BUDDY: molecular formula discovery via bottom-up MS/MS interrogation.

A substantial fraction of metabolic features remains undetermined in mass spectrometry (MS)-based metabolomics, and molecular formula annotation is the starting point for unraveling their chemical identities. Here we present bottom-up tandem MS (MS/MS) interrogation, a method for de novo formula annotation. Our approach prioritizes MS/MS-explainable formula candidates, implements machine-learned ranking and offers false discovery rate estimation. Compared with the mathematically exhaustive formula enumeration, our approach shrinks the formula candidate space by 42.8% on average. Method benchmarking on annotation accuracy was systematically carried out on reference MS/MS libraries and real metabolomics datasets. Applied on 155,321 recurrent unidentified spectra, our approach confidently annotated >5,000 novel molecular formulae absent from chemical databases. Beyond the level of individual metabolic features, we combined bottom-up MS/MS interrogation with global optimization to refine formula annotations while revealing peak interrelationships. This approach allowed the systematic annotation of 37 fatty acid amide molecules in human fecal data. All bioinformatics pipelines are available in a standalone software, BUDDY ( https://github.com/HuanLab/BUDDY ).

A small-molecule activation mechanism that directly opens the KCNQ2 channel.

Pharmacological activation of voltage-gated ion channels by ligands serves as the basis for therapy and mainly involves a classic gating mechanism that augments the native voltage-dependent open probability. Through structure-based virtual screening, we identified a new scaffold compound, Ebio1, serving as a potent and subtype-selective activator for the voltage-gated potassium channel KCNQ2 and featuring a new activation mechanism. Single-channel patch-clamp, cryogenic-electron microscopy and molecular dynamic simulations, along with chemical derivatives, reveal that Ebio1 engages the KCNQ2 activation by generating an extended channel gate with a larger conductance at the saturating voltage (+50 mV). This mechanism is different from the previously observed activation mechanism of ligands on voltage-gated ion channels. Ebio1 caused S6 helices from residues S303 and F305 to perform a twist-to-open movement, which was sufficient to open the KCNQ2 gate. Overall, our findings provide mechanistic insights into the activation of KCNQ2 channel by Ebio1 and lend support for KCNQ-related drug development.

Ectopic expression of BOTRYTIS SUSCEPTIBLE1 reveals its function as a positive regulator of wound-induced cell death and plant susceptibility to Botrytis.

Programmed cell death (PCD) is integral to plant life and required for stress responses, immunity, and development. Our understanding of the regulation of PCD is incomplete, especially concerning regulators involved in multiple divergent processes. The botrytis-susceptible (bos1) mutant of Arabidopsis is highly susceptible to fungal infection by Botrytis cinerea (Botrytis). BOS1 (also known as MYB108) regulates cell death propagation during plant responses to wounding. The bos1-1 allele contains a T-DNA insertion in the 5'-untranslated region upstream of the start codon. This insertion results in elevated expression of BOS1/MYB108. We used clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease 9 (Cas9) system (CRISPR/Cas9) to create new bos1 alleles with disrupted exons, and found that these lines lacked the typical bos1-1 wounding and Botrytis phenotypes. They did exhibit reduced fertility, as was previously observed in other bos1 alleles. Resequencing of the bos1-1 genome confirmed the presence of a mannopine synthase (MAS) promoter at the T-DNA left border. Expression of the BOS1 gene under control of the MAS promoter in wild-type plants conferred the characteristic phenotypes of bos1-1: Botrytis sensitivity and response to wounding. Multiple overexpression lines demonstrated that BOS1 was involved in regulation of cell death propagation in a dosage-dependent manner. Our data indicate that bos1-1 is a gain-of-function mutant and that BOS1 function in regulation of fertility and Botrytis response can both be understood as misregulated cell death.

Regulation of spermatogonial stem cell differentiation by Sertoli cells-derived exosomes through paracrine and autocrine signaling.

In the orchestrated environment of the testicular niche, the equilibrium between self-renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously maintained, ensuring a stable stem cell reserve and robust spermatogenesis. Within this milieu, extracellular vesicles, specifically exosomes, have emerged as critical conveyors of intercellular communication. Despite their recognized significance, the implications of testicular exosomes in modulating SSC fate remain incompletely characterized. Given the fundamental support and regulatory influence of Sertoli cells (SCs) on SSCs, we were compelled to explore the role of SC-derived exosomes (SC-EXOs) in the SSC-testicular niche. Our investigation hinged on the hypothesis that SC-EXOs, secreted by SCs from the testes of 5-day-old mice-a developmental juncture marking the onset of SSC differentiation-participate in the regulation of this process. We discovered that exposure to SC-EXOs resulted in an upsurge of PLZF, MVH, and STRA8 expression in SSC cultures, concomitant with a diminution of ID4 and GFRA1 levels. Intriguingly, obstructing exosomal communication in a SC-SSC coculture system with the exosome inhibitor GW4869 attenuated SSC differentiation, suggesting that SC-EXOs may modulate this process via paracrine signaling. Further scrutiny revealed the presence of miR-493-5p within SC-EXOs, which suppresses Gdnf mRNA in SCs to indirectly restrain SSC differentiation through the modulation of GDNF expression-an indication of autocrine regulation. Collectively, our findings illuminate the complex regulatory schema by which SC-EXOs affect SSC differentiation, offering novel perspectives and laying the groundwork for future preclinical and clinical investigations.

Unraveling resistance mechanisms in anti-CD19 chimeric antigen receptor-T therapy for B-ALL: a novel in vitro model and insights into target antigen dynamics.

BACKGROUND: Cellular immunotherapy, represented by the chimeric antigen receptor T cell (CAR-T), has exhibited high response rates, durable remission, and safety in vitro and in clinical trials. Unfortunately, anti-CD19 CAR-T (CART-19) treatment alone is prone to relapse and has a particularly poor prognosis in relapsed/refractory (r/r) B-ALL patients. To date, addressing or reducing relapse remains one of the research priorities to achieve broad clinical application. METHODS: We manufactured second generation CART-19 cells and validated their efficacy and safety in vitro and in vivo. Through co-culture of Nalm-6 cells with short-term cultured CART-19 cells, CD19-negative Nalm-6 cells were detected by flow cytometry, and further investigation of the relapsed cells and their resistance mechanisms was evaluated in vitro. RESULTS: In this study, we demonstrated that CART-19 cells had enhanced and specific antileukemic activities, and the survival of B-ALL mouse models after CART-19 treatment was significantly prolonged. We then shortened the culture time and applied the serum-free culture to expand CAR-T cells, followed by co-culturing CART-19 cells with Nalm-6 cells. Surprisingly, we observed the proliferation of CD19-negative Nalm-6 cells around 28 days. Identification of potential resistance mechanisms showed that the relapsed cells express truncated CD19 proteins with decreased levels and, more importantly, CAR expression was detected on the relapsed cell surface, which may ultimately keep them antigen-negative. Furthermore, it was validated that CART-22 and tandem CART-22/19 cells could effectively kill the relapsed cells, but neither could completely eradicate them. CONCLUSIONS: We successfully generated CART-19 cells and obtained a CD19-negative refractory relapsed B-ALL cell line, providing new insights into the underlying mechanisms of resistance and a new in vitro model for the treatment of r/r B-ALL patients with low antigen density.

The mediation effects of malalignment on the relation of sex to the risk of incidence tibiofemoral osteoarthritis.

OBJECTIVE: To investigate to what extent the higher risk of tibiofemoral radiographic osteoarthritis (TFROA) in females vs. males can be explained by knee malalignment. DESIGN: Using data from Multicenter Osteoarthritis Study (MOST) and Osteoarthritis Initiative (OAI), we examined the relation of sex to the incident medial and lateral TFROA and performed mediation analyses to assess to what extent varus and valgus malalignments account for sex differences in the incident medial or lateral TFROA. RESULTS: Of the 3462 knees without medial and lateral TFROA in MOST, the 7-year risks of medial and lateral TFROA were 16.9% and 10.0% in females, and 15.8% and 4.2% in males, respectively. Females had 2.31-fold (95% confidence interval [95% CI]: 1.73 to 3.08) higher incident lateral TFROA than males, and the relative risk (RR) of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.15 (95% CI: 1.09 to 1.20), accounting for 23% of its total effect on lateral TFROA. In OAI (n = 3095 knees), females had 1.54-fold (95% CI: 1.15 to 2.04) higher incident lateral TFROA than males, and RR of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.10 (95% CI: 1.04 to 1.21), accounting for 26% of its total effect on lateral TFROA. No apparent sex difference in the incident medial TFROA was found in MOST (RR = 1.05, 95% CI: 0.89 to 1.25) or OAI (RR = 1.02, 95% CI: 0.84 to 1.19). CONCLUSION: Females had a higher risk of developing lateral TFROA than males; however, valgus malalignment only modestly explained such a difference.

ETHYLENE INSENSITIVE3/EIN3-LIKE1 modulate FLOWERING LOCUS C expression via histone demethylase interaction.

Time to flowering (vegetative to reproductive phase) is tightly regulated by endogenous factors and environmental cues to ensure proper and successful reproduction. How endogenous factors coordinate with environmental signals to regulate flowering time in plants is unclear. Transcription factors ETHYLENE INSENSITIVE 3 (EIN3) and its homolog EIN3 LIKE 1 (EIL1) are the core downstream regulators in ethylene signal transduction, and their null mutants exhibit late flowering in Arabidopsis (Arabidopsis thaliana); however, the precise mechanism of floral transition remains unknown. Here, we reveal that FLOWERING LOCUS D (FLD), encoding a histone demethylase acting in the autonomous pathway of floral transition, physically associates with EIN3 and EIL1. Loss of EIN3 and EIL1 upregulated transcriptional expression of the floral repressor FLOWERING LOCUS C (FLC) and its homologs in Arabidopsis, and ethylene-insensitive mutants displayed inhibited flowering in an FLC-dependent manner. We further demonstrated that EIN3 and EIL1 directly bind to FLC loci, modulating their expression by recruiting FLD and thereafter removing di-methylation of lysine 4 on histone H3 (H3K4me2). In plants treated with 1-aminocyclopropane-1-carboxylic acid, decreased expression of FLD resulted in increased enrichment of H3K4me2 at FLC loci and transcriptional activation of FLC, leading to floral repression. Our study reveals the role of EIN3 and EIL1 in FLC-dependent and ethylene-induced floral repression and elucidates how phytohormone signals are transduced into chromatin-based transcriptional regulation.

Genetic and epigenetic basis of phytohormones control of floral transition in plants.

The timing of the developmental transition from the vegetative to the reproductive stages is critical for angiosperm and fine-tuned by the integration of endogenous factors and external environmental cues to ensure proper and successful reproduction. Plants have evolved sophisticated mechanisms to response to diverse environmental or stress signals, which may be mediated by plant hormones which coordinate their flowering time. Endogenous and exogenous phytohormones such as gibberellin (GA), auxin, cytokinin (CK), jasmonate (JA), abscisic acid (ABA), ethylene (ET), brassinosteroids (BR) and the cross-talk among them are critical for the precise regulating of flowering time. Recent studies on the model flowering plant Arabidopsis thaliana revealed that diverse transcription factors and epigenetic regulators play key roles in the phytohormones that regulate floral transition. This review aims to summarize current knowledge on the genetic and epigenetic mechanisms that underlying the phytohormone control of floral transition in Arabidopsis, offering insights into how these processes are regulated and their implications for plant biology.

M2 macrophage-derived exosomes induce angiogenesis and increase skin flap survival through HIF1AN/HIF-1α/VEGFA control.

BACKGROUND: Skin flap transplantation is a routine strategy in plastic and reconstructive surgery for skin-soft tissue defects. Recent research has shown that M2 macrophages have the potential for pro-angiogenesis during tissue healing. METHODS: In our research, we extracted the exosomes from M2 macrophages(M2-exo) and applied the exosomes in the model of skin flap transplantation. The flap survival area was measured, and the choke vessels were assessed by morphological observation. Hematoxylin and eosin (H&E) staining and Immunohistochemistry were applied to assess the neovascularization. The effect of M2-exo on the function of Human umbilical vein endothelial cells (HUVECs) was also investigated. We also administrated 2-methoxyestradiol (2-ME2, an inhibitor of HIF-1α) to explore the underlying mechanism. We tested the effects of M2-Exo on the proliferation of HUVECs through CCK8 assay and EdU staining assay. RESULTS: The survival area and number of micro-vessels in the skin flaps were increased in the M2-exo group. Besides, the dilation rate of choke vessels was also enhanced in the M2-exo group. Additionally, compared with the control group, M2-exo could accelerate the proliferation, migration and tube formation of HUVECs in vitro. Furthermore, the expression of the pro-angiogenesis factors, HIF-1α and VEGFA, were overexpressed with the treatment of the M2-exo. The expression of HIF1AN protein level was decreased in the M2-exo group. Finally, treatment with HIF-1α inhibitor reverses the pro-survival effect of M2-exo on skin flaps by interfering with the HIF1AN/HIF-1α/VEGFA signaling pathway. CONCLUSION: This study showed that M2-exosomes promote skin flap survival by enhancing angiogenesis, with HIF1AN/HIF-1α/VEGFA playing a crucial role in this process.

Evaluation of the diagnostic performance of colposcopy in the detection of cervical high-grade squamous intraepithelial lesions among women with transformation zone type 3.

BACKGROUND: Inaccurate colposcopy diagnosis may lead to inappropriate management and increase the incidence of cervical cancer. This study aimed to evaluate the diagnostic accuracy of colposcopy in the detection of histologic cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women with transformation zone type 3 (TZ3). METHODS: Records from 764 patients with TZ3 who underwent colposcopy-directed biopsy and/or endocervical curettage in Putuo Hospital China between February 2020 and March 2023 were retrospectively collected. Colposcopy was carried out based on 2011 International Federation of Cervical Pathology and Colposcopy (IFCPC) and Colposcopy nomenclature. The diagnostic performance of colposcopy for identifying CIN2 + was evaluated compared with biopsies. The Kappa and McNemar tests were used to perform statistical analyses. RESULTS: Among the study population, 11.0% had pathologic CIN2+. The relative sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of colposcopy for histologic CIN2 + were 51.2%, 96.5%, 64.2% and 94.1%, respectively. The senior colposcopists (80.6%) had a higher colposcopic accuracy to diagnose histologic CIN2 + than junior colposcopists (68.6%). In subgroup analyses, age group ≥ 60 years (70.3%) showed lowest diagnostic accuracy when compared with age groups of < 45 years (84.4%) and 45-59 years (74.9%). CONCLUSION: Our findings suggest an increased risk of diagnostic inaccuracy of colposcopy in identifying CIN2 + in those ≥ 60 years of age with TZ3, and the accuracy of colposcopy is required to be further improved.

High-density mapping of durable and broad-spectrum stripe rust resistance gene Yr30 in wheat.

KEY MESSAGE: The durable stripe rust resistance gene Yr30 was fine-mapped to a 610-kb region in which five candidate genes were identified by expression analysis and sequence polymorphisms. The emergence of genetically diverse and more aggressive races of Puccinia striiformis f. sp. tritici (Pst) in the past twenty years has resulted in global stripe rust outbreaks and the rapid breakdown of resistance genes. Yr30 is an adult plant resistance (APR) gene with broad-spectrum effectiveness and its durability. Here, we fine-mapped the YR30 locus to a 0.52-cM interval using 1629 individuals derived from residual heterozygous F5:6 plants in a Yaco"S"/Mingxian169 recombinant inbred line population. This interval corresponded to a 610-kb region in the International Wheat Genome Sequencing Consortium (IWGSC) RefSeq version 2.1 on chromosome arm 3BS harboring 30 high-confidence genes. Five genes were identified as candidate genes based on functional annotation, expression analysis by RNA-seq and sequence polymorphisms between cultivars with and without Yr30 based on resequencing. Haplotype analysis of the target region identified six haplotypes (YR30_h1-YR30_h6) in a panel of 1215 wheat accessions based on the 660K feature genotyping array. Lines with YR30_h6 displayed more resistance to stripe rust than the other five haplotypes. Near-isogenic lines (NILs) with Yr30 showed a 32.94% higher grain yield than susceptible counterparts when grown in a stripe rust nursery, whereas there was no difference in grain yield under rust-free conditions. These results lay a foundation for map-based cloning Yr30.

GDPD3 Deficiency Alleviates Neuropathic Pain and Reprograms Macrophagic Polarization Through PGE2 and PPARγ Pathway.

The complex mechanism of neuropathic pain involves various aspects of both central and peripheral pain conduction pathways. An effective cure for neuropathic pain therefore remains elusive. We found that deficiency of the gene Gdpd3, encoding a lysophospholipase D enzyme, alleviates the inflammatory responses in dorsal root ganglia (DRG) of mice under neuropathic pain and reduces PE (20:4) and PGE2 in DRG. Gdpd3 deficiency had a stronger analgesic effect on neuropathic pain than Celecoxib, a nonsteroidal anti-inflammatory drug. Gdpd3 deficiency also interferes with the polarization of macrophages, switching from M1 towards M2 phenotype. The PPARγ/ FABP4 pathway was screened by RNA sequencing as functional related with Gdpd3 deficient BMDMs stimulated with LPS. Both protein and mRNA levels of PPARγ in GDPD3 deficient BMDMs were higher than those of the litter control mice. However, GW9962 (inhibitor of PPARγ) could reverse the reprogramming polarization of macrophages caused by GDPD3 deficiency. Therefore, our study suggests that GDPD3 deficiency exerts a relieving effect on neuropathic pain and alleviates neuroinflammation in DRG by switching the phenotype of macrophages from M1 to M2, which was mediated through PGE2 and PPARγ/ FABP4 pathway.

[18F]FDG PET-CT radiomics signature to predict pathological complete response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer: a multicenter study.

OBJECTIVES: This study aims to develop and validate a radiomics model based on 18F-fluorodeoxyglucose positron emission tomography-computed tomography ([18F]FDG PET-CT) images to predict pathological complete response (pCR) to neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: One hundred eighty-five patients receiving neoadjuvant chemoimmunotherapy for NSCLC at 5 centers from January 2019 to December 2022 were included and divided into a training cohort and a validation cohort. Radiomics models were constructed via the least absolute shrinkage and selection operator (LASSO) method. The performances of models were evaluated by the area under the receiver operating characteristic curve (AUC). In addition, genetic analyses were conducted to reveal the underlying biological basis of the radiomics score. RESULTS: After the LASSO process, 9 PET-CT radiomics features were selected for pCR prediction. In the validation cohort, the ability of PET-CT radiomics model to predict pCR was shown to have an AUC of 0.818 (95% confidence interval [CI], 0.711, 0.925), which was better than the PET radiomics model (0.728 [95% CI, 0.610, 0.846]), CT radiomics model (0.732 [95% CI, 0.607, 0.857]), and maximum standard uptake value (0.603 [95% CI, 0.473, 0.733]) (p < 0.05). Moreover, a high radiomics score was related to the upregulation of pathways suppressing tumor proliferation and the infiltration of antitumor immune cell. CONCLUSION: The proposed PET-CT radiomics model was capable of predicting pCR to neoadjuvant chemoimmunotherapy in NSCLC patients. CLINICAL RELEVANCE STATEMENT: This study indicated that the generated 18F-fluorodeoxyglucose positron emission tomography-computed tomography radiomics model could predict pathological complete response to neoadjuvant chemoimmunotherapy, implying the potential of our radiomics model to personalize the neoadjuvant chemoimmunotherapy in lung cancer patients. KEY POINTS: • Recognizing patients potentially benefiting neoadjuvant chemoimmunotherapy is critical for individualized therapy of lung cancer. • [18F]FDG PET-CT radiomics could predict pathological complete response to neoadjuvant immunotherapy in non-small cell lung cancer. • [18F]FDG PET-CT radiomics model could personalize neoadjuvant chemoimmunotherapy in lung cancer patients.

Nontarget Identification of Novel Organophosphorus Flame Retardants and Plasticizers in Indoor Air and Dust from Multiple Microenvironments in China.

The indoor environment is a typical source for organophosphorus flame retardants and plasticizers (OPFRs), yet the source characteristics of OPFRs in different microenvironments remain less clear. This study collected 109 indoor air samples and 34 paired indoor dust samples from 4 typical microenvironments within a university in Tianjin, China, including the dormitory, office, library, and information center. 29 target OPFRs were analyzed, and novel organophosphorus compounds (NOPs) were identified by fragment-based nontarget analysis. Target OPFRs exhibited the highest air and dust concentrations of 46.2-234 ng/m3 and 20.4-76.0 µg/g, respectively, in the information center, where chlorinated OPFRs were dominant. Triphenyl phosphate (TPHP) was the primary OPFR in office air, while tris(2-chloroethyl) phosphate dominated in the dust. TPHP was predominant in the library. Triethyl phosphate (TEP) was ubiquitous in the dormitory, and tris(2-butoxyethyl) phosphate was particularly high in the dust. 9 of 25 NOPs were identified for the first time, mainly from the information center and office, such as bis(chloropropyl) 2,3-dichloropropyl phosphate. Diphenyl phosphinic acid, two hydroxylated and methylated metabolites of tris(2,4-ditert-butylphenyl) phosphite (AO168), and a dimer phosphate were newly reported in the indoor environment. NOPs were widely associated with target OPFRs, and their human exposure risk and environmental behaviors warrant further study.

Stability and Biotransformation of 6:2 Fluorotelomer Sulfonic Acid, Sulfonamide Amine Oxide, and Sulfonamide Alkylbetaine in Aerobic Sludge.

The 6:2 fluorotelomer sulfonamide (6:2 FTSAm)-based compounds signify a prominent group of per- and polyfluoroalkyl substances (PFAS) widely used in contemporary aqueous film-forming foam (AFFF) formulations. Despite their widespread presence, the biotransformation behavior of these compounds in wastewater treatment plants remains uncertain. This study investigated the biotransformation of 6:2 FTSAm-based amine oxide (6:2 FTNO), alkylbetaine (6:2 FTAB), and 6:2 fluorotelomer sulfonic acid (6:2 FTSA) in aerobic sludge over a 100-day incubation period. The biotransformation of 6:2 fluorotelomer sulfonamide alkylamine (6:2 FTAA), a primary intermediate product of 6:2 FTNO, was indirectly assessed. Their stability was ranked based on the estimated half-lives (t1/2): 6:2 FTAB (no obvious products were detected) ≫ 6:2 FTSA (t1/2 ≈28.8 days) > 6:2 FTAA (t1/2 ≈11.5 days) > 6:2 FTNO (t1/2 ≈1.2 days). Seven transformation products of 6:2 FTSA and 15 products of 6:2 FTNO were identified through nontarget and suspect screening using high-resolution mass spectrometry. The transformation pathways of 6:2 FTNO and 6:2 FTSA in aerobic sludge were proposed. Interestingly, 6:2 FTSAm was hardly hydrolyzed to 6:2 FTSA and further biotransformed to perfluoroalkyl carboxylic acids (PFCAs). Furthermore, the novel pathways for the generation of perfluoroheptanoic acid (PFHpA) from 6:2 FTSA were revealed.

The Significant Role of New Particle Composition and Morphology on the HNO3-Driven Growth of Particles down to Sub-10 nm.

New particle formation and growth greatly influence air quality and the global climate. Recent CERN Cosmics Leaving OUtdoor Droplets (CLOUD) chamber experiments proposed that in cold urban atmospheres with highly supersaturated HNO3 and NH3, newly formed sub-10 nm nanoparticles can grow rapidly (up to 1000 nm h-1). Here, we present direct observational evidence that in winter Beijing with persistent highly supersaturated HNO3 and NH3, nitrate contributed less than ∼14% of the 8-40 nm nanoparticle composition, and overall growth rates were only ∼0.8-5 nm h-1. To explain the observed growth rates and particulate nitrate fraction, the effective mass accommodation coefficient of HNO3 (αHNO3) on the nanoparticles in urban Beijing needs to be 2-4 orders of magnitude lower than those in the CLOUD chamber. We propose that the inefficient uptake of HNO3 on nanoparticles is mainly due to the much higher particulate organic fraction and lower relative humidity in urban Beijing. To quantitatively reproduce the observed growth, we show that an inhomogeneous "inorganic core-organic shell" nanoparticle morphology might exist for nanoparticles in Beijing. This study emphasized that growth for nanoparticles down to sub-10 nm was largely influenced by their composition, which was previously ignored and should be considered in future studies on nanoparticle growth.

Modeling the Formation of Organic Compounds across Full Volatility Ranges and Their Contribution to Nanoparticle Growth in a Polluted Atmosphere.

Nanoparticle growth influences atmospheric particles' climatic effects, and it is largely driven by low-volatility organic vapors. However, the magnitude and mechanism of organics' contribution to nanoparticle growth in polluted environments remain unclear because current observations and models cannot capture organics across full volatility ranges or track their formation chemistry. Here, we develop a mechanistic model that characterizes the full volatility spectrum of organic vapors and their contributions to nanoparticle growth by coupling advanced organic oxidation modeling and kinetic gas-particle partitioning. The model is applied to Nanjing, a typical polluted city, and it effectively captures the volatility distribution of low-volatility organics (with saturation vapor concentrations <0.3 µg/m3), thus accurately reproducing growth rates (GRs), with a 4.91% normalized mean bias. Simulations indicate that as particles grow from 4 to 40 nm, the relative fractions of GRs attributable to organics increase from 59 to 86%, with the remaining contribution from H2SO4 and its clusters. Aromatics contribute much to condensable organic vapors (∼37%), especially low-volatility vapors (∼61%), thus contributing the most to GRs (32-46%) as 4-40 nm particles grow. Alkanes also contribute 19-35% of GRs, while biogenic volatile organic compounds contribute minimally (<13%). Our model helps assess the climatic impacts of particles and predict future changes.

Mechanistic study on ursolic acid inhibiting the growth of colorectal cancer cells through the downregulation of TGF-ß3 by miR-140-5p.

Colorectal cancer (CRC) is a common digestive tract tumor with a high incidence and a poor prognosis. Traditional chemotherapy drugs are usually accompanied by unpleasant side effects, highlighting the importance of exploring new adjunctive drugs. In this study, we aimed to explore the role of ursolic acid (UA) in CRC cells. Specifically, HT-29 cells were treated with UA at different concentrations (10, 20, 30, and 40 µM), and the expression of miR-140-5p, tumor growth factor-ß3 (TGF-ß3), ß-catenin, and cyclin D1 was determined by real-time quantitative PCR. The cell cycle and apoptosis were checked by flow cytometry, and cell proliferation was detected by Cell Counting Kit-8 assay. The HT-29 cell model was established through overexpression (miR-140-5p mimics) and interference (miR-140-5p inhibitor) of miR-140-5p. Western blot was used to detect the protein expression of TGF-ß3. We found that UA could inhibit the proliferation of HT-29 cells, block cells in the G1 phase, and promote cell apoptosis. After UA treatment, the expression of miR-140-5p increased and TGF-ß3 decreased. Notably, miR-140-5p downregulated the expression of TGF-ß3, while the overexpression of miR-140-5p exerted a similar function to UA in HT-29 cells. Additionally, the messenger RNA expression of TGF-ß3, ß-catenin, and cyclin D1 was decreased in HT-29 cells after UA treatment. In conclusion, UA inhibited CRC cell proliferation and cell cycle and promoted apoptosis by regulating the miR-140-5p/TGF-ß3 axis, which may be related to the inhibition of Wnt/ß-catenin signaling pathway.

Kazakh adults in Xinjiang have a prevalent obesity problem but a low prevalence of diabetes.

BACKGROUND: The prevalence of diabetes and obesity has been continuously rising worldwide over the last three decades, particularly in China. The prevalence varies widely among different ethnicities. In this study, we investigated the prevalence of diabetes and obesity, as well as the associated factors for diabetes in Kazakh adults in Xinjiang to improve diabetes screening. METHODS: We collected data from the Xinjiang physical examination in 2018, including a total sample of 118,505 Kazakh adults in Altay District. Data on demographic characteristics, medical history, physical examination, fasting plasma glucose (FPG) and serum lipid profiles were collected. The chi-square test was used to examine the differences between multiple variables. Multivariate logistic regression was performed to identify the factors associated with diabetes. RESULTS: The mean age was 43. 66 years (SD 14.14). 49.3% of the population were women and 75.5% were rural residents. The mean FPG was 5.33 mmol/L (SD 1.22). The prevalence of diabetes was 6.3% and 4.1% received a new diagnosis by FPG. 26.6% were diagnosed with impaired fasting glucose (IFG). The mean body mass index (BMI) was 26.29 kg/m2 (SD 14.14) and the mean waist circumference was 87.69 cm (SD 12.74). 33.2% of the population were overweight, and 33.0% were obese. The prevalence of central obesity was 51.4%. Diabetes was mostly positively associated with hypertension (OR = 3.821, P<0.001), hypertriglyceridemia (OR = 2.757, P<0.001), and hyper-LDL-cholesterolemia (OR = 2.331, P<0.001) in the Kazakh population. The ORs for overweight, obesity and central obesity predictive of diabetes were 1.265, 1.453 and 1.222 ( all P<0.001), respectively. CONCLUSIONS: Despite having a high prevalence of obesity and central obesity, the Kazakh population had a considerably low prevalence of diabetes. Obesity was not the most important risk factor for diabetes in Kazakh individuals. The awareness of diabetes was low. When screening for diabetes in Kazakhs, those with hypertension or dyslipidemia should receive more attention.

Voltage-gating and cytosolic Ca2+ activation mechanisms of Arabidopsis two-pore channel AtTPC1.

Arabidopsis thaliana two-pore channel AtTPC1 is a voltage-gated, Ca2+-modulated, nonselective cation channel that is localized in the vacuolar membrane and responsible for generating slow vacuolar (SV) current. Under depolarizing membrane potential, cytosolic Ca2+ activates AtTPC1 by binding at the EF-hand domain, whereas luminal Ca2+ inhibits the channel by stabilizing the voltage-sensing domain II (VSDII) in the resting state. Here, we present 2.8 to 3.3 Å cryoelectron microscopy (cryo-EM) structures of AtTPC1 in two conformations, one in closed conformation with unbound EF-hand domain and resting VSDII and the other in a partially open conformation with Ca2+-bound EF-hand domain and activated VSDII. Structural comparison between the two different conformations allows us to elucidate the structural mechanisms of voltage gating, cytosolic Ca2+ activation, and their coupling in AtTPC1. This study also provides structural insight into the general voltage-gating mechanism among voltage-gated ion channels.