Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity.

The activation of Homo sapiens Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone ONC201. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC50 = 0.79 ± 0.03 µM) and antitumor activity in vitro (IC50 = 0.038 ± 0.003 µM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo. This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.

Epigenetic regulation of FOXI2 promotes clear cell renal cell carcinoma progression.

In recent decades, substantial advancements in epigenetics have unveiled a profound understanding of its mechanisms in tumorigenesis and have offered promising strategies for epigenetic therapy in cancer patients. In our study, through bioinformatics analysis, we discovered a significant downregulation and hypermethylation of FOXI2 in clear cell renal cell carcinoma (ccRCC), while the expression in chromophobe cell carcinoma (chRCC) exhibited the opposite trend. Moreover, we established a strong correlation between FOXI2 expression levels and the prognosis of ccRCC. Gene enrichment analysis and cell function experiments unequivocally demonstrate that FOXI2 possesses the capability to induce cell cycle arrest and inhibit cell proliferation. Our research findings demonstrate that the expression of FOXI2 in ccRCC is under the regulation of promoter hypermethylation. Furthermore, in vitro experiments have conclusively shown that the overexpression of FOXI2 induces cell cycle arrest and inhibits cell proliferation.

Quantized Zeroth-Order Gradient Tracking Algorithm for Distributed Nonconvex Optimization Under Polyak- [Formula: see text] ojasiewicz Condition.

This article focuses on distributed nonconvex optimization by exchanging information between agents to minimize the average of local nonconvex cost functions. The communication channel between agents is normally constrained by limited bandwidth, and the gradient information is typically unavailable. To overcome these limitations, we propose a quantized distributed zeroth-order algorithm, which integrates the deterministic gradient estimator, the standard uniform quantizer, and the distributed gradient tracking algorithm. We establish linear convergence to a global optimal point for the proposed algorithm by assuming Polyak- [Formula: see text] ojasiewicz condition for the global cost function and smoothness condition for the local cost functions. Moreover, the proposed algorithm maintains linear convergence at low-data rates with a proper selection of algorithm parameters. Numerical simulations validate the theoretical results.

Mass-Produced Skin-Inspired Piezoresistive Sensing Array with Interlocking Interface for Object Recognition.

E-skins, capable of responding to mechanical stimuli, hold significant potential in the field of robot haptics. However, it is a challenge to obtain e-skins with both high sensitivity and mechanical stability. Here, we present a bioinspired piezoresistive sensor with hierarchical structures based on polyaniline/polystyrene core-shell nanoparticles polymerized on air-laid paper. The combination of laser-etched reusable templates and sensitive materials that can be rapidly synthesized enables large-scale production. Benefiting from the substantially enlarged deformation of the hierarchical structure, the developed piezoresistive electronics exhibit a decent sensitivity of 21.67 kPa-1 and a subtle detection limit of 3.4 Pa. Moreover, an isolation layer is introduced to enhance the interface stability of the e-skin, with a fracture limit of 66.34 N/m. Furthermore, the e-skin can be seamlessly integrated onto gloves without any detachment issues. With the assistance of deep learning, it achieves a 98% accuracy rate in object recognition. We anticipate that this strategy will render e-skin with more robust interfaces and heightened sensing capabilities, offering a favorable pathway for large-scale production.

Optimized Tribological Performance of Nitrogen-Doped Diamond-like Carbon Films on NBR: Influence of Bias Voltage of DC Magnetron Sputtering.

In this research, nitrogen-doped diamond-like carbon (N-DLC) coatings were deposited on Nitrile Butadiene Rubber (NBR) substrates using direct current magnetron sputtering (DC-MS) under varying bias voltages. This study aimed to explore environmentally friendly, low-wear, and non-lubricating seal coatings to enhance the durability of rubber sealing products, which predominantly operate under dynamic sliding conditions. By reducing the coefficient of friction (CoF), the friction and wear on rubber products can be significantly minimized, extending their lifespan. This investigation thoroughly examined the microstructure, mechanical properties, and tribological behavior of the N-DLC films. Among the coatings, the one produced at a bias voltage of -50 V demonstrated superior hardness, elastic modulus, and the lowest CoF in comparison to those prepared with 0, -100, and -200 bias voltages. This optimal combination of properties resulted in an exceptionally low wear rate of 10-9 for the film deposited at -50 V, indicating its outstanding wear resistance.

Sucrose-associated SnRK1a1-mediated phosphorylation of Opaque2 modulates endosperm filling in maize.

During maize endosperm filling, sucrose not only serves as a source of carbon skeletons for storage-reserve synthesis, but also acts as a stimulus to promote this process. However, the molecular mechanism details about sucrose and endosperm filling are poorly understood. Here, we found that sucrose promoted the expression of endosperm-filling hub Opaque2 (O2), coordinating with storage-reserve accumulation. A protein kinase called SnRK1a1 attenuated O2-mediated transactivation, but sucrose released the suppression. SnRK1a1 phosphorylated O2 at Serine 41 (S41), negatively affecting its protein stability and transactivation ability. Mutation of SnRK1a1 resulted in larger seeds with increased kernel weight and storage reserves, while overexpression of SnRK1a1 had the opposite effect. Overexpression of the native O2 (O2-OE), phospho-dead (O2-SA) and phospho-mimetic (O2-SD) variants all increased 100-kernel weight. Although O2-SA seeds exhibited smaller kernel size, they synthesized higher starch and proteins, thereby resulting in larger vitreous endosperm and increased test weight. O2-SD seeds displayed larger kernel size, but had unchanged levels of storage reserves and test weight. O2-OE seeds represented an admixture of O2-SA and O2-SD, showing elevated kernel dimensions and nutrient storage. Overall, this study discovered a novel mechanism to modulate endosperm filling and S41 in O2 offered potential for engineering efforts to enhance storage-reserve accumulation and yield in maize.

A spatiotemporal atlas of cholestatic injury and repair in mice.

Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFß in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

A spatiotemporal atlas of mouse liver homeostasis and regeneration.

The mechanism by which mammalian liver cell responses are coordinated during tissue homeostasis and perturbation is poorly understood, representing a major obstacle in our understanding of many diseases. This knowledge gap is caused by the difficulty involved with studying multiple cell types in different states and locations, particularly when these are transient. We have combined Stereo-seq (spatiotemporal enhanced resolution omics-sequencing) with single-cell transcriptomic profiling of 473,290 cells to generate a high-definition spatiotemporal atlas of mouse liver homeostasis and regeneration at the whole-lobe scale. Our integrative study dissects in detail the molecular gradients controlling liver cell function, systematically defining how gene networks are dynamically modulated through intercellular communication to promote regeneration. Among other important regulators, we identified the transcriptional cofactor TBL1XR1 as a rheostat linking inflammation to Wnt/ß-catenin signaling for facilitating hepatocyte proliferation. Our data and analytical pipelines lay the foundation for future high-definition tissue-scale atlases of organ physiology and malfunction.

Methanetriol─Formation of an Impossible Molecule.

Orthocarboxylic acids─organic molecules carrying three hydroxyl groups at the same carbon atom─have been distinguished as vital reactive intermediates by the atmospheric science and physical (organic) chemistry communities as transients in the atmospheric aerosol cycle. Predicted short lifetimes and their tendency to dehydrate to a carboxylic acid, free orthocarboxylic acids, signify one of the most elusive classes of organic reactive intermediates, with even the simplest representative methanetriol (CH(OH)3)─historically known as orthoformic acid─not previously been detected experimentally. Here, we report the first synthesis of the previously elusive methanetriol molecule in low-temperature mixed methanol (CH3OH) and molecular oxygen (O2) ices subjected to energetic irradiation. Supported by electronic structure calculations, methanetriol was identified in the gas phase upon sublimation via isomer-selective photoionization reflectron time-of-flight mass spectrometry combined with isotopic substitution studies and the detection of photoionization fragments. The first synthesis and detection of methanetriol (CH(OH)3) reveals its gas-phase stability as supported by a significant barrier hindering unimolecular decomposition. These findings progress our fundamental understanding of the chemistry and chemical bonding of methanetriol, hydroxyperoxymethane (CH3OOOH), and hydroxyperoxymethanol (CH2(OH)OOH), which are all prototype molecules in the oxidation chemistry of the atmosphere.

Merging total synthesis and NMR technology for deciphering the realistic structure of natural 2,6-dideoxyglycosides.

The structural identification and efficient synthesis of bioactive 2,6-dideoxyglycosides are daunting challenges. Here, we report the total synthesis and structural revision of a series of 2,6-dideoxyglycosides from folk medicinal plants Ecdysanthera rosea and Chonemorpha megacalyx, which feature pregnane steroidal aglycones bearing an 18,20-lactone and glycans consisting of 2,6-dideoxy-3-O-methyl-ß-pyranose residues, including ecdysosides A, B, and F and ecdysantheroside A. All the eight possible 2,6-dideoxy-3-O-methyl-ß-pyranoside stereoisomers (of the proposed ecdysantheroside A) have been synthesized that testify the effective gold(I)-catalyzed glycosylation methods for the synthesis of various 2-deoxy-ß-pyranosidic linkages and lays a foundation via nuclear magnetic resonance data mapping to identify these sugar units which occur promiscuously in the present and other natural glycosides. Moreover, some synthetic natural compounds and their isomers have shown promising anticancer, immunosuppressive, anti-inflammatory, and anti-Zika virus activities.

LettuceDB: an integrated multi-omics database for cultivated lettuce.

Crop genomics has advanced rapidly during the past decade, which generated a great abundance of omics data from multi-omics studies. How to utilize the accumulating data becomes a critical and urgent demand in crop science. As an attempt to integrate multi-omics data, we developed a database, LettuceDB (https://db.cngb.org/lettuce/), aiming to assemble multidimensional data for cultivated and wild lettuce germplasm. The database includes genome, variome, phenome, microbiome and spatial transcriptome. By integrating user-friendly bioinformatics tools, LettuceDB will serve as a one-stop platform for lettuce research and breeding in the future. Database URL: https://db.cngb.org/lettuce/.

Functional analysis of fasciclin-like arabinogalactan in carotenoid synthesis during tomato fruit ripening.

Carotenoids are important pigmented nutrients synthesized by tomato fruits during ripening. To reveal the molecular mechanism underlying carotenoid synthesis during tomato fruit ripening, we analyzed carotenoid metabolites and transcriptomes in six development stages of tomato fruits. A total of thirty different carotenoids were detected and quantified in tomato fruits from 10 to 60 DPA. Based on differential gene expression profiles and WGCNA, we explored several genes that were highly significant and negatively correlated with lycopene, all of which encode fasciclin-like arabinogalactan proteins (FLAs). The FLAs are involved in plant signal transduction, however the functional role of these proteins has not been studied in tomato. Genome-wide analysis revealed that cultivated and wild tomato species contained 18 to 22 FLA family members, clustered into four groups, and mainly evolved by means of segmental duplication. The functional characterization of FLAs showed that silencing of SlFLA1, 5, and 13 were found to contribute to the early coloration of tomato fruits, and the expression of carotenoid synthesis-related genes was up-regulated in fruits that changed phenotypically, especially in SlFLA13-silenced plants. Furthermore, the content of multiple carotenoids (including (E/Z)-phytoene, lycopene, γ-carotene, and α-carotene) was significantly increased in SlFLA13-silenced fruits, suggesting that SlFLA13 has a potential inhibitory function in regulating carotenoid synthesis in tomato fruits. The results of the present study broaden the idea of analyzing the biological functions of tomato FLAs and preliminary evidence for the inhibitory role of SlFLA13 in carotenoid synthesis in fruit, providing the theoretical basis and a candidate for improving tomato fruit quality.

Nitrogen Application Timing and Levels Affect the Fate and Budget of Fertilizer Nitrogen in the Apple-Soil System.

This study aimed to determine the effects of the nitrogen (N) application period and level on the fate of fertilizer N and the contribution of N absorption and translocation to apple organ N. Two N application periods (labeled by the 15N tracer technique in spring and summer, represented by SP and SU, respectively) and three N levels (N0, MN, and HN) were used to determine the physiological indexes and aboveground, root, and soil 15N content of 4-year-old dwarf ('Red Fuji'/M9T337) and arborized ('Red Fuji'/Malus hupehensis Rehd.) apple trees. The results showed that HN led to shoot overgrowth, which was not conducive to the growth of the apple root system (root length, root tips, root surface area, and root volume) or the improvement of root activity. The contribution of soil N to apple organ N accounted for more than 50%, and the contribution of N application in summer to fruit N was higher than that in spring. Under HN treatment, the proportion of soil N absorbed by trees decreased, while that of fertilizer N increased; however, the highest proportion was still less than 50%, so apple trees were highly dependent on soil N. Under MN treatment, fertilizer N residue was similar to soil N consumption, and soil N fertility maintained a basic balance. Under HN treatment, fertilizer N residue was significantly higher than soil N consumption, indicating that excessive N application increased fertilizer N residue in the soil. Overall, the 15N utilization rate of arborized trees (17.33-22.38%) was higher than that of dwarf trees (12.89-16.91%). A total of 12.89-22.38% of fertilizer 15N was absorbed by trees, 30.37-35.41% of fertilizer 15N remained in the soil, and 44.65-54.46% of fertilizer 15N was lost. The 15N utilization rate and 15N residual rate of summer N application were higher than those of spring N application, and the 15N loss rate was lower than that of spring N application. High microbial biomass N (MBN) may be one of the reasons for the high N utilization rate and the low loss rate of N application in summer.

Hierarchical Piezoelectric Composites for Noninvasive Continuous Cardiovascular Monitoring.

Continuous monitoring of blood pressure (BP) and multiparametric analysis of cardiac functions are crucial for the early diagnosis and therapy of cardiovascular diseases. However, existing monitoring approaches often suffer from bulky and intrusive apparatus, cumbersome testing procedures, and challenging data processing, hampering their applications in continuous monitoring. Here, a heterogeneously hierarchical piezoelectric composite is introduced for wearable continuous BP and cardiac function monitoring, overcoming the rigidity of ceramic and the insensitivity of polymer. By optimizing the hierarchical structure and components of the composite, the developed piezoelectric sensor delivers impressive performances, ensuring continuous and accurate monitoring of BP at Grade A level. Furthermore, the hemodynamic parameters are extracted from the detected signals, such as local pulse wave velocity, cardiac output, and stroke volume, all of which are in alignment with clinical results. Finally, the all-day tracking of cardiac function parameters validates the reliability and stability of the developed sensor, highlighting its potential for personalized healthcare systems, particularly in early diagnosis and timely intervention of cardiovascular disease.

Evolution of groundwater system in the Pearl River Delta and its adjacent shelf since the late Pleistocene.

Our extensive field studies demonstrate that saline groundwater inland and freshened groundwater offshore coexist in the same aquifer system in the Pearl River delta and its adjacent shelf. This counterintuitive phenomenon challenges the commonly held assumption that onshore groundwater is typically fresh, while offshore groundwater is saline. To address this knowledge gap, we conduct a series of sophisticated paleo-hydrogeological models to explore the formation mechanism and evolution process of the groundwater system in the inland-shelf systems. Our findings indicate that shelf freshened groundwater has formed during the lowstands since late Pleistocene, while onshore saline groundwater is generated by paleo-seawater intrusion during the Holocene transgression. This reveals that terrestrial and offshore groundwater systems have undergone alternating changes on a geological timescale. The groundwater system exhibits hysteresis responding to paleoclimate changes, with a lag of 7 to 8 thousand years, suggesting that paleoclimatic forcings exert a significantly residual influence on the present-day groundwater system.

Harnessing artificial intelligence for prostate cancer management.

Prostate cancer (PCa) is a common malignancy in males. The pathology review of PCa is crucial for clinical decision-making, but traditional pathology review is labor intensive and subjective to some extent. Digital pathology and whole-slide imaging enable the application of artificial intelligence (AI) in pathology. This review highlights the success of AI in detecting and grading PCa, predicting patient outcomes, and identifying molecular subtypes. We propose that AI-based methods could collaborate with pathologists to reduce workload and assist clinicians in formulating treatment recommendations. We also introduce the general process and challenges in developing AI pathology models for PCa. Importantly, we summarize publicly available datasets and open-source codes to facilitate the utilization of existing data and the comparison of the performance of different models to improve future studies.

Causal impact of gut microbiota and associated metabolites on pulmonary arterial hypertension: a bidirectional Mendelian randomization study.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. METHODS: Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. RESULTS: Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI] 1.100-4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019-2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358-0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245-0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367-0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231-0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide [TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids (SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increased the levels of Butyricicoccus and Holdemania, while decreasing the levels of Clostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. CONCLUSIONS: Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically.

Oligometastatic colorectal adenocarcinoma to the spleen and ovaries.

In the context of colorectal cancer, splenic and ovarian metastases are rare outside of widely disseminated disease. Growing evidence suggests that 'oligometastatic' or limited metastatic disease can be treated surgically with good oncological outcomes. Splenic and ovarian metastases are not well represented in studies of oligometastatic colorectal cancer, resulting in uncertainty in the best management for these patients. We present the case of a 78-year-old woman diagnosed with oligometastatic colorectal cancer to bilateral ovaries and spleen, 5 years after resection of a primary colon cancer. The patient was treated with a bilateral salpingo-oopherectomy and subsequent open splenectomy. We discuss the role of surgery and peri-operative chemotherapy in the management of oligometastatic colorectal cancer involving atypical sites.

Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.

CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.