Using artificial intelligence to document the hidden RNA virosphere.

Current metagenomic tools can fail to identify highly divergent RNA viruses. We developed a deep learning algorithm, termed LucaProt, to discover highly divergent RNA-dependent RNA polymerase (RdRP) sequences in 10,487 metatranscriptomes generated from diverse global ecosystems. LucaProt integrates both sequence and predicted structural information, enabling the accurate detection of RdRP sequences. Using this approach, we identified 161,979 potential RNA virus species and 180 RNA virus supergroups, including many previously poorly studied groups, as well as RNA virus genomes of exceptional length (up to 47,250 nucleotides) and genomic complexity. A subset of these novel RNA viruses was confirmed by RT-PCR and RNA/DNA sequencing. Newly discovered RNA viruses were present in diverse environments, including air, hot springs, and hydrothermal vents, with virus diversity and abundance varying substantially among ecosystems. This study advances virus discovery, highlights the scale of the virosphere, and provides computational tools to better document the global RNA virome.

A vision chip with complementary pathways for open-world sensing.

Image sensors face substantial challenges when dealing with dynamic, diverse and unpredictable scenes in open-world applications. However, the development of image sensors towards high speed, high resolution, large dynamic range and high precision is limited by power and bandwidth. Here we present a complementary sensing paradigm inspired by the human visual system that involves parsing visual information into primitive-based representations and assembling these primitives to form two complementary vision pathways: a cognition-oriented pathway for accurate cognition and an action-oriented pathway for rapid response. To realize this paradigm, a vision chip called Tianmouc is developed, incorporating a hybrid pixel array and a parallel-and-heterogeneous readout architecture. Leveraging the characteristics of the complementary vision pathway, Tianmouc achieves high-speed sensing of up to 10,000 fps, a dynamic range of 130 dB and an advanced figure of merit in terms of spatial resolution, speed and dynamic range. Furthermore, it adaptively reduces bandwidth by 90%. We demonstrate the integration of a Tianmouc chip into an autonomous driving system, showcasing its abilities to enable accurate, fast and robust perception, even in challenging corner cases on open roads. The primitive-based complementary sensing paradigm helps in overcoming fundamental limitations in developing vision systems for diverse open-world applications.

Atomic-engineered gradient tunable solid-state metamaterials.

Metamaterial has been captivated a popular notion, offering photonic functionalities beyond the capabilities of natural materials. Its desirable functionality primarily relies on well-controlled conditions such as structural resonance, dispersion, geometry, filling fraction, external actuation, etc. However, its fundamental building blocks-meta-atoms-still rely on naturally occurring substances. Here, we propose and validate the concept of gradient and reversible atomic-engineered metamaterials (GRAM), which represents a platform for continuously tunable solid metaphotonics by atomic manipulation. GRAM consists of an atomic heterogenous interface of amorphous host and noble metals at the bottom, and the top interface was designed to facilitate the reversible movement of foreign atoms. Continuous and reversible changes in GRAM's refractive index and atomic structures are observed in the presence of a thermal field. We achieve multiple optical states of GRAM at varying temperature and time and demonstrate GRAM-based tunable nanophotonic devices in the visible spectrum. Further, high-efficiency and programmable laser raster-scanning patterns can be locally controlled by adjusting power and speed, without any mask-assisted or complex nanofabrication. Our approach casts a distinct, multilevel, and reversible postfabrication recipe to modify a solid material's properties at the atomic scale, opening avenues for optical materials engineering, information storage, display, and encryption, as well as advanced thermal optics and photonics.

A system hierarchy for brain-inspired computing.

Neuromorphic computing draws inspiration from the brain to provide computing technology and architecture with the potential to drive the next wave of computer engineering1-13. Such brain-inspired computing also provides a promising platform for the development of artificial general intelligence14,15. However, unlike conventional computing systems, which have a well established computer hierarchy built around the concept of Turing completeness and the von Neumann architecture16-18, there is currently no generalized system hierarchy or understanding of completeness for brain-inspired computing. This affects the compatibility between software and hardware, impairing the programming flexibility and development productivity of brain-inspired computing. Here we propose 'neuromorphic completeness', which relaxes the requirement for hardware completeness, and a corresponding system hierarchy, which consists of a Turing-complete software-abstraction model and a versatile abstract neuromorphic architecture. Using this hierarchy, various programs can be described as uniform representations and transformed into the equivalent executable on any neuromorphic complete hardware-that is, it ensures programming-language portability, hardware completeness and compilation feasibility. We implement toolchain software to support the execution of different types of program on various typical hardware platforms, demonstrating the advantage of our system hierarchy, including a new system-design dimension introduced by the neuromorphic completeness. We expect that our study will enable efficient and compatible progress in all aspects of brain-inspired computing systems, facilitating the development of various applications, including artificial general intelligence.

Towards artificial general intelligence with hybrid Tianjic chip architecture.

There are two general approaches to developing artificial general intelligence (AGI)1: computer-science-oriented and neuroscience-oriented. Because of the fundamental differences in their formulations and coding schemes, these two approaches rely on distinct and incompatible platforms2-8, retarding the development of AGI. A general platform that could support the prevailing computer-science-based artificial neural networks as well as neuroscience-inspired models and algorithms is highly desirable. Here we present the Tianjic chip, which integrates the two approaches to provide a hybrid, synergistic platform. The Tianjic chip adopts a many-core architecture, reconfigurable building blocks and a streamlined dataflow with hybrid coding schemes, and can not only accommodate computer-science-based machine-learning algorithms, but also easily implement brain-inspired circuits and several coding schemes. Using just one chip, we demonstrate the simultaneous processing of versatile algorithms and models in an unmanned bicycle system, realizing real-time object detection, tracking, voice control, obstacle avoidance and balance control. Our study is expected to stimulate AGI development by paving the way to more generalized hardware platforms.

Structural and biochemical characterization of Schlafen11 N-terminal domain.

Schlafen11 (SLFN11) is one of the most studied Schlafen proteins that plays vital roles in cancer therapy and virus-host interactions. Herein, we determined the crystal structure of the Sus scrofa SLFN11 N-terminal domain (NTD) to 2.69 Å resolution. sSLFN11-NTD is a pincer-shaped molecule that shares an overall fold with other SLFN-NTDs but exhibits distinct biochemical characteristics. sSLFN11-NTD is a potent RNase cleaving type I and II tRNAs and rRNAs, and with preference to type II tRNAs. Consistent with the codon usage-based translation suppression activity of SLFN11, sSLFN11-NTD cleaves synonymous serine and leucine tRNAs with different efficiencies in vitro. Mutational analysis revealed key determinates of sSLFN11-NTD nucleolytic activity, including the Connection-loop, active site, and key residues essential for substrate recognition, among which E42 constrains sSLFN11-NTD RNase activity, and all nonconservative mutations of E42 stimulated RNase activities. sSLFN11 inhibited the translation of proteins with a low codon adaptation index in cells, which mainly dependent on the RNase activity of the NTD because E42A enhanced the inhibitory effect, but E209A abolished inhibition. Our findings provide structural characterization of an important SLFN11 protein and expand our understanding of the Schlafen family.

Unmodificated stepless regulation of CRISPR/Cas12a multi-performance.

As CRISPR technology is promoted to more fine-divided molecular biology applications, its inherent performance finds it increasingly difficult to cope with diverse needs in these different fields, and how to more accurately control the performance has become a key issue to develop CRISPR technology to a new stage. Herein, we propose a CRISPR/Cas12a regulation strategy based on the powerful programmability of nucleic acid nanotechnology. Unlike previous difficult and rigid regulation of core components Cas nuclease and crRNA, only a simple switch of different external RNA accessories is required to change the reaction kinetics or thermodynamics, thereby finely and almost steplessly regulating multi-performance of CRISPR/Cas12a including activity, speed, specificity, compatibility, programmability and sensitivity. In particular, the significantly improved specificity is expected to mark advance the accuracy of molecular detection and the safety of gene editing. In addition, this strategy was applied to regulate the delayed activation of Cas12a, overcoming the compatibility problem of the one-pot assay without any physical separation or external stimulation, and demonstrating great potential for fine-grained control of CRISPR. This simple but powerful CRISPR regulation strategy without any component modification has pioneering flexibility and versatility, and will unlock the potential for deeper applications of CRISPR technology in many finely divided fields.

Advanced glycation end products promote the progression of endometrial cancer via activating the RAGE/CHKA/PI3K/AKT signaling pathway.

Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of reducing sugars with the amino groups of biomacromolecules, mediating the occurrence and development of many chronic metabolic diseases. Recent research has demonstrated that the accumulation of AGEs can affect the tumor microenvironment, metabolism, and signaling pathways, thereby affecting the malignant progression of tumors. However, the mechanism by which AGEs affect EC is unclear. Our research aimed to investigate how AGEs promote the development of EC through metabolic pathways and to explore their potential underlying mechanisms. Our experimental results demonstrated that AGEs upregulated the choline metabolism mediated by choline kinase alpha (CHKA) through the receptor for advanced glycation end products (RAGE), activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin A3 (timo A3) could target CHKA to inhibit AGE-induced progression of EC and that a newly discovered CHKA inhibitor could be a novel targeted inhibitor for the treatment of EC. This study provides new therapeutic strategies and contributes to the treatment of EC.

The m6A reader IGF2BP2 promotes the progression of esophageal squamous cell carcinoma cells by increasing the stability of OCT4 mRNA.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy with high morbidity and mortality. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) serves as a reader of RNA m6A (N6 methyladenosine) modification to regulate gene expression at the post-transcriptional level. Emerging evidence suggests that IGF2BP2 plays critical roles in tumorigenesis and malignant development. However, the biological function and molecular mechanism of IGF2BP2 in ESCC are not well understood. Here, we found that IGF2BP2 expression was upregulated in esophageal cancer tissues and ESCC cells, and IGF2BP2 overexpression enhanced proliferation, migration, invasion, and stem cell-like properties of ESCC cells. Conversely, the knockdown of IGF2BP2 expression inhibited malignant phenotype of ESCC cells. Mechanistically, IGF2BP2 upregulated octomer-binding transcription factor 4 (OCT4) mRNA expression, and RNA immunoprecipitation (RIP) assay proved that IGF2BP2 could interact with OCT4 mRNA. Moreover, OCT4 was modified at m6A confirmed by methylated m6A RNA immunoprecipitation (Me-RIP)-qPCR assay, and IGF2BP2 knockdown reduced OCT4 mRNA stability. These results suggested that IGF2BP2 served as a reader for m6A-modified OCT4, thus increased OCT4 mRNA expression by regulating its stability. Furthermore, the knockdown of OCT4 could reverse the effects of IGF2BP2 on ESCC cells. In conclusion, these data indicate that IGF2BP2, as a reader for m6A, plays an oncogenic role by regulating OCT4 expression in ESCC, which provides new insights into targeting IGF2BP2/OCT4 axis for the therapy of ESCC.

G protein-coupled estrogen receptor activates PI3K/AKT/mTOR signaling to suppress ferroptosis via SREBP1/SCD1-mediated lipogenesis.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored. METHODS: The effects of GPER1 on the cytotoxicity of H2O2, the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models. RESULTS: GPER1 and G1 alleviated the cytotoxicity of H2O2, reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo. CONCLUSION: GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects.

The conversion of monolignans to sesquilignans and dilignans is closely correlated to the regulation of Arctium lappa seed germination.

MAIN CONCLUSION: The secondary metabolic conversion of monolignans to sesquilignans/dilignans was closely related to seed germination and seedling establishment in Arctium lappa. Arctium lappa plants are used as a kind of traditional Chinese medicines for nearly 1500 years, and so far, only a few studies have put focus on the key secondary metabolic changes during seed germination and seedling establishment. In the current study, a combined approach was used to investigate the correlation among secondary metabolites, plant hormone signaling, and transcriptional profiles at the early critical stages of A. lappa seed germination and seedling establishment. Of 50 metabolites in methonolic extracts of A. lappa samples, 35 metabolites were identified with LC-MS/MS and 15 metabolites were identified with GC-MS. Their qualitative properties were examined according to the predicted chemical structures. The quantitative analysis was performed for deciphering their metabolic profiles, discovering that the secondary metabolic conversion from monolignans to sesquilignans/dilignans was closely correlated to the initiation of A. lappa seed germination and seedling establishment. Furthermore, the critical transcriptional changes in primary metabolisms, translational regulation at different cellular compartments, and multiple plant hormone signaling pathways were revealed. In addition, the combined approach provides unprecedented insights into key regulatory mechanisms in both gene transcription and secondary metabolites besides many known primary metabolites during seed germination of an important traditional Chinese medicinal plant species. The results not only provide new insights to understand the regulation of key medicinal components of 'ARCTII FRUCTUS', arctiin and arctigenin at the stages of seed germination and seedling establishment, but also potentially spur the development of seed-based cultivation in A. lappa plants.

Phylogenomic analyses of the pantropical Platycerium Desv. (Platycerioideae) reveal their complex evolution and historical biogeography.

Platycerium is a genus of pantropical epiphytic ferns consisting of ca. 18 species and are highly sought after by horticultural enthusiasts. Although the monophyly of this genus has been well supported in previous molecular studies, as an intercontinentally disjunct genus, the origin and distribution pattern of Platycerium were elusive and controversial. This is mainly due to limited taxon sampling, a plastid representing only a single coalescent history, the lack of fossil evidence, and so on. Here, by utilizing genome-skimming sequencing, transcriptome sequencing, and flow cytometry, we integrated chloroplast genomes, data of single-copy nuclear genes, ploidy levels, morphology, and geographic distribution to understand the species phylogeny and the evolutionary and biogeographic history of Platycerium. Our major results include: (1) based on both plastid and nuclear datasets, Platycerium is consistently resolved into three fully supported clades: the Afro-American (AA) clade, the Javan-Australian (JA) clade, and the Malayan-Asian (MA) clade. The AA clade and MA clade are further divided into three and two subclades, respectively; (2) a large amount of gene tree conflict, as well as cytonuclear discordance, was found and can be explained by hybridization and incomplete lineage sorting, and most of the hybridization hypotheses represented ancient hybridization events; (3) through molecular dating, the crown age of Platycerium is determined to be at approximately 32.79 Ma based on the plastid dataset or 29.08 Ma based on the nuclear dataset in the Middle Oligocene; (4) ancestral area reconstruction analysis from different datasets showed that Platycerium most likely originated from Indochina; (5) current distribution patterns are resultant from long-distance dispersals, ancient orogeny, and an ancient climate event; and (6) species diversification was driven by polyploidization, dispersal, and hybridization. This study presented here will help understand the evolution of tropical plant flora and provide a reference for the cultivation and breeding of staghorn ferns.

Deciphering the evolution and biogeography of ant-ferns Lecanopteris s.s.

Southeast Asia is a biodiversity hotspot characterized by a complex paleogeography, and its Polypodiopsida flora is particularly diverse. While hybridization is recognized as common in ferns, further research is needed to investigate the relationship between hybridization events and fern diversity. Lecanopteris s.s., an ant-associated fern, has been subject to debate regarding species delimitations primarily due to limited DNA markers and species sampling. Our study integrates 22 newly generated plastomes, 22 transcriptomes, and flow cytometry of all native species along with two cultivated hybrids. Our objective is to elucidate the reticulate evolutionary history within Lecanopteris s.s. through the integration of phylobiogeographic reconstruction, gene flow inference, and genome size estimation. Key findings of our study include: (1) An enlarged plastome size (178-187 Kb) in Lecanopteris s.s., attributed to extreme expansion of the Inverted Repeat (IR) regions; (2) The traditional 'pumila' and 'crustacea' groups are paraphyletic; (3) Significant cytonuclear discordance attributed to gene flow; (4) Natural hybridization and introgression in the 'pumila' and 'darnaedii' groups; (5) L. luzonensis is the maternal parent of L. 'Yellow Tip', with L. pumila suggested as a possible paternal parent; (6) L. 'Tatsuta' is a hybrid between L. luzonensis and L. crustacea; (7) Lecanopteris s.s. first diverged during the Neogene and then during the middle Miocene climatic optimum in the Indochina and Sundaic regions. In conclusion, the biogeographic history and speciation of Lecanopteris have been profoundly shaped by past climate changes and geodynamics of Southeast Asia. Dispersals, hybridization and introgression between species act as pivotal factors in the evolutionary trajectory of Lecanopteris s.s.. This research provides a robust framework for further exploration and understanding of the complex dynamics driving the diversification and distribution patterns within Polypodiaceae subfamily Microsoroideae.

Femtosecond laser direct writing large-area fiber Bragg grating based on diaphragm shaping.

We propose and demonstrate a new method of direct writing large-area fiber Bragg grating by femtosecond laser through the coating. By adding an adjustable diaphragm before the focusing objective, we can precisely control the length of the refractive index modulation line along the femtosecond laser incident direction up to 29.1 µm. In combination with femtosecond laser scanning fabrication technology, a uniform refractive index modulation plane can be inscribed in the fiber in a single scanning. Based on the plane-by-plane inscription method, we have fabricated a high-quality high-reflectivity fiber Bragg grating and a chirped fiber Bragg grating on 20/400 double-clad fiber core. The reflectivity of both gratings is greater than 99%, and the insertion loss is as low as 0.165 dB and 0.162 dB, respectively. The thermal slope of chirped fiber Bragg grating without any refrigeration is 0.088 °C/W and there is no obvious temperature increase when using the water cooling. Therefore, the fabrication method of large-area fiber Bragg grating based on diaphragm shaping can efficiently fabricate high-quality fiber Bragg grating in the large core diameter fiber, which has an important application prospect in high-power all-fiber oscillators, especially all-fiber oscillators in special wavebands.

Promoting reactive oxygen species accumulation to overcome tyrosine kinase inhibitor resistance in cancer.

BACKGROUND: In tumor treatment, protein tyrosine kinase inhibitors (TKIs) have been extensively utilized. However, the efficacy of TKI is significantly compromised by drug resistance. Consequently, finding an effective solution to overcome TKI resistance becomes crucial. Reactive oxygen species (ROS) are a group of highly active molecules that play important roles in targeted cancer therapy including TKI targeted therapy. In this review, we concentrate on the ROS-associated mechanisms of TKI lethality in tumors and strategies for regulating ROS to reverse TKI resistance in cancer. MAIN BODY: Elevated ROS levels often manifest during TKI therapy in cancers, potentially causing organelle damage and cell death, which are critical to the success of TKIs in eradicating cancer cells. However, it is noteworthy that cancer cells might initiate resistance pathways to shield themselves from ROS-induced damage, leading to TKI resistance. Addressing this challenge involves blocking these resistance pathways, for instance, the NRF2-KEAP1 axis and protective autophagy, to promote ROS accumulation in cells, thereby resensitizing drug-resistant cancer cells to TKIs. Additional effective approaches inducing ROS generation within drug-resistant cells and providing exogenous ROS stimulation. CONCLUSION: ROS play pivotal roles in the eradication of tumor cells by TKI. Harnessing the accumulation of ROS to overcome TKI resistance is an effective and widely applicable approach.

Evaluating Factors Associated With Telehealth Appropriateness in Outpatient Rheumatoid Arthritis Encounters Using the Encounter Appropriateness Score for You (EASY).

OBJECTIVE: Telehealth has been proposed as a safe and effective alternative to in-person care for rheumatoid arthritis (RA). The purpose of this study was to evaluate factors associated with telehealth appropriateness in outpatient RA encounters. METHODS: A prospective cohort study (January 1, 2021, to August 31, 2021) was conducted using electronic health record data from outpatient RA encounters in a single academic rheumatology practice. Rheumatology providers rated the telehealth appropriateness of their own encounters using the Encounter Appropriateness Score for You (EASY) immediately following each encounter. Robust Poisson regression with generalized estimating equations modeling was used to evaluate the association of telehealth appropriateness with patient demographics, RA clinical characteristics, comorbid noninflammatory causes of joint pain, previous and current encounter characteristics, and provider characteristics. RESULTS: During the study period, 1823 outpatient encounters with 1177 unique patients with RA received an EASY score from 25 rheumatology providers. In the final multivariate model, factors associated with increased telehealth appropriateness included higher average provider preference for telehealth in prior encounters (relative risk [RR] 1.26, 95% CI 1.21-1.31), telehealth as the current encounter modality (RR 2.27, 95% CI 1.95-2.64), and increased patient age (RR 1.05, 95% CI 1.01-1.09). Factors associated with decreased telehealth appropriateness included moderate (RR 0.81, 95% CI 0.68-0.96) and high (RR 0.57, 95% CI 0.46-0.70) RA disease activity and if the previous encounters were conducted by telehealth (RR 0.83, 95% CI 0.73-0.95). CONCLUSION: In this study, telehealth appropriateness was most associated with provider preference, the current and previous encounter modality, and RA disease activity. Other factors like patient demographics, RA medications, and comorbid noninflammatory causes of joint pain were not associated with telehealth appropriateness.

Zwitterion-Modified MXene Quantum Dot as a Nanocarrier for Traditional Chinese Medicine Sanguinarine Delivery and Its Application for Photothermal-Chemotherapy Synergistic Antibacterial and Wound Healing.

The nanomaterialization of traditional Chinese medicine (TCM) has aroused widespread interest among researchers. Sanguinarine (SAN) is a kind of TCM with good antibacterial properties, which has important applications in anti-infection of wounds. Additionally, the combination of photothermal therapy and chemotherapy can overcome bacterial resistance, further improving bactericidal and wound healing efficiency. In this paper, we prepared an antibacterial agent by loading SAN on the zwitterion-modified MXene quantum dot nanocarrier (SAN@AHEP@Ta4C3), realizing pH/NIR controlled drug release and photothermal/chemotherapy synergistic antibacterial and wound healing. The particle size of SAN@AHEP@Ta4C3 is about 120 nm, and it has a good water solubility and stability. In addition, it also has excellent photothermal conversion performance (η = 39.2%), which can effectively convert light energy into heat energy under near-infrared (NIR) laser irradiation, further promoting drug release and achieving bactericidal effects by synergistic chemotherapy and photothermal therapy. The in vitro and in vivo experiments show that SAN@AHEP@Ta4C3 exhibits an excellent antibacterial effect against Staphylococcus aureus and Escherichia coli, and it can effectively promote the wound healing of mice. Moreover, the SAN@AHEP@Ta4C3 also has good biocompatibility and has no side effects on normal tissue and organs. This work introduces a multifunctional antibacterial agent based on TCM and hot-spot material MXene, which will have considerable application prospects in biomedical fields.

LNCHC directly binds and regulates YBX1 stability to ameliorate metabolic dysfunction-associated steatotic liver disease progression.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the foremost cause of chronic liver disease, yet its underlying mechanisms remain elusive. Our group previously discovered a novel long non-coding RNA (lncRNA) in rats, termed lncHC and its human counterpart, LNCHC. This study aimed to explore the role of LNCHC in the progression of MASLD. METHODS: RNA-binding proteins bound to LNCHC were searched by mass spectrometry. The target genes of LNCHC and Y-Box binding protein 1 (YBX1) were identified by RNA-seq. MASLD animal models were utilised to examine the roles of LNCHC, YBX1 and patatin-like phospholipase domain containing 3 (PNPLA3) in MASLD progression. RESULTS: Here, we identified LNCHC as a native restrainer during MASLD development. Notably, LNCHC directly binds YBX1 and prevents protein ubiquitination. Up-regulation of YBX1 then stabilises PNPLA3 mRNA to alleviate lipid accumulation in hepatocytes. Furthermore, both cell and animal studies demonstrate that LNCHC, YBX1 and PNPLA3 function to improve hepatocyte lipid accumulation and exacerbate metabolic dysfunction-associated steatohepatitis development. CONCLUSIONS: In summary, our findings unveil a novel LNCHC functionality in regulating YBX1 and PNPLA3 mRNA stability during MASLD development, providing new avenues in MASLD treatment.

Advances in D-dimer testing: progress in harmonization of clinical assays and innovative detection methods.

The D-dimer is a sensitive indicator of coagulation and fibrinolysis activation, especially valuable as a biomarker of intravascular thrombosis. Measurement of plasma D-dimer levels plays a crucial role in the diagnosis and monitoring of conditions such as deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation. A variety of immunoassays, including enzyme-linked immunosorbent assays, latex-enhanced immunoturbidimetric assays, whole-blood aggregation analysis, and immunochromatography assays, are widely used in clinical settings to determine D-dimer levels. However, the results obtained from different D-dimer assays vary significantly. These assays exhibit intra-method coefficients of variation ranging from 6.4% to 17.7%, and the measurement discrepancies among different assays can be as high as 20-fold. The accuracy and reliability of D-dimer testing cannot be guaranteed due to the lack of an internationally endorsed reference measurement system (including reference materials and reference measurement procedures), which may lead to misdiagnosis and underdiagnosis, limiting its full clinical application. In this review, we present an in-depth analysis of clinical D-dimer testing, summarizing the existing challenges, the current state of metrology, and progress towards harmonization. We also review the latest advancements in D-dimer detection techniques, which include mass spectrometry and electrochemical and optical immunoassays. By comparing the basic principles, the definition of the measurand, and analytical performance of these methods, we provide an outlook on the potential improvements in D-dimer clinical testing.

Naringin attenuates Actinobacillus pleuropneumoniae-induced acute lung injury via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway.

Actinobacillus pleuropneumoniae (APP) causes porcine pleuropneumonia (PCP), which is clinically characterized by acute hemorrhagic, necrotizing pneumonia, and chronic fibrinous pneumonia. Although many measures have been taken to prevent the disease, prevention and control of the disease are becoming increasingly difficult due to the abundance of APP sera, weak vaccine cross-protection, and increasing antibiotic resistance in APP. Therefore, there is an urgent need to develop novel drugs against APP infection to prevent the spread of APP. Naringin (NAR) has been reported to have an excellent therapeutic effect on pulmonary diseases, but its therapeutic effect on lung injury caused by APP is not apparent. Our research has shown that NAR was able to alleviate APP-induced weight loss and quantity of food taken and reduce the number of WBCs and NEs in peripheral blood in mice; pathological tissue sections showed that NAR was able to prevent and control APP-induced pathological lung injury effectively; based on the establishment of an in vivo/in vitro model of APP inflammation, it was found that NAR was able to play an anti-inflammatory role through inhibiting the MAPK/NF-κB signaling pathway and exerting anti-inflammatory effects; additionally, NAR activating the Nrf2 signalling pathway, increasing the secretion of antioxidant enzymes Nqo1, CAT, and SOD1, inhibiting the secretion of oxidative damage factors NOS2 and COX2, and enhancing the antioxidant stress ability, thus playing an antioxidant role. In summary, NAR can relieve severe lung injury caused by APP by reducing excessive inflammatory response and improving antioxidant capacity.