Human DUS1L catalyzes dihydrouridine modification at tRNA positions 16/17, and DUS1L overexpression perturbs translation.

Human cytoplasmic tRNAs contain dihydrouridine modifications at positions 16 and 17 (D16/D17). The enzyme responsible for D16/D17 formation and its cellular roles remain elusive. Here, we identify DUS1L as the human tRNA D16/D17 writer. DUS1L knockout in the glioblastoma cell lines LNZ308 and U87 causes loss of D16/D17. D formation is reconstituted in vitro using recombinant DUS1L in the presence of NADPH or NADH. DUS1L knockout/overexpression in LNZ308 cells shows that DUS1L supports cell growth. Moreover, higher DUS1L expression in glioma patients is associated with poorer prognosis. Upon vector-mediated DUS1L overexpression in LNZ308 cells, 5' and 3' processing of precursor tRNATyr(GUA) is inhibited, resulting in a reduced mature tRNATyr(GUA) level, reduced translation of the tyrosine codons UAC and UAU, and reduced translational readthrough of the near-cognate stop codons UAA and UAG. Moreover, DUS1L overexpression increases the amounts of several D16/D17-containing tRNAs and total cellular translation. Our study identifies a human dihydrouridine writer, providing the foundation to study its roles in health and disease.

Multi-omics analysis uncovers the transcriptional regulatory mechanism of magnesium Ions in the synthesis of active ingredients in Sophora tonkinensis.

Magnesium (Mg) plays a pivotal role as an essential component of plant chlorophyll and functions as a critical coenzyme. However, research exploring the regulatory mechanisms of magnesium ions on the synthesis of secondary metabolites is still in its early stages. Sophora tonkinensis is a widely utilized medicinal plant in China, recognized for its diverse secondary metabolites with active properties. This study investigates variations in these ingredients in tissue-cultured seedlings under varying magnesium concentrations. Simultaneously, an omics data analysis was conducted on tissue-cultured seedlings subjected to treatments with magnesium and low magnesium. These comprehensive omics analyses aimed to elucidate the mechanisms through which magnesium influences active components, growth, and development. Magnesium exerts a pervasive influence on various metabolic pathways, forming an intricate network. Research findings indicate that magnesium impacts diverse metabolic processes, including the absorption of potassium and calcium, as well as photosynthetic activity. Consequently, these influences lead to discernible changes in the levels of pharmacologically active compounds and the growth and developmental status.This study is the first to employ a multi-omics data analysis in S. tonkinensis. This methodology allows us to uncover the overarching impact of metabolic networks on the levels of various active ingredients and specific phenotypes.

No Difference in Liver Damage Induced by Isocaloric Fructose or Glucose in Mice with a High-Fat Diet.

Background/Objectives: The diverse effects of fructose and glucose on the progression of metabolic dysfunction-associated steatotic liver disease remain uncertain. This study investigated the effects, in animal models, of high-fat diets (HFDs) supplemented with either glucose or fructose. Methods: Six-week-old, male C57BL/6J mice were randomly allocated to four groups: normal diet (ND), HFD, HFD supplemented with fructose (30% w/v, HFD + Fru), and HFD supplemented with glucose (initially 30%, HFD + Glu). After 24 weeks, liver and plasma samples were gathered for analysis. In addition, 39 patients with obesity undergoing bariatric surgery with wedge liver biopsy were enrolled in the clinical study. Results: The HFD + Glu group consumed more water than did the HFD and HFD + Fru groups. Thus, we reduced the glucose concentration from 30% at baseline to 15% at week 2 and 10% starting from week 6. The HFD + Fru and HFD + Glu groups had a similar average caloric intake (p = 0.463). The HFD increased hepatic steatosis, plasma lipid levels, lipogenic enzymes, steatosis-related oxidative stress, hepatic inflammation, and early-stage liver fibrosis. Supplementation with fructose or glucose exacerbated liver damage, but no significant differences were identified between the two. The expression patterns of hepatic ceramides in HFD-fed mice (with or without supplemental fructose or glucose) were similar to those observed in patients with obesity and severe hepatic steatosis or metabolic dysfunction-associated steatohepatitis. Conclusions: Fructose and glucose similarly exacerbated liver damage when added to an HFD. Ceramides may be involved in the progression of hepatic lipotoxicity.

Clinical efficacy of oXiris-continuous hemofiltration adsorption in septic shock patients: A retrospective analysis.

OBJECTIVE: This study aimed to assess the clinical impact of oXiris-continuous hemofiltration adsorption on patients with septic shock and their prognosis. DESIGN: A retrospective study. PARTICIPANTS: Septic shock patients. INTERVENTIONS: The oXiris group underwent hemofiltration adsorption using oXiris hemofilters and septic shock standard treatment, while the control group received septic shock standard treatment. MAIN VARIABLES OF INTEREST: The changes in inflammatory indicators and short-term mortality rate were evaluated. Propensity score matching (PSM) was conducted based on the 1:2 ratio between the oXiris and control groups to account for any baseline data differences. RESULTS: Results showed that after 24 h, 48 h, and 72 h of treatment, PCT, IL-6, and hs-CRP levels in the oXiris group were significantly lower than those in the control group (P < 0.05). However, there were no significant differences in norepinephrine equivalents and organ function status (APACHE II score, SOFA score, Lac) between the two groups at the same time points. The 72-h mortality rate (21.88% vs. 34.04%) and the 7-day mortality rate (28.12% vs. 44.68%) were lower in the oXiris group compared to the control group, but not statistically significant. The 28-day mortality rate did not show a significant difference between the two groups (53.19% vs. 56.25%). CONCLUSIONS: oXiris continuous hemofiltration adsorption technology may reduce the levels of inflammatory factors in patients with septic shock; however, it does not appear to enhance organ function or improve the 28-day mortality rate in these patients.

Unveiling Metabolic Engineering Strategies by Quantitative Heterologous Pathway Design.

Constructing efficient cell factories requires the rational design of metabolic pathways, yet quantitatively predicting the potential pathway for breaking stoichiometric yield limit in hosts remains challenging. This leaves it uncertain whether the pathway yield of various products can be enhanced to surpass the stoichiometric yield limit and whether common strategies exist. Here, a high-quality cross-species metabolic network model (CSMN) and a quantitative heterologous pathway design algorithm (QHEPath) are developed to address this challenge. Through systematic calculations using CSMN and QHEPath, 12,000 biosynthetic scenarios are evaluated across 300 products and 4 substrates in 5 industrial organisms, revealing that over 70% of product pathway yields can be improved by introducing appropriate heterologous reactions. Thirteen engineering strategies, categorized as carbon-conserving and energy-conserving, are identified, with 5 strategies effective for over 100 products. A user-friendly web server is developed to quantitatively calculate and visualize the product yields and pathways, which successfully predicts biologically plausible strategies validated in literature for multiple products.

The risk of postherpetic neuralgia in COVID-19 vaccination-associated herpes zoster: A retrospective cohort study using TriNetX.

BACKGROUND: The administration of the COVID-19 vaccine has been linked to the development of herpes zoster (HZ). However, studies examining the clinical outcomes in COVID-19 vaccination-associated and non-COVID-19 vaccination-associated HZ are lacking. OBJECTIVE: To investigate the risk of postherpetic neuralgia (PHN) in COVID-19 vaccination associated HZ. METHODS: A total of 7200 patients with COVID-19 vaccination-associated HZ and 7200 matched controls were enrolled from the US Collaborative Network in the TriNetX database. The main outcome of this study was the development of PHN. Patients were followed-up from 3 months after HZ until PHN diagnoses, withdrawal from the database, or October 8, 2024. RESULTS: We observed that patients with COVID-19 vaccination-associated HZ had a significantly higher risk of developing PHN as compared to the control group, with hazard ratio of 1.69 (> 3 months), 1.80 (> 6 months), 1.86 (> 1 year), and 1.93 (>2 years), respectively. Additionally, the association remained significant in the stratified analysis, which included sex, age, malignancy status, and initial use of antiviral agents. CONCLUSION: This study showed that COVID-19 vaccination-associated HZ demonstrated a significantly higher risk of developing PHN.

Exploring the biogeography, morphology, and phylogeny of the condylostomatid ciliates (Alveolata, Ciliophora, Heterotrichea), with establishment of four new Condylostoma species and a revision including redescriptions of five species found in China.

Species of the ciliate class Heterotrichea Stein, 1859 are a cosmopolitan group of unicellular eukaryotic microorganisms, many of which have been widely used as models in various fields of research such as regenerative biology, functional ecology, environmental toxicology, and symbiotic behavior. However, species identification in the heterotrich family Condylostomatidae, especially the most species-rich and type genus Condylostoma Bory de Saint-Vincent, 1824, remains challenging due to incomplete original descriptions, few reliable distinguishing characters, and overlapping features between different species. This study presents an updated revision of Condylostoma and its related genus Condylostomides da Silva Neto, 1994 based on descriptions of five species, including nine populations collected from China, using both morphological and molecular methods. The main findings are as follows: (1) 43 nominal species and about 130 populations are reviewed, resulting in the recognition of 30 valid species of Condylostoma and eight valid species of Condylostomides; (2) keys, synonyms, biogeographic distributions and amended/improved diagnoses of all valid species are provided; (3) based on the available data, four new Condylostoma species (C. marinum sp. nov., C. petzi sp. nov., C. villeneuvei sp. nov., and C. microstomum sp. nov.), one new combination (Condylostomides minimus (Dragesco, 1954) comb. nov. & nom. corr.), and two corrected names (Condylostoma ancestrale Villeneuve-Brachon, 1940 nom. corr. and Condylostomides nigrus (Dragesco, 1960) nom. corr.) are suggested; (4) cryptic species are detected and proposed for the first time to form the Condylostoma curvum species complex; (5) three highly confusing Condylostoma species, C. kris, C. spatiosum, and C. minutum, are redefined for the first time based on modern taxonomic methods; (6) a 'flagship' species, Condylostomides coeruleus, is recorded for the first time from the continent of Asia, substantially expanding its biogeography; (7) ciliature adjacent to the distal end of the paroral membrane within the family Condylostomatidae is uniformly defined as frontal membranelles and is classified into three patterns according to the arrangement of kinetosomes, which serve as important key features. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00223-3.

Accumulation of mitochondrial DNA with a point mutation in tRNALeu(UUR) gene induces brain dysfunction in mice.

Brain functions are mediated via the complex interplay between several complex factors, and hence, identifying the underlying cause of an abnormality within a certain brain region can be challenging. In mitochondrial disease, abnormalities in brain function are thought to be attributed to accumulation of mitochondrial DNA (mtDNA) with pathogenic mutations; however, only few previous studies have directly demonstrated that accumulation of mutant mtDNA induced abnormalities in brain function. Herein, we examined the effects of mtDNA mutations on brain function via behavioral analyses using a mouse model with an A2748G point mutation in mtDNA tRNALeu(UUR). Our results revealed that mice with a high percentage of mutant mtDNA showed a characteristic trend toward reduced prepulse inhibition and memory-dependent test performance, similar to that observed in psychiatric disorders, such as schizophrenia; however, muscle strength and motor coordination were not markedly affected. Upon examining the hippocampus and frontal lobes of the brain, mitochondrial morphology was abnormal, and the brain weight was slightly reduced. These results indicate that the predominant accumulation of a point mutation in the tRNALeu(UUR) gene may affect brain functions, particularly the coordination of sensory and motor functions and memory processes. These abnormalities probably caused by both direct effects of accumulation of the mutant mtDNA in neuronal cells and indirect effects via changes of systemic extracellular environments. Overall, these findings will lead to a better understanding of the pathogenic mechanism underlying this complex disease and facilitate the development of optimal treatment methods.

Arabidopsis thaliana MYC2 and MYC3 Are Involved in Ethylene-Regulated Hypocotyl Growth as Negative Regulators.

The ethylene-regulated hypocotyl elongation of Arabidopsis thaliana involves many transcription factors. The specific role of MYC transcription factors in ethylene signal transduction is not completely understood. The results here revealed that two MYCs, MYC2 and MYC3, act as negative regulators in ethylene-suppressed hypocotyl elongation. Etiolated seedlings of the loss-of-function mutant of MYC2 or MYC3 were significantly longer than wild-type seedlings. Single- or double-null mutants of MYC2 and MYC3 displayed remarkably enhanced response to ACC(1-aminocyclopropane-1-carboxylate), the ethylene precursor, compared to wild-type seedlings. MYC2 and MYC3 directly bind to the promoter zone of ERF1, strongly suppressing its expression. Additionally, EIN3, a key component in ethylene signaling, interacts with MYC2 or MYC3 and significantly suppresses their binding to ERF1's promoter. MYC2 and MYC3 play crucial roles in the ethylene-regulated expression of functional genes. The results revealed the novel role and functional mechanism of these transcription factors in ethylene signal transduction. The findings provide valuable information for deepening our understanding of their role in regulating plant growth and responding to stress.

Advances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion.

Acute myocardial infarction (AMI) is the leading cause of death worldwide, and reperfusion therapy is a critical therapeutic approach to reduce myocardial ischemic injury and minimize infarct size. However, ischemia/reperfusion (I/R) itself also causes myocardial injury, and inflammation is an essential mechanism by which it leads to myocardial injury, with macrophages as crucial immune cells in this process. Macrophages are innate immune cells that maintain tissue homeostasis, host defence during pathogen infection, and repair during tissue injury. During the acute phase of I/R, M1-type macrophages generate a pro-inflammatory milieu, clear necrotic myocardial tissue, and further recruit mononuclear (CCR2+) macrophages. Over time, the reparative (M2 type) macrophages gradually became dominant. In recent years, metabolic studies have shown a clear correlation between the metabolic profile of macrophages and their phenotype and function. M1-type macrophages are mainly characterized by glycolytic energy supply, and their tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS) processes are impaired. In contrast, M2 macrophages rely primarily on OXPHOS for energy. Changing the metabolic profile of macrophages can alter the macrophage phenotype. Altered energy pathways are also present in macrophages during I/R, and intervention in this process contributes to earlier and greater M2 macrophage infiltration, which may be a potential target for the treatment of myocardial I/R injury. Therefore, this paper mainly reviews the characteristics of macrophage energy metabolism alteration and phenotypic transition during I/R and its mechanism of mediating myocardial injury to provide a basis for further research in this field.

Clinical Predictors of Nontuberculous Mycobacteria Lung Disease and Coisolates of Potential Pathogenic Microorganisms in Noncystic Fibrosis Bronchiectasis.

Background: In bronchiectasis, nontuberculous mycobacteria (NTM) lung disease (NTM-LD) is a well-known coexisting infection. However, microorganism coisolates and clinical NTM-LD predictors are poorly studied. Methods: Patients with bronchiectasis diagnosed by means of computed tomography between January 2017 and June 2020 were screened, using the date of computed tomography as the index date. Those with a major bronchiectasis diagnosis in ≥2 follow-up visits after the index date were enrolled in the study, and NTM-LD occurrence and its association with pneumonia and hospitalization within 1 year were analyzed. Results: Of the 2717 participants, 79 (2.9%) had NTM-LD diagnosed. The factors associated with NTM-LD included hemoptysis, postinfectious bronchiectasis, a tree-in-bud score ≥2, a modified Reiff score ≥4, and chronic obstructive pulmonary disease (adjusted odds ratios, 1.80, 2.36, 1.78, 2.95, and 0.51, respectively). Compared with patients in the non-NTM group, those with NTM-LD had higher rates of hospitalization (15.9% vs 32.9%; P < .001) and pneumonia (9.8% vs 20.3%; P = .003). Pseudomonas aeruginosa was the most common microorganism in those with NTM-LD and those in the non-NTM group (10.1% vs 7.8%; P = .40). However, compared with those in the non-NTM group, Acinetobacter baumannii and Escherichia coli were more prevalent in patients with NTM-LD (0.7% vs 3.8% [P = .03%] and 1.0% vs 3.8% [P = .05], respectively). Conclusions: Postinfectious bronchiectasis with hemoptysis, higher radiological involvement, and a tree-in-bud pattern were associated with NTM-LD risk. The rate of A baumannii and E coli coisolation was higher in bronchiectasis populations with NTM-LD.

Chromosome-level assembly and evolution analysis of the Trichosanthes truncata genome.

Trichosanthes truncata C. B. Clarke, an important medicinal plant, is a dioecious plant belonging to the Cucurbitaceae family. This study presents a chromosomal-level reference genome assembly for T. truncata. Through the integration of PacBio high-fidelity sequencing and high-throughput chromosome conformation capture technology, a final genome sequence of 637.41 Mb was assembled, with an N50 of 57.24 Mb and consisting of 11 pseudochromosomes. Additionally, 97.21 Mb of repetitive sequences and 36,172 protein-coding genes were annotated. This high-quality genome assembly is of utmost significance for studying the molecular mechanisms underlying the biosynthesis of bioactive compounds. Furthermore, this study provided valuable insights into plant comparative genomics research.

Global, regional, and national burden of HIV-negative tuberculosis, 1990-2021: findings from the Global Burden of Disease Study 2021.

BACKGROUND: Tuberculosis (TB) is a major infectious disease with significant public health implications. Its widespread transmission, prolonged treatment duration, notable side effects, and high mortality rate pose severe challenges. This study examines the epidemiological characteristics of TB globally and across major regions, providing a scientific basis for enhancing TB prevention and control measures worldwide. METHODS: The ecological study used data from the Global Burden of Disease (GBD) Study 2021. It assessed new incidence cases, deaths, disability-adjusted life years (DALYs), and trends in age-standardized incidence rates (ASIRs), mortality rates (ASMRs), and DALY rates for drug-susceptible tuberculosis (DS-TB), multidrug-resistant tuberculosis (MDR-TB), and extensively drug-resistant tuberculosis (XDR-TB) from 1990 to 2021. A Bayesian age-period-cohort model was applied to project ASIR and ASMR. RESULTS: In 2021, the global ASIR for all HIV-negative TB was 103.00 per 100,000 population [95% uncertainty interval (UI): 92.21, 114.91 per 100,000 population], declining by 0.40% (95% UI: - 0.43, - 0.38%) compared to 1990. The global ASMR was 13.96 per 100,000 population (95% UI: 12.61, 15.72 per 100,000 population), with a decline of 0.44% (95% UI: - 0.61, - 0.23%) since 1990. The global age-standardized DALY rate for HIV-negative TB was 580.26 per 100,000 population (95% UI: 522.37, 649.82 per 100,000 population), showing a decrease of 0.65% (95% UI: - 0.69, - 0.57 per 100,000 population) from 1990. The global ASIR of MDR-TB has not decreased since 2015, instead, it has shown a slow upward trend in recent years. The ASIR of XDR-TB has exhibited significant increase in the past 30 years. The projections indicate MDR-TB and XDR-TB are expected to see significant increases in both ASIR and ASMR from 2022 to 2035, highlighting the growing challenge of drug-resistant TB. CONCLUSIONS: This study found that the ASIR of MDR-TB and XDR-TB has shown an upward trend in recent years. To reduce the TB burden, it is essential to enhance health infrastructure and increase funding in low-SDI regions. Developing highly efficient, accurate, and convenient diagnostic reagents, along with more effective therapeutic drugs, and improving public health education and community engagement, are crucial for curbing TB transmission.

Epidemiological features and temporal trends of the co-infection between HIV and tuberculosis, 1990-2021: findings from the Global Burden of Disease Study 2021.

BACKGROUND: The co-infection of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and tuberculosis (TB) poses a significant clinical challenge and is a major global public health issue. This study aims to elucidate the disease burden of HIV-TB co-infection in global, regions and countries, providing critical information for policy decisions to curb the HIV-TB epidemic. METHODS: The ecological time-series study used data from the Global Burden of Disease (GBD) Study 2021. The data encompass the numbers of incidence, prevalence, mortality, and disability-adjusted life year (DALY), as well as age-standardized incidence rate (ASIR), prevalence rate (ASPR), mortality rate (ASMR), and DALY rate for HIV-infected drug-susceptible tuberculosis (HIV-DS-TB), HIV-infected multidrug-resistant tuberculosis (HIV-MDR-TB), and HIV-infected extensively drug-resistant tuberculosis (HIV-XDR-TB) from 1990 to 2021. from 1990 to 2021. The estimated annual percentage change (EAPC) of rates, with 95% confidence intervals (CIs), was calculated. RESULTS: In 2021, the global ASIR for HIV-DS-TB was 11.59 per 100,000 population (95% UI: 0.37-13.05 per 100,000 population), 0.55 per 100,000 population (95% UI: 0.38-0.81 per 100,000 population), for HIV-MDR-TB, and 0.02 per 100,000 population (95% UI: 0.01-0.03 per 100,000 population) for HIV-XDR-TB. The EAPC for the ASIR of HIV-MDR-TB and HIV-XDR-TB from 1990 to 2021 were 4.71 (95% CI: 1.92-7.59) and 13.63 (95% CI: 9.44-18.01), respectively. The global ASMR for HIV-DS-TB was 2.22 per 100,000 population (95% UI: 1.73-2.74 per 100,000 population), 0.21 per 100,000 population (95% UI: 0.09-0.39 per 100,000 population) for HIV-MDR-TB, and 0.01 per 100,000 population (95% UI: 0.00-0.03 per 100,000 population) for HIV-XDR-TB in 2021. The EAPC for the ASMR of HIV-MDR-TB and HIV-XDR-TB from 1990 to 2021 were 4.78 (95% CI: 1.32-8.32) and 10.00 (95% CI: 6.09-14.05), respectively. CONCLUSIONS: The findings indicate that enhancing diagnostic and treatment strategies, strengthening healthcare infrastructure, increasing access to quality medical care, and improving public health education are essential to combat HIV-TB co-infection.

Toll-like receptor 4 deficiency in Purkinje neurons drives cerebellar ataxia by impairing the BK channel-mediated after-hyperpolarization and cytosolic calcium homeostasis.

Toll-like receptor (TLR) 4 contributes to be the induction of neuroinflammation by recognizing pathology-associated ligands and activating microglia. In addition, numerous physiological signaling factors act as agonists or antagonists of TLR4 expressed by non-immune cells. Recently, TLR4 was found to be highly expressed in cerebellar Purkinje neurons (PNs) and involved in the maintenance of motor coordination through non-immune pathways, but the precise mechanisms remain unclear. Here we report that mice with PN specific TLR4 deletion (TLR4PKO mice) exhibited motor impairments consistent with cerebellar ataxia, reduced PN dendritic arborization and spine density, fewer parallel fiber (PF) - PN and climbing fiber (CF) - PN synapses, reduced BK channel expression, and impaired BK-mediated after-hyperpolarization, collectively leading to abnormal PN firing. Moreover, the impaired PN firing in TLR4PKO mice could be rescued with BK channel opener. The PNs of TLR4PKO mice also exhibited abnormal mitochondrial structure, disrupted mitochondrial endoplasmic reticulum tethering, and reduced cytosolic calcium, changes that may underly abnormal PN firing and ultimately drive ataxia. These results identify a previously unknown role for TLR4 in regulating PN firing and maintaining cerebellar function.

Improving the Purity of Extracellular Vesicles by Removal of Lipoproteins from Size Exclusion Chromatography- and Ultracentrifugation-Processed Samples Using Glycosaminoglycan-Functionalized Magnetic Beads.

Extracellular vesicles (EVs) are present in blood at much lower concentrations (5-6 orders of magnitude) compared to lipoprotein particles (LP). Because LP and EV overlap in size and density, isolating high-purity EVs is a significant challenge. While the current two-step sequential EV isolation process using size-expression chromatography (SEC) followed by a density gradient (DG) achieves high purity, the time-consuming ultracentrifugation (UC) step in DG hinders workflow efficiency. This paper introduces an optimized magnetic bead reagent, LipoMin, functionalized with glycosaminoglycans (GAGs), as a rapid alternative for LP removal during the second-step process in about 10 minutes. We evaluated LipoMin's efficacy on two sample types: (a) EV fractions isolated by size exclusion chromatography (SEC + LipoMin) and (b) the pellet obtained from ultracentrifugation (UC + LipoMin). The workflow is remarkably simple, involving a 10 min incubation with LipoMin followed by magnetic separation of the LP-depleted EV-containing supernatant. Results from enzyme-linked immunosorbent assay (ELISA) revealed that LipoMin removes 98.2% ApoB from SEC EV fractions, comparable to the LP removal ability of DG in the SEC + DG two-step process. Importantly, the EV yield (CD81 ELISA) remained at 93.0% and Western blot analysis confirmed that key EV markers, flotillin and CD81, were not compromised. Recombinant EV (rEV), an EV reference standard, was spiked into SEC EV fractions and recovered 89% of CD81 protein. For UC + LipoMin, ApoA1 decreased by 76.5% while retaining 90.7% of CD81. Notably, both colorectal cancer (CRC) and Alzheimer's disease (AD) samples processed by SEC + LipoMin and UC + LipoMin displayed clear expression of relevant EV and clinical markers. With a 10 min workflow (resulting in a 96% time saving compared to the traditional method), the LipoMin reagent offers a rapid and efficient alternative to DG for LP depletion, paving the way for a streamlined SEC + LipoMin two-step EV isolation process.

Immunotherapy vs Best Supportive Care for Patients With Hepatocellular Cancer With Child-Pugh B Dysfunction.

Importance: Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated. Objective: To evaluate the association of immune checkpoint inhibitor (ICI)-based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction. Design, Setting, and Participants: This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status. Exposures: Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46). Main Outcomes and Measures: OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups. Results: The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death. Conclusions and Relevance: The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.

Benefits of NGS in Advanced Lung Adenocarcinoma Vary by Populations and Timing of Examination.

Despite the widespread application of next-generation sequencing (NGS) in advanced lung adenocarcinoma, its impact on survival and the optimal timing for the examination remain uncertain. This cohort study included advanced lung adenocarcinoma patients who underwent NGS testing. We categorized patients into four groups: Group 1: treatment-naïve, upfront NGS; Group 2: Treatment-naïve, exclusionary EGFR/ALK/ROS1; Group 3: post-treatment, no known EGFR/ALK/ROS1; Group 4: known driver mutation and post-TKI treatment. A total of 424 patients were included. There were 128, 126, 90, and 80 patients in Groups 1, 2, 3, and 4, respectively. In Groups 1, 2, 3, and 4, targetable mutations were identified in 76.6%, 49.2%, 41.1%, and 33.3% of the patients, respectively (p < 0.001). Mutation-targeted treatments were applied in 68.0%, 15.1%, 27.8%, and 22.5% of the patients, respectively (p < 0.001). In the overall population, patients receiving mutation-targeted treatments exhibited significantly longer overall survival (OS) (aHR 0.54 [95% CI 0.37-0.79], p = 0.001). The most profound benefit was seen in the Group 1 patients (not reached vs. 40.4 months, p = 0.028). The median OS of patients with mutation-targeted treatments was also significantly longer among Group 2 patients. The median post-NGS survival of patients receiving mutation-targeted treatments was numerically longer in Group 3 and Group 4 patients. In conclusion, mutation-targeted therapy is associated with a favorable outcome. However, the opportunities of NGS-directed treatment and the survival benefits of mutation-targeted treatment were various among different populations.

Widely targeted metabolomics reveals the phytoconstituent changes in Platostoma palustre leaves and stems at different growth stages.

Platostoma palustre (Blume) A. J. Paton is an important edible and medicinal plant. To gain a comprehensive and clear understanding of the variation patterns of metabolites in P. palustre, we employed the UPLC-MS platform along with widely targeted metabolomics techniques to analyze the metabolites in the stems and leaves of P. palustre at different stages. Our results revealed a total of 1228 detected metabolites, including 241 phenolic acids, 203 flavonoids, 152 lipids, 128 terpenes, 106 amino acids, 79 organic acids, 74 saccharides, 66 alkaloids, 44 lignans, etc. As the growth time increased, the differential metabolites (DAMs) mainly enriched in P. palustre leaves were terpenoids, phenolic acids, and lipids, while the DAMs primarily enriched in stems were terpenoids. Compared to stems, there were more differential flavonoids in leaves, and saccharides and flavonoids were significantly enriched in leaves during the S1 and S2 stages. Additionally, we identified 13, 10, and 23 potential markers in leaf, stem, and leaf vs. stem comparison groups. KEGG enrichment analysis revealed that arginine biosynthesis was the common differential metabolic pathway in different growth stages and tissues. Overall, this study comprehensively analyzed the metabolic profile information of P. palustre, serving as a solid foundation for its further development and utilization.

TRMT10A dysfunction perturbs codon translation of initiator methionine and glutamine and impairs brain functions in mice.

In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1-methylguanosine modification at position nine of various cytoplasmic tRNAs. Pathogenic mutations in TRMT10A cause intellectual disability, microcephaly, diabetes, and short stature in humans, and generate cytotoxic tRNA fragments in cultured cells; however, it is not clear how TRMT10A supports codon translation or brain functions. Here, we generated Trmt10a null mice and showed that tRNAGln(CUG) and initiator methionine tRNA levels were universally decreased in various tissues; the same was true in a human cell line lacking TRMT10A. Ribosome profiling of mouse brain revealed that dysfunction of TRMT10A causes ribosome slowdown at the Gln(CAG) codon and increases translation of Atf4 due to higher frequency of leaky scanning of its upstream open reading frames. Broadly speaking, translation of a subset of mRNAs, especially those for neuronal structures, is perturbed in the mutant brain. Despite not showing discernable defects in the pancreas, liver, or kidney, Trmt10a null mice showed lower body weight and smaller hippocampal postsynaptic densities, which is associated with defective synaptic plasticity and memory. Taken together, our study provides mechanistic insight into the roles of TRMT10A in the brain, and exemplifies the importance of universal tRNA modification during translation of specific codons.