Constitutive knockout of interleukin-6 ameliorates memory deficits and entorhinal astrocytosis in the MRL/lpr mouse model of neuropsychiatric lupus.

BACKGROUND: Neuropsychiatric lupus (NPSLE) describes the cognitive, memory, and affective emotional burdens faced by many lupus patients. While NPSLE's pathogenesis has not been fully elucidated, clinical imaging studies and cerebrospinal fluid (CSF) findings, namely elevated interleukin-6 (IL-6) levels, point to ongoing neuroinflammation in affected patients. Not only linked to systemic autoimmunity, IL-6 can also activate neurotoxic glial cells the brain. A prior pre-clinical study demonstrated that IL-6 can acutely induce a loss of sucrose preference; the present study sought to assess the necessity of chronic IL-6 exposure in the NPSLE-like disease of MRL/lpr lupus mice. METHODS: We quantified 1308 proteins in individual serum or pooled CSF samples from MRL/lpr and control MRL/mpj mice using protein microarrays. Serum IL-6 levels were plotted against characteristic NPSLE neurobehavioral deficits. Next, IL-6 knockout MRL/lpr (IL-6 KO; n = 15) and IL-6 wildtype MRL/lpr mice (IL-6 WT; n = 15) underwent behavioral testing, focusing on murine correlates of learning and memory deficits, depression, and anxiety. Using qPCR, we quantified the expression of inflammatory genes in the cortex and hippocampus of MRL/lpr IL-6 KO and WT mice. Immunofluorescent staining was performed to quantify numbers of microglia (Iba1 +) and astrocytes (GFAP +) in multiple cortical regions, the hippocampus, and the amygdala. RESULTS: MRL/lpr CSF analyses revealed increases in IL-17, MCP-1, TNF-α, and IL-6 (a priori p-value < 0.1). Serum levels of IL-6 correlated with learning and memory performance (R2 = 0.58; p = 0.03), but not motivated behavior, in MRL/lpr mice. Compared to MRL/lpr IL-6 WT, IL-6 KO mice exhibited improved novelty preference on object placement (45.4% vs 60.2%, p < 0.0001) and object recognition (48.9% vs 67.9%, p = 0.002) but equivalent performance in tests for anxiety-like disease and depression-like behavior. IL-6 KO mice displayed decreased cortical expression of aif1 (microglia; p = 0.049) and gfap (astrocytes; p = 0.044). Correspondingly, IL-6 KO mice exhibited decreased density of GFAP + cells compared to IL-6 WT in the entorhinal cortex (89 vs 148 cells/mm2, p = 0.037), an area vital to memory. CONCLUSIONS: The inflammatory composition of MRL/lpr CSF resembles that of human NPSLE patients. Increased in the CNS, IL-6 is necessary to the development of learning and memory deficits in the MRL/lpr model of NPSLE. Furthermore, the stimulation of entorhinal astrocytosis appears to be a key mechanism by which IL-6 promotes these behavioral deficits.

Epidermal oxysterols function as alarm substances in zebrafish.

Alarm substances signal imminent predation thread and enable anti-predation strategies. In shoaling fish, alarm cues diffuse from injured skins that induce intense fear and anti-predation behaviors in other members. While these "fear substances" are shown to be present in numerous fishes and thought to exist in roughly 8,000 Ostariophysan species, their chemical nature remains largely unknown. We posited that fish alarm cues comprise small compounds and induce specific behaviors characteristic of fish exposed to skin extracts. Using the behaviors as bioassays, we tracked the alarm function of zebrafish skin extract to two compounds, 24-methyl-5α-cholestane-3α,7α,12α,24,28-pentahydroxy 28-sulfate, an oxysterol sulfate, and 5α-cyprinol sulfate. At concentrations of less than one nanomolar, each compound induced anti-predator behaviors and increased cortisol levels in zebrafish. Their mixture, at the natural ratio, replicated the skin extract in eliciting the full suite of anti-predator behavior patterns. Our findings reveal a molecular mechanism whereby fish escape predation danger.

The NFκB Signaling Pathway Is Involved in the Pathophysiological Process of Preeclampsia.

The high prevalence of preeclampsia (PE) is a major cause of maternal and fetal mortality and affects the long-term prognosis of both mother and baby. Termination of pregnancy is currently the only effective treatment for PE, so there is an urgent need for research into its pathogenesis and the development of new therapeutic approaches. The NFκB family of transcription factors has an essential role in inflammation and innate immunity. In this review, we summarize the role of NFκB in normal and preeclampsia pregnancies, the role of NFκB in existing treatment strategies, and potential NFκB treatment strategies.

Triterpene Glycosides from the Viscera of Sea Cucumber Apostichopus japonicus with Embryotoxicity.

Sea cucumbers release chemical repellents from their guts when they are in danger from predators or a hostile environment. To investigate the chemical structure of the repellent, we collected and chemically analyzed the viscera of stressed sea cucumbers (Apostichopus japonicus) in the Yellow Sea of China. Two undescribed triterpene glycosides (1 and 2), together with a known cladoloside A (3), were identified and elucidated as 3ß-O-{2-O-[ß-d-quinovopyranosyl]-4-O-[3-O-methyl-ß-d-glucopyranosyl-(1→3)-ß-d-glucopyranosyl]-ß-d-xylopyranosyl}-holosta-9(11),25(26)-dien-16-one (1), 3ß-O-{2-O-[ß-d-glucopyranosyl]-4-O-[3-O-methyl-ß-d-glucopyranosyl-(1→3)-ß-d-glucopyranosyl]-ß-d-xylopyranosyl}-holosta-9(11),25(26)-dien-16-one (2), 3ß-O-{2-O-[3-O-methyl-ß-d-glucopyranosyl-(1→3)-ß-d-xylopyranosyl-(1→4)-ß-d-quinovopyranosyl]-ß-d-xylopyranosyl}-holosta-9(11),25(26)-dien-16-one (3) by spectroscopic analysis, including HR-ESI-MS and NMR spectra. Compounds 1, 2, and 3 display embryonic toxicity, as indicated by their 96-hour post-fertilization lethal concentration (96 hpf-LC50) values of 0.289, 0.536, and 0.091 µM, respectively. Our study discovered a class of triterpene glycoside compounds consisting of an oligosaccharide with four sugar units and a holostane aglycone. These compounds possess embryotoxicity and may serve as chemical defense molecules in marine benthic ecosystems.

Sea Cucumber Viscera Contains Novel Non-Holostane-Type Glycoside Toxins that Possess a Putative Chemical Defense Function.

Sea cucumbers frequently expel their guts in response to predators and an aversive environment, a behavior perceived as releasing repellents involved in chemical defense mechanisms. To investigate the chemical nature of the repellent, the viscera of stressed sea cucumbers (Apostichopus japonicus) in the Yellow Sea of China were collected and chemically analyzed. Two novel non-holostane triterpene glycosides were isolated, and the chemical structures were elucidated as 3ꞵ-O-[ꞵ-D-glucopyranosyl-(1→2)-ꞵ-D-xylopyranosyl]-(20S)-hydroxylanosta-7,25-diene-18(16)-lactone (1) and 3ꞵ-O-[ꞵ-D-quinovopyranosyl-(1→2)-ꞵ-D-xylopyranosyl]-(20S)-hydroxylanosta-7,25-diene-18(16)-lactone (2) by spectroscopic and mass-spectrometric analyses, exemplifying a triterpene glycoside constituent of an oligosaccharide containing two sugar-units and a non-holostane aglycone. Zebrafish embryos were exposed to various doses of 1 and 2 from 4 to 96 hpf. Compound 1 exposure showed 96 h-LC50 41.5 µM and an increased zebrafish mortality rates in roughly in a dose- and time-dependent manner. Compound 2, with different sugar substitution, exhibited no mortality and moderate teratogenic toxicity with a 96 h-EC50 of 173.5 µM. Zebrafish embryos exhibited teratogenic effects, such as reduced hatchability and total body length. The study found that triterpene saponin from A. japonicus viscera had acute toxicity in zebrafish embryos, indicating a potential chemical defense role in the marine ecosystem.

Autoimmune and neuropsychiatric phenotypes in a Mecp2 transgenic mouse model on C57BL/6 background.

Introduction: Systemic Lupus Erythematosus (SLE) impacts the central nervous system (CNS), leading to severe neurological and psychiatric manifestations known as neuropsychiatric lupus (NPSLE). The complexity and heterogeneity of clinical presentations of NPSLE impede direct investigation of disease etiology in patients. The limitations of existing mouse models developed for NPSLE obstruct a comprehensive understanding of this disease. Hence, the identification of a robust mouse model of NPSLE is desirable. Methods: C57BL/6 mice transgenic for human MeCP2 (B6.Mecp2Tg1) were phenotyped, including autoantibody profiling through antigen array, analysis of cellularity and activation of splenic immune cells through flow cytometry, and measurement of proteinuria. Behavioral tests were conducted to explore their neuropsychiatric functions. Immunofluorescence analyses were used to reveal altered neurogenesis and brain inflammation. Various signaling molecules implicated in lupus pathogenesis were examined using western blotting. Results: B6.Mecp2Tg1 exhibits elevated proteinuria and an overall increase in autoantibodies, particularly in female B6.Mecp2Tg1 mice. An increase in CD3+CD4+ T cells in the transgenic mice was observed, along with activated germinal center cells and activated CD11b+F4/80+ macrophages. Moreover, the transgenic mice displayed reduced locomotor activity, heightened anxiety and depression, and impaired short-term memory. Immunofluorescence analysis revealed IgG deposition and immune cell infiltration in the kidneys and brains of transgenic mice, as well as altered neurogenesis, activated microglia, and compromised blood-brain barrier (BBB). Additionally, protein levels of various key signaling molecules were found to be differentially modulated upon MeCP2 overexpression, including GFAP, BDNF, Albumin, NCoR1, mTOR, and NLRP3. Discussion: Collectively, this work demonstrates that B6.Mecp2Tg1 mice exhibit lupus-like phenotypes as well as robust CNS dysfunctions, suggesting its utility as a new animal model for NPSLE.

Seasonal distribution of caffeine in the Bohai Sea, Yellow Sea, and estuaries of Yantai City, China.

We employed a validated method to assess the seasonal variation and distribution of caffeine in the Bohai and Yellow Seas, as well as in Yantai urban estuaries and offshore region in northern China. Caffeine concentrations were highest during the summer in the Yellow Sea (1436.4 ng/L) and lowest in the Yantai urban offshore region during the spring and autumn and in the Yantai urban estuarine area and Bohai Sea during the winter (0.1 ng/L). There was significant variation in maximum caffeine levels among seasons across all regions examined, reaching a difference of 5980.5 times at the same sampling site between summer and winter. The caffeine concentration in the Yantai offshore region was significantly higher than in the Bohai and Yellow Seas. This study is the first investigation of seasonal fluctuations in the pollution levels of neurotoxic substances in the northern seas of China.

Proximity extension assay proteomics and renal single cell transcriptomics uncover novel urinary biomarkers for active lupus nephritis.

OBJECTIVE: To identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). METHODS: Urine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. RESULTS: Systems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). CONCLUSION: In addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.

Faslpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus.

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.

Novel biomarker discovery through comprehensive proteomic analysis of lupus mouse serum.

OBJECTIVES: The difficulty of monitoring organ-specific pathology in systemic lupus erythematosus (SLE) often complicates disease prognostication and treatment. Improved non-invasive biomarkers of active organ pathology, particularly lupus nephritis, would improve patient care. We sought to validate and apply a novel strategy to generate the first comprehensive serum proteome of a lupus mouse model and identify mechanism-linked lupus biomarker candidates for subsequent clinical investigation. METHODS: Serum levels of 1308 diverse proteins were measured in eight adult female MRL/lpr lupus mice and eight control MRL/mpj mice. ELISA validation confirmed fold increases. Protein enrichment analysis provided biological relevance to findings. Individual protein levels were correlated with measures of lymphoproliferative, humoral, and renal disease. RESULTS: Four hundred and six proteins were increased in MRL/lpr serum, including proteins increased in human SLE such as VCAM-1, L-selectin, TNFRI/II, TWEAK, CXCL13, MCP-1, IP-10, IL-10, and TARC. Newly validated proteins included IL-6, IL-17, and MDC. Results of pathway enrichment analysis, which revealed enhancement of cytokine signaling and immune cell migration, reinforced the similarity of the MRL/lpr disease to human pathology. Fifty-two proteins positively correlated with at least one measure of lupus-like disease. TECK, TSLP, PDGFR-alpha, and MDC were identified as novel candidate biomarkers of renal disease. CONCLUSIONS: We successfully validated a novel serum proteomic screening strategy in a spontaneous murine lupus model that highlighted potential new biomarkers. Importantly, we generated a comprehensive snapshot of the serum proteome which will enable identification of other candidates and serve as a reference for future mechanistic and therapeutic studies in lupus.

Adverse effects of type 2 diabetes mellitus on ovarian reserve and pregnancy outcomes during the assisted reproductive technology process.

Objective: To study the effect of type 2 diabetes mellitus(T2DM)on overall ovarian reserve and pregnancy outcomes during assisted reproductive technology (ART) among childbearing infertile women. Design: Retrospective cohort study. Setting: The Reproductive Medicine Special Hospital, The First Hospital of Lanzhou University, between January 2019 and December 2022. Patients: A total of 265 infertile female patients aged 20-45 years who underwent in vitro fertilization-embryo transfer (IVF-ET), intracytoplasmic sperm injection-embryo transfer (ICSI-ET), or rescue intracytoplasmic sperm injection-embryo transfer (RICSI-ET) in the first fresh cycle. Interventions: None. Main Outcome Measures: Serum Anti-Müllerian Hormone (AMH) levels, clinical pregnancy rate (CPR), live birth rate (LBR), and abortion rate (AR) in the T2DM group and non-T2DM group. Results: Patients with T2DM showed statistically decreased levels of AMH compared to the non-T2DM group. During ovarian stimulation, those with T2DM required significantly higher total and initial doses of gonadotropin (GN), although they had fewer retrieved oocytes and worse pregnancy outcomes than the non-T2DM group. Multivariate logistic regression analysis adjusting for confounding factors showed that T2DM alone was an independent risk factor for CPR and LBR (adjusted odds ratio [a OR], 0.458, adjusted 95% confidence interval [CI], 0.235-0.891, P = 0.022; a OR, 0.227, 95% CI, 0.101-0.513, P<0.001; respectively), and the abortion rate in the T2DM group was 3.316 times higher than the non-T2DM group(a OR, 3.316, 95%CI, 1.248-8.811, P = 0.016). Conclusion: Infertile patients with T2DM have decreased ovarian reserve, and T2DM has a deleterious impact on clinical pregnancy outcomes during the ART process compared with non-T2DM infertile women. Capsule: Infertile women with T2DM have decreased ovarian reserve and pregnancy outcomes during the assisted reproductive technology process compared with non-T2DM infertile women.

Dual-view transport of intensity phase imaging flow cytometry.

In this work, we design multi-parameter phase imaging flow cytometry based on dual-view transport of intensity (MPFC), which integrates phase imaging and microfluidics to a microscope, to obtain single-shot quantitative phase imaging on cells flowing in the microfluidic channel. The MPFC system has been proven with simple configuration, accurate phase retrieval, high imaging contrast, and real-time imaging and has been successfully employed not only in imaging, recognizing, and analyzing the flowing cells even with high-flowing velocities but also in tracking cell motilities, including rotation and binary rotation. Current results suggest that our proposed MPFC provides an effective tool for imaging and analyzing cells in microfluidics and can be potentially used in both fundamental and clinical studies.

Changes in physical activity and all-cause mortality in the oldest old population: Findings from the Chinese Longitudinal Healthy Longevity Survey (CLHLS).

BACKGROUND: Insufficient or decreasing physical activity is common in older adults. Most studies on physical activity changes and mortality were conducted in adults younger than 80 years old in developed countries. We aimed to investigate the relationship between changes in physical activity and longevity in the oldest old (80 years or older) population using the Chinese Longitudinal Healthy Longevity Survey. METHODS: Participants aged 80 or older at baseline were categorized into four groups: 1) remaining physically inactive (n = 14,287), 2) remaining physically active (n = 5411), 3) shifting from being inactive to active (n = 1364), and 4) shifting from being active to inactive (n = 1401). We fitted accelerated failure time Weibull survival regression models, adjusting for baseline sociodemographics, lifestyle factors and disease status. We further examined whether the associations differed by subgroups. RESULTS: A total of 15,707 participants died during follow-up (median duration of follow-up = 3.0 years). Compared with participants who remained physically inactive, those who remained active (fully adjusted event time ratio (ETR): 1.14, 95%CI: 1.11-1.17) or shifted from being inactive to active (fully adjusted ETR: 1.14, 95%CI: 1.08-1.20) had statistically significant longer survival time. No significant association was observed between remaining physically inactive and shifting from being active to inactive. Subgroup analyses showed consistent associations in nearly all strata. CONCLUSION: Maintaining frequent physical activity or shifting from being physically inactive to active was consistently associated with longer survival time in the oldest old population. Our findings provide evidence for encouraging older adults to regularly engage in physical activity to gain longevity benefits.

Development of a trace quantitative method to investigate caffeine distribution in the Yellow and Bohai Seas, China, and assessment of its potential neurotoxic effect on fish larvae.

Caffeine is an emerging contaminant in aquatic environments. The study utilized a validated method to investigate the presence and distribution of caffeine in the surface water of the Yellow and Bohai Seas, urban rivers, and the Yantai estuary area. The analytical method conforms to EPA guidelines and exhibits a limit of quantification that is 200 times lower than that of prior investigations. The study revealed that the highest concentration of 1436.4 ng/L was found in convergence of ocean currents in the Yellow and Bohai Seas. The presence of larger populations and the process of urban industrialization have been observed to result in elevated levels of caffeine in offshore regions, confirming that caffeine can serve as a potential indicator of anthropogenic contamination. Fish larvae exhibited hypoactivity in response to caffeine exposure at environmentally relevant concentrations. The study revealed that caffeine pollution can have adverse effects on marine and offshore ecosystems. This emphasizes the importance of decreasing neurotoxic pollution in the aquatic environment.

Microwave Regenerable Nickel, Zinc Co-doped Nitrogen-Coordinated Porous Carbon Catalyst for Nitrogen Fixation.

More than 90% of the global NH3 synthesis is dominated by the Haber-Bosch process, which consumes 2% of the worldwide energy and generates 1.44% of the global carbon emission. The electrochemical N2 reduction reaction (NRR) is regarded as an attractive alternative route to produce NH3 under mild reaction conditions, but the electrocatalysts suffer from the difficulty of N≡N cleavage. In this work, we report a leaf-like MOF-derived Ni/Zn bimetallic co-doped nitrogen-coordinated porous carbon (Ni/Zn-NPC) as a cost-effective NH3 synthesis electrocatalyst. The resultant electrocatalyst achieved a high NH3 production rate of 22.68 µg h-1 mgcat-1 at -1.0 V vs a reversible hydrogen electrode (RHE) in a 0.1 M Na2SO4 electrolyte. The Ni/Zn-NPC material can be called a microwave regenerable catalyst because microwave treatment has proven to be a crucial part of the multi-field coupling to detoxify and make the catalyst reactive, further improving its stability. Density functional theory (DFT) was chosen to explore the mechanism of Ni/Zn-NPC for NRR, providing a profound prediction of the structure of the active site and related reaction pathways and revealing that trace Ni doping optimizes the local coordination environment and N2 adsorption of Zn atoms.

Oxygen Vacancy Engineering of Fe-Doped NiMoO4 for Electrocatalytic N2 Fixation to NH3.

Electrochemical nitrogen reduction reaction (NRR) is a promising method for ammonia synthesis under ambient conditions. However, the NRR performance is limited to an extremely strong N≡N bond in N2 and the competing hydrogen evolution reaction. Introducing oxygen vacancies (OVs) has been considered as a forceful means to accelerate the sluggish NRR reaction kinetics. Herein, we reported the design of Fe-doped NiMoO4 catalysts for NRR. Fe doping can increase the amount of OVs in the catalyst and contribute to lattice strain enhancement, thereby leading to the improvement of the electron transport rate and catalytic active for NRR. In 0.1 M Na2SO4 solution, the 5% Fe-NiMoO4 catalyst achieves a NH3 yield rate of 15.36 µg h-1 mgcat.-1 and a Faradaic efficiency of 26.85% under -0.5 V versus RHE. Furthermore, the 5% Fe-NiMoO4 catalyst exhibits excellent stability (up to 13 h) during the reaction.

Analytical validation of urine ALCAM ELISA as a test for lupus nephritis.

OBJECTIVES: Urinary activated leukocyte cell adhesion molecule (uALCAM) is emerging as an outstanding biomarker for active lupus nephritis (ALN). This study aims to evaluate the analytic performance of the human ALCAM ELISA as an assay method to quantify uALCAM in patients with lupus nephritis. METHODS: A commercially available human ALCAM ELISA kit was validated for its analytical performance as per Clinical & Laboratory Standards Institute guidelines. RESULTS: Assaying 30 sets of serial dilutions of ALCAM exhibited an average CV of 10% and 97%-105% recovery. The assay also exhibited overall acceptable imprecision (CV < 20%) in day-to-day, site-to-site, and lot-to-lot reproducibility. The assay exhibited a reportable range from 4018 pg/ml down to 62 pg/ml with an r2 of 0.999 in urine, with a limit of detection of 16-45 pg/ml. Most tested chemicals did not interfere with the assay, and no diurnal variations were observed in uALCAM levels. uALCAM was stable for at least 3 months at -20°C or -80°C. CONCLUSION: This analytic-validated uALCAM ELISA may provide physicians with an accurate and reliable tool for use in early detection of renal involvement in lupus, routine outpatient monitoring of disease activity, and long-term prognostication.

Chemical cues in the interaction of herbivory-prey induce consumer-specific morphological and chemical defenses in Phaeocystis globosa.

Bloom-forming algae Phaeocystis globosa is one of the most successful blooming algae in the oceans due to its capacity to sense grazer-associated chemical cues and respond adaptively to these grazer-specific cues with opposing shifts in phenotype. P. globosa produces toxic and deterrent compounds as chemical defenses. However, the origin of the signals and underlying mechanisms that triggered the morphological and chemical defenses remain enigmatic. Rotifer was chosen to establish an herbivore-phytoplankton interaction with P. globosa. The influences of rotifer kairomone and conspecific-grazed cue on morphological and chemical defenses in P. globosa were investigated. As a result, rotifer kairomones elicited morphological defenses and broad-spectrum chemical defenses, whereas algae-grazed cues elicited morphological defenses and consumer-specific chemical defenses. According to multi-omics findings, the difference in hemolytic toxicity caused by different stimuli may be related to the upregulation of lipid metabolism pathways and increased lipid metabolite content, while the inhibition of colonial formation and development of P. globosa may be caused by the downscaled production and secretion of glycosaminoglycans. The study demonstrated that zooplankton consumption cues were recognized by intraspecific prey and elicited consumer-specific chemical defenses, highlighting the chemical ecology of herbivore-phytoplankton interactions in the marine ecosystem.

Tuning the Organ Tropism of Polymersome for Spleen-Selective Nanovaccine Delivery to Boost Cancer Immunotherapy.

The past few decades have witnessed explosive development in drug delivery systems. However, in vivo delivery suffers from non-specific distribution in non-targeted organs or tissues, which may cause undesired side effects and even genotoxicity. Here, a general strategy that enables tuning the tropism of polymersomes for liver- and spleen-selective delivery is reported. By using a library screening approach, spleen-targeted polymersome PH9-Aln-8020 and liver-targeted polymersome PA9-ZP3-5050 are identified accordingly. Meanwhile, the second near-infrared (NIR-II) fluorescence imaging allows for in vivo dynamic evaluation of their spatial and temporal accumulation in specific tissues. O ur findings indicate that both polymer composition and protein corona on the surface are essential to determine the in vivo fate of polymersomes and tendency for specific organs. Importantly, PH9-Aln-8020 is employed as a systemic nanocarrier to co-deliver the antigen and adjuvant, which remarkably boost splenic immune responses in acute myeloid leukemia, melanoma, and melanoma lung metastasis mouse models. This study may open a new frontier for polymersomes in organ-selective delivery and other biomedical applications.