Advancements on the impact of hydroxychloroquine in systemic lupus erythematosus.

Hydroxychloroquine (HCQ) has gained significant attention as a therapeutic option for systemic lupus erythematosus (SLE) because of its multifaceted mechanism of action. It is a lipophilic, lysosomotropic drug, that easily traverses cell membranes and accumulates in lysosomes. Once accumulated, HCQ alkalizes lysosomes within the cytoplasm, thereby disrupting their function and interfering with processes like antigen presentation. Additionally, HCQ has shown potential in modulating T-cell responses, inhibiting cytokine production, and influencing Toll-like receptor signaling. Its immunomodulatory effects have generated interest in its application for autoimmune disorders. Despite its established efficacy, uncertainties persist regarding the optimal therapeutic concentrations and their correlation with adverse effects such as retinal toxicity. Therefore, standardized dosing and monitoring guidelines are crucial. In this study, we provide a comprehensive review of the mechanisms, efficacy, dosing variations, and retinal toxicity profiles of HCQ, which are essential to optimize SLE treatment protocols and ensure patient safety.

Clinical application of ERCP concurrent laparoscopic cholecystectomy in the treatment of cholecystolithiasis complicated with extrahepatic bile duct stones.

Objective: To compare the clinical efficacy of endoscopic retrograde cholangiopancreatography (ERCP) combined with laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration and lithotomy (LCBDE) in the treatment of cholecystolithiasis combined with bile duct stones. Methods: From September 2018 to January 2022, 195 patients with cholecystolithiasis complicated with extrahepatic bile duct stones from Department of Department of General Surgery, Shanghai Jiading Central Hospital met the inclusion criteria, including 60 cases in the LC group and 86 cases in the LCBDE group. The general condition, operation success rate, complications and residual stone rate of the two groups were retrospectively analyzed. Results: In the simultaneous operation group, 58 patients successfully performed ERCP, and the indwelling rate of the abdominal drainage tube (41.7 % vs. 95.3 %) was significantly better than that in the LCBDE group. There was no significant difference in the conversion rate to open surgery, operation time, and intraoperative blood loss between the two groups. In the simultaneous surgery group, 4 patients (6.7 %) developed pancreatitis after ERCP, which was cured by conservative treatment. The pain score at 6 h after operation was significantly lower than that in the LCBDE group (3.9 ± 1.6 vs 6.5 ± 2.4). There were no significant differences in biliary leakage (1.7 % vs. 4.7 %), postoperative cholangitis (5.0 % vs. 5.8 %), incision infection (3.3 % vs. 3.5 %), and bile duct stone residue rate (5.0 % vs 3.5 %) between the two groups. There was no severe pancreatitis, second operation or death. The duration of hospital stay was shortened in the concurrent operation group (5.1 ± 2.3d vs 7.9 ± 3.7d), and the operation cost was significantly higher than that in the LCBDE group (48839.9 ± 8549.5 vs 34635.9 ± 5893.7 yuan). Conclusion: ERCP combined with LC and LCBDE are both safe and effective methods for the treatment of cholecystolithiasis combined with extrahepatic bile duct stones. The simultaneous operation group has certain advantages in patient comfort and rapid rehabilitation, which can be popularized in qualified units.

Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice.

Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8+ T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, D-serine interacted with WDR24 and inhibited mTORC1 activation in CD8+ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8+ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.

Cryptic diversity and rampant hybridization in annual gentians on the Qinghai-Tibet Plateau revealed by population genomic analysis.

Understanding the evolutionary and ecological processes involved in population differentiation and speciation provides critical insights into biodiversity formation. In this study, we employed 29,865 single nucleotide polymorphisms (SNPs) and complete plastomes to examine genomic divergence and hybridization in Gentiana aristata, which is endemic to the Qinghai-Tibet Plateau (QTP) region. Genetic clustering revealed that G. aristata is characterized by geographic genetic structures with five clusters (West, East, Central, South and North). The West cluster has a specific morphological character (i.e., blue corolla) and higher values of FST compared to the remaining clusters, likely the result of the geological barrier formed by the Yangtze River. The West cluster diverged from the other clusters in the Early Pliocene; these remaining clusters diverged from one another in the Early Quaternary. Phylogenetic reconstructions based on SNPs and plastid data revealed substantial cyto-nuclear conflicts. Genetic clustering and D-statistics demonstrated rampant hybridization between the Central and North clusters, along the Bayankala Mountains, which form the geological barrier between the Central and North clusters. Species distribution modeling demonstrated the range of G. aristata expanded since the Last Interglacial period. Our findings provide genetic and morphological evidence of cryptic diversity in G. aristata, and identified rampant hybridization between genetic clusters along a geological barrier. These findings suggest that geological barriers and climatic fluctuations have an important role in triggering diversification as well as hybridization, indicating that cryptic diversity and hybridization are essential factors in biodiversity formation within the QTP region.

No genetic causal association between iron status and pulmonary artery hypertension: Insights from a two-sample Mendelian randomization.

To explore the genetic causal association between pulmonary artery hypertension (PAH) and iron status through Mendelian randomization (MR), we conducted MR analysis using publicly available genome-wide association study (GWAS) summary data. Five indicators related to iron status (serum iron, ferritin, total iron binding capacity (TIBC), soluble transferrin receptor (sTfR), and transferrin saturation) served as exposures, while PAH was the outcome. The genetic causal association between these iron status indicators and PAH was assessed using the inverse variance weighted (IVW) method. Cochran's Q statistic was employed to evaluate heterogeneity. We assessed pleiotropy using MR-Egger regression and MR-Presso test. Additionally, we validated our results using the Weighted median, Simple mode, and Weighted mode methods. Based on the IVW method, we found no causal association between iron status (serum iron, ferritin, TIBC, sTfR, and transferrin saturation) and PAH (p ß > 0.05). The Weighted median, Simple mode, and Weighted mode methods showed no potential genetic causal association (p ß > 0.05 in the three analyses). Additionally, no heterogeneity or horizontal pleiotropy was detected in any of the analyses. Our results show that there are no genetic causal association between iron status and PAH.

SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.

A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.

A new simplified sequence-dependent loop-mediated isothermal amplification (LAMP) detection method.

Fluorescence dye-based loop-mediated isothermal amplification (LAMP) is a sensitive nucleic acid detection method, but is limited to single-plex detection and may yield non-specific signals. In this study, we propose a bifunctional probe-based real-time LAMP amplification method for single-plexed or multiplexed detection. The bifunctional probe is derived by modifying the 5' end of the fluorophore and an internal quencher on one of the LAMP primers; therefore, it can simultaneously be involved in the LAMP process and signal amplification. The fluorescence intensity undergoes a cumulative exponential increase during the incorporation of the bifunctional probe into double-stranded DNA amplicons. The bifunctional probe-based LAMP method is simplified and cost-effective, as the primer design and experimental operations align entirely with the ordinary LAMP. Different from other current probe-based methods, this method does not require additional enzymes, sequences, or special probe structures. Also, it is 10 min faster than several other probe-based LAMP methods. The bifunctional probe-based LAMP method allows the simultaneous detection of the target Vibrio parahaemolyticus DNA and the internal amplification control in a one-pot reaction, demonstrating its potential for multiplexed detection.

Glial and glioneuronal tumors: Navigating the complexity of evolving concepts and new classification.

The World Health Organization (WHO) published the 5th edition classification of tumors of central nervous system in 2021, commonly abbreviated as WHO CNS5, which became the new standard for brain tumor diagnosis and therapy. This edition dramatically impacted tumor diagnostics. In short it introduced new tumors, changed the names of previously recognized tumors, and modified the working definition of previously known tumors. The new system appears complex due to the integration of morphological and multiple molecular criteria. The most radical changes occurred in the field of glial and glioneuronal tumors, which constitutes the lengthy first chapter of this new edition. Herein we present an illustrative outline of the evolving concepts of glial and glioneuronal tumors. We also attempt to explain the rationales behind this substantial change in tumor classification and the challenges to update and integrate it into clinical practice. We aim to present a concise and precise roadmap to aid navigation through the intricate conceptual framework of glial and glioneuronal tumors in the context of WHO CNS5.

Development of a Menglà virus minigenome and comparison of its polymerase complexes those of other filoviruses.

Ebola virus (EBOV) and Marburg virus (MARV), members of the Filoviridae family, are highly pathogenic and can cause hemorrhagic fevers, significantly impacting human society. Bats are considered reservoirs of these viruses because related filoviruses have been discovered in bats. However, due to requirement for maximum containment laboratories when studying infectious virus, the characterization of bat filoviruses often relies on pseudoviruses and minigenome systems. In this study, we used RACE technology to sequence the 3'-leader and 5'-trailer of MLAV and constructed a minigenome. Similar to MARV, the transcription activities of the MLAV minigenome are independent of VP30. We further assessed the effects of polymorphisms at the 5' end on MLAV minigenome activity and identified certain mutations that decrease minigenome reporter efficiency, probably due to alterations in the RNA secondary structure. The reporter activity upon recombination of the 3'-leaders and 5'-trailers of MLAV, MARV, and EBOV with those of the homologous or heterologous minigenomes was compared and it was found that the polymerase complex and leader and trailer sequences exhibit intrinsic specificities. Additionally, we investigated whether the polymerase complex proteins from EBOV and MARV support MLAV minigenome RNA synthesis and found that the homologous system is more efficient than the heterologous system. Remdesivir efficiently inhibited MLAV as well as EBOV replication. In summary, this study provided new information about bat filoviruses and the minigenome will be a useful tool for high-throughput antiviral drug screening.

A potent Henipavirus cross-neutralizing antibody reveals a dynamic fusion-triggering pattern of the G-tetramer.

The Hendra and Nipah viruses (HNVs) are highly pathogenic pathogens without approved interventions for human use. In addition, the interaction pattern between the attachment (G) and fusion (F) glycoproteins required for virus entry remains unclear. Here, we isolate a panel of Macaca-derived G-specific antibodies that cross-neutralize HNVs via multiple mechanisms. The most potent antibody, 1E5, confers adequate protection against the Nipah virus challenge in female hamsters. Crystallography demonstrates that 1E5 has a highly similar binding pattern to the receptor. In cryo-electron microscopy studies, the tendency of 1E5 to bind to the upper or lower heads results in two distinct quaternary structures of G. Furthermore, we identify the extended outer loop ß1S2-ß1S3 of G and two pockets on the apical region of fusion (F) glycoprotein as the essential sites for G-F interactions. This work highlights promising drug candidates against HNVs and contributes deeper insights into the viruses.

Dipole Moment Influences the Reversibility and Corrosion of Lithium Metal Anodes.

Lithium metal batteries (LMBs) must have both long cycle life and calendar life to be commercially viable. However, "trial and error" methodologies remain prevalent in contemporary research endeavors to identify favorable electrolytes. Here, a guiding principle for the selection of solvents for LMBs is proposed, which aims to achieve high Coulombic efficiency while minimizing the corrosion. For the first time, this study reveals that the dipole moment and orientation of solvent molecules have significant impacts on lithium metal reversibility and corrosion. Solvents with high dipole moments are more likely to adsorb onto lithium metal surfaces, which also influence the solid electrolyte interphase. Using this principle, the use of LiNO3 is demonstrated as the sole salt in LiNi0.8Co0.1Mn0.1O2/Li cells can achieve excellent cycling stability. Overall, this work bridges the molecular structure of solvents to the reversibility and corrosion of lithium metal, and these concepts can be extended to other metal-based batteries.

Realization of fractional quantum Hall state with interacting photons.

Fractional quantum Hall (FQH) states are known for their robust topological order and possess properties that are appealing for applications in fault-tolerant quantum computing. An engineered quantum platform would provide opportunities to operate FQH states without an external magnetic field and enhance local and coherent manipulation of these exotic states. We demonstrate a lattice version of photon FQH states using a programmable on-chip platform based on photon blockade and engineering gauge fields on a two-dimensional circuit quantum electrodynamics system. We observe the effective photon Lorentz force and butterfly spectrum in the artificial gauge field, a prerequisite for FQH states. After adiabatic assembly of Laughlin FQH wave function of 1/2 filling factor from localized photons, we observe strong density correlation and chiral topological flow among the FQH photons. We then verify the unique features of FQH states in response to external fields, including the incompressibility of generating quasiparticles and the smoking-gun signature of fractional quantum Hall conductivity. Our work illustrates a route to the creation and manipulation of novel strongly correlated topological quantum matter composed of photons and opens up possibilities for fault-tolerant quantum information devices.

A comprehensive review of miR-21 in liver disease: Big impact of little things.

microRNAs (miRNAs), a class of non-coding RNA with 20-24 nucleotides, are defined as the powerful regulators for gene expression. miR-21 is a multifunctional miRNA enriched in the circulatory system and multiple organs, which not only serves as a non-invasive biomarker in disease diagnosis, but also participates in many cellular activities. In various chronic liver diseases, the increase of miR-21 affects glycolipid metabolism, viral infection, inflammatory and immune cell activation, hepatic stellate cells activation and tissue fibrosis, and autophagy. Moreover, miR-21 is also a liaison in the deterioration of chronic liver disease to hepatocellular carcinoma (HCC), and it impacts on cell proliferation, apoptosis, migration, invasion, angiogenesis, immune escape, and epithelial-mesenchymal transformation by regulating target genes expression in different signaling pathways. In current research on miRNA therapy, some natural products can exert the hepatoprotective effects depending on the inhibition of miR-21 expression. In addition, miR-21-based therapeutic also play a role in regulating intracellular miR-21 levels and enhancing the efficacy of chemotherapy drugs. Herein, we systemically summarized the recent progress of miR-21 on biosynthesis, biomarker function, molecular mechanism and miRNA therapy in chronic liver disease and HCC, and looked forward to outputting some information to enable it from bench to bedside.

Improvement in Tol2 transposon for efficient large-cargo capacity transgene applications in cultured cells and zebrafish ( Danio rerio).

Most viruses and transposons serve as effective carriers for the introduction of foreign DNA up to 11 kb into vertebrate genomes. However, their activity markedly diminishes with payloads exceeding 11 kb. Expanding the payload capacity of transposons could facilitate more sophisticated cargo designs, improving the regulation of expression and minimizing mutagenic risks associated with molecular therapeutics, metabolic engineering, and transgenic animal production. In this study, we improved the Tol2 transposon by increasing protein expression levels using a translational enhancer ( QBI SP163, ST) and enhanced the nuclear targeting ability using the nuclear localization protein H2B (SHT). The modified Tol2 and ST transposon efficiently integrated large DNA cargos into human cell cultures (H1299), comparable to the well-established super PiggyBac system. Furthermore, mRNA from ST and SHT showed a significant increase in transgene delivery efficiency of large DNA payloads (8 kb, 14 kb, and 24 kb) into zebrafish ( Danio rerio). This study presents a modified Tol2 transposon as an enhanced nonviral vector for the delivery of large DNA payloads in transgenic applications.

Sustainable thermal regulation improves stability and efficiency in all-perovskite tandem solar cells.

Mixed Sn-Pb perovskites have emerged as promising photovoltaic materials for both single- and multi-junction solar cells. However, achieving their scale-up and practical application requires further enhancement in stability. We identify that their poor thermal conductivity results in insufficient thermal transfer, leading to heat accumulation within the absorber layer that accelerates thermal degradation. A thermal regulation strategy by incorporating carboranes into perovskites is developed; these are electron-delocalized carbon-boron molecules known for their efficient heat transfer capability. We specifically select ortho-carborane due to its low thermal hysteresis. We observe its existence through the perovskite layer showing a decreasing trend from the buried interface to the top surface, effectively transferring heat and lowering the surface temperature by around 5 °C under illumination. o-CB also facilitates hole extraction at the perovskite/PEDOT:PSS interface and reduces charge recombination. These enable mixed Sn-Pb cells to exhibit improved thermal stability, retaining 80% of their initial efficiencies after aging at 85 °C for 1080 hours. When integrated into monolithic all-perovskite tandems, we achieve efficiencies of over 27%. A tandem cell maintains 87% of its initial PCE after 704 h of continuous operation under illumination.

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis.

Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-ß (TGF-ß)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.

Rapid, on-site quantitative determination of mycotoxins in grains using a multiple time-resolved fluorescent microsphere immunochromatographic test strip.

The label probe plays a crucial role in enhancing the sensitivity of lateral flow immunoassays. However, conventional fluorescent microspheres (FMs) have limitations due to their short fluorescence lifetime, susceptibility to background fluorescence interference, and inability to facilitate multi-component detection. In this study, carboxylate-modified Eu(III)-chelate-doped polystyrene nanobeads were employed as label probes to construct a multiple time-resolved fluorescent microsphere-based immunochromatographic test strip (TRFM-ICTS). This novel TRFM-ICTS facilitated rapid on-site quantitative detection of three mycotoxins in grains: Aflatoxin B1 (AFB1), Zearalenone (ZEN), and Deoxynivalenol (DON). The limit of detection (LOD) for AFB1, ZEN, and DON were found to be 0.03 ng/g, 0.11 ng/g, and 0.81 ng/g, respectively. Furthermore, the TRFM-ICTS demonstrated a wide detection range for AFB1 (0.05-8.1 ng/g), ZEN (0.125-25 ng/g), and DON (1.0-234 ng/g), while maintaining excellent selectivity. Notably, the test strip exhibited remarkable stability, retaining its detection capability even after storage at 4 °C for over one year. Importantly, the detection of these mycotoxins relied solely on simple manual operations, and with a portable reader, on-site detection could be accomplished within 20 min. This TRFM-ICTS presents a promising solution for sensitive on-site mycotoxin detection, suitable for practical application in various settings due to its sensitivity, accuracy, simplicity, and portability.

Gender Impacted Gut Microbiota and Growth Performance in the Blotched Snakehead (Channa maculata).

The blotched snakehead Channa maculata is an important economical freshwater species in East Asia. However, there has been relatively little research conducted on the correlation between gender and gut microbes. In this study, 36 of 1000 blotched snakeheads were randomly selected for growth performance measurement and gut microbiota high-throughput sequencing. Results showed that microbial diversity, composition, and metabolic functions were altered by gender and growth performance except the microbial network. In our study, Proteobacteria were the most abundant phylum, with Fusobacteria showing enrichment in males and Bacteroidetes in females. Notably, phylum Deinococcus-Thermus was identified as a significant biomarker. The Cetobacterium was the most abundant genus-level taxon. Furthermore, gut microbes specializing in the production of gut-healthy substances, such as coenzymes and vitamins, were identified as biomarkers in the fast-growing group. Our investigation highlighted the impact of gender on the composition and abundance of gut microbial biomarkers in both males and females, thereby influencing differential growth performance through the modulation of specific metabolic functions.

Engineered endolysin of Klebsiella pneumoniae phage is a potent and broad-spectrum bactericidal agent against "ESKAPEE" pathogens.

The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins' bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively.