Genome-wide identification and analyses of ZmAPY genes reveal their roles involved in maize development and abiotic stress responses.

Apyrase is a class of enzyme that catalyzes the hydrolysis of nucleoside triphosphates/diphosphates (NTP/NDP), which widely involved in regulation of plant growth and stress responses. However, apyrase family genes in maize have not been identified, and their characteristics and functions are largely unknown. In this study, we identified 16 apyrases (named as ZmAPY1-ZmAPY16) in maize genome, and analyzed their phylogenetic relationships, gene structures, chromosomal distribution, upstream regulatory transcription factors and expression patterns. Analysis of the transcriptome database unveiled tissue-specific and abiotic stress-responsive expression of ZmAPY genes in maize. qPCR analysis further confirmed their responsiveness to drought, heat, and cold stresses. Association analyses indicated that variations of ZmAPY5 and ZmAPY16 may regulate maize agronomic traits and drought responses. Our findings shed light on the molecular characteristics and evolutionary history of maize apyrase genes, highlighting their roles in various biological processes and stress responses. This study forms a basis for further exploration of apyrase functions in maize. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01474-9.

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer.

Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. SIGNIFICANCE: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.

Higher-order singularities in phase-tracked electromechanical oscillators.

Singularities ubiquitously exist in different fields and play a pivotal role in probing the fundamental laws of physics and developing highly sensitive sensors. Nevertheless, achieving higher-order (≥3) singularities, which exhibit superior performance, typically necessitates meticulous tuning of multiple (≥3) coupled degrees of freedom or additional introduction of nonlinear potential energies. Here we propose theoretically and confirm using mechanics experiments, the existence of an unexplored cusp singularity in the phase-tracked (PhT) steady states of a pair of coherently coupled mechanical modes without the need for multiple (≥3) coupled modes or nonlinear potential energies. By manipulating the PhT singularities in an electrostatically tunable micromechanical system, we demonstrate an enhanced cubic-root response to frequency perturbations. This study introduces a new phase-tracking method for studying interacting systems and sheds new light on building and engineering advanced singular devices with simple and well-controllable elements, with potential applications in precision metrology, portable nonreciprocal devices, and on-chip mechanical computing.

Gene editing of ZmGA20ox3 improves plant architecture and drought tolerance in maize.

KEY MESSAGE: Editing ZmGA20ox3 can achieve the effect similar to applying Cycocel, which can reduce maize plant height and enhance stress resistance. Drought stress, a major plant abiotic stress, is capable of suppressing crop yield performance severely. However, the trade-off between crop drought tolerance and yield performance turns out to be significantly challenging in drought-resistant crop breeding. Several phytohormones [e.g., gibberellin (GA)] have been reported to play a certain role in plant drought response, which also take on critical significance in plant growth and development. In this study, the loss-of-function mutations of GA biosynthesis enzyme ZmGA20ox3 were produced using the CRISPR-Cas9 system in maize. As indicated by the result of 2-year field trials, the above-mentioned mutants displayed semi-dwarfing phenotype with the decrease of GA1, and almost no yield loss was generated compared with wild-type (WT) plants. Interestingly, as revealed by the transcriptome analysis, differential expressed genes (DEGs) were notably enriched in abiotic stress progresses, and biochemical tests indicated the significantly increased ABA, JA, and DIMBOA levels in mutants, suggesting that ZmGA20ox3 may take on vital significance in stress response in maize. The in-depth analysis suggested that the loss function of ZmGA20ox3 can enhance drought tolerance in maize seedling, reduce Anthesis-Silking Interval (ASI) delay while decreasing the yield loss significantly in the field under drought conditions. The results of this study supported that regulating ZmGA20ox3 can improve plant height while enhancing drought resistance in maize, thus serving as a novel method for drought-resistant genetic improvement in maize.

Exploring the roles of ZmARM gene family in maize development and abiotic stress response.

Armadillo (ARM) was a gene family important to plants, with crucial roles in regulating plant growth, development, and stress responses. However, the properties and functions of ARM family members in maize had received limited attention. Therefore, this study employed bioinformatics methods to analyze the structure and evolution of ARM-repeat protein family members in maize. The maize (Zea mays L.) genome contains 56 ARM genes distributed over 10 chromosomes, and collinearity analysis indicated 12 pairs of linkage between them. Analysis of the physicochemical properties of ARM proteins showed that most of these proteins were acidic and hydrophilic. According to the number and evolutionary analysis of the ARM genes, the ARM genes in maize can be divided into eight subgroups, and the gene structure and conserved motifs showed similar compositions in each group. The findings shed light on the significant roles of 56 ZmARM domain genes in development and abiotic stress, particularly drought stress. RNA-Seq and qRT-PCR analysis revealed that drought stress exerts an influence on specific members of the ZmARM family, such as ZmARM4, ZmARM12, ZmARM34 and ZmARM36. The comprehensive profiling of these genes in the whole genome, combined with expression analysis, establishes a foundation for further exploration of plant gene function in the context of abiotic stress and reproductive development.

Analysis of periodic pulsating blood flow of fractional Maxwell power-law fluid in carotid artery with elastic vessel wall.

Hemodynamic analysis reveals a highly significant effect on the prevention, diagnosis, and treatment of human vascular diseases. This article goes deeply into the periodic pulsatile blood flow in the carotid artery with an elastic vessel wall. In view of blood rheological experimental data, the constitutive equation of fractional Maxwell power-law fluid with yield stress, which can describe the four characteristics of yield stress, viscoelasticity, shear thinning, and thixotropy is established. Meanwhile, drawing support from the data of pulsatile flow, the finite Fourier series of pressure gradient with a period of 1 s has been proposed. Leading into Hooke's law can build the fluid-structure coupling boundary condition of blood flow and elastic vessel wall. The numerical solutions are got hold of finite difference method integrated with the newly developed L1-algorithm, and their convergence and stability of which are verified. The axial velocities of blood under different constitutive relationships are compared. The results throw light that other constitutive relationships underestimate the velocity of blood. Furthermore, the flow rate and wall shear stress on different fluid are calculated. It can be concluded that compared with Bingham fluid, the maximum and minimum flow rate/wall shear stress of fractional Maxwell power-law fluid with yield stress increases by 19% and 32%, respectively. The flow rate lags behind the pressure gradient and has time delay effect, on the contrary, the velocity of blood vessel wall is keeping pace with the pressure gradient. The effects of relevant physical parameters on velocity are discussed. In addition, the spatiotemporal distribution of blood flow in cerebral artery and femoral artery are analyzed.

Fractional Maxwell power-law fluid is proposed to describe hemorheology property.Based on Hooke's law, the boundary condition of elastic wall is established.The finite Fourier series of pulsating pressure gradient has been fitted firstly.Blood flow promoted by the pressure gradient has a hysteresis effect.The velocity of blood vessel wall is keeping pace with the pressure gradient.

Proteome profiling of hippocampus reveals the neuroprotective effect of mild hypothermia on global cerebral ischemia-reperfusion injury in rats.

Cerebral ischemia is one of the leading causes of disability and mortality worldwide. Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (IR) injury. In this study, a rat model of global cerebral I/R injury was established via Pulsinelli's four-vessel occlusion (4-VO) method. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis were employed to examine the ipsilateral hippocampus proteome profiles of rats with/without MH (32 °C) treatment after IR injury. Totally 2 122 proteins were identified, among which 153 proteins were significantly changed associated with MH (n = 7 per group, fold change-1.5, p < 0.05). GO annotation of the differentially expressed proteins (DEPs) revealed that cellular oxidant detoxification, response to zinc ions, aging, oxygen transport, negative regulation of catalytic activity, response to hypoxia, regulation of protein phosphorylation, and cellular response to vascular endothelial growth factor stimulus were significantly enriched with MH treatment. The KEGG analysis indicated that metabolic pathways, thermogenesis, pathways of neurodegeneration, chemical carcinogenesis-reactive oxygen species, fluid shear stress and atherosclerosis, and protein processing in endoplasmic reticulum were significantly enriched with MH treatment. Importantly, changes in 16 DEPs were reversed by MH treatment. Among them, VCAM-1, S100A8, CaMKK2 and MKK7 were verified as potential markers associated with MH neuroprotection by Western blot analysis. This study is one of the first to investigate the neuroprotective effects of MH on the hippocampal proteome of experimental models of cerebral IR injury. These DEPs may be involved in the most fundamental molecular mechanisms of MH neuroprotection, and provide a scientific foundation for further promotion of reparative strategies in cerebral IR injury.

[The expression of autophagy-related proteins in peripheral blood mononuclear cells of patients with lupus nephritis is upregulated and related to kidney damage].

Objective To identify the relationship between nephritis activity, autophagy and inflammation in patients with SLE. Methods Western blot analysis was used to detect the expression of microtubule-associated protein 1 light chain 3 (LC3) and P62 in peripheral blood mononuclear cells (PBMCs) of SLE patients with lupus nephritis and non-lupus nephritis patients. Tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) in the serum of SLE patients were determined by ELISA. The correlation between LC3II/LC3I ratio and SLE disease activity score (SLEDAI), urinary protein, TNF-α and IFN-γ levels was analyzed by Pearson method. Results The expression of LC3 was increased and P62 was decreased in SLE patients. TNF-α and IFN-γ were increased in the serum of SLE patients. LC3II/LC3I ratio was positively correlated with SLEDAI (r=0.4560), 24 hour urine protein (r=0.3753), IFN-γ (r=0.5685), but had no correlation with TNF-α (r=0.04 683). Conclusion Autophagy is found in PBMCs of SLE, and the autophagy is correlated with renal damage and inflammation in patients with lupus nephritis.

Ameliorative effect of mussel-derived ACE inhibitory peptides on spontaneous hypertension rats.

PURPOSE: The purpose of this study was to prepare the novel mussel-derived ACE inhibitory peptides (MEPs) by enzymatic hydrolysis of Mytilus edulis and investigate their antihypertensive effects in vivo. METHODS: After assessing the stability of MEPs in vitro, we investigated the effect of MEPs on hypertension using spontaneously hypertensive rats (SHRs). Subsequently, MEPs were purified and identified by ultrafiltration, gel filtration chromatography and liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Our study demonstrated that MEPs could keep stable ACE inhibitory activity after treatment with heat, acid, alkali, metal ions and simulated gastrointestinal digestive fluid. Additionally, the animal experiments showed that both short-term and long-term treatment with MEPs resulted in a significant reduction in systolic and diastolic blood pressure in SHRs. Mechanistically, the results suggested that MEPs could reduce vascular remodeling, regulate renin-angiotensin system (RAS), and inhibit kidney and myocardial fibrosis. Finally, we isolated and identified five peptides from MEPs, with the peptide Ile-Leu-Thr-Glu-Arg showed the highest ACE inhibition rate. CONCLUSION: Our findings demonstrate the potential use of MEPs as active components in functional foods designed to lower blood pressure.

Efficacy and safety of immune checkpoint inhibitors in young adults with metastatic melanoma.

BACKGROUND: The integration of immune checkpoint inhibitors (ICI) for the treatment of melanoma has resulted in remarkable and durable responses. Given the potential role of immunosenescence, age may contribute to differential ICI efficacy and toxicity. While older patients have been studied in detail, outcomes from ICI in young patients (≤40 years) are not well characterised. METHODS: We performed a multi-institutional, retrospective study of patients with advanced melanoma treated with anti-PD-1 monotherapy or ICI combination (ipilimumab and anti-PD-1). Response rates, survival, and toxicities were examined based on age comparing those under 40 years of age with older patients (age 41-70 and ≥ 71 years). RESULTS: A total of 676 patients were included: 190 patients (28%) aged ≤40 years, 313 (46%) between ages 41-70, and 173 patients (26%) aged ≥71. Patients ≤40 years had higher response rates (53% vs 38%, p = 0.035) and improved progression-free survival (median 13.7 vs 4.0 months, p = 0.032) with combination ICI compared to monotherapy. Progression-free survival was similar among groups while overall survival was inferior in patients >70 years, who had low response rates to combination therapy (28%). ICIs had a similar incidence of severe toxicities, though hepatotoxicity was particularly common in younger patients vs. patients >40 with monotherapy (9% vs. 2%, p = 0.007) or combination ICI (37% vs. 10%, p < 0.001). CONCLUSIONS: ICIs had comparable efficacy between younger and older patients, although outcomes were superior with combination ICI compared to monotherapy in patients aged ≤40 years. Toxicity incidence was similar across age groups, though organs affected were substantially different.

Magnetic and Dielectric Switchings Actuated by the Rotation of the Picoline Ligand in an Iron-Based Dinuclear Phase-Transition Complex.

Multifunctional materials with switchable magnetic and dielectric properties are crucial for the development of memory and sensor devices. Herein, we report a methoxy-bridged dinuclear iron-pyridyl complex [Fe2(4-picoline)4(NCS)4(µ-OCH3)2] (1), which shows simultaneous thermal-induced magnetic and dielectric switchings. Within the phase-transition temperature range, both magnetic switching and the dielectric anomaly were detected, in which the thermal hysteresis loops were 23 and 21 K, respectively. Detailed structural analyses revealed that these simultaneous switchings were rooted in the flexible rotatable ligands, which were actuated by readjusting the π-π intermolecular interactions between the pyridine ligands in the trans positions of the metal centers. These results were comprehensively investigated both experimentally and theoretically. This study presents a new guideline to control both the magnetic and dielectric properties of molecular complexes by external stimuli.

The role of transposon inverted repeats in balancing drought tolerance and yield-related traits in maize.

The genomic basis underlying the selection for environmental adaptation and yield-related traits in maize remains poorly understood. Here we carried out genome-wide profiling of the small RNA (sRNA) transcriptome (sRNAome) and transcriptome landscapes of a global maize diversity panel under dry and wet conditions and uncover dozens of environment-specific regulatory hotspots. Transgenic and molecular studies of Drought-Related Environment-specific Super eQTL Hotspot on chromosome 8 (DRESH8) and ZmMYBR38, a target of DRESH8-derived small interfering RNAs, revealed a transposable element-mediated inverted repeats (TE-IR)-derived sRNA- and gene-regulatory network that balances plant drought tolerance with yield-related traits. A genome-wide scan revealed that TE-IRs associate with drought response and yield-related traits that were positively selected and expanded during maize domestication. These results indicate that TE-IR-mediated posttranscriptional regulation is a key molecular mechanism underlying the tradeoff between crop environmental adaptation and yield-related traits, providing potential genomic targets for the breeding of crops with greater stress tolerance but uncompromised yield.

MicroRNA-588 regulates the invasive, migratory and vasculogenic mimicry-forming abilities of hypoxic glioma cells by targeting ROBO1.

BACKGROUND: The microenvironment of hypoxia is an important factor contributing to the development of glioblastoma (GBM). MicroRNA-588 and its potential target Roundabout-directed receptor 1 (ROBO1) have been reported to promote tumor invasion and proliferation in diseases such as gastric, pancreatic and hepatocellular carcinoma, while their function in GBM and response to hypoxic states remain elusive. METHODS: A microarray was leveraged to identify differentially expressed microRNAs in U251 glioma cells cultured under normoxic and hypoxic conditions. The expression of miR-588 was assessed using quantitative real-time PCR (qRT‒PCR). Gain- and loss-of-function studies were used to evaluate the role of miR-588 under hypoxic and normoxic conditions. Cell invasion, migration, proliferation, and vasculogenic mimicry (VM) formation experiments were performed. The relationship between miR-588 and ROBO1 was confirmed using western blot and luciferase reporter assays. Intracranial xenograft tumor mouse models were used to study the function of miR-588 in vivo. RESULTS: The expression of miR-588 was significantly upregulated in hypoxic glioma cells relative to normoxic glioma cells. miR-588 inhibited the invasive, migratory and VM-forming abilities of glioma cells in vitro and in vivo. Mechanistically, roundabout guidance receptor 1 (ROBO1) is a direct, functionally relevant target of miR-588 in glioma. ROBO1 knockdown suppressed the expression of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9), thereby inhibiting the invasive, migratory and VM-forming abilities of glioma. CONCLUSIONS: MiR-588 regulated the behaviors of hypoxic glioma cells by targeting ROBO1. miR-588 can be used as a prognostic marker for glioma and has potential implications in glioma gene therapy.

Numerical simulation of the fractional Maxwell fluid flow in locally narrow artery.

Research on hemorheology and blood flow behavior in non-uniform vessels is of extreme significance for diagnosis and treatment of many cardiovascular diseases. The aim of this study is to reveal the hemodynamics in stenotic vessels, and provide a reference for formulating a clinical operation plan. A set of rheological data of human blood at 37° is utilized in the paper to construct the fractional Maxwell constitutive equation of blood. Consequently, the continuity and momentum equations of a fractional Maxwell fluid passing through a stenosis artery in a two-dimensional cylindrical coordinate system are established. With the help of the vorticity and stream function, the finite difference method combined with the fractional order derivative L1 algorithm is applied to acquire the numerical solutions of the velocity, wall shear stress and intravascular pressure gradient, and the validity of the algorithm is verified. Furthermore, the effects of the stenosis degree, stenosis shoulder length, various Reynolds numbers and fractional parameter α on the blood flow characteristics in stenosis are analyzed.

Polycomb repressor complex 2 suppresses interferon-responsive MHC-II expression in melanoma cells and is associated with anti-PD-1 resistance.

BACKGROUND: Despite the remarkable success of immunotherapy in treating melanoma, understanding of the underlying mechanisms of resistance remains limited. Emerging evidence suggests that upregulation of tumor-specific major histocompatibility complex-II (tsMHC-II) serves as a predictive marker for the response to anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) therapy in various cancer types. The genetic and epigenetic pathways modulating tsMHC-II expression remain incompletely characterized. Here, we provide evidence that polycomb repressive complex 2 (PRC2)/EZH2 signaling and resulting H3K27 hypermethylation suppresses tsMHC-II. METHODS: RNA sequencing data from tumor biopsies from patients with cutaneous melanoma treated with or without anti-PD-1, targeted inhibition assays, and assays for transposase-accessible chromatin with sequencing were used to observe the relationship between EZH2 inhibition and interferon (IFN)-γ inducibility within the MHC-II pathway. RESULTS: We find that increased EZH2 pathway messenger RNA (mRNA) expression correlates with reduced mRNA expression of both presentation and T-cell genes. Notably, targeted inhibition assays revealed that inhibition of EZH2 influences the expression dynamics and inducibility of the MHC-II pathway following IFN-γ stimulation. Additionally, our analysis of patients with metastatic melanoma revealed a significant inverse association between PRC2-related gene expression and response to anti-PD-1 therapy. CONCLUSIONS: Collectively, our findings demonstrate that EZH2 inhibition leads to enhanced MHC-II expression potentially resulting from improved chromatin accessibility at CIITA, the master regulator of MHC-II. These insights shed light on the molecular mechanisms involved in tsMHC-II suppression and highlight the potential of targeting EZH2 as a therapeutic strategy to improve immunotherapy efficacy.

Regulating Spin-State Switching by Integrating Polyoxometalate Anion into Spin Crossover System.

Polyoxometalate (POM) anions were successfully integrated into Fe(II) spin crossover (SCO) system, which demonstrates an effective role in regulating spin-state switching properties. Specifically, three drastically different magnetic behaviors of Fe(II) ion in the identical cation [Fe(bpp)2]2+ were achieved by leveraging [Mo6O19]2-, [Mo8O26]4-, and [Na(Mo8O26)]3-, respectively.

T cells specific for α-myosin drive immunotherapy-related myocarditis.

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.

Positive Effect of a Pea-Clam Two-Peptide Composite on Hypertension and Organ Protection in Spontaneously Hypertensive Rats.

In the present study, we prepared pea peptides with high angiotensin-converting enzyme (ACE) inhibitory activity in vitro using an enzymatic hydrolysis of pea protein and compounded them with clam peptides to obtain a pea-clam double peptide. The effects of the two-peptide composite and pea peptides on hypertension and the damage-repair of corresponding organs were studied in spontaneously hypertensive rats (SHRs). We found that both pea peptides and the two-peptide composite significantly reduced the blood pressure upon a single or long-term intragastric administration, with the two-peptide composite being more effective. Mechanistically, we found that the two-peptide composite could regulate the renal renin-angiotensin system (RAS), rebalance gut microbial dysbiosis, decrease renal and myocardial fibrosis, and improve renal and cardiac function and vascular remodeling. Additionally, hippocampal lesions caused by hypertension were also eliminated after two-peptide composite administration. Our research provides a scientific basis for the use of this two-peptide composite as a safe antihypertension ingredient in functional foods.

Peripheral Blood Monocyte Abundance Predicts Outcomes in Patients with Breast Cancer.

Biomarkers of response are needed in breast cancer to stratify patients to appropriate therapies and avoid unnecessary toxicity. We used peripheral blood gene expression and cell type abundance to identify biomarkers of response and recurrence in neoadjuvant chemotherapy treated breast cancer patients. We identified a signature of interferon and complement response that was higher in the blood of patients with pathologic complete response. This signature was preferentially expressed by monocytes in single cell RNA sequencing. Monocytes are routinely measured clinically, enabling examination of clinically measured monocytes in multiple independent cohorts. We found that peripheral monocytes were higher in patients with good outcomes in four cohorts of breast cancer patients. Blood gene expression and cell type abundance biomarkers may be useful for prognostication in breast cancer. Significance: Biomarkers are needed in breast cancer to identify patients at risk for recurrence. Blood is an attractive site for biomarker identification due to the relative ease of longitudinal sampling. Our study suggests that blood-based gene expression and cell type abundance biomarkers may have clinical utility in breast cancer.