Prognosis prediction models for post-stroke depression: a protocol for systematic review, meta-analysis, and critical appraisal.

INTRODUCTION: Post-stroke depression (PSD) is a prevalent complication that has been shown to have a negative impact on rehabilitation outcomes and quality of life and poses a significant risk for suicidal intention. However, models for discriminating and predicting PSD in stroke survivors for effective secondary prevention strategies are inadequate as the pathogenesis of PSD remains unknown. Prognostic prediction models that exhibit greater rule-in capacity have the potential to mitigate the issue of underdiagnosis and undertreatment of PSD. Thus, the planned study aims to systematically review and critically evaluate published studies on prognostic prediction models for PSD. METHODS AND ANALYSIS: A systematic literature search will be conducted in PubMed and Embase through Ovid. Two reviewers will complete study screening, data extraction, and quality assessment utilizing appropriate tools. Qualitative data on the characteristics of the included studies, methodological quality, and the appraisal of the clinical applicability of models will be summarized in the form of narrative comments and tables or figures. The predictive performance of the same model involving multiple studies will be synthesized with a random effects meta-analysis model or meta-regression, taking into account heterogeneity. ETHICS AND DISSEMINATION: Ethical approval is considered not applicable for this systematic review. Findings will be shared through dissemination at academic conferences and/or publication in peer-reviewed academic journals. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023388548.

NR1D1-transactivated lncRNA NUTM2A-AS1 promotes chemoresistance and immune evasion in neuroblastoma via inhibiting B7-H3 degradation.

Neuroblastoma (NB), a common solid tumour in young children originating from the sympathetic nervous system during embryonic development, poses challenges despite therapeutic advances like high-dose chemotherapy and immunotherapy. Some survivors still grapple with severe side effects and drug resistance. The role of lncRNA NUTM2A-AS1 has been explored in various cancers, but its function in drug-resistant NB progression is unclear. Our study found that NUTM2A-AS1 expression in cisplatin-resistant NB cells increased in a time- and dose-dependent manner. Knockdown of NUTM2A-AS1 significantly improved NB cell sensitivity to cisplatin and inhibited metastatic abilities. Additionally, we identified B7-H3, an immune checkpoint-related protein, as a NUTM2A-AS1-associated protein in NB cells. NUTM2A-AS1 was shown to inhibit the protein degradation of B7-H3. Moreover, NUTM2A-AS1 modulated immune evasion in cisplatin-resistant NB cells through B7-H3. Furthermore, NUTM2A-AS1 expression in cisplatin-resistant NB cells was transactivated by NR1D1. In summary, our results unveil the molecular or biological relationship within the NR1D1/NUTM2A-AS1/B7-H3 axis in NB cells under cisplatin treatment, providing an intriguing avenue for fundamental research into cisplatin-resistant NB.

Retroperitoneal Laparoscopic Debridement and Drainage for Pancreatic Abscess.

In patients with severe necrotizing pancreatitis, pancreatic necrosis and secondary infection of surrounding tissues can quickly spread to the whole retroperitoneal space. Treatment of pancreatic abscess complicating necrotizing pancreatitis is difficult and has a high mortality rate. The well-accepted treatment strategy is early debridement of necrotic tissues, drainage, and postoperative continuous retroperitoneal lavage. However, traditional open surgery has several disadvantages, such as severe trauma, interference with abdominal organs, a high rate of postoperative infection and adhesion, and hardness with repeated debridement. The retroperitoneal laparoscopic approach has the advantages of minimal invasion, a better drainage route, convenient repeated debridement, and avoidance of the spread of retroperitoneal infection to the abdominal cavity. In addition, retroperitoneal drainage leads to fewer drainage tube problems, including miscounting, displacement, or siphon. The debridement and drainage of pancreatic abscess tissue via the retroperitoneal laparoscopic approach plays an increasingly irreplaceable role in improving patient prognosis and saving healthcare resources and costs. The main procedures described here include laying the patient on the right side, raising the lumbar bridge and then arranging the trocar; establishing the pneumoperitoneum and cleaning the pararenal fat tissues; opening the lateral pyramidal fascia and the perirenal fascia outside the peritoneal reflections; opening the anterior renal fascia and entering the anterior pararenal space from the rear; clearing the necrotic tissue and accumulating fluid; and placing drainage tubes and performing postoperative continuous retroperitoneal lavage.

Relationships between rumination and different types of rapid eye movement sleep in patients with chronic insomnia disorder.

BACKGROUND AND OBJECTIVE: Rumination, a common factor of chronic insomnia disorder (CID) caused by cognitive-emotional arousal, is associated with an increased amount of rapid eye movement (REM) sleep. However, the specific subtypes, such as phasic REM and tonic REM, that contribute to the increased REM sleep have not been reported. This study aimed to determine the association between rumination and different REM sleep subtypes in patients with CID. METHODS: This study enrolled 35 patients with CID and 27 age- and sex-matched healthy controls. The Immersion-Rumination Questionnaire evaluated participants' rumination, and the Insomnia Severity Index was used to assess insomnia severity. Finally, polysomnography was used to monitor objective sleep quality and quantification of different types of REM. RESULTS: The CID patients had higher rumination scores than the healthy controls. They had a shorter REM sleep duration, less phasic REM, a lower percentage of phasic REM time, and a higher percentage of tonic REM time. Spectral analysis revealed that the patients affected by insomnia had higher ß power during REM sleep, higher ß and σ power during phasic REM sleep, and higher ß, and γ power during tonic REM sleep. Partial correlation analysis showed that rumination in the CID patients correlated negatively with the duration of phasic REM sleep. Additionally, rumination correlated negatively with δ power in REM sleep and positively with ß power in REM sleep, tonic REM sleep, phasic REM sleep, N3and N2 sleep in the patients with CID. CONCLUSION: The CID patients had stronger rumination, reduced total and phasic REM sleep, and the stronger rumination was, the shorter phasic REM was and the higher fast (ß) wave power in REM sleep.

Argyrodite-Li6PS5Cl/Polymer-based Highly Conductive Composite Electrolyte for All-Solid-State Batteries.

Solid-state batteries (SSBs) that incorporate the argyrodite-Li6PS5Cl (LPSCl) electrolyte hold potential as substitutes for conventional lithium-ion batteries (LIBs). However, the mismatched interface between the LPSCl electrolyte and electrodes leads to increased interfacial resistance and the rapid growth of lithium (Li) dendrites. These factors significantly impede the feasibility of their widespread industrial application. In this study, we developed a composite electrolyte of the LPSCl/polymer to enhance the contact between the electrolyte and electrodes and suppress dendrite formation at the grain boundary of the LPSCl ceramic. The monomer, triethylene glycol dimethacrylate (TEGDMA), is utilized for in situ polymerization through thermal curing to create the argyrodite LPSCl/polymer composite electrolyte. Additionally, the ball-milling technique was employed to modify the morphology and particle size of the LPSCl ceramic. The ball-milled LPSCl/polymer composite electrolyte demonstrates slightly higher ionic conductivity (ca. 2.21 × 10-4 S/cm) compared to the as-received LPSCl/polymer composite electrolyte (ca. 1.65 × 10-4 S/cm) at 25 °C. Furthermore, both composite electrolytes exhibit excellent compatibility with Li-metal and display cycling stability for up to 1000 h (375 cycles), whereas the as-received LPSCl and ball-milled LPSCl electrolytes maintain stability for up to 600 h (225 cycles) at a current density of 0.4 mA/cm2. The SSB with the ball-milled LPSCl/polymer composite electrolyte delivers high specific discharge capacity (138 mA h/g), Coulombic efficiency (99.97%), and better capacity retention at 0.1C, utilizing the battery configuration of coated NMC811//electrolyte//Li-Indium (In) at 25 °C.

Degraders in epigenetic therapy: PROTACs and beyond.

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.

Advanced lung cancer inflammation index predicts overall survival of hepatocellular carcinoma after hepatectomy.

Aim: Limited data are available regarding ALI's clinical relevance and prognostic value in patients with hepatocellular carcinoma (HCC) after hepatectomy. Materials and methods: HCC patients who received hepatectomy at the Meizhou People's Hospital from May 2011 to February 2022 were enrolled in the study cohort. The ALI was calculated as follows: ALI = BMI (kg/m2) × ALB (g/dL)/(absolute neutrophil count/absolute lymphocyte count). The primary outcome was overall survival (OS). The secondary outcome was cancer-specific survival (CSS). Univariate and multivariate Cox regression analyses were performed, followed by nomogram construction and decision curve analysis (DCA). Results: 425 HCC patients were enrolled for analyses. Lower preoperative ALI was significantly correlated with incomplete tumor capsule and advanced tumor stage. Lower preoperative ALI was an adverse independent prognostic factor for OS (HR: 1.512, 95% CI: 1.122-2.039, P 0.007) and CSS (HR: 1.754, 95% CI: 1.262-2.438, P <0.001) in HCC patients. The nomogram plot was built based on three (including age, TNM stage, and ALI) and two (including TNM stage and ALI) independent prognostic factors for OS and CSS, respectively. Further analyses indicated that the nomogram had better predictive value and some net benefit than the traditional TNM stage alone, especially in long-term OS. Conclusions: Our study further indicated that ALI could be a prognostic marker for OS and CSS in HCC patients after hepatectomy, especially in long-term OS.

Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma.

Patients with hepatocellular carcinoma (HCC) are vulnerable to drug resistance. Although drug resistance has been taken much attention to HCC therapy, little is known of regorafenib and regorafenib resistance (RR). This study aimed to determine the drug resistance pattern and the role of RhoA in RR. Two regorafenib-resistant cell lines were constructed based on Huh7 and Hep3B cell lines. In vitro and in vivo assays were conducted to study RhoA expression, the activity of Hippo signaling pathway and cancer stem cell (CSC) traits. The data showed that RhoA was highly expressed, Hippo signaling was hypoactivated and CSC traits were more prominent in RR cells. Inhibiting RhoA could reverse RR, and the alliance of RhoA inhibition and regorafenib synergistically attenuated CSC phenotype. Furthermore, inhibiting LARG/RhoA increased Kibra/NF2 complex formation, prevented YAP from shuttling into the nucleus and repressed CD44 mRNA expression. Clinically, the high expression of RhoA correlated with poor prognosis. LARG, RhoA, YAP1 and CD44 show positive correlation with each other. Thus, inhibition of RhoGEF/RhoA has the potential to reverse RR and repress CSC phenotype in HCC.

An enriched environment ameliorates maternal sleep deprivation-induced cognitive impairment in aged mice by improving mitochondrial function via the Sirt1/PGC-1α pathway.

BACKGROUND: Early life stress can cause cognitive impairment in aged offspring. Environmental enrichment (EE) is considered to be an effective non-pharmacological treatment for improving cognitive decline. The aim of this research was to evaluate the effect of EE, on cognitive impairment in aged offspring induced by maternal sleep deprivation (MSD) and the underlying mechanisms involved to investigate its potential value in clinical practice. METHODS: CD-1 damns were subjected or not to sleep deprivation during late gestation. Twenty-one days after birth, the offspring were assigned to standard or EE cages. At 18 months-old, the learning and memory function of the offspring mice was evaluated using Morris water maze. The hippocampal and prefrontal cortical levels of protein, gene, proinflammation cytokines, and oxidative stress indicators was examined by Western blot, real-time polymerase chain reaction, enzyme linked immunosorbent assay, and biochemical assays. RESULTS: Offspring in MSD group exhibited declined learning and memory abilities compared with control animals. Moreover, the hippocampal and prefrontal cortical levels of Sirtuin1 (Sirt1), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), postsynaptic density protein-95, and synaptophysin were lower and those of proinflammation cytokines higher in the MSD group; meanwhile, the superoxide dismutase content was higher and the malondialdehyde and reactive oxygen species contents were lower. However, these deleterious changes were ameliorated by exposure to EE. CONCLUSIONS: EE attenuates MSD-induced cognitive impairment, oxidative stress, and neuroinflammation and reverses the reduction in synaptic protein levels in aged offspring mice via the Sirt1/PGC-1α pathway.

Dual-targets fluorescent nanoprobe for precise subtyping of lung cancer.

A Au-Se bond-based nanoprobe using 3',3-diselenopropionic acid to simultaneously link response chains for Pro-GRP protein and Cyfra21-1 was developed. Early diagnosis and subtyping of lung cancer can be achieved based on the nanoprobes' differential response of the probes to the two targets in lung cancer patients' serum.

Trimethylamine N-oxide aggravates vascular permeability and endothelial cell dysfunction under diabetic condition: in vitro and in vivo study.

AIM: To provide the direct evidence for the crucial role of trimethylamine N-oxide (TMAO) in vascular permeability and endothelial cell dysfunction under diabetic condition. METHODS: The role of TMAO on the in vitro biological effect of human retinal microvascular endothelial cells (HRMEC) under high glucose conditions was tested by a cell counting kit, wound healing, a transwell and a tube formation assay. The inflammation-related gene expression affected by TMAO was tested by real-time polymerase chain reaction (RT-PCR). The expression of the cell junction was measured by Western blotting (WB) and immunofluorescence staining. In addition, two groups of rat models, diabetic and non-diabetic, were fed with normal or 0.1% TMAO for 16wk, and their plasma levels of TMAO, vascular endothelial growth factor (VEGF), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were tested. The vascular permeability of rat retinas was measured using FITC-Dextran, and the expression of zonula occludens (ZO)-1 and claudin-5 in rat retinas was detected by WB or immunofluorescence staining. RESULTS: TMAO administration significantly increased the cell proliferation, migration, and tube formation of primary HRMEC either in normal or high-glucose conditions. RT-PCR showed elevated inflammation-related gene expression of HRMEC under TMAO stimulation, while WB or immunofluorescence staining indicated decreased cell junction ZO-1 and occludin expression after high-glucose and TMAO treatment. Diabetic rats showed higher plasma levels of TMAO as well as retinal vascular leakage, which were even higher in TMAO-feeding diabetic rats. Furthermore, TMAO administration increased the rat plasma levels of VEGF, IL-6 and TNF-α while decreasing the retinal expression levels of ZO-1 and claudin-5. CONCLUSION: TMAO enhances the proliferation, migration, and tube formation of HRMEC, as well as destroys their vascular integrity and tight connection. It also regulates the expression of VEGF, IL-6, and TNF-α.

Prognostic impact and immunotherapeutic implications of NETosis-related gene signature in gastric cancer patients.

The role of NETosis and its related molecules remains unclear in gastric cancer. The data used in this study was directly downloaded from the Cancer Genome Atlas (TCGA) database. All analysis and plots are completed in R software using diverse R packages. In our study, we collected the list of NETosis-related genes from previous publications. Based on the list and expression profile of gastric cancer patients from the TCGA database, we identified the NETosis-related genes significantly correlated with patients survival. Then, CLEC6A, BST1 and TLR7 were identified through LASSO regression and multivariate Cox regression analysis for prognosis model construction. This prognosis model showed great predictive efficiency in both training and validation cohorts. We noticed that the high-risk patients might have a worse survival performance. Next, we explored the biological enrichment difference between high- and low-risk patients and found that many carcinogenic pathways were upregulated in the high-risk patients. Meanwhile, we investigated the genomic instability, mutation burden and immune microenvironment difference between high- and low-risk patients. Moreover, we noticed that low-risk patients were more sensitive to immunotherapy (85.95% vs. 56.22%). High-risk patients were more sensitive to some small molecules compounds like camptothecin_1003, cisplatin_1005, cytarabine_1006, nutlin-3a (-)_1047, gemcitabine_1190, WZ4003_1614, selumetinib_1736 and mitoxantrone_1810. In summary, our study comprehensively explored the role of NETosis-related genes in gastric cancer, which can provide direction for relevant studies.

Examining and prioritizing the effect of sustainable energy on the job market to advance China's green workforce.

China, the world's greatest emitter of greenhouse gases, has committed to reaching peak carbon dioxide emissions by 2030 and carbon neutrality by 2060. One strategy to accomplish this aim is switching to a low-carbon economy via advancing renewable energy (RE) projects. Therefore, this study focuses on solar, wind, biomass, and hydropower and examines the beneficial employment effects of RE projects in China. The study uses fuzzy-based Multi-Criteria Decision Making (MCDM) methodologies, such as the Analytical Hierarchy Process (AHP) and Weighted Aggregated Sum Product Assessment (WASPAS), to evaluate numerous employment effect criteria and sub-criteria. Based on these evaluations, the report prioritizes four main types of RE projects. According to the fuzzy AHP technique results, direct employment, skill requirements, and local employment are the most crucial employment effect factors. The study then employed the fuzzy WASPAS approach to assessing various RE initiatives' employment prospects. According to the findings, hydropower is the best choice for creating jobs, followed by wind and solar power initiatives. In recent years, the hydro, wind, and solar power industries have experienced rapid expansion, creating numerous job possibilities in production, installation, operation, and maintenance. Additionally, creating RE projects can boost regional economic growth and lessen poverty.

Single-cell and spatial architecture of primary liver cancer.

Primary liver cancer (PLC) poses a leading threat to human health, and its treatment options are limited. Meanwhile, the investigation of homogeneity and heterogeneity among PLCs remains challenging. Here, using single-cell RNA sequencing, spatial transcriptomic and bulk multi-omics, we elaborated a molecular architecture of 3 PLC types, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). Taking a high-resolution perspective, our observations revealed that CHC cells exhibit internally discordant phenotypes, whereas ICC and HCC exhibit distinct tumor-specific features. Specifically, ICC was found to be the primary source of cancer-associated fibroblasts, while HCC exhibited disrupted metabolism and greater individual heterogeneity of T cells. We further revealed a diversity of intermediate-state cells residing in the tumor-peritumor junctional zone, including a congregation of CPE+ intermediate-state endothelial cells (ECs), which harbored the molecular characteristics of tumor-associated ECs and normal ECs. This architecture offers insights into molecular characteristics of PLC microenvironment, and hints that the tumor-peritumor junctional zone could serve as a targeted region for precise therapeutical strategies.

Biochemical and molecular characterization of a novel glycerol dehydratase from Klebsiella pneumoniae 2e with high tolerance against crude glycerol impurities.

BACKGROUND: The direct bioconversion of crude glycerol, a byproduct of biodiesel production, into 1,3-propanediol by microbial fermentation constitutes a remarkably promising value-added applications. However, the low activity of glycerol dehydratase, which is the key and rate-limiting enzyme in the 1,3-propanediol synthetic pathway, caused by crude glycerol impurities is one of the main factors affecting the 1,3-propanediol yield. Hence, the exploration of glycerol dehydratase resources suitable for crude glycerol bioconversion is required for the development of 1,3-propanediol-producing engineered strains. RESULTS: In this study, the novel glycerol dehydratase 2eGDHt, which has a tolerance against crude glycerol impurities from Klebsiella pneumoniae 2e, was characterized. The 2eGDHt exhibited the highest activity toward glycerol, with Km and Vm values of 3.42 mM and 58.15 nkat mg-1, respectively. The optimum pH and temperature for 2eGDHt were 7.0 and 37 °C, respectively. 2eGDHt displayed broader pH stability than other reported glycerol dehydratases. Its enzymatic activity was increased by Fe2+ and Tween-20, with 294% and 290% relative activities, respectively. The presence of various concentrations of the crude glycerol impurities, including NaCl, methanol, oleic acid, and linoleic acid, showed limited impact on the 2eGDHt activity. In addition, the enzyme activity was almost unaffected by the presence of an impurity mixture that mimicked the crude glycerol environment. Structural analyses revealed that 2eGDHt possesses more coil structures than reported glycerol dehydratases. Moreover, molecular dynamics simulations and site-directed mutagenesis analyses implied that the existence of unique Val744 from one of the increased coil regions played a key role in the tolerance characteristic by increasing the protein flexibility. CONCLUSIONS: This study provides insight into the mechanism for enzymatic action and the tolerance against crude glycerol impurities, of a novel glycerol dehydratase 2eGDHt, which is a promising glycerol dehydratase candidate for biotechnological conversion of crude glycerol into 1,3-PDO.

Improved mammalian family phylogeny using gap-rare multiple sequence alignment: A timetree of extant placentals and marsupials.

The timing of mammalian diversification in relation to the Cretaceous-Paleogene (KPg) mass extinction continues to be a subject of substantial debate. Previous studies have either focused on limited taxonomic samples with available whole-genome data or relied on short sequence alignments coupled with extensive species samples. In the present study, we improved an existing dataset from the landmark study of Meredith et al. (2011) by filling in missing fragments and further generated another dataset containing 120 taxa and 98 exonic markers. Using these two datasets, we then constructed phylogenies for extant mammalian families, providing improved resolution of many conflicting relationships. Moreover, the timetrees generated, which were calibrated using appropriate molecular clock models and multiple fossil records, indicated that the interordinal diversification of placental mammals initiated before the Late Cretaceous period. Additionally, intraordinal diversification of both extant placental and marsupial lineages accelerated after the KPg boundary, supporting the hypothesis that the availability of numerous vacant ecological niches subsequent to the mass extinction event facilitated rapid diversification. Thus, our results support a scenario of placental radiation characterized by both basal cladogenesis and active interordinal divergences spanning from the Late Cretaceous into the Paleogene.

Acetylated rice starch nanocrystals improved the physical, mechanical, and structural properties of native rice starch based films.

Rice starch nanocrystals (SNC) and acetylated rice starch nanocrystals (ASNC) with three different substitution degrees (DS) for 0.22 (ASNCa), 0.56 (ASNCb), and 0.83 (ASNCc), respectively, were synthesized. Starch nanocrystals (SNC, ASNCa, ASNCb and ASNCc) with varying concentrations (0-25 %) were used in the production of composite rice starch-based films plasticized with glycerol using the solvent casting technique. Films were compared concerning their morphology, moisture content and solubility, transmittance, tensile strength, elongation at break. The SNC and ASNC content and acetylated DS had a significant effect (p ≤ 0.05) on all the properties investigated when compared to the control film. The addition of ASNC resulted in less hydrophilic films and UV light barrier properties, and the addition of SNC and ASNC increased the rigidity of starch film. There was an increase of 156.7 % in tensile strength for 10 % ASNCc composite films and a reduction of 68.1 % in water vapor permeability for 20 % ASNCc composite films. The rice starch/ASNCb nanocomposite films with the addition of 5 % and 10 % ASNCb exhibited a compact, smooth, and flat surface structure. Therefore, these results showed that ASNC significantly improved the mechanical properties, surface morphology and thermal stability of the films.

China Medicinal Plants of the Ampelopsis grossedentata-A Review of Their Botanical Characteristics, Use, Phytochemistry, Active Pharmacological Components, and Toxicology.

Ampelopsis grossedentata (AG) is mainly distributed in Chinese provinces and areas south of the Yangtze River Basin. It is mostly concentrated or scattered in mountainous bushes or woods with high humidity. Approximately 57 chemical components of AG have been identified, including flavonoids, phenols, steroids and terpenoids, volatile components, and other chemical components. In vitro studies have shown that the flavone of AG has therapeutic properties such as anti-bacteria, anti-inflammation, anti-oxidation, enhancing immunity, regulating glucose and lipid metabolism, being hepatoprotective, and being anti-tumor with no toxicity. Through searching and combing the related literature, this paper comprehensively and systematically summarizes the research progress of AG, including morphology, traditional and modern uses, chemical composition and structure, and pharmacological and toxicological effects, with a view to providing references for AG-related research.

Discovery and Characterization of an Acid-Labile Serine-Lysine Cross-Link in Antibody High-Molecular-Weight Species Using a Multipronged Mass Spectrometry Approach.

Characterizing the cross-links responsible for the covalent high-molecular-weight (HMW) species in therapeutic monoclonal antibodies (mAbs) is of great importance as it not only provides a framework for risk assessment but also offers insights for process improvement. However, owing to the complexity and low abundance, identification of novel and unknown cross-links in mAb products can be very challenging. Here, applying a multipronged MS-based approach, we report the discovery of a novel covalent cross-link formed via an imine bond between lysine and serine residues. In particular, this Ser-Lys cross-link was found to be acid-labile and can be easily overlooked by conventional LC-MS techniques operated at low pH. It is worth noting that although imine-based cross-link has been previously reported in collagen protein cross-linking, this is the first time that a Ser-Lys cross-link has been found in a mAb product that contributes to covalent HMW species formation.

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies.