Developing Covalent Protein Drugs via Proximity-Enabled Reactive Therapeutics.

Small molecule covalent drugs provide desirable therapeutic properties over noncovalent ones for treating challenging diseases. The potential of covalent protein drugs, however, remains unexplored due to protein's inability to bind targets covalently. We report a proximity-enabled reactive therapeutics (PERx) approach to generate covalent protein drugs. Through genetic code expansion, a latent bioreactive amino acid fluorosulfate-L-tyrosine (FSY) was incorporated into human programmed cell death protein-1 (PD-1). Only when PD-1 interacts with PD-L1 did the FSY react with a proximal histidine of PD-L1 selectively, enabling irreversible binding of PD-1 to only PD-L1 in vitro and in vivo. When administrated in immune-humanized mice, the covalent PD-1(FSY) exhibited strikingly more potent antitumor effect over the noncovalent wild-type PD-1, attaining therapeutic efficacy equivalent or superior to anti-PD-L1 antibody. PERx should provide a general platform technology for converting various interacting proteins into covalent binders, achieving specific covalent protein targeting for biological studies and therapeutic capability unattainable with conventional noncovalent protein drugs.

The Arabidopsis pre-mRNA 3' end processing related protein FIP1 promotes seed dormancy via the DOG1 and ABA pathways.

Seed dormancy is an important adaptive trait to prevent germination occurring at an inappropriate time. The mechanisms governing seed dormancy and germination are complex. Here, we report that FACTOR INTERACTING WITH POLY(A) POLYMERASE 1 (FIP1), a component of the pre-mRNA 3' end processing machinery, is involved in seed dormancy and germination processes in Arabidopsis thaliana. FIP1 is mainly expressed in seeds and the knockout of FIP1 causes reduced seed dormancy, indicating that FIP1 positively influences seed dormancy. Meanwhile, fip1 mutants are insensitive to exogenous ABA during seed germination and early seedling establishment. The terms 'seed maturation' and 'response to ABA stimulus' are significantly enriched in a gene ontology analysis based on genes differentially expressed between fip1-1 and the wild type. Several of these genes, including ABI5, DOG1 and PYL12, show significantly decreased transcript levels in fip1. Genetic analysis showed that either cyp707a2 or dog1-5 partially, but in combination completely, represses the reduced seed dormancy of fip1, indicating that the double mutant cyp707a2 dog1-5 is epistatic to fip1. Moreover, FIP1 is required for CFIM59, another component of pre-mRNA 3' end processing machinery, to govern seed dormancy and germination. Overall, we identified FIP1 as a regulator of seed dormancy and germination that plays a crucial role in governing these processes through the DOG1 and ABA pathways.

Apigenin intervenes in liver fibrosis by regulating PKM2-HIF-1α mediated oxidative stress.

Apigenin (API) is a natural flavonoid compound with antioxidant, anti fibrotic, anti-inflammatory and other effects, but there is limited research on the effect of API on liver fibrosis. This study aims to explore the effect and potential mechanism of API on liver fibrosis induced by CCl4 in mice. The results indicate that API reduces oxidative stress levels, inhibits hepatic stellate cell (HSC) activation, and exerts anti liver fibrosis effects by regulating the PKM2-HIF-1α pathway. We observed that API alleviated liver tissue pathological damage and collagen deposition in CCl4 induced mouse liver fibrosis model, promoting the recovery of liver function in mice with liver fibrosis. In addition, the API inhibits the transition of Pyruvate kinase isozyme type M2 (PKM2) from dimer to tetramer formation by regulating the EGFR-MEK1/2-ERK1/2 pathway, thereby preventing dimer from entering the nucleus and blocking PKM2-HIF-1α access. This change leads to a decrease in malondialdehyde (MDA) and Catalase (CAT) levels and an increase in glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) levels, as well as total antioxidant capacity (T-AOC) in the liver of liver fibrosis mice. At the same time, API downregulated the expression of α-smooth muscle actin (α-SMA), Vimentin and Desmin in the liver tissue of mice with liver fibrosis, inhibited the activation of HSC, and reduced collagen deposition. These results indicate that API can inhibit HSC activation and alleviate CCl4 induced liver fibrosis by inhibiting the PKM2-HIF-1α pathway and reducing oxidative stress, laying an important foundation for the development and clinical application of API as a novel drug for treating liver fibrosis.

Soil application of FeCl3 and Fe2(SO4)3 reduced grain cadmium concentration in Polish wheat (Triticum polonicum L.).

BACKGROUND: Wheat is one of major sources of human cadmium (Cd) intake. Reducing the grain Cd concentrations in wheat is urgently required to ensure food security and human health. In this study, we performed a field experiment at Wenjiang experimental field of Sichuan Agricultural University (Chengdu, China) to reveal the effects of FeCl3 and Fe2(SO4)3 on reducing grain Cd concentrations in dwarf Polish wheat (Triticum polonicum L., 2n = 4x = 28, AABB). RESULTS: Soil application of FeCl3 and Fe2(SO4)3 (0.04 M Fe3+/m2) significantly reduced grain Cd concentration in DPW at maturity by 19.04% and 33.33%, respectively. They did not reduce Cd uptake or root-to-shoot Cd translocation, but increased Cd distribution in lower leaves, lower internodes, and glumes. Meanwhile, application of FeCl3 and Fe2(SO4)3 up-regulated the expression of TpNRAMP5, TpNRAMP2 and TpYSL15 in roots, and TpYSL15 and TpZIP3 in shoots; they also downregulated the expression of TpZIP1 and TpZIP3 in roots, and TpIRT1 and TpNRAMP5 in shoots. CONCLUSIONS: The reduction in grain Cd concentration caused by application of FeCl3 and Fe2(SO4)3 was resulted from changes in shoot Cd distribution via regulating the expression of some metal transporter genes. Overall, this study reports the physiological pathways of soil applied Fe fertilizer on grain Cd concentration in wheat, suggests a strategy for reducing grain Cd concentration by altering shoot Cd distribution.

Tailoring Stress-Relieved Structure for SnSe Toward High Performance Potassium Ion Batteries.

Metal chalcogenides as an ideal family of anode materials demonstrate a high theoretical specific capacity for potassium ion batteries (PIBs), but the huge volume variance and poor cyclic stability hinder their practical applications. In this study, a design of a stress self-adaptive structure with ultrafine SnSe nanoparticles embedded in carbon nanofiber (SnSe@CNF) via the electrospinning technology is presented. Such an architecture delivers a record high specific capacity (272 mAh g-1 at 50 mA g-1) and high-rate performance (125 mAh g-1 at 1 A g-1) as a PIB anode. It is decoded that the fundamental understanding for this great performance is that the ultrafine SnSe particles enhance the full utilization of the active material and achieve stress relief as the stored strain energy from cycling is insufficient to drive crack propagation and thus alleviates the intrinsic chemo-mechanical degradation of metal chalcogenides.

Image-Guided Photothermal and Immune Therapy of Tumors via Melanin-Producing Genetically Engineered Bacteria.

Photothermal therapy (PTT) is a new treatment modality for tumors. However, the efficient delivery of photothermal agents into tumors remains difficult, especially in hypoxic tumor regions. In this study, an approach to deliver melanin, a natural photothermal agent, into tumors using genetically engineered bacteria for image-guided photothermal and immune therapy is developed. An Escherichia coli MG1655 is transformed with a recombinant plasmid harboring a tyrosinase gene to produce melanin nanoparticles. Melanin-producing genetically engineered bacteria (MG1655-M) are systemically administered to 4T1 tumor-bearing mice. The tumor-targeting properties of MG1655-M in the hypoxic environment integrate the properties of hypoxia targeting, photoacoustic imaging, and photothermal therapeutic agents in an "all-in-one" manner. This eliminates the need for post-modification to achieve image-guided hypoxia-targeted cancer photothermal therapy. Tumor growth is significantly suppressed by irradiating the tumor with an 808 nm laser. Furthermore, strong antitumor immunity is triggered by PTT, thereby producing long-term immune memory effects that effectively inhibit tumor metastasis and recurrence. This work proposes a new photothermal and immune therapy guided by an "all-in-one" melanin-producing genetically engineered bacteria, which can offer broad potential applications in cancer treatment.

Design and evaluation of peptide inhibitors targeting the dimerization of SARS-CoV-2 main protease.

The severe acute respiratory syndrome virus 2 (SARS-CoV-2) seriously impacted public health. The evolutionarily conserved viral chymotrypsin-like main protease (Mpro) is an important target for anti-SARS-CoV-2 drug development. Previous studies have shown that the eight N-terminal amino acids (N8) of SARS-CoV Mpro are essential for its dimerization, and are used to design inhibitors against SARS-CoV Mpro dimerization. Here, we established a simple readout assay using SDS-PAGE and Coomassie blue staining to measure inhibitory activity of N8 peptide derived from SARS-CoV-2 Mpro. To optimize its inhibitory effect, we then modified the side-chain length, charge, and hydrophilicity of the N8 peptide, and introduced a mutated Mpro recognition sequence. As a result, we obtained a series of potent peptide inhibitors against SARS-CoV-2 Mpro, with N8-A24 being the most efficient with an IC50 value of 1.44 mM. We observed that N8-A24 reduced Mpro dimerization with an IC50 value of 0.86 mM. Molecular docking revealed that N8-A24 formed hydrogen bond interactions with critical dimeric interface residues, thus inhibiting its dimerization and activity. In conclusion, our study not only discovers a series of peptide inhibitors targeting the SARS-CoV-2 Mpro dimerization, but also provides a promising strategy for the rational design of new inhibitors against COVID-19.

The role of the indoleamine 2,3-dioxygenase gene in preventing ovarian transplant rejection in rats†.

Indoleamine 2,3-dioxygenase (IDO) plays important roles in maternal immune tolerance. Female Sprague Dawley rats (9-11 weeks old) were randomly divided into an autoplastic transplantation group (n = 75) and an allograft transplantation group (n = 300) was further divided into subgroups of ovarian transplantation, allograft ovarian transplantation, allograft ovarian transplantation with cyclosporine A treatment, allograft ovarian transplantation and transfection with IDO-expressing lentiviruses, and allograft ovarian transplantation and transfection with control lentiviruses. IDO was successfully transfected into the transplanted ovarian tissue. The survival rate, success rate of ovarian transplantation, period until estrous cycle restoration, and estrogen levels of rats that received IDO-expressing lentiviruses were significantly different from those of rats that underwent allograft transplantation and with control transfection (all P < 0.05), but not significantly different from those rats that received autoplastic transplantation (all P > 0.05). The number of ovarian follicles in the transplanted ovarian tissue of rats that received IDO-expressing lentiviruses was also significantly higher. The expression level of IDO protein detected by immunohistochemistry and western blotting was especially high in ovaries that had received IDO-containing lentiviruses. Naturally pregnant rats were found in each group postoperatively. These results indicated that IDO-expressing lentiviruses were successfully transfected into transplanted ovarian tissues of rats and that IDO was stably expressed within a certain time. These findings suggest that the expression level of IDO protein is associated with an enhanced success rate of ovarian tissue transplantation and a short restoration period of endocrine function.

A natural variation in OsDSK2a modulates plant growth and salt tolerance through phosphorylation by SnRK1A in rice.

Plants grow rapidly for maximal production under optimal conditions; however, they adopt a slower growth strategy to maintain survival when facing environmental stresses. As salt stress restricts crop architecture and grain yield, identifying genetic variations associated with growth and yield responses to salinity is critical for breeding optimal crop varieties. OsDSK2a is a pivotal modulator of plant growth and salt tolerance via the modulation of gibberellic acid (GA) metabolism; however, its regulation remains unclear. Here, we showed that OsDSK2a can be phosphorylated at the second amino acid (S2) to maintain its stability. The gene-edited mutant osdsk2aS2G showed decreased plant height and enhanced salt tolerance. SnRK1A modulated OsDSK2a-S2 phosphorylation and played a substantial role in GA metabolism. Genetic analysis indicated that SnRK1A functions upstream of OsDSK2a and affects plant growth and salt tolerance. Moreover, SnRK1A activity was suppressed under salt stress, resulting in decreased phosphorylation and abundance of OsDSK2a. Thus, SnRK1A preserves the stability of OsDSK2a to maintain plant growth under normal conditions, and reduces the abundance of OsDSK2a to limit growth under salt stress. Haplotype analysis using 3 K-RG data identified a natural variation in OsDSK2a-S2. The allele of OsDSK2a-G downregulates plant height and improves salt-inhibited grain yield. Thus, our findings revealed a new mechanism for OsDSK2a stability and provided a valuable target for crop breeding to overcome yield limitations under salinity stress.

Association between pre-diagnosis and post-diagnosis Alternate Mediterranean Diet and ovarian cancer survival: evidence from a prospective cohort study.

BACKGROUND: There is currently a lack of comprehensive evidence regarding the correlation between Alternate Mediterranean Diet (AMED) and the survival of patients with ovarian cancer (OC). This prospective cohort study first assessed the association of AMED, not only pre-diagnosis and post-diagnosis but also the change from pre-diagnosis to post-diagnosis with OC survival. METHODS: A total of 560 OC patients were included in the study, and their dietary intake was assessed using a reliable 111-item food frequency questionnaire. The overall survival (OS) of the patients was monitored through active follow-up and review of medical records until February 16th, 2023. Cox proportional hazard regression models were utilized to compute the hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). RESULTS: Out of the total 560 patients with OC, 211 (37.68%) succumbed during a median follow-up period of 44.40 months (interquartile range: 26.97-61.37). Comparative analysis indicated a significant association between the highest tertiles of pre-diagnosis (HR = 0.59; 95% CI 0.38-0.90; Ptrend < 0.05) and post-diagnosis (HR = 0.61; 95% CI 0.41-0.91; Ptrend < 0.05) AMED intake and improved OS as opposed to the lowest tertile. Additionally, a significant linear trend was observed for AMED and OC survival. Notably, decreased intake (more than 5% change) and significantly increased intake (more than 15% change) of AMED from pre-diagnosis to post-diagnosis were linked to worse and better OS, respectively, when compared to the stable intake group (change within 5%). Furthermore, patients displaying consistently higher AMED intake both before and after diagnosis experienced enhanced OS in comparison to those with consistently low AMED intake (HRHigh-High vs. Low-Low = 0.47; 95% CI 0.31-0.70). CONCLUSION: High pre-diagnosis and post-diagnosis AMED was associated with an improved OS in patients with OC, suggesting that maintaining a consistently high intake of AMED could potentially benefit the prognosis of OC.

Genotypic and phenotypic characteristics of sodium channel-associated epilepsy in Chinese population.

Variants in voltage-gated sodium channel (VGSC) genes are implicated in seizures, epilepsy, and neurodevelopmental disorders, constituting a significant aspect of hereditary epilepsy in the Chinese population. Through retrospective analysis utilizing next-generation sequencing (NGS), we examined the genotypes and phenotypes of VGSC-related epilepsy cases from a cohort of 691 epilepsy subjects. Our findings revealed that 5.1% of subjects harbored VGSC variants, specifically 22 with SCN1A, 9 with SCN2A, 1 with SCN8A, and 3 with SCN1B variants; no SCN3A variants were detected. Among these, 14 variants were previously reported, while 21 were newly identified. SCN1A variant carriers predominantly presented with Dravet Syndrome (DS) and Genetic Epilepsy with Febrile Seizures Plus (GEFS + ), featuring a heightened sensitivity to fever-induced seizures. Statistically significant disparities emerged between the SCN1A-DS and SCN1A-GEFS+ groups concerning seizure onset and genetic diagnosis age, incidence of status epilepticus, mental retardation, anti-seizure medication (ASM) responsiveness, and familial history. Notably, subjects with SCN1A variants affecting the protein's pore region experienced more frequent cluster seizures. All SCN2A variants were of de novo origin, and 88.9% of individuals with SCN2A variations exhibited cluster seizures. This research reveals a significant association between variations in VGSC-related genes and the clinical phenotype diversity of epilepsy subjects in China, emphasizing the pivotal role of NGS screening in establishing accurate disease diagnoses and guiding the selection of ASM.

Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2.

BACKGROUND AND AIMS: Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of HSCs and hepatic fibrosis was examined. APPROACH AND RESULTS: PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl 4 )-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl 4 , MCD, or western diet, plus low-dose CCl 4 -induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl 4 -treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of TGFß in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl 4 -treated mice. CONCLUSIONS: In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs through Crebl2/SMAD3/TGFß regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.

Tailoring the spectro-temporal mode of photon pairs generated from interspatial-mode four-wave mixing.

We investigate the spectro-temporal mode property of the photon pairs generated via interspatial-mode spontaneous four-wave mixing (FWM) in a few-mode fiber (FMF) that supports two linearly polarized spatial modes in the 1550 nm telecom band. The two pulsed pumps for the process are in distinct spatial modes, while the created signal and idler photon pairs are also occupying different spatial modes. By exploiting the unique inter-mode phase matching condition in the FMF, we can tailor the spectro-temporal mode structure of the photon pairs by changing the pulse duration (spectral bandwidth) of the two pumps. Especially, photon pairs with a nearly round-shaped factorable joint spectrum are experimentally realized. The techniques are valuable for generating and manipulating quantum states in multi-mode waveguides and exploiting the spatial degree of freedom in quantum information processing.

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation.

BACKGROUND: Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression and organ degeneration, but the mechanism and regulation of the crosstalk network remain unclear. Cellular stress disrupts mitochondrial homeostasis, facilitates the opening of mitochondrial permeability transition pore and the leakage of mitochondrial DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, and subsequently induces inflammasomes activation and the onset of pyroptosis. Meanwhile, the inflammasome-associated protein caspase-1, Gasdermin D, the CARD domain of ASC and the potassium channel are involved in regulating cGAS-STING pathway. Importantly, this crosstalk network has a cascade amplification effect that exacerbates the immuno-inflammatory response, worsening the pathological process of inflammatory and autoimmune diseases. Given the importance of this crosstalk network of cGAS-STING, inflammasomes and pyroptosis in the regulation of innate immunity, it is emerging as a new avenue to explore the mechanisms of multiple disease pathogenesis. Therefore, efforts to define strategies to selectively modulate cGAS-STING, inflammasomes and pyroptosis in different disease settings have been or are ongoing. In this review, we will describe how this mechanistic understanding is driving possible therapeutics targeting this crosstalk network, focusing on the interacting or regulatory proteins, pathways, and a regulatory mitochondrial hub between cGAS-STING, inflammasomes, and pyroptosis. SHORT CONCLUSION: This review aims to provide insight into the critical roles and regulatory mechanisms of the crosstalk network of cGAS-STING, inflammasomes and pyroptosis, and to highlight some promising directions for future research and intervention.

Safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma.

PURPOSE: To retrospectively investigate the safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma. METHODS: 109 patients were enrolled in this study, including 44 patients in the radiochemotherapy group and 65 patients in the chemotherapy group. Propensity score matching (PSM) was used to balance the baseline characteristics of the two groups by 1:1 matching. Kaplan-Meier method was used to calculate PFS and OS. Cox regression model was used for multivariate analysis. The side effects were evaluated by CTCAE v5.0 RESULTS: The median follow-up time was 14.5 months. Multivariate analysis showed that radiotherapy was a good independent prognostic factor for OS (HR: 0.327, 95% CI 0.157-0.680, P = 0.003). After matching, there were 40 patients in both groups, and the median PFS and OS in the radiochemotherapy group were longer than those in the chemotherapy group (PFS: 10.4 vs. 6.7 months, P = 0.035; OS: 43.5 vs. 18.8 months, P < 0.001). In addition, in the radiochemotherapy group, patients treated with radiotherapy before first-line chemotherapy failure had a longer PFS than those treated with radiotherapy after chemotherapy failure (median PFS: 15.7 vs. 6 months, P = 0.003). There was no significant difference in the incidence of grade 3-4 toxicities between the two groups (52.3% vs. 50.8%, P = 0.878). CONCLUSION: For patients with recurrent metastatic renal pelvic and ureteral carcinoma, radiotherapy combined with chemotherapy is well tolerable and expected to bring long-term survival benefits, and the benefits of early interventional radiotherapy may be more obvious.

Transition-Metal-Free Hydrodefluoroamination of Trifluoromethyl Enones for the Synthesis of α-Fluoroenamides.

A three-component strategy was developed to enable hydrodefluoroamination of ß-trifluoromethyl enones by selectively activating two C(sp3)-F bonds in the trifluoromethyl group. The method involved a sequence of carbonyl reduction, hydrodefluorination, and defluoroamination under transition-metal-free conditions. Synthetically useful (E)-stereospecific α-fluoroenamides were obtained in good yields with diverse functional group tolerance, which could be easily transformed into valuable organofluorides and heterocycles. The carbonyl auxiliary exerts both electronic and steric impacts on the CF3-alkenes, allowing for controllable and selective defluorination.

Habitat Imaging With Tumoral and Peritumoral Radiomics for Prediction of Lung Adenocarcinoma Invasiveness on Preoperative Chest CT: A Multicenter Study.

BACKGROUND. Tumor growth processes result in spatial heterogeneity, with the development of tumor subregions (i.e., habitats) having unique biologic characteristics. OBJECTIVE. The purpose of our study was to develop and validate a habitat model combining tumor and peritumoral radiomic features on chest CT for predicting invasiveness of lung adenocarcinoma. METHODS. This retrospective study included 1156 patients (mean age, 57.5 years; 464 men, 692 women), from three centers and a public dataset, who underwent chest CT before lung adenocarcinoma resection (variable date ranges across datasets). Patients from one center formed training (n = 500) and validation (n = 215) sets; patients from the other sources formed three external test sets (n = 249, 113, 79). For each patient, a single nodule was manually segmented on chest CT. The nodule segmentation was combined with an automatically generated 4-mm peritumoral region into a whole-volume volume of interest (VOI). A gaussian mixture model (GMM) identified voxel clusters with similar first-order energy across patients. GMM results were used to divide each patient's whole-volume VOI into multiple habitats, which were defined consistently across patients. Radiomic features were extracted from each habitat. After feature selection, a habitat model was developed for predicting invasiveness, with the use of pathologic assessment as a reference. An integrated model was constructed, combining features extracted from habitats and whole-volume VOIs. Model performance was evaluated, including in subgroups based on nodule density (pure ground-glass, part-solid, and solid). The code for habitat imaging and model construction is publicly available (https://github.com/Shangyoulan/Habitat/). RESULTS. Invasive cancer was diagnosed in 626 of 1156 patients. GMM identified four as the optimal number of voxel clusters and thus of per-patient tumor habitats. The habitat model had an AUC of 0.932 in the validation set and 0.881, 0.880, and 0.764 in the three external test sets. The integrated model had an AUC of 0.947 in the validation set and 0.936, 0.908, and 0.800 in the three external test sets. In the three external test sets combined, across nodule densities, AUCs for the habitat model were 0.836-0.869 and for the integrated model were 0.846-0.917. CONCLUSION. Habitat imaging combining tumoral and peritumoral radiomic features could help predict lung adenocarcinoma invasiveness. Prediction is improved when combining information on tumor subregions and the tumor overall. CLINICAL IMPACT. The findings may aid personalized preoperative assessments to guide clinical decision-making in lung adenocarcinoma.

C/EBPß isoform-specific regulation of podocyte pyroptosis in lupus nephritis-induced renal injury.

As an essential factor in the prognosis of systemic lupus erythematosus (SLE), lupus nephritis (LN) can accelerate the rate at which patients with SLE can transition to chronic kidney disease or even end-stage renal disease. Podocytes now appear to be a possible direct target in LN in addition to being prone to collateral damage from glomerular capillary lesions induces by immune complexes and inflammatory processes. The NLRP3 inflammasome is regulated by CCAAT/enhancer-binding protein ß (C/EBPß), which is involved in the pathogenesis of SLE. However, the role and mechanism of C/EBPß in LN remain unclear. In this investigation, glomerular podocytes treated with LN serum and MRL/lpr mice were employed as in vivo and in vitro models of LN, respectively. In vivo, the expression of C/EBPß isoforms was detected in kidney specimens of humans and mice with LN. Then we assessed the effect of C/EBPß inhibition on renal structure and function by injecting RNAi adeno-associated virus of C/EBPß shRNA into MRL/lpr mice. In vitro, glomerular podocytes were treated with LN serum and C/EBPß siRNA to explore the role of C/EBPß in the activation of the AIM2 inflammasome and podocyte injury. C/EBPß-LAP and C/EBPß-LIP were significantly overexpressed in kidney tissue samples from LN patients and mice, and C/EBPß inhibition significantly alleviated renal function damage and ameliorated renal structural deficiencies. Inflammatory pathways downstream from the AIM2 inflammasome could be suppressed by C/EBPß knockdown. Furthermore, the upregulation of C/EBPß-LAP could activate the AIM2 inflammasome and podocyte pyroptosis by binding to the promoters of AIM2 and CASPASE1 to enhance their expression, and the knockdown of AIM2 or (and) caspase-1 reversed the effects of C/EBPß-LAP overexpression. Interestingly, C/EBPß-LIP overexpression could transcriptionally inhibit IRAG and promote Ca2+ release-mediated activation of the AIM2 inflammasome. This finding suggests that C/EBPß is not only involved in the regulation of the expression of key proteins of the AIM2 inflammasome but also affects the polymerization of key proteins of the AIM2 inflammasome through the regulation of Ca2+ release. In conclusion, this study provides a new idea for studying the regulatory mechanism of C/EBPß and provides a theoretical basis for the early diagnosis and treatment of LN in the future. © 2023 The Pathological Society of Great Britain and Ireland.

Cohort profile: Beijing Healthy Aging Cohort Study (BHACS).

The Beijing Healthy Aging Cohort Study (BHACS) was established to supplement the limited data of a large representative cohort of older people based on the general population and was designed to evaluate the prevalence, incidence, and natural history of cognitive decline, functional disability, and conventional vascular risk factors. The aim was to determine the evolution of these conditions by estimating the rates and determinants of progression and regression to adverse outcomes, including dementia, cardiovascular events, cancer, and all-cause death. It can therefore provide evidence to help policy makers develop better policies to promote healthy aging in China. BHACS consisted of three cohorts (BLSA, CCHS-Beijing, and BECHCS) in Beijing with a total population of 11 235 (6281 in urban and 4954 in rural areas) and an age range of 55 years or older (55-101 years) with a mean age of 70.35 ± 7.71 years (70.69 ± 7.62 years in urban and 69.92 ± 7.80 years in rural areas). BHACS-BLSA conducted the baseline survey in 2009 with a multistage stratification-random clustering procedure for people aged 55 years or older; BHACS-CCHS-Beijing conducted the baseline survey in 2013-2015 with a stratified multistage cluster random sampling method for people aged 55 years or older; and BHACS-BECHCS conducted the baseline survey in 2010-2014 with two-stage cluster random sampling method for people aged 60 years or older. Data were collected through questionnaires, physical measurements, and laboratory analyses. Topics covered by BHACS include a wide range of physical and mental health indicators, lifestyles and personal, family, and socio-economic determinants of health. There are no immediate plans to make the cohort data freely available to the public, but specific proposals for further collaboration are welcome. For further information and collaboration, please contact the corresponding author Yao He (e-mail: yhe301@x263.net).

Identifying sesterterpenoids via feature-based molecular networking and small-scale fermentation.

Terpenoids are known for their diverse structures and broad bioactivities with significant potential in pharmaceutical applications. However, natural products with low yields are usually ignored in traditional chemical analysis. Feature-based molecular networking (FBMN) was developed recently to cluster compounds with similar skeletons, which can highlight trace amounts of unknown compounds. Fusoxypene A is a sesterterpene synthesized by Fusarium oxysporum fusoxypene synthase (FoFS) with a unique 5/6/7/3/5 ring system. In this study, the FoFS-containing biosynthetic gene cluster was identified from F. oxysporum FO14005, and an efficient FBMN-based strategy was established to characterize four new sesterterpenoids, fusoxyordienoid A-D (1-4), based on a small-scale fermentation strategy. A cytochrome P450 monooxygenase, FusB, was found to be involved in the functionalization of fusoxypene A at C-17 and C-24 and responsible for the hydroxylation of fusoxyordienoid A at C-1 and C-8. This study highlights the potential of FBMN as a powerful tool for the discovery and characterization of natural compounds with low abundance. KEY POINTS: Combined small-scale fermentation and FBMN for rapid discovery of fusoxyordienoids Characterization of four new fusoxyordienoids with 5/6/7/3/5 ring system Biosynthetic pathway elucidation via tandem expression and substrate feeding.