both protocols, we inhibited TP53 retrogenes, which are hypothesized to confer unique cancer resistance in elephants. To confirm their reprogrammed state, we generated a functional omics catalog of emiPS cells. While these emiPS cells remain transgene-dependent, we inactivated the transgenes and differentiated emiPS cells into all three germ layers via tri-lineage differentiation, embryoid body generation and direct differentiation into putative cell types from all three layers. These methods will open new frontiers for cellular models of nonmodel organisms, including for genetic rescue and conservation.
To address the insufficient bearing capacity of roadside backfill bodies and the tilting or failure induced by uneven pressure relief of the coal seam during gob-side entry retaining in thick coal seams with hard roofs, combined compression-shear loading tests incorporating rapid resistance build-up and varying inclination angles were performed. A novel Compression Shear Coupling Test system (CSCT) was developed, and a fitted relationship between backfill width and roof subsidence was established. The strength degradation behavior of backfill specimens subjected to different shear stress components was systematically investigated. The results reveal that the peak strength of the specimens declines with increasing shear stress component, and the failure mode transitions progressively from compressive to shear-dominated failure. The high-resistance backfill material derived from this study was implemented at the N2302 gob-side entry retaining working face, accompanied by an anti-tilting design for the backfill wall. The measured roof subsidence was reduced by 59.4% relative to the theoretically predicted value, and no evident signs of failure or deterioration were observed in the backfill body. These findings provide both data support and theoretical reference for gob-side entry retaining under similar mining conditions.
RHEBL1 (RHEB2), a member of the Ras superfamily, has established roles in tumor-promoting signaling pathways including mTOR activation and NF-κB transcription; however, its specific role in oral squamous cell carcinoma (OSCC) and its regulation by the stem cell transcription factors Oct4 and Sox2 have not been previously characterized. This study aimed to elucidate the function and mechanism of RHEBL1 in OSCC development and analyze the regulatory influence of Oct4 and Sox2 on RHEBL1 expression. Immunohistochemistry and immunofluorescence assessed RHEBL1, Oct4, and Sox2 expression in normal and precancerous tissues. RHEBL1-overexpressing and knockout cell lines were created for in vitro assessment of proliferation and self-renewal; mice models were used to evaluate tumor formation in vivo. Bioinformatics analyses predicted Oct4 and Sox2 binding sites within the RHEBL1 promoter, validated by dual-luciferase reporter assays and ChIP-PCR. RHEBL1 showed high expression in OSCC and adjacent tissues, with linear arrangement of positive cells in the basal layer. High levels of RHEBL1, Oct4, and Sox2 were observed at the tumor invasion front and the basal layer of adjacent oral epithelia. RHEBL1 overexpression enhanced sphere formation and induced subcutaneous tumor-like lesions in immunodeficient mice, characterized histologically by invasive growth patterns and vascular structures, whereas control cells showed no such phenomenon. Furthermore, RHEBL1 knockout significantly reduced in vitro sphere formation and in vivo tumorigenicity. Oct4-Sox2 complexes bound two sites in the RHEBL1 promoter; mutations in these sites reduced transcriptional activation. Thus, this study demonstrated that Oct4 and Sox2 promote OSCC initiation and proliferation by regulating RHEBL1 expression. Clinical trial number: not applicable.
Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase for those born 1965-1974 versus 1950-1954, and was associated with early-onset solid cancer risk (hazard ratio (HR)per s.d. 1.08; 95% confidence interval (CI), 1.03-1.13), driven by lung, gastrointestinal and uterine cancers, independent of genetic risks of aging and cancer. Patterns were consistent using alternative systemic aging measures, including the Klemera-Doubal method-defined age gap and metabolomic-based age gap. These findings were validated partially among 10,262 participants in the United States All of Us Research Program. Proteomics-based organ-specific aging analyses linked immune aging with early-onset lung cancer (HRper s.d. 1.89; CI, 1.20-2.97) and adipose tissue aging to early-onset colorectal cancer (HR 1.60; CI, 1.11-2.32). Greater age gap, reflecting more advanced biological aging relative to chronological age, may serve as a driver associated with risk of early-onset solid cancers, highlighting the importance of uncovering underlying mechanisms to guide effective prevention strategies.