The association between changes in muscle mass and function and mortality in individuals receiving peritoneal dialysis.

BACKGROUND/OBJECTIVE: Data in terms of how dynamic changes of muscle mass and function affect mortality in end-stage kidney disease (ESKD) patients undergoing dialysis have led to inconclusive results. The main goal of this research was to determine the association between dynamic deterioration of muscle mass and function and all-cause mortality in ESKD patient on continuous ambulatory peritoneal dialysis (CAPD). METHODS: Eligible ESKD patients on CAPD were prospectively included, and followed up at 3-month intervals in the tertiary care center for 2 years. Dynamic deterioration of muscle mass and function during a 12-month follow-up period before patients enrolled was the exposure of interest. The deterioration of muscle mass and function was identified utilizing the criteria set by the Asian Working Group on Sarcopenia in 2019 (AWGS 2019). Primary outcome was defined as the all-cause mortality during the next 2-year follow-up period. Kaplan-Meier analysis with log-rank test was used to compare overall survival between groups. Association of dynamic deterioration of muscle mass and function with all-cause mortality was examined by employing Cox proportional hazards models. A sensitivity analysis was also conducted to examine whether the potential association was modified. RESULTS: A total of 217 eligible patients on CAPD were included. The prevalence of dynamic deterioration of muscle mass and function was 42.9% (93/217), of which that evolving to sarcopenia (nonsevere sarcopenia or severe sarcopenia) from nonsarcopenia was 24.9% (54/217) and that evolving to severe sarcopenia from nonsevere sarcopenia was 18.0% (39/217). A total of 35.0% (76/217) participants died during the 2-year follow-up period, of which the group with deterioration of muscle mass and function was 50.5% (47/93), and the group without deterioration was 23.4% (29/124), with an absolute difference of 27.1% (95%CI 14.5%-39.7%). Kaplan-Meier survival curve revealed that the participants with dynamic deterioration of muscle mass and function had a worse survival rate than those without deterioration (log-rank test, χ2 = 17.46, p < 0.001). After adjustment for potential confounding factors, the dynamic deterioration of muscle mass and function was still significantly associated with increased risk of all-cause mortality (hazard ratio [HR] = 2.40, 95%CI 1.44-4.00, p = 0.001). In sensitivity analysis, the relationship between dynamic deterioration of muscle mass and function (nonsarcopenia to sarcopenia vs without deterioration) and all-cause mortality was consistent (HR = 4.01, 95%CI 2.22-7.22, p < 0.001). Nevertheless, no significant relationship was found in participants who evolved to severe sarcopenia from nonsevere sarcopenia (HR = 1.41, 95%CI 0.72-2.74, p = 0.313). CONCLUSION: This research demonstrated a significant association between dynamic deterioration of muscle mass and function and higher risk of mortality in ESKD patients on CAPD, and we recommend individualized lifestyle intervention that may be implemented to intervene in the progression of their muscle mass and function across the health care spectrum.

Lower risk of the deterioration of muscle mass and function in oral active vitamin D users among Incident peritoneal dialysis patients: a 12-month follow-up cohort study.

Data in terms of how active vitamin D supplementation affects muscle mass and function in end-stage renal disease (ESRD) patients has led to inconclusive results. The main goal of this research was to examine the association of active vitamin D supplementation and risk of the deterioration of muscle mass and function among ESRD patients on peritoneal dialysis (PD). Eligible ESRD patients on PD were prospectively included, and followed up at 3-month intervals in the tertiary care center. Based on the medications during the 12-month follow-up period, the patients were divided into two groups (vitamin D users and non-users). The deterioration of muscle mass and function was identified utilizing the criteria set by the Asian Working Group on Sarcopenia in 2019 (AWGS 2019). Primary outcome was defined as the deterioration of muscle mass and function at the end of the 12-month follow-up. The absolute diffecence and 95% confidence interval (CI) of the incidence of deterioration between vitamin D users and non-users was estimated. The association of vitamin D supplementation with risk of the deterioration of muscle mass and function during the 12-month follow-up period, was examined by employing multivariate logistic regression models. A total of 229 incident PD patients (6 of whom were lost in follow-up) were included. During the entire study period, 54.7% (122/223) of the remaining patients were considered users of oral active vitamin D. The incidence of deterioration in muscle mass and function was 30.5% (68/223) throughout the entire follow-up. In this regard, the rate was 23.0% (28/122) that received oral active vitamin D, while it was 39.6% (40/101) in the group that did not receive it, with an absolute diffecence of -16.6% (95% CI - 4.5, - 28.7) and an estimated relative risk (RR) of 0.784 (95% CI 0.651-0.943). After adjustment for potential confounding factors in logistic regression model, vitamin D users group was still associated with decreased risk of the deterioration of muscle mass and function (OR 0.330, 95% CI 0.159-0.683, P = 0.003). In secondary analysis, the relationship between oral active vitamin D and the deterioration of muscle mass and function remained consistent (≤ 0.25 µg per day vs. non-users; OR 0.300, 95% CI 0.131-0.688, P = 0.004); however, no significant relationship was identified in patients receiving a mean daily dose of > 0.25 µg compared with non-users (OR 0.389, 95% CI 0.146-1.034, P = 0.058). These results indicate that active vitamin D supplementation was significantly associated with a decreased risk of the deterioration of muscle mass and function in incident PD patients with ESRD. However, the amount and type of vitamin D used and the duration of the intervention warrant further randomized controlled trials to confirm the possibility that such medication improves sarcopenia in ESRD patients.

Fenton-like nanoparticles capable of H2O2 self-supply and glutathione consumption for chemodynamic and chemotherapy of cancer.

Chemodynamic therapy (CDT) utilizing the Fenton reaction to convert hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (˙OH) has recently drawn extensive interest in tumor treatment. However, the therapeutic efficiency of CDT often suffers from high concentrations of glutathione (GSH), insufficient endogenous H2O2 and inefficient Fenton activity. Herein, a GSH-depleting and H2O2 self-providing nanosystem that can efficiently load copper ions and doxorubicin (DOX) (MSN-Cu2+-DOX) to induce enhanced CDT and chemotherapy is proposed. The results show that MSN-Cu2+-DOX could release Cu2+ and DOX under acidic conditions. Particularly, both the released Cu2+ and Cu2+ in MSN-Cu2+-DOX are available for ˙OH production via a Fenton-like reaction for CDT. Meanwhile, Cu2+ undergoes a reduction to Cu+ by depleting overexpressed GSH, thereby enhancing CDT. Moreover, the released DOX could not only be used for chemotherapy, but also promote the generation of endogenous H2O2 to improve the efficiency of a Cu-based Fenton-like reaction. Resultantly, this nanosystem featuring Fenton-like activity, GSH consumption, H2O2 self-sufficiency and chemotherapy exhibits a great antitumor effect with a tumor inhibition ratio of 93.05%. Overall, this study provides a promising strategy to enhance CDT for effective tumor therapy.

A review of HSV pathogenesis, vaccine development, and advanced applications.

Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons.

Enhancing the effectiveness of anti-respiratory virus vaccines by bolstering mucosal immunity and cellular defenses.

A schematic diagram of intratracheal (IT) boosting, which leads to enhanced mucosal immunity and protective efficacy. IT boosting leads to significant expansion of mucosal neutralizing antibodies, along with robust CD8+ and CD4+ T-cell responses. Notably, IT boosting results in substantial and sustained activation of cytokine, natural killer, T, and B-cell pathways in the lung, contributing to enhanced mucosal immunity and overall protective efficacy.

Labor patterns of spontaneous first-stage labor in Chinese women with normal neonatal outcomes.

BACKGROUND: Friedman's standards, developed almost 50 years ago, may no longer align with the needs of today's obstetric population and current pregnancy management practices. This study aims to analyze contemporary labor patterns and estimate labor duration in China, focusing on first-stage labor data from Chinese parturients with a spontaneous onset of labor. METHODS: This retrospective observational study utilized data from electronic medical records of a tertiary hospital in Changsha, Hunan. Out of a total of 2,689 parturients, exclusions were made for multiple gestations, preterm, post-term, or stillbirth, cesarean delivery, non-vertex presentation, and neonatal intensive care unit admission. Average labor curves were constructed by parity using repeated-measure analysis, and labor duration was estimated through interval-censored regression, stratified by cervical dilation at admission. We performed an analysis to assess the impact of oxytocin augmentation and amniotomy on labor progression and conducted a sensitivity analysis using women with complicated outcomes. RESULTS: Nulliparous women take over 180 minutes for cervical dilation from 3 to 4 cm, and the duration from 5 to 6 cm exceeds 145 minutes. Multiparous women experience shorter labor durations than nulliparous. Labor acceleration is observed after 5 cm in nulliparous, but no distinct inflection point is evident in the average labor curve. In the second stage of labor, the 95th percentile for nulliparous, with and without epidural analgesia, is 142 minutes and 127 minutes, respectively. CONCLUSIONS: These findings provide valuable insights for the reassessment of labor and delivery processes in contemporary obstetric populations, including current Chinese obstetric practice.

Diselenide-Bridged Mesoporous Silica-Based Nanoplatform with a Triple ROS-Scavenging Effect for Intracerebral Hemorrhage Treatment.

Oxidative stress (OS) is a major mediator of secondary brain injury following intracerebral hemorrhage (ICH). Thus, antioxidant therapy is emerging as an attractive strategy to combat ICH. To achieve both reactive oxygen species (ROS) scavenging ability and on-demand drug release ability, we constructed a novel polydopamine (PDA)-coated diselenide-bridged mesoporous silica nanoparticle (DSeMSN) drug delivery system (PDA-DSeMSN). Edaravone (Eda) was blocked in the pores of DSeMSN by covering the pores with PDA as a gatekeeper. The drug maintained nearly "zero release" before reaching the lesion site, while in the ROS-enriched circumstances, the PDA shell went through degradation and the doped diselenide bonds broke up, triggering the disintegration of nanoparticles and leading to Eda release. Interestingly, the ROS-degradable property of the PDA shell and diselenide bond endowed the system with enhanced ROS-eliminating capacity. The synergistic effect of ROS-responsive drug delivery and ROS-scavenging PDA-DSeMSN showed efficient antioxidative and mitochondria protective performance without apparent toxicity in vitro. Importantly, PDA-DSeMSN@Eda through intravenous administration specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model through antioxidative and antiapoptotic effects with high biological safety. Thus, the PDA-DSeMSN platform holds tremendous potential as an excellent carrier for on-demand delivery of drugs and provides a new and effective strategy for the clinical treatment of ICH.

A Prospective Cohort Study Evaluating Impact of Sarcopenia on Hospitalization in Patients on Continuous Ambulatory Peritoneal Dialysis.

Data regarding the association of sarcopenia with hospitalization has led to inconclusive results in patients undergoing dialysis. The main goal of this research was to investigate the association between sarcopenia and hospitalization in Chinese individuals on continuous ambulatory peritoneal dialysis (CAPD). Eligible patients on CAPD were prospectively included, and followed up for 48 weeks in our PD center. Sarcopenia was identified utilizing the criteria set by the Asian Working Group on Sarcopenia in 2019 (AWGS 2019). Participants were categorized into sarcopenia (non-severe sarcopenia + severe sarcopenia) and non-sarcopenia groups. The primary outcome was all-cause hospitalization during the 48-week follow-up period. Association of sarcopenia with all-cause hospitalization was examined by employing multivariate logistic regression models. The risk of cumulative incidence of hospitalization in the 48-week follow-up was estimated using relative risk (RR and 95% CI). The cumulative hospitalization time and frequency at the end of 48-week follow-up were described as categorical variables, and compared by χ2 test or fisher's exact test as appropriate. Subgroup and sensitivity analyses were also conducted to examine whether the potential association between sarcopenia and hospitalization was modified. A total of 220 patients on CAPD (5 of whom were lost in follow-up) were included. Prevalences of total sarcopenia and severe sarcopenia were 54.1% (119/220) and 28.2% (62/220) according to AWGS 2019, respectively. A total of 113 (51.4%) participants were hospitalized during the 48-week follow-up period, of which, the sarcopenia group was 65.5% (78/119) and the non-sarcopenia group was 34.7% (35/101), with an estimated RR of 1.90 (95%CI 1.43-2.52). The cumulative hospitalization time and frequency between sarcopenia and non-sarcopenia groups were significantly different (both P < 0.001). Participants with sarcopenia (OR = 3.21, 95%CI 1.75-5.87, P < 0.001), non-severe sarcopenia (OR = 2.84, 95%CI 1.39-5.82, P = 0.004), and severe sarcopenia (OR = 3.66, 95%CI 1.68-8.00, P = 0.001) demonstrated a significant association with all-cause hospitalization compared to individuals in non-sarcopenia group in the 48-week follow-up. Moreover, participants in subgroups (male or female; < 60 or ≥ 60 years) diagnosed with sarcopenia, as per AWGS 2019, were at considerably high risk for hospitalization compared to those with non-sarcopenia. In sensitivity analyses, excluding participants lost in the follow-up, the relationships between sarcopenia and hospitalization (sarcopenia vs. non-sarcopenia; severe sarcopenia/non-severe sarcopenia vs. non-sarcopenia) were consistent. This research involving Chinese patients on CAPD demonstrated a significant association between sarcopenia and incident hospitalization, thereby emphasizing the importance of monitoring sarcopenia health in this population.

Polydopamine modified colloidal gold nanotag-based lateral flow immunoassay platform for highly sensitive detection of pathogenic bacteria and fast evaluation of antibacterial agents.

Bacterial infection is a great threat to human health. Lateral flow immunoassays (LFIAs) with the merits of low cost, quick screening, and on-site detection are competitive technologies for bacteria detection, but their detection limits depend on the optical performance of the adopted nanotags. Herein, we presented a LFIA platform for bacteria detection using polydopamine (PDA) functionalized Au nanoparticles (denoted as Au@PDA) as the nanotag. The introduction of PDA could provide enhanced light absorption of Au, as well as numerous functional groups for conjugation. Small recognition molecules i.e. vancomycin (Van) and p-mercaptophenylboronic acid (PMBA) were covalently anchored to Au@PDA, and selected as the specific probes towards Gram-positive (G+) and Gram-negative (G-) bacteria, respectively. Taken Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) as the representative targets of G+ and G- bacteria, two LFA strips were successfully constructed based on the immuno-sandwich principle. They could quantitatively detect S. aureus and E. coli both down to 102 cfu/mL, a very competitive detection limit in comparison with other colorimetric or luminescent probes-based LFIAs. Furthermore, the proposed two strips were applied for the quantitative, accurate, and rapid detection of S. aureus and E. coli in food and human urine samples with good analytical results obtained. In addition, they were integrated as a screening platform for quick evaluation of diverse antibacterial agents within 3 h, which is remarkably shortened compared with that of the two traditional methods i.e. bacterial culture and plate-counting.

UCHL5 is a putative prognostic marker in renal cell carcinoma: a study of UCHL family.

A macroscopic perspective is indispensable for understanding the intricate relationship between deubiquitinases and tumorigenesis. Proteomics has been proposed as a viable approach for elucidating the complex role of deubiquitylation in cellular progression. Instead of studying the function of a single ubiquitinase, research on a deubiquitinase family with similar catalytic core(s) may provide a new perspective for the pathological understanding of cancer. The Ubiquitin C-terminal hydrolase L (UCHL) family consists of four members: UCHL1, UCHL3, UCHL5, and BRAC1 associated protein-1 (BAP1), and they have been implicated in tumorigenesis and metastasis. Some members are considered hallmarks of intracranial lesions, colon cancer, chromatin remodeling, and histone stability. The present study uncovered an unknown correlation between the UCHL family and renal cancer. We discovered that UCHLs exhibit diverse regulatory effects in renal cancer, establishing connections between the renal cancer and truncated gene mutations, mitochondrial energetic metastasis, immune cell infiltration, and chromosomal stability of UCHLs family. Notably, we found that the increase of UCHL5 expression in renal cancer cells decreases the antigen processing and presentation of RCC tumor-infiltrating B cells. Further research identified that the expression of UCHL5 in RCC tumors is correlated with transport proteins, which led us to find that the abundance of UCHL5 in the blood of late-stage renal cell cancer patients is upregulated from 18 ng/L to 500 ng/L. Therefore, we propose that the abundance of UCHL5 in patients' blood can be a possible indicator of poor prognosis for renal cell cancer.

An alternative 3' splice site of PeuHKT1;3 improves the response to salt stress through enhancing affinity to K+ in Populus.

Alternative splicing (AS) serves as a crucial post-transcriptional regulator in plants that contributes to the resistance to salt stress. However, the underlying mechanism is largely unknown. In this research, we identified an important AS transcript in Populus euphratica, PeuHKT1:3a, generated by alternative 3' splice site splicing mode that resulted in the removal of 252 bases at the 5' end of the first exon in PeuHKT1:3. Protein sequence comparison showed that the site of AS occurred in PeuHKT1:3 is located at a crucial Ser residue within the first pore-loop domain, which leads to inefficient K+ transport in HKT I-type transporters. Expressing PeuHKT1;3a in an axt3 mutant yeast strain can effectively compensate for the lack of intracellular K+, whereas the expression of PeuHKT1;3 cannot yield the effect. Furthermore, in transgenic Arabidopsis and poplar plants, it was observed that lines expressing PeuHKT1;3a exhibited greater salt tolerance compared to those expressing the PeuHKT1;3 strain. Analysis of ion content and flux demonstrated that the transgenic PeuHKT1;3a line exhibited significantly higher K+ content compared to the PeuHKT1;3 line, while there was no significant difference in Na+ content. In conclusion, our findings revealed that AS can give rise to novel variants of HKT I-type proteins in P. euphratica with modified K+ selectivity to keep a higher K+/Na+ ratio to enhanced salt tolerance.

TRIM25 predominately associates with anti-viral stress granules.

Stress granules (SGs) are induced by various environmental stressors, resulting in their compositional and functional heterogeneity. SGs play a crucial role in the antiviral process, owing to their potent translational repressive effects and ability to trigger signal transduction; however, it is poorly understood how these antiviral SGs differ from SGs induced by other environmental stressors. Here we identify that TRIM25, a known driver of the ubiquitination-dependent antiviral innate immune response, is a potent and critical marker of the antiviral SGs. TRIM25 undergoes liquid-liquid phase separation (LLPS) and co-condenses with the SG core protein G3BP1 in a dsRNA-dependent manner. The co-condensation of TRIM25 and G3BP1 results in a significant enhancement of TRIM25's ubiquitination activity towards multiple antiviral proteins, which are mainly located in SGs. This co-condensation is critical in activating the RIG-I signaling pathway, thus restraining RNA virus infection. Our studies provide a conceptual framework for better understanding the heterogeneity of stress granule components and their response to distinct environmental stressors.

Exploring the role of innate immunity in Cholangiocarcinoma: implications for prognosis, immune infiltration, and tumor metastasis.

The innate immune system serves as the body's primary physiological defense against the intrusion of pathogenic microorganisms, playing a pivotal role in restricting viral infections. However, current research on the interplay between innate immune pathways and cancer is limited, with reported effects often inconsistent. Therefore, we aimed to elucidate the relationship between innate immune pathways and tumors through an amalgamation of bioinformatics and extensive data analysis. Conducting a pan-cancer analysis encompassing expression, genomic alterations, and clinical prognosis, we identified a close association between the innate immune pathway and cholangiocarcinoma. Subsequently, our focus shifted to unraveling the role of innate immune pathway proteins in cholangiocarcinoma. TIMER database analysis showed that the innate immune pathway predominantly influences the infiltration of macrophages and B cells in cholangiocarcinoma. Additionally, gene ontology (GO) and pathway analyses were performed for significantly differentially expressed genes correlated with the innate immune pathway in cholangiocarcinoma. Single-cell transcriptome analysis in cholangiocarcinoma demonstrated that genes in the innate immune pathway are primarily expressed in malignant cells, endothelial cells, monocytes and macrophages. To further validate the expression of proteins in the innate immune pathway in the tumor tissues of patients with cholangiocarcinoma, tumor tissue slices from patients with liver intrahepatic cholangiocarcinoma and normal tissue slices from the HPA database were analyzed. These results indicated pronounced activation of the innate immune pathway in the tumor tissues of patients with cholangiocarcinoma. Finally, proteomic data from patients with or without intrahepatic cholangiocarcinoma metastasis were analyzed. The results revealed a significant correlation between the expression and phosphorylation of IKKε and the occurrence of intrahepatic cholangiocarcinoma metastasis. These findings not only demonstrate the significance of the innate immune pathway in cholangiocarcinoma but also its potential as a prospective prognostic biomarker and therapeutic target for this malignancy.

PARP1-DNA co-condensation: the driver of broken DNA repair.

DNA double-strand break (DSB) sites that prevent the disjunction of broken DNA ends are formed through poly (ADP-ribose) (PAR) polymerase 1 (PARP1)-DNA co-condensation. The co-condensates apply mechanical forces to hold the DNA ends together and generate enzymatic activity for the synthesis of PAR. PARylation can promote the release of PARP1 from DNA ends and recruit various proteins, such as Fused in sarcoma (FUS) proteins, thereby stabilizing broken DNA ends and preventing their separation.

Effect of care bundles for acute kidney injury: A systematic review and meta-analysis.

PURPOSE: Acute kidney injury (AKI) is frequent among in-hospital patients with high incidence and mortality. Implementing a series of evidence-based AKI care bundles may improve patient outcomes by reducing changeable standards of care. The aim of this meta-analysis was therefore to appraise the influences of AKI care bundles on patient outcomes. MATERIALS AND METHODS: We explored three international databases (PubMed, Embase, and Cochrane Central Register of Controlled Trials) and two Chinese databases (Wanfang Data and China National Knowledge Infrastructure) for studies from databases inception until November 30, 2022, comparing the impact of different AKI care bundles with usual standards of care in patients with or at risk for AKI. The study quality of non-randomized controlled trials and randomized controlled trials was evaluated by the NIH Study Quality Assessment Tool and the Cochrane risk of bias tool. Heterogeneity between studies was appraised by Cochran's Q test and I2 statistics. The possible origins of heterogeneity between studies were assessed adopting Meta-regression and subgroup analyses. Funnel plot asymmetry and Egger regression and Begg correlation tests were performed to discover potential publication bias. Data analysis was completed by software (RevMan 5.3 and Stata 15.0). The primary outcome was short- or long-term mortality. The secondary outcomes involved the incidence and severity of AKI. RESULTS: Sixteen studies containing 25,690 patients and 25,903 AKI episodes were included. In high-risk AKI patients determined by novel biomarkers, electronic alert or risk prediction score, the application of AKI care bundles significantly reduced the AKI incidence (OR, 0.71; 95% CI, 0.53-0.96; p = 0.02; I2 = 84%) and AKI severity (OR, 0.59; 95% CI, 0.39-0.89; p = 0.01; I2 = 65%). No strong evidence is available to prove that care bundles can significantly reduce mortality (OR, 1.16; 95% CI, 0.58-2.30; p = 0.68; I2 = 97%). CONCLUSIONS: The introduction of AKI care bundles in routine clinical practice can effectively improve the outcomes of patients with or at-risk of AKI. However, the accumulated evidence is limited and not strong enough to make definite conclusions.

Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.

Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. ß-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.

Serotonin signaling: a new player and therapeutic target beyond Long-haul coronavirus disease.

During the coronavirus disease 2019 (COVID-19) pandemic, a subset of individuals continues to suffer from symptoms including fatigue, post-exertional malaise, dyspnea, bone loss, and memory and neurocognitive dysfunction for months and even years after infection. This clinical phenomenon has been labeled 'Long-haul COVID' or 'post-acute sequelae of COVID-19 (PASC)'; however, the underlying pathophysiological mechanisms remain unclear. In a recent study published in Cell, Wong et al. revealed that viral infection and type I interferon-driven reduction of peripheral serotonin impaired hippocampal responses and short-term memory through vagal neurons in patients with PASC. Therefore, the study provided novel insights into how serotonin links persistent viral inflammation with the neurocognitive symptoms of Long-haul COVID and actionable therapeutic targets for patients with PASC.

Accumulation patterns of tobacco root allelopathicals across different cropping durations and their correlation with continuous cropping challenges.

Introduction: Continuous cropping challenges have gradually emerged as pivotal factors limiting the sustainable development of agricultural production. Allelopathicals are considered to be the primary obstacles. However, there is limited information on allelopathic accumulation across various continuous cropping years and its correlation with the associated challenges. Methods: Tobacco was subjected to varying planting durations: 1 year (CR), 5 years (CC5), 10 years (CC10), and 15 years (CC15). Results: Our findings unveiled discernible disparities in tobacco growth patterns across diverse continuous cropping periods. Notably, the most pronounced challenges were observed in the CC5 category, characterized by yield reduction, tobacco black shank outbreaks, and a decline in beneficial flora. Conversely, CC15 exhibited a substantial reduction in challenges as the continuous cropping persisted with no significant differences when compared to CR. Within the tobacco rhizosphere, we identified 14 distinct allelopathic compounds, with 10 of these compounds displaying noteworthy variations among the four treatments. Redundancy analysis (RDA) revealed that eight allelopathic compounds exhibited autotoxic effects on tobacco growth, with MA, heptadecanoic acid, and VA ranking as the most potent inhibitors. Interaction network highlighted the pivotal roles of VA and EA in promoting pathogen proliferation and impeding the enrichment of 13 beneficial bacterial genera. Furthermore, a structural equation model elucidated that MA and EA primarily exert direct toxic effects on tobacco, whereas VA fosters pathogen proliferation, inhibits the enrichment of beneficial bacteria, and synergistically exacerbates the challenges associated with continuous cropping alongside EA. Discussion: These findings suggested discernible disparities in tobacco growth patterns across the various continuous cropping periods. The most pronounced challenges were observed in CC5, whereas CC15 exhibited a substantial reduction in challenges as continuous cropping persisted. VA may play a pivotal role in this phenomenon by interacting with pathogens, beneficial bacterial genera, and EA.

TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence.

Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NP's ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviral immune response is suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation and a newly identified SUMO-interacting motif in SARS2-NP. Importantly, the widespread SARS2-NP R203K mutation gains a novel site of SUMOylation which further increases SARS2-NP's LLPS and immunosuppression. Notably, the SUMO E3 ligase TRIM28 is responsible for catalyzing SARS2-NP SUMOylation. An interfering peptide targeting the TRIM28 and SARS2-NP interaction was screened out to block SARS2-NP SUMOylation and LLPS, and consequently inhibit SARS-CoV-2 replication and rescue innate antiviral immunity. Collectively, these data support SARS2-NP SUMOylation is critical for SARS-CoV-2 virulence, and therefore provide a strategy to antagonize SARS-CoV-2.