A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR).

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

Impact of COVID-19-Induced Academic Stress on Insomnia and Suicidal Ideation among Taiwanese Health Trainees and Junior Doctors.

BACKGROUND Clinical training for allied health trainees (AHTs) and postgraduate-year (PGY) doctors needed to go online during the outbreak of coronavirus disease 2019 (COVID-19), which may have caused academic stress and consequent outcomes among this cohort. MATERIAL AND METHODS To evaluate academic-related stress, clinical confidence, psychological distress, and insomnia, an online survey-based study was conducted among Taiwanese AHTs and PGY doctors between July and December, 2022, during the COVID-19 pandemic. The survey included the 21-item Depression, Anxiety, and Stress Scale (DASS-21), the Insomnia Severity Index (ISI), and self-designed questions. It was distributed using convenience sampling and snowball sampling and was completed by 522 participants. RESULTS Structural equational modelling showed that academic stress was negatively associated with clinical confidence (standardized coefficient [ß]=-0.382, p<0.001). Clinical confidence was negatively associated with psychological distress (ß=-0.397, p<0.001), which was associated with insomnia (ß=0.648, p<0.001). Additionally, clinical confidence and psychological distress were the significant mediators. Results indicated that higher academic stress was associated with higher level of insomnia via the mediation of clinical confidence and psychological distress. CONCLUSIONS Academic stress related to changes in clinical training may have led to insomnia among AHTs and PGY doctors during the pandemic. Factors to reduce academic stress should be investigated to promote good mental health while providing sufficient clinical training, especially during events that can cause increased stress (eg, epidemics, pandemics).

Fluorogenic Aptamer-Based Hybridization Chain Reaction for Signal-Amplified Imaging of Apurinic/Apyrimidinic Endonuclease 1 in Living Cells.

A fluorogenic aptamer (FA)-based hybridization chain reaction (HCR) could provide a sensitive and label-free signal amplification method for imaging molecules in living cells. However, existing FA-HCR methods usually face some problems, such as a complicated design and significant background leakage, which greatly limit their application. Herein, we developed an FA-centered HCR (FAC-HCR) method based on a remote toehold-mediated strand displacement reaction. Compared to traditional HCRs mediated by four hairpin probes (HPs) and two HPs, the FAC-HCR displayed significantly decreased background leakage and improved sensitivity. Furthermore, the FAC-HCR was used to test a non-nucleic acid target, apurinic/apyrimidinic endonuclease 1 (APE1), an important BER-involved endonuclease. The fluorescence analysis results confirmed that FAC-HCR can reach a detection limit of 0.1174 U/mL. By using the two HPs for FAC-HCR with polyetherimide-based nanoparticles, the activity of APE1 in living cells can be imaged. In summary, this study could provide a new idea to design an FA-based HCR and improve the performance of HCRs in live cell imaging.

Nutrient enrichment, propagule pressure, and herbivory interactively influence the competitive ability of an invasive alien macrophyte Myriophyllum aquaticum.

Introduction: Freshwater ecosystems are susceptible to invasion by alien macrophytes due to their connectivity and various plant dispersal vectors. These ecosystems often experience anthropogenic nutrient enrichment, favouring invasive species that efficiently exploit these resources. Propagule pressure (reflecting the quantity of introduced individuals) and habitat invasibility are key determinants of invasion success. Moreover, the enemy release hypothesis predicts that escape from natural enemies, such as herbivores, allows alien species to invest more resources to growth and reproduction rather than defense, enhancing their invasive potential. Yet, the combined impact of propagule pressure, herbivory, and nutrient enrichment on the competitive dynamics between invasive alien macrophytes and native macrophyte communities is not well understood due to a paucity of studies. Methods: We conducted a full factorial mesocosm experiment to explore the individual and combined effects of herbivory, nutrient levels, propagule pressure, and competition on the invasion success of the alien macrophyte Myriophyllum aquaticum into a native macrophyte community comprising Vallisneria natans, Hydrilla verticillata, and Myriophyllum spicatum. This setup included varying M. aquaticum densities (low vs. high, simulating low and high propagule pressures), two levels of herbivory by the native snail Lymnaea stagnalis (herbivory vs no-herbivory), and two nutrient conditions (low vs. high). Myriophyllum aquaticum was also grown separately at both densities without competition from native macrophytes. Results: The invasive alien macrophyte M. aquaticum produced the highest shoot and total biomass when simultaneously subjected to conditions of high-density intraspecific competition, no herbivory, and low-nutrient availability treatments. Moreover, a high propagule pressure of M. aquaticum significantly reduced the growth of the native macrophyte community in nutrient-rich conditions, but this effect was not observed in nutrient-poor conditions. Discussion: These findings indicate that M. aquaticum has adaptive traits enabling it to flourish in the absence of herbivory (supporting the enemy release hypothesis) and in challenging environments such as intense intraspecific competition and low nutrient availability. Additionally, the findings demonstrate that when present in large numbers, M. aquaticum can significantly inhibit the growth of native macrophyte communities, particularly in nutrient-rich environments. Consequently, reducing the propagule pressure of M. aquaticum could help control its spread and mitigate its ecological impact. Overall, these findings emphasize that the growth and impacts of invasive alien plants can vary across different habitat conditions and is shaped by the interplay of biotic and abiotic factors.

Obscured Contribution of Oxygenated Intermediate-Volatility Organic Compounds to Secondary Organic Aerosol Formation from Gasoline Vehicle Emissions.

Secondary organic aerosol (SOA) formation from gasoline vehicles spanning a wide range of emission types was investigated using an oxidation flow reactor (OFR) by conducting chassis dynamometer tests. Aided by advanced mass spectrometric techniques, SOA precursors, including volatile organic compounds (VOCs) and intermediate/semivolatile organic compounds (I/SVOCs), were comprehensively characterized. The reconstructed SOA produced from the speciated VOCs and I/SVOCs can explain 69% of the SOA measured downstream of an OFR upon 0.5-3 days' OH exposure. While VOCs can only explain 10% of total SOA production, the contribution from I/SVOCs is 59%, with oxygenated I/SVOCs (O-I/SVOCs) taking up 20% of that contribution. O-I/SVOCs (e.g., benzylic or aliphatic aldehydes and ketones), as an obscured source, account for 16% of total nonmethane organic gas (NMOG) emission. More importantly, with the improvement in emission standards, the NMOG is effectively mitigated by 35% from China 4 to China 6, which is predominantly attributed to the decrease of VOCs. Real-time measurements of different NMOG components as well as SOA production further reveal that the current emission control measures, such as advances in engine and three-way catalytic converter (TWC) techniques, are effective in reducing the "light" SOA precursors (i.e., single-ring aromatics) but not for the I/SVOC emissions. Our results also highlight greater effects of O-I/SVOCs to SOA formation than previously observed and the urgent need for further investigation into their origins, i.e., incomplete combustion, lubricating oil, etc., which requires improvements in real-time molecular-level characterization of I/SVOC molecules and in turn will benefit the future design of control measures.

The effect of social support and resource support on emotional exhaustion, insomnia, and suicidal ideation among allied health trainees and post-graduate year doctors in Taiwan.

BACKGROUND: COVID-19-related stigmatization refers to COVID-19-related judgements by others that devalue the individual. Such stigmatization towards healthcare workers may cause psychological burden and negative consequences. Such stigmatization may have particularly overwhelmed allied health trainees (AHTs) and post-graduate year doctors (PGYDs) because they just started their medical career. Social support and resource support have been reported to benefit psychological health and reduce stigmatization. Therefore, the present study used a cross-sectional study design to investigate the association between perceived stigma, self-stigma, psychological distress, and negative outcomes (including emotional exhaustion, insomnia and suicidal ideation) among AHTs and PGYDs in Taiwan. METHODS: An online survey distributed between July and December, 2022 received 522 responses. Variables were assessed using the 21-item Depression, Anxiety and Stress Scale, Insomnia Severity Index and a series of self-designed questions to assess social support, resource support, perceived stigma, self-stigma, emotional exhaustion, and suicidal ideation. RESULTS: Structural equation modeling showed that perceived stigma was associated with self-stigma (standardized coefficient [ß] = 0.428, p < 0.001), and self-stigma was associated with psychological distress (ß = 0.197, p < 0.001), as well as being associated with emotional exhaustion, insomnia, and suicidal ideation (ß = 0.349, 0.556 and 0.212, all p-values < 0.001). While social support and resource support were negatively associated with perceived stigma (ß= - 0.175 and - 0.152, p < 0.01), additional associations were found between social support and emotional exhaustion (ß= - 0.093, p < 0.001), as well as between resource support and insomnia (ß= - 0.120, p < 0.001). CONCLUSIONS: The results showed that COVID-19 related stigmatization was correlated to the detrimental consequences of emotional exhaustion, insomnia and suicidal ideation. Clear paths regarding the associations of social support and resource support with the three negative associations were found as the possible solutions. Strategies to reduce the stigmatization and these negative outcomes, or improve the psychological health will benefit AHTs and PGYDs in maintaining a healthy mental status.

Widespread 2013-2020 decreases and reduction challenges of organic aerosol in China.

High concentrations of organic aerosol (OA) occur in Asian countries, leading to great health burdens. Clean air actions have resulted in significant emission reductions of air pollutants in China. However, long-term nation-wide trends in OA and their causes remain unknown. Here, we present both observational and model evidence demonstrating widespread decreases with a greater reduction in primary OA than in secondary OA (SOA) in China during the period of 2013 to 2020. Most of the decline is attributed to reduced residential fuel burning while the interannual variability in SOA may have been driven by meteorological variations. We find contrasting effects of reducing NOx and SO2 on SOA production which may have led to slight overall increases in SOA. Our findings highlight the importance of clean energy replacements in multiple sectors on achieving air-quality targets because of high OA precursor emissions and fluctuating chemical and meteorological conditions.

Bioengineering autologous cartilage grafts for functional posterior lamellar eyelid reconstruction: A preliminary study in rabbits.

The reconstruction of posterior lamellar eyelid defects remains a significant challenge in clinical practice due to anatomical complexity, specialized function, and aesthetic concerns. The ideal substitute for the posterior lamellar should replicate the native tarsoconjunctival tissue, providing both mechanical support for the eyelids and a smooth surface for the globe after implantation. In this study, we present an innovative approach utilizing tissue-engineered cartilage (TEC) grafts generated from rabbit auricular chondrocytes and a commercialized type I collagen sponge to reconstruct critical-sized posterior lamellar defects in rabbits. The TEC grafts demonstrated remarkable mechanical strength and maintained a stable cartilaginous phenotype both in vitro and at 6 months post-implantation in immunodeficient mice. When employed as autografts to reconstruct tarsal plate defects in rabbits' upper eyelids, these TEC grafts successfully restored normal eyelid morphology, facilitated smooth eyelid movement, and preserved the histological structure of the conjunctival epithelium. When applied in bilayered tarsoconjunctival defect reconstruction, these TEC grafts not only maintained the normal contour of the upper eyelid but also supported conjunctival epithelial cell migration and growth from the defect margin towards the centre. These findings highlight that auricular chondrocyte-based TEC grafts hold great promise as potential candidates for clinical posterior lamellar reconstruction. STATEMENT OF SIGNIFICANCE: The complex structure and function of the posterior lamellar eyelid continue to be significant challenges for clinical reconstructive surgeries. In this study, we utilized autologous auricular chondrocyte-based TEC grafts for posterior lamellar eyelid reconstruction in a preclinical rabbit model. The TEC grafts exhibited native cartilaginous histomorphology and comparable mechanical strength to those of the native human tarsal plate. In rabbit models with either tarsal plate defects alone or bilayered tarsoconjunctival defects, TEC grafts successfully restored the normal eyelid contour and movement, as well as supported preservation and growth of conjunctival epithelium. This is the first study to demonstrate autologous TEC grafts can be employed for repairing tarsal plate defects, thereby offering an alternative therapeutic approach for treating posterior lamellar defects in clinic settings.

CIP1, a CIPK23-interacting transporter, is implicated in Cd tolerance and phytoremediation.

Environmental pollution from cadmium (Cd) presents a serious threat to plant growth and development. Therefore, it's crucial to find out how plants resist this toxic metal to develop strategies for remediating Cd-contaminated soils. In this study, we identified CIP1, a transporter protein, by screening interactors of the protein kinase CIPK23. CIP1 is located in vesicles membranes and can transport Cd2+ when expressed in yeast cells. Cd stress specifically induced the accumulation of CIP1 transcripts and functional proteins, particularly in the epidermal cells of the root tip. CIKP23 could interact directly with the central loop region of CIP1, phosphorylating it, which is essential for the efficient transport of Cd2+. A loss-of-function mutation of CIP1 in wild-type plants led to increased sensitivity to Cd stress. Conversely, tobacco plants overexpressing CIP1 exhibited improved Cd tolerance and increased Cd accumulation capacity. Interestingly, this Cd accumulation was restricted to roots but not shoots, suggesting that manipulating CIP1 does not risk Cd contamination of plants' edible parts. Overall, this study characterizes a novel Cd transporter, CIP1, with potential to enhance plant tolerance to Cd toxicity while effectively eliminating environmental contamination without economic losses.

Isoform-independent promotion of contractility and proliferation, and suppression of survival by with no lysine/K kinases in prostate stromal cells.

With no lysine/K kinases (WNKs) promote vasocontraction and vascular smooth muscle cell proliferation. In the prostate, smooth muscle contraction and growth may be critical for the development and medical treatment of voiding symptoms in benign prostatic hyperplasia. Here, we examined the effects of isoform-specific WNK silencing and of the WNK inhibitor WNK463 on growth-related functions and contraction in prostate stromal cells, and in human prostate tissues. Impacts of WNK silencing by transfection of cultured stromal cells with isoform-specific siRNAs were qualitatively and quantitatively similar for each WNK isoform. Effects of silencing were largest on cell death (3-5 fold increase in annexin V-positive/7-AAD-positive cells), on proliferation rate, Ki-67 mRNA expression and actin organization (reduced around two-thirds). Contraction in matrix contraction assays and viability were reduced to a lower degree (approximately half), but again to a similar extent for each WNK isoform. Effects of silencing were quantitatively and qualitatively reproduced by 10 µM WNK463, while 1 µM still induced cell death and breakdown in actin organization, without affecting proliferation or viability. Using 500 nM and 10 µM, WNK463 partly inhibited neurogenic and U46619-induced contractions of human prostate tissues (around half), while inhibition of α1-adrenergic contractions (around half) was limited to 10 µM. All four WNK isoforms suppress cell death and promote proliferation in prostate stromal cells. WNK-driven contraction of stromal cells appears possible, even though to a limited extent. Outcomes of isoform-specific WNK silencing can be fully reproduced by WNK463, including inhibition of smooth muscle contraction in human prostate tissues, but require high concentrations.

Exploration of treatment in childhood Langerhans cell histiocytosis based on inflammatory and malignant symptoms: a pilot study.

BACKGROUND: Multisystem childhood Langerhans cell histiocytosis (LCH) patients, especially those with risk organ (RO) involved, had not been satisfactorily treated under the international traditional schemes as high incidences of reactivation with late sequelae were largely reported. Over years, we have observed that LCH patients with varied clinical symptoms responded differently to different drugs, suggesting the current grouping strategies based only on the number of organs involved might be inadequate. LCH has been defined as an inflammatory myeloid tumor, thus this study has innovatively divided LCH pediatric patients into inflammatory or malignant symptoms group, and given different intensity treatment regimens to different groups. AIM: This clinical study aimed to explore a more appropriate patient grouping system according to the LCH symptom presentations and examine the clinical outcomes of treatment strategies in different groups. METHODS: According to the clinical manifestations, 37 cases of children were divided into Group A (only inflammatory symptoms) and Group B (malignant symptoms with or without inflammatory symptoms). Patients in Group A and B were initially treated with vindesine (VDS) and methylprednisolone (PSL), and VDS, PSL, pirarubicin (THP) and cyclophosphamide (CTX), respectively. Treatment responses were evaluated six weeks after the induction therapy in all patients, and the criteria were disease status and clinical scores of symptoms. RESULTS: Pre- and post-treatment scores were 1.22 ± 0.547 and 0.00 ± 0.00 in Group A, and 14.79 ± 1.686 and 1.00 ± 1.563 in Group B, respectively. All patients had subsequentlly received maintenance therapy without progressive disease. The 4-year overall survival (OS) rate was 100% in both groups and the 4-year event-free survival (EFS) was 94.4% in Group A and 89.5% in Group B, respectively. There were no obvious adverse events (AE) in Group A, whereas the main AE in Group B were alopecia and non-lethal hematological toxicity. CONCLUSION: Stratification according to patients' clinical symptoms, with low-intensity treatment for inflammatory symptoms (mild manifestations) and intensive treatment with multiple drugs for malignant symptoms (severe manifestations), is a positive exploration that simplifies stratification method, achieves good long-term remission of the disease, and obtains a higher survival rate and quality of life, which seemed to be more appropriate for LCH patients.

Coronary Artery Disease Risk Variant Dampens the Expression of CALCRL by Reducing HSF Binding to Shear Stress Responsive Enhancer in Endothelial Cells In Vitro.

BACKGROUND: CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells. METHODS: To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells. RESULTS: We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production. CONCLUSIONS: Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates CALCRL expression. A better understanding of CALCRL gene regulation and the role of single-nucleotide polymorphisms in the modulation of CALCRL expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.

Tree-ring based summer temperature variability since 1790 CE in the Hindu Kush region of northern Pakistan.

The Hindu Kush high-altitude regions of Pakistan are currently experiencing severe consequences as a result of global warming. In this sense, increasing soil erosion and the quick melting of glaciers are two particularly evident effects. In such a scenario, understanding long-term temperature changes is crucial for making accurate forecasts about how the Hindu Kush region may experience regional temperature changes in the future. In this study, the climate tree-ring width (TRW) analysis designated a positive and significant correlation (r = 0.622, p < 0.001) between the TRW chronology and the June to September (summer) mean maximum temperature (MMT). Using the tree-ring width of Pinus wallichiana A. B. Jackson, we reconstructed summer temperatures in the Hindu Kush region from 1790 CE. Statistical analysis showed that the reconstruction model has explained 38.7% of the climate variance during the instrumental period of 1967 to 2018 CE. Five extremely warm summer periods (≥ 4 years; before the instrumental period 1967-2018 CE) of 1804-1830, 1839-1862, 1876-1879, 1905-1910, 1923-1935 CE, and six cold summer periods of 1790-1803, 1832-1838, 1863-1875, 1880-1904, 1911-1922, and 1936-1945 CE have been observed during the past 229 years. Individually, the year 1856 CE experienced severe warmth (31.85 °C), whereas 1794 CE was relatively cooler (29.60 °C). The spectral multi-taper method (MTM) shows significant (p < 0.05) cycles, which take place about every 9.3, 5.7, 4.2, and 3.6 years. In particular, the 9.3-year cycle, which closely aligns with the 11-year solar activity cycle, suggests a potential correlation between solar activity and local temperature fluctuations. Moreover, our reconstruction demonstrates a significant degree of consistency when compared to actual climate data and regional temperature reconstruction series, reporting a strong logic of trust in the reliability and accuracy of our findings. This evidence reaffirms that our reconstruction shows significant and dependable regional temperature signals, notably being representative for the Hindu Kush region.

[Retrospective cross-sectional survey of clinical characteristics and syndrome elements distribution at different stages of coronary heart disease].

The clinical data of coronary heart disease(CHD) patients treated in the First Affiliated Hospital of Guangzhou University of Chinese Medicine and Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine from January 2022 to March 2023 were retrospectively collected. This study involved the descriptive analysis of demographic characteristics, clinical symptoms, and tongue and pulse features. The χ~2 test was conducted to analyze the distribution of syndrome elements and their combinations at diffe-rent stages of CHD, so as to reveal the clinical characteristics and syndrome patterns at various pathological stages of CHD. This study extracted 28 symptom entries, 10 tongue manifestation entries, and 7 pulse manifestation entries, summarized the 5 main disease locations of the heart, lung, liver, spleen, and kidney, and the 8 main disease natures of blood stasis, phlegm turbidity, Qi stagnation, heat(fire), fluid retention, Qi deficiency, Yin deficiency, and Yang deficiency and 8 combinations of disease natures. The χ~2 test showed significant differences in the distribution of syndrome elements including the lung, liver, spleen, kidney, blood stasis, heat(fire), Qi stagnation, heat syndrome, water retention, Qi deficiency, Yin deficiency, and Yang deficiency between different disease stages. Specifically, the liver, blood stasis, heat(fire), and Qi stagnation accounted for the highest proportion during unstable stage, and the lung, spleen, kidney, water retention, Qi deficiency, Yin deficiency, and Yang deficiency accounted for the highest proportion at the end stage. The distribution of Qi deficiency varied in the different time periods after percutaneous coronary intervention(PCI). As shown by the χ~2 test of the syndrome elements combination, the distribution of single disease location, multiple disease locations, single disease nature, double disease natures, multiple natures, excess syndrome, and mixture of deficiency and excess varied significantly at different stages of CHD. Specifically, single disease location, single disease nature, and excess syndrome accounted for the highest proportion during the stable stage, and double disease natures accounted for the highest proportion during the unstable stage. Multiple disease locations, multiple disease natures, and mixture of deficiency and excess accounted for the highest proportion during the end stage. In conclusion, phlegm turbidity and blood stasis were equally serious during the stable stage, and a pathological mechanism caused by blood stasis and toxin existed during the unstable stage. The overall Qi deficiency worsened after PCI, and the end stage was accompanied by the Yin and Yang damage and the aggravation of water retention. There were significant differences in the distribution of clinical characteristics and syndrome elements at different stages of CHD. The pathological process of CHD witnessed the growth and decline of deficiency and excess and the combination of phlegm turbidity and blood stasis, which constituted the basic pathogenesis.

Tbl1 promotes Wnt-ß-catenin signaling-induced degradation of the Tcf7l1 protein in mouse embryonic stem cells.

Activation of the Wnt-ß-catenin signaling pathway by CHIR99021, a specific inhibitor of GSK3ß, induces Tcf7l1 protein degradation, which facilitates the maintenance of an undifferentiated state in mouse embryonic stem cells (mESCs); however, the precise mechanism is still unclear. Here, we showed that the overexpression of transducin-ß-like protein 1 (Tbl1, also known as Tbl1x) or its family member Tblr1 (also known as Tbl1xr1) can decrease Tcf7l1 protein levels, whereas knockdown of each gene increases Tcf7l1 levels without affecting Tcf7l1 transcription. Interestingly, only Tbl1, and not Tblr1, interacts with Tcf7l1. Mechanistically, Tbl1 translocates from the cytoplasm into the nucleus in association with ß-catenin (CTNNB1) after the addition of CHIR99021 and functions as an adaptor to promote ubiquitylation of the Tcf7l1 protein. Functional assays further revealed that enforced expression of Tbl1 is capable of delaying mESC differentiation. In contrast, knockdown of Tbl1 attenuates the effect of CHIR99021 on Tcf7l1 protein stability and mESC self-renewal. Our results provide insight into the regulatory network of the Wnt-ß-catenin signaling pathway involved in promoting the maintenance of naïve pluripotency.

Molecular-Level Insights into the Relationship between Volatility of Organic Aerosol Constituents and PM2.5 Air Pollution Levels: A Study with Ultrahigh-Resolution Mass Spectrometry.

Volatility of organic aerosols (OAs) significantly influences new particle formation and the occurrence of particulate air pollution. However, the relationship between the volatility of OA and the level of particulate air pollution (i.e., particulate matter concentration) is not well understood. In this study, we compared the chemical composition (identified by an ultrahigh-resolution Orbitrap mass spectrometer) and volatility (estimated based on a predeveloped parametrization method) of OAs in urban PM2.5 (particulate matter with aerodynamic diameter ≤ 2.5 µm) samples from seven German and Chinese cities, where the PM2.5 concentration ranged from a light (14 µg m-3) to heavy (319 µg m-3) pollution level. A large fraction (71-98%) of compounds in PM2.5 samples were attributable to intermediate-volatility organic compounds (IVOCs) and semivolatile organic compounds (SVOCs). The fraction of low-volatility organic compounds (LVOCs) and extremely low-volatility organic compounds (ELVOCs) decreased from clean (28%) to heavily polluted urban regions (2%), while that of IVOCs increased from 34 to 62%. We found that the average peak area-weighted volatility of organic compounds in different cities showed a logarithmic correlation with the average PM2.5 concentration, indicating that the volatility of urban OAs increases with the increase of air pollution level. Our results provide new insights into the relationship between OA volatility and PM pollution levels and deepen the understanding of urban air pollutant evolution.

Epigenetic modification of a pectin methylesterase gene activates apoplastic iron reutilization in tomato roots.

Iron (Fe) distribution and reutilization are crucial for maintaining Fe homeostasis in plants. Here, we demonstrate that the tomato (Solanum lycopersicum) Colorless nonripening (Cnr) epimutant exhibits increased Fe retention in cell wall pectin due to an increase in pectin methylesterase (PME) activity. This ultimately leads to Fe deficiency responses even under Fe-sufficient conditions when compared to the wild type (WT). Whole-genome bisulfite sequencing revealed that modifications to cell wall-related genes, especially CG hypermethylation in the intron region of PECTIN METHYLESTERASE53 (SlPME53), are involved in the Cnr response to Fe deficiency. When this intron hypermethylation of SlPME53 was artificially induced in WT, we found that elevated SlPME53 expression was accompanied by increased PME activity and increased pectin-Fe retention. The manipulation of SlPME53, either through overexpression in WT or knockdown in Cnr, influenced levels of pectin methylesterification and accumulation of apoplast Fe in roots. Moreover, CG hypermethylation mediated by METHYLTRANSFERASE1 (SlMET1) increased SlPME53 transcript abundance, resulting in greater PME activity and higher Fe retention in cell wall pectin. Therefore, we conclude that the Cnr mutation epigenetically modulates SlPME53 expression by SlMET1-mediated CG hypermethylation, and thus the capacity of the apoplastic Fe pool, creating opportunities for genetic improvement of crop mineral nutrition.

Trimethylamine from Subtropical Forests Rival Total Farmland Emissions in China.

Many types of living plants release gaseous trimethylamine (TMA), making it a potentially important contributor to new particle formation (NPF) in remote areas. However, a panoramic view of the importance of forest biogenic TMA at the regional scale is lacking. Here, we pioneered nationwide mobile measurements of TMA across a transect of contiguous farmland in eastern China and a transect of subtropical forests in southern China. In contrast to the farmland route, TMA concentrations measured during the subtropical forest route correlated significantly with isoprene, suggesting potential TMA emissions from leaves. Our high time-resolved concentrations obtained from a weak photo-oxidizing atmosphere reflected freshly emitted TMA, indicating the highest emission intensity from irrigated dryland (set as the baseline of 10), followed by paddy field (7.1), subtropical evergreen forests (5.9), and subtropical broadleaf and mixed forests (4.3). Extrapolating their proportions roughly to China, subtropical forests alone, which constitute half of the total forest area, account for nearly 70% of the TMA emissions from the nation's total farmland. Our estimates, despite the uncertainties, take the first step toward large-scale assessment of forest biogenic amines, highlighting the need for observational and modeling studies to consider this hitherto overlooked source of TMA.