Identification of Hypoxia-ALCAMhigh Macrophage- Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance.

Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAMhigh macrophages, and exhausted CD8+ T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF-1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAMhigh macrophages co-localize with exhausted CD8+ T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF-1ɑ inhibition reduces ALCAM expression in macrophages and exhausted CD8+ T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single-cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAMhigh macrophage-exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia-induced resistance in cancers.

Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.

Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PD-L1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type).

Mass spectrometry detection of organophosphorus pesticide adducts on butyrylcholinesterase and albumin.

This study established a method to prepare and detect OPs adducts on butyrylcholinesterase (BChE) and human serum albumin (HSA). OPs (methyl paraoxon, ethyl paraoxon, methyl parathion, parathion) were incubated with BChE or HSA in vitro, and the adducts of OPs-BChE or OPs-HSA were prepared and qualitatively analyzed by ultra-performance liquid chromatography data-dependent high-resolution tandem mass spectrometry (UPLC-ddHRMS/MS). The amounts of BChE and HSA in the incubating systems were varied and the resulting amounts of the adducts were determined using linear regression. OPs-BChE in the blood were isolated by immunomagnetic separation (IMS), and then digested into the OPs-nonapeptide adduct by pepsin. The proteins in the remaining blood plasma were precipitated and digested by pronase to OPs-tyrosines(OPs-Tyr), which were quantified by UPLC-ddHRMS/MS. 4 OPs-nonapeptides and 4 OPs-Tyr adducts were obtained through the process above. The relative mass deviation of incubated adducts between the actual and theoretical exact masses was less than 10 ppm, and further confirmed by fragmentation mass spectra analysis. Calibration curves were linear for all adducts with a coefficient of determination value (R2) ≥0.995. The limits of detection (LOD) and limits of quantification (LOQ) for adducts detected by MS ranged from 0.05 to 1.0 ng/mL, and from 0.1 to 2.0 ng/mL, respectively. The recovery percentages for adducts ranged from 76.1 % to 107.1 %, matrix effects ranged from 83.4 % to 102.1 %. The inter-day and intra-day precision were 6.1-10.1 % and 6.9-12.9 % for adducts. This study provides a new reference method for the detection of organophosphorus pesticide poisoning. In addition, two blood samples with organophosphorus poisoning were tested by the designed method, and the corresponding adducts were detected in both samples.

Predictive model of the efficiency of hematopoietic stem cell collection in patients with multiple myeloma and lymphoma based on multiple peripheral blood markers.

INTRODUCTION: Autologous hematopoietic stem cell transplantation (ASCT) has gained extensive application in the treatment of lymphoma and multiple myeloma (MM). Plenty of studies demonstrate that peripheral blood indicators could be considered potential predictive biomarkers for hematopoietic stem cells (HSCs) collection efficiency, including white blood cell count (WBC), monocyte count (Mono), platelet count (PLT), hematocrit, and hemoglobin levels. Currently, clinically practical predictive models based on these peripheral detection indicators to quickly, conveniently, and accurately predict collection efficiency are lacking. METHODS: In total, 139 patients with MM and lymphoma undergoing mobilization and collection of ASCT were retrospectively studied. The study endpoint was successful collection of autologous HSCs. We analyzed the effects of clinical characteristics and peripheral blood markers on collection success, and screened variables to establish a prediction model. We determined the optimal cutoff value of peripheral blood markers for predicting successful stem cell collection and the clinical value of a multi-marker prediction approach. We also established a prediction model for collection efficacy. RESULTS: Univariate and multivariate logistic regression analyses showed that the mobilization regimen, Mono, PLT, mononuclear cell count (MNC), and peripheral blood CD34+ cell count (PB CD34+ counts) were significant predictors of successful collection of peripheral blood stem cells (PBSC). Two predictive models were constructed based on the results of multivariate logistic analyses. Model 1 included the mobilization regimen, Mono, PLT, and MNC, whereas Model 2 included the mobilization regimen, Mono, PLT, MNC, and PB CD34+ counts. Receiver operating characteristic (ROC) curve analysis showed that the PB CD34+ counts, Model 1, and Model 2 could predict successful HSCs collection, with cutoff values of 26.92 × 106/L, 0.548, and 0.355, respectively. Model 1 could predict successful HSCs collection with a sensitivity of 84.62%, specificity of 75.73%, and area under the curve (AUC) of 0.863. Model 2 could predict successful HSCs collection with a sensitivity of 83.52%, specificity of 94.17%, and AUC of 0.946; thus, it was superior to the PB CD34+ counts alone. CONCLUSION: Our findings suggest that the combination of the mobilization regimen, Mono, PLT, MNC, and PB CD34+ counts before collection has predictive value for the efficacy of autologous HSCs collection in patients with MM and lymphoma. Using models based on these predictive markers may help to avoid over-collection and improve patient outcomes.

Combined effects of microplastics and pharmaceutical and personal care products on algae: A critical review.

Microplastics (MPs) and pharmaceuticals and personal care products (PPCPs) are ubiquitous in aquatic environments. Algae play an important role in aquatic environments. Thus, it is important to study the response of algae to combined exposure of MPs and PPCPs. Here, we review the effects of MPs and PPCPs on algae. First, the individual effects of MPs and PPCPs on algae were summarized. Second, the combined effects of MPs and PPCPs on algae were systematically analyzed. (1) Antagonism: ① when the MPs are too large to enter the algal cells, the adsorption of PPCPs onto MPs results in decreased the contact of MPs and PPCPs with algae; ② PPCPs and MPs have opposing actions on the same biological target; ③ MPs increase the activity of metabolic enzymes in algae, thus promoting the PPCP degradation. (2) Synergy: ① when the MPs are small enough to enter algal cells, the adsorption of PPCPs on MPs promotes the entry of PPCPs; ② when MPs are negatively charged, the adsorption of positively charged PPCPs by MPs decreases the electrostatic repulsion, increasing the interaction between algae and MPs; ③ complementary modes of action between MPs and PPCPs show combined effects on the same biological target. Third, the relative importance of the factors that impact the combined effects are evaluated using the random forest model decreased in the following order: PPCP types > algal species > MP size > MP concentration > MP types > exposure time. Finally, future directions for the combined effects of MPs and PPCPs are proposed, which will facilitate a better understanding of the environmental fate and risks of both MPs and PPCPs.

Disproportionality Analysis of Nusinersen in the Food and Drug Administration Adverse Event Reporting System: A Real-World Postmarketing Pharmacovigilance Assessment.

BACKGROUND: Nusinersen is the first drug for precise targeted therapy of spinal muscular atrophy, a rare disease that occurs in one of 10,000 to 20,000 live births. Therefore, thorough and comprehensive reports on the safety of nusinersen in large, real-world populations are necessary. This study aimed to mine the adverse event (AE) signals related to nusinersen through the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: We extracted reports of AEs with nusinersen as the primary suspect from FAERS between December 2016 and March 2023. Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) were used for AE signal detection. RESULTS: We extracted a total of 4807 suspected AE cases with nusinersen as the primary suspect from the FAERS database. Among them, 106 positive signals were obtained using the ROR and BCPNN. The highest frequency reported systemic organ class was general disorders and administration site conditions. Common clinical AEs of nusinersen were detected in the FAERS database, such as pneumonia, vomiting, back pain, headache, pyrexia, and post-lumbar puncture syndrome. In addition, we identified potential unexpected serious AEs through disproportionality analysis, including sepsis, seizure, epilepsy, brain injury, cardiorespiratory arrest, and cardiac arrest. CONCLUSIONS: Analyzing large amounts of real-world data from the FAERS database, we identified potential new AEs of nusinersen by disproportionate analysis. It is advantageous for health care professionals and pharmacists to concentrate on effectively managing high-risk AEs of nusinersen, improve medication levels in clinical settings, and uphold patient medication safety.

M6A modification in cardiovascular disease: With a focus on programmed cell death.

N6-methyladenosine (m6A) methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years. Cardiovascular diseases (CVDs) are a leading cause of death globally. Emerging evidence demonstrates that RNA modifications, such as the m6A modification, are associated with the development and progression of many diseases, including CVDs. An increasing body of studies has indicated that programmed cell death (PCD) plays a vital role in CVDs. However, the molecular mechanisms underlying m6A modification and PCD in CVDs remain poorly understood. Herein, elaborating on the highly complex connections between the m6A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m6A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs. There is great potential for clinical application.

VEGFA locus amplification potentially predicts a favorable prognosis in gastric adenocarcinoma.

Gastric adenocarcinoma harbors a range of genetic and epigenetic alterations, including alterations in DNA copy number. However, the key genes that promote the development and progression of gastric adenocarcinoma remain unknown. To identify the key genes amplified in gastric adenocarcinoma, we performed array comparative genomic hybridization on formalin-fixed paraffin-embedded samples of surgically resected gastric adenocarcinoma. We detected a relatively wide genomic region of gain containing the vascular endothelial growth factor A (VEGFA) gene locus on chromosome 6p. VEGFA locus amplification in gastric adenocarcinoma was validated by fluorescence in situ hybridization. To assess the frequency of VEGFA locus amplification in gastric adenocarcinoma, we conducted multiplex ligation-dependent probe amplification (MLPA) assays using homemade probes designed to target the VEGFA gene locus. Eleven of 54 (20 %) gastric adenocarcinomas with MLPA values above 1.3 were defined as having VEGFA locus amplification. Next, we investigated the effect of VEGFA locus amplification on the clinicopathological characteristics of gastric adenocarcinomas and patient survival. VEGFA locus amplification demonstrated a significantly close relationship with pathological intestinal type and lower rates of venous invasion Furthermore, a Kaplan-Meier analysis showed that patients with VEGFA locus amplification had significantly better overall survival than those without amplification (p = 0.038), particularly in the long-term follow-up period. In conclusion, VEGFA locus amplification can predict modest aggressiveness and good outcomes, suggesting the possibility that it may predict a favorable prognosis in patients with gastric adenocarcinoma.

Tetracycline-induced gut community dysbiosis and Israeli Acute Paralysis Virus infection synergistically negatively affect honeybees.

Antibiotics are frequently employed to control bacterial diseases in honeybees, but their broad-spectrum action can disrupt the delicate balance of the gut microbiome, leading to dysbiosis. This imbalance in the gut microbiota of honeybees adversely affects their physiological health and weakens their resistance to pathogens, including viruses that significantly threaten honeybee health. In this study, we investigated whether tetracycline-induced gut microbiome dysbiosis promotes the replication of Israeli acute paralysis virus (IAPV), a key virus associated with colony losses and whether IAPV infection exacerbates gut microbiome dysbiosis. Our results demonstrated that tetracycline-induced gut microbiome dysbiosis increases the susceptibility of honeybees to IAPV infection. The viral titer in worker bees with antibiotic-induced gut microbiome dysbiosis prior to IAPV inoculation was significantly higher than in those merely inoculated with IAPV. Furthermore, we observed a synergistic effect between tetracycline and IAPV on the disruption of the honeybee gut microbiome balance. The progression of IAPV replication could, in turn, exacerbate antibiotic-induced gut microbiome dysbiosis in honeybees. Our research provides novel insights into the role of the gut microbiota in host-virus interactions, emphasizing the complex interplay between antibiotic use, gut microbiome health, and viral susceptibility in honeybees. We highlight the crucial role of a balanced gut microbiota in honey bees for their immune response against pathogens and emphasize the importance of careful, safe antibiotic use in beekeeping to protect these beneficial microbes.

Developing a deep learning model for predicting ovarian cancer in Ovarian-Adnexal Reporting and Data System Ultrasound (O-RADS US) Category 4 lesions: A multicenter study.

PURPOSE: To develop a deep learning (DL) model for differentiating between benign and malignant ovarian tumors of Ovarian-Adnexal Reporting and Data System Ultrasound (O-RADS US) Category 4 lesions, and validate its diagnostic performance. METHODS: A retrospective analysis of 1619 US images obtained from three centers from December 2014 to March 2023. DeepLabV3 and YOLOv8 were jointly used to segment, classify, and detect ovarian tumors. Precision and recall and area under the receiver operating characteristic curve (AUC) were employed to assess the model performance. RESULTS: A total of 519 patients (including 269 benign and 250 malignant masses) were enrolled in the study. The number of women included in the training, validation, and test cohorts was 426, 46, and 47, respectively. The detection models exhibited an average precision of 98.68% (95% CI: 0.95-0.99) for benign masses and 96.23% (95% CI: 0.92-0.98) for malignant masses. Moreover, in the training set, the AUC was 0.96 (95% CI: 0.94-0.97), whereas in the validation set, the AUC was 0.93(95% CI: 0.89-0.94) and 0.95 (95% CI: 0.91-0.96) in the test set. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive values for the training set were 0.943,0.957,0.951,0.966, and 0.936, respectively, whereas those for the validation set were 0.905,0.935, 0.935,0.919, and 0.931, respectively. In addition, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for the test set were 0.925, 0.955, 0.941, 0.956, and 0.927, respectively. CONCLUSION: The constructed DL model exhibited high diagnostic performance in distinguishing benign and malignant ovarian tumors in O-RADS US category 4 lesions.

HIV associated lymphoma: latest updates from 2023 ASH annual meeting.

The incidence, clinical characteristics, and prognostic factors of HIV-associated lymphoma remain poorly defined compared to HIV-negative lymphoma. Currently, there are no standard guidelines for treatment of these patients. We summarized several latest reports of HIV associated lymphoma from the 2023 ASH Annual Meeting (ASH2023).

Human cytomegalovirus infection impairs neural differentiation via repressing sterol regulatory element binding protein 2-mediated cholesterol biosynthesis.

Congenital human cytomegalovirus (HCMV) infection is a major cause of abnormalities and disorders in the central nervous system (CNS) and/or the peripheral nervous system (PNS). However, the complete pathogenesis of neural differentiation disorders caused by HCMV infection remains to be fully elucidated. Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells (MSCs) with a high proliferation and neurogenic differentiation capacity. Since SHEDs originate from the neural crest of the early embryonic ectoderm, SHEDs were hypothesized to serve as a promising cell line for investigating the pathogenesis of neural differentiation disorders in the PNS caused by congenital HCMV infection. In this work, SHEDs were demonstrated to be fully permissive to HCMV infection and the virus was able to complete its life cycle in SHEDs. Under neurogenic inductive conditions, HCMV infection of SHEDs caused an abnormal neural morphology. The expression of stem/neural cell markers was also disturbed by HCMV infection. The impairment of neural differentiation was mainly due to a reduction of intracellular cholesterol levels caused by HCMV infection. Sterol regulatory element binding protein-2 (SREBP2) is a critical transcription regulator that guides cholesterol synthesis. HCMV infection was shown to hinder the migration of SREBP2 into nucleus and resulted in perinuclear aggregations of SREBP2 during neural differentiation. Our findings provide new insights into the prevention and treatment of nervous system diseases caused by congenital HCMV infection.

Low Macular Pigment Optical Density Is Associated with Manifest Primary Open-Angle Glaucoma in Older Women.

Background: Lower density of carotenoids lutein and zeaxanthin (L/Z) in the macula (i.e., macular pigment) has been linked to greater risk for age-related eye disease. Objectives: We evaluated whether macular pigment optical density (MPOD) was associated with manifest primary open-angle glaucoma (POAG) among older women in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2). Methods: MPOD was measured with customized heterochromatic flicker photometry in women who attended CAREDS2 (2016-2019) and CAREDS1 (2001-2004) study visits. Manifest POAG at CAREDS2 was assessed using visual fields, disc photos, optical coherence tomography, and medical records. Age-adjusted linear and logistic regression models were used to investigate the cross-sectional association between POAG and MPOD at CAREDS2, and MPOD measured 15 years earlier at CAREDS1. Results: Among 426 CAREDS2 participants (mean age: 80 y; range: 69-98 y), 26 eyes with manifest POAG from 26 participants were identified. Glaucomatous eyes had 25% lower MPOD compared to nonglaucomatous eyes [mean (SE): 0.40 (0.05) compared with 0.53 (0.01)] optical density units (ODU), respectively (P = 0.01). Compared with MPOD quartile 1, odds for POAG were lower for women in quartiles 2-4 (P-trend = 0.01). After excluding eyes with age-related macular degeneration, associations were similar but not statistically significant (P-trend = 0.16). Results were similar for MPOD measured at CAREDS1. Conclusions: Our results add to growing evidence that low MPOD may be a novel glaucoma risk factor and support further studies to assess the utility of dietary interventions for glaucoma prevention.

A pH ultra-sensitive hydrated iridium oxyhydroxide films electrochemical sensor for label-free detection of Vibrio parahaemolyticus.

Vibrio parahaemolyticus (V. parahaemolyticus) is a major foodborne pathogen, which can cause serious foodborne illnesses like diarrhoea. Rapid on-site detection of foodborne pathogens is an ideal way to respond to foodborne illnesses. Herein, we provide an electrochemical sensor for rapid on-site detection. This sensor utilized a pH-sensitive metal-oxide material for the concurrent isothermal amplification and label-free detection of nucleic acids. Based on a pH-sensitive hydrated iridium oxide oxyhydroxide film (HIROF), the electrode transforms the hydrogen ion compound generated during nucleic acid amplification into potential, so as to achieve a real-time detection. The results can be transmitted to a smartphone via Bluetooth. Moreover, HIROF was applied in nucleic acid device detection, with a super-Nernst sensitivity of 77.6 mV/pH in the pH range of 6.0-8.5, and the sensitivity showed the best results so far. Detection of V. parahaemolyticus by this novel method showed a detection limit of 1.0 × 103 CFU/mL, while the time consumption was only 30 min, outperforming real-time fluorescence loop-mediated isothermal amplification (LAMP). Therefore, the characteristics of compact, portable, and fast make the sensor more widely used in on-site detection.

An Energy Efficient and Temperature Stable Digital FLL-based Wakeup Timer with Time-Domain Temperature Compensation.

This brief presents an on-chip digital intensive frequency-locked loop (DFLL)-based wakeup timer with a time-domain temperature compensation featuring a embedded temperature sensor. The proposed compensation exploits the deterministic temperature characteristics of two complementary resistors to stabilize the timer's operating frequency across the temperature by modulating the activation time window of the two resistors. As a result, it achieves a fine trimming step (± 1 ppm), allowing a small frequency error after trimming (<± 20 ppm). By reusing the DFLL structure, instead of employing a dedicated sensor, the temperature sensing operates in the background with negligible power (2 %) and hardware overhead (< 1 %). The chip is fabricated in 40 nm CMOS, resulting in 0.9 pJ/cycle energy efficiency while achieving 8 ppm/ºC from -40ºC to 80ºC.

Blood pressure is associated with knee pain severity in middle-aged and elderly individuals with or at risks for osteoarthritis: data from the Osteoarthritis Initiative.

BACKGROUND: Hypertension is a common comorbidity of osteoarthritis (OA). Joint pain is the main clinical manifestation of OA. Knowledge about the relationship between hypertension and OA pain is limited. This study aimed to investigate whether blood pressure parameters are associated with knee pain severity in individuals with or at risks for OA. METHODS: Our sample consisted of 2598 subjects (60.7% female, aged 45-79 years) collected from the Osteoarthritis Initiative. Blood pressure parameters included blood pressure stage, systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP). Radiographic evaluation using Kellgren-Lawrence system and pain severity evaluation using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), and Numeric Rating Scale (NRS) were performed for right knee. Linear regression was used to examine the relationship between blood pressure parameters and knee pain severity. RESULTS: For the overall sample, blood pressure stage, SBP, and PP were positively correlated with WOMAC and NRS pain scores when adjusting for age, sex, and body mass index (BMI) (p ≤ 0.024) and were inversely correlated with KOOS score (p ≤ 0.004). After further adjusting for all covariates, PP remained a positive correlation with WOMAC score (p = 0.037) while other associations between blood pressure parameters and pain scores did not reach the statistical significance. In female, higher blood pressure stage, SBP, and PP were significantly associated with increased WOMAC and NRS scores and decreased KOOS score after adjustments of age and BMI (p ≤ 0.018). When adjusting for all covariates, the correlations of PP with WOMAC, KOOS and NRS scores remained significant (p = 0.008-0.049). In male sample, SBP was positively correlated with WOMAC score when adjusting for age and BMI (p = 0.050), but other associations between blood pressure parameters and pain scores were not statistically significant. No significant correlation was observed in male when further adjusting for other covariates. CONCLUSIONS: Increased PP is a risk factor for knee pain and mainly affects females, which suggested that controlling PP may be beneficial in preventing or reducing knee pain in females with or at risks for OA.

Litsea cubeba essential oil: Extraction, chemical composition, antioxidant and antimicrobial properties, and applications in the food industry.

Litsea cubeba (Lour.) Pers. (Lauraceae) is a valuable industrial crop that produces essential oil. The essential oil extracted from L. cubeba (LCEO) has broad-spectrum antimicrobial activity and high antioxidant properties, with great potential for increased usage in the food industry. This literature review summarizes the extraction techniques, content and chemical composition, and antioxidant and antimicrobial activities of LCEO, with a focus on its usage in the food industry, which is an area of substantial recent research. The chemical composition of LCEO, which is affected by various factors, plays a key role in determining its bioactivity and usage in food. The potent antimicrobial activity of LCEO against various foodborne pathogens gives it potential for use in food packaging and preservation to extend shelf life. Future research challenges include the elucidation of the role and mechanism of individual chemical components of LCEO in inhibiting specific foodborne microorganisms; cultivar development to produce germplasm that yields essential oils of the desired chemical composition; and the development of commercial products that can be used in the food industry.

Lower energy intake associated with higher risk of cardiovascular mortality in chronic kidney disease patients on a low-protein diets.

OBJECTIVE: An increasing number of studies shown that inadequate energy intake causes an increase in adverse incidents in chronic kidney disease (CKD) patients on low-protein diets (LPD). The study aimed to investigate the relationship between energy intake and cardiovascular mortality in CKD patients on a LPD. METHODS: This was a cross-sectional study, a total of 4264 CKD patients were enrolled from the NHANES database between 2009 and 2018. Restricted cubic spline plots and Cox regression analysis were used to analyze the association between energy intake and cardiovascular mortality in CKD patients on a LPD. Additionally, a nomogram was constructed to estimate cardiovascular survival in CKD patients on a LPD. RESULTS: Among CKD patients on a LPD in the United States, 90.05% had an energy intake of less than 25 kcal/kg/day, compared to 36.94% in CKD patients on a non-LPD. Energy intake and cardiovascular mortality showed a linear relationship in CKD patients on a LPD, while a 'U-shaped' relationship was observed in CKD patients on a non-LPD. Multifactorial Cox regression models revealed that for Per-standard deviation (Per-SD) decrement in energy intake, the risk of cardiovascular mortality increased by 41% (HR: 1.41, 95% CI: 1.12, 1.77; P = 0.004) in CKD patients on a LPD. The concordance index of the nomogram was 0.79 (95% CI, 0.75, 0.83). CONCLUSION: CKD patients, especially those on a LPD, have significantly inadequate energy intake. Lower energy intake is associated with higher cardiovascular mortality in CKD patients on a LPD.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation.

Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.

Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvß3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvß3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvß3. Activation of the integrin αvß3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.