Improving drug response prediction via integrating gene relationships with deep learning.

Predicting the drug response of cancer cell lines is crucial for advancing personalized cancer treatment, yet remains challenging due to tumor heterogeneity and individual diversity. In this study, we present a deep learning-based framework named Deep neural network Integrating Prior Knowledge (DIPK) (DIPK), which adopts self-supervised techniques to integrate multiple valuable information, including gene interaction relationships, gene expression profiles and molecular topologies, to enhance prediction accuracy and robustness. We demonstrated the superior performance of DIPK compared to existing methods on both known and novel cells and drugs, underscoring the importance of gene interaction relationships in drug response prediction. In addition, DIPK extends its applicability to single-cell RNA sequencing data, showcasing its capability for single-cell-level response prediction and cell identification. Further, we assess the applicability of DIPK on clinical data. DIPK accurately predicted a higher response to paclitaxel in the pathological complete response (pCR) group compared to the residual disease group, affirming the better response of the pCR group to the chemotherapy compound. We believe that the integration of DIPK into clinical decision-making processes has the potential to enhance individualized treatment strategies for cancer patients.

MlrA, an Essential Enzyme for Microcystins and Nodularin on First Step Biodegradation in Microcystin-Degrading Bacteria.

Microcystin-degrading bacteria first degrade microcystins by microcystinase A (MlrA) to cleave the cyclic structure of microcystins at the Adda-Arg site of microcystin-LR, microcystin-RR, and microcystin-YR, but the cleavage of the other microcystins was not clear. In our study, the microcystin-degrading bacterium Sphingopyxis sp. C-1 as wild type and that of mlrA-disrupting mutant, Sphingopyxis sp. CMS01 were used for microcystins biodegradation. The results showed MlrA degraded microcystin-LA, microcystin-LW, microcystin-LY, microcystin-LF, and nodularin. MlrA could cleave the Adda-L-amino acid site.

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis.

AIMS: Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. METHODS AND RESULTS: Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4-/-, and Il13-/- mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-ß receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries. CONCLUSION: Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.

Lipoprotein(a) Is Associated With the Progression and Vulnerability of New-Onset Carotid Atherosclerotic Plaque.

BACKGROUND: Although important progress has been made in understanding Lp(a) (lipoprotein[a])-mediated stroke risk, the contribution of Lp(a) to the progression of vulnerable plaque features associated with stroke risk remains unclear. This study aims to evaluate whether Lp(a) is associated with carotid plaque progression, new-onset plaque features, and plaque vulnerability in a prospective community-based cohort study. METHODS: Baseline Lp(a) levels were measured using latex-enhanced turbidimetric immunoassay among 804 participants aged 45 to 74 years and free of cardiovascular disease in the Chinese Multi-provincial Cohort Study-Beijing project. Carotid atherosclerosis was measured twice by B-mode ultrasonography over a 10-year interval during the 2002 and 2012 surveys to assess the progression of total, vulnerable and stable plaques, and plaque vulnerability. The total plaque area and plaque vulnerability score were calculated. RESULTS: The median baseline Lp(a) level was 10.20 mg/dL (interquartile range, 6.20 to 17.18 mg/dL). Modified Poisson regression analysis showed that Lp(a) ≥50 mg/dL was significantly associated with 10-year progression of total carotid plaque (relative risk [RR], 1.41 [95% CI, 1.21-1.64]; E-value=2.17), vulnerable plaque (RR, 1.93 [95% CI, 1.54-2.41]), and stable plaque (RR, 1.51 [95% CI, 1.11-2.07]) compared with Lp(a) <50 mg/dL. Moreover, among participants without plaque at baseline, Lp(a) ≥50 mg/dL was related to an increased total plaque area (ß=0.36 [95% CI, 0.06-0.65]; P=0.018) and increased plaque vulnerability score (ß=0.30 [95% CI, 0.01-0.60]; P=0.045) in multivariable linear regression. CONCLUSIONS: Elevated Lp(a) levels were associated with 10-year carotid plaque progression and plaque vulnerability, providing a basis for Lp(a) as a treatment target for stroke prevention.

Eosinophils Protect Mice From Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm.

RATIONALE: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease. OBJECTIVE: To test whether and how eosinophils affect AAA growth. METHODS AND RESULTS: Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 109/L, P<0.001). Univariate (odds ratio, 1.381, P<0.001) and multivariate (odds ratio, 1.237, P=0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in Apoe-/- and eosinophil-deficient Apoe-/-ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b+Ly6Clo monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and Il13-/- mice, but not eosinophil from Il4-/- mice, blocked AAA growth in Apoe-/-ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells. CONCLUSIONS: Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

Type 2 innate lymphoid cells regulation by regulatory T cells attenuates atherosclerosis.

Regulatory T cells (Tregs) have been shown to attenuate the development and progression of atherosclerosis; however, the exact mechanism is still unclear. In our study, Tregs were adoptively transferred into ApoE-/- mice, and type 2 innate lymphoid cells (ILC2s) were expanded by the IL-2/Jes6-1 complex or depleted by anti-CD90.2 mAb in ApoE-/-Rag1-/- mice to study their effects on atherosclerosis. Then, Tregs were cocultured with ILC2s in vitro to analyze ILC2s number and IL-13 production. In vivo, ApoE-/-Rag1-/- mice were treated with activated Tregs with or without anti-CD90.2 mAb to explore whether Tregs reduced atherosclerosis through ILC2s. Finally, neutralizing antibodies and Transwell assay were used to investigate how Tregs regulate ILC2s. Our results show that both Tregs and ILC2s reduce atherosclerosis lesions and macrophage infiltration. Moreover, Tregs effectively expanded the number of ILC2s and increased their production of IL-13 in vivo and in vitro. Furthermore, the reductions in plaque size and macrophage infiltration by Tregs were partly reversed by anti-CD90.2 mAb. Mechanistically, our data reveal that IL-10, TGF-ß and cell-cell contacts are required for Tregs-ILC2s regulation. These results show that Tregs may play a partial protective role against atherosclerosis by expanding the number of ILC2s and consequently increasing IL-13 production.

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability.

BACKGROUND/AIMS: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. METHODS: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. RESULTS: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4+ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. CONCLUSION: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.

Helical tomotherapy to LINAC plan conversion utilizing RayStation Fallback planning.

RaySearch RayStation Fallback (FB) planning module can generate an equivalent backup radiotherapy treatment plan facilitating treatment on other linear accelerators. FB plans were generated from the RayStation FB module by simulating the original plan target and organ at risk (OAR) dose distribution and delivered in various backup linear accelerators. In this study, helical tomotherapy (HT) backup plans used in Varian TrueBeam linear accelerator were generated with the RayStation FB module. About 30 patients, 10 with lung cancer, 10 with head and neck (HN) cancer, and 10 with prostate cancer, who were treated with HT, were included in this study. Intensity-modulated radiotherapy Fallback plans (FB-IMRT) were generated for all patients, and three-dimensional conformal radiotherapy Fallback plans (FB-3D) were only generated for lung cancer patients. Dosimetric comparison study evaluated FB plans based on dose coverage to 95% of the PTV volume (R95), PTV mean dose (Dmean), Paddick's conformity index (CI), and dose homogeneity index (HI). The evaluation results showed that all IMRT plans were statistically comparable between HT and FB-IMRT plans except that PTV HI was worse in prostate, and PTV R95 and HI were worse in HN multitarget plans for FB-IMRT plans. For 3D lung cancer plans, only the PTV R95 was statistically comparable between HT and FB-3D plans, PTV Dmean was higher, and CI and HI were worse compared to HT plans. The FB plans using a TrueBeam linear accelerator generally offer better OAR sparing compared to HT plans for all the patients. In this study, all cases of FB-IMRT plans and 9/10 cases of FB-3D plans were clinically acceptable without further modification and optimization once the FB plans were generated. However, the statistical differences between HT and FB-IMRT/3D plans might not be of any clinically significant. One FB-3D plan failed to simulate the original plan without further optimization.

RanGAP1 maintains chromosome stability in limb bud mesenchymal cells during bone development.

BACKGROUND: Bone development involves the rapid proliferation and differentiation of osteogenic lineage cells, which makes accurate chromosomal segregation crucial for ensuring cell proliferation and maintaining chromosomal stability. However, the mechanism underlying the maintenance of chromosome stability during the rapid proliferation and differentiation of Prx1-expressing limb bud mesenchymal cells into osteoblastic precursor cells remains unexplored. METHODS: A transgenic mouse model of RanGAP1 knockout of limb and head mesenchymal progenitor cells was constructed to explore the impact of RanGAP1 deletion on bone development by histomorphology and immunostaining. Subsequently, G-banding karyotyping analysis and immunofluorescence staining were used to examine the effects of RanGAP1 deficiency on chromosome instability. Finally, the effects of RanGAP1 deficiency on chromothripsis and bone development signaling pathways were elucidated by whole-genome sequencing, RNA-sequencing, and qPCR. RESULTS: The ablation of RanGAP1 in limb and head mesenchymal progenitor cells expressing Prx1 in mice resulted in embryonic lethality, severe cartilage and bone dysplasia, and complete loss of cranial vault formation. Moreover, RanGAP1 loss inhibited chondrogenic or osteogenic differentiation of mesenchymal stem cells (MSCs). Most importantly, we found that RanGAP1 loss in limb bud mesenchymal cells triggered missegregation of chromosomes, resulting in chromothripsis of chromosomes 1q and 14q, further inhibiting the expression of key genes involved in multiple bone development signaling pathways such as WNT, Hedgehog, TGF-ß/BMP, and PI3K/AKT in the chromothripsis regions, ultimately disrupting skeletal development. CONCLUSIONS: Our results establish RanGAP1 as a critical regulator of bone development, as it supports this process by preserving chromosome stability in Prx1-expressing limb bud mesenchymal cells.

Transfer of massive mitochondria from astrocytes reduce propofol neurotoxicity.

Studies have shown that propofol-induced neurotoxicity is mediated by disruption of mitochondrial fission and fusion, leading to an imbalance in energy supply for developing neurons. Healthy mitochondria released from astrocytes migrate to compromised neurons to mitigate propofol-induced neurotoxicity, yet the precise mechanisms involved require further clarification. In our investigation, primary neurons were incubated with propofol, which decreased ATP synthesis and mitochondrial membrane potential, increased ROS generation and neuronal apoptosis. Notably, astrocytes did not respond to the deleterious effects of propofol. The culture medium of neurons or astrocytes incubated with propofol was collected. It was found that mitochondrial ratio was decreased and mitochondrial function was impaired. Non-contact co-culture of neuro-astrocytes facilitated transcellular mitochondrial transfer in both physiological and propofol interventions, but failed to reverse propofol-induced neurotoxicity. The more pronounced damage to neuronal mitochondria induced by propofol compared to that in astrocytes alludes to secondary injury. Damaged neurons incubated with large, functional extracellular mitochondria derived from astrocytes demonstrates transfer of mitochondria to neurons, effectively reversing propofol-induced neurotoxicity. This discovery presents a novel mitochondrial transfer of neuro-astrocytes crosstalk that contributes to neuroprotection and neurological recovery in neurotoxicity.

Eliminating Halogen Vacancies Enables Efficient MACL-Assisted Formamidine Perovskite Solar Cells.

Methylammonium chloride (MACl) additive is almost irreplaceable in high-performance formamidine perovskite photovoltaics. Nevertheless, Some of the problems that can arise from adding MACl are rarely mentioned. Herein, it is proposed for the first time that the addition of MACl would cause the non-stoichiometric ratio in the perovskite film, resulting in the halogen vacancy. It is demonstrated that the non-synchronous volatilization of methylamine cations and chloride ions leads to the formation of halogen vacancy defects. To solve this problem, the NH4 HCOO is introduced into the perovskite precursor solution to passivate the halogen vacancy. The HCOO- ions have a strong force with lead ions and can fill the halogen vacancy defects. Consequently, the champion devices' power conversion efficiency (PCE) can be improved from 21.23% to 23.72% with negligible hysteresis. And the unencapsulated device can still retain >90% of the initial PCE even operating in N2 atmosphere for over 1200 h. This work illustrates another halogen defect source in the MACl-assisted formamidine perovskite photovoltaics and provides a new route to obtain high-performance perovskite solar cells.

Efficient and Stable Air-Processed Organic Solar Cells Enabled by an Antioxidant Additive.

Current high-efficiency organic solar cells (OSCs) are generally fabricated in an inert atmosphere that limits their real-world scalable manufacturing, while the efficiencies of air-processed OSCs lag far behind. The impacts of ambient factors on solar cell fabrication remain unclear. In this work, the effects of ambient factors on cell fabrication are systematically investigated, and it is unveiled that the oxidation and doping of organic light absorbers are the dominant reasons causing cell degradation when fabricated in air. To address this issue, a new strategy for fabricating high-performance air-processed OSCs by introducing an antioxidant additive (4-bromophenylhydrazine, BPH) into the precursor solutions, is developed. BPH can effectively inhibit oxygen infiltration from the ambient to the photoactive layer and suppress trap formation caused by oxidation. Compared with conventional air-processed OSCs, this strategy remarkably increases the cell power conversion efficiency (PCE) from 16.7% to 19.3% (independently certified as 19.2%), representing the top value of air-processed OSCs. Furthermore, BPH significantly improves the operational stability of the cells in air by two times with a T80 lifetime of over 500 h. This study highlights the potential of using antioxidant additives to fabricate high-efficiency and stable OSCs in air, significantly promoting the industrialization of OSCs.

Air-Processed Perovskite Solar Cells with >25% Efficiency and High Stability Enabled by Crystallization Modulation and Holistic Passivation.

Organic semiconductors (e.g., PCBM and IDIC) frequently serve as interface passivants for perovskite solar cells (PSCs) due to their beneficial passivation effects on perovskite interfaces. However, their passivation to the interiors of perovskite films is greatly limited by their poor solubility in polar solvents and compatibility issues. Here the facile synthesis of organic semiconductor nanoparticle (NP) passivants that readily disperse in perovskite inks is reported. Adding these NPs into perovskite inks not only modulates perovskite crystallization, improves film quality and conductivity, but also achieves holistic bulk film passivation. Consequently, blade-coated p-i-n PSCs with ICBA NPs achieve an impressive efficiency of 25.1% (independently certified as 25.0%), the highest reported value for air-processed PSCs irrespective of fabrication methods or device structures. This work develops a novel approach for effective and holistic perovskite passivation by converting conventional passivants to perovskite-compatible NPs, paving the way for more efficient and stable perovskite solar devices.

Enhanced economic benefit of recycling Fe3O4 for promotion of volatile fatty acids production in anaerobic fermentation of food waste.

Fe3O4 addition in anaerobic fermentation of food waste (FW) is promising for enhancing volatile fatty acids (VFAs) production. However, the large amount of Fe3O4 in the digestate fertilizer leads to the waste of resources and possible toxicity to organisms. Thus, this study investigated the feasibility of Fe3O4 recycling for VFAs enhancement in anaerobic fermentation of FW and performed the cost-benefit evaluation of this process. Results revealed that Fe3O4 could be successfully recycled twice with recovery rates of 71.5% and 65.5%, respectively. X-ray diffraction analysis revealed a slight change to the Fe2O3-like structure after 2-time recycling. The VFAs yields were enhanced by 17.2% and 17.0% in Cycles 1 and 2 owing to the enhanced activities of hydrolytic and acid-forming enzymes. The net income of the Fe3O4 recycling process was about 13-fold higher than that of the conventional treatment process, suggesting a promising and economically feasible strategy for enhancing VFAs production.

Association between Intermediate-Density Lipoprotein Particles and the Progression of Carotid Atherosclerosis: A Community-Based Cohort Study.

AIM: Experimental studies report that intermediate-density lipoprotein (IDL), the precursor of low-density lipoprotein, promotes atherosclerotic plaque formation. However, whether IDL is involved in the development of atherosclerosis in humans is still unclear. The aim of this community-based study is to examine the association between IDL particle (IDL-P) concentrations and the 5-year progression of carotid atherosclerosis. METHODS: Baseline IDL-P concentrations were measured using nuclear magnetic resonance spectroscopy in 927 participants aged 45-74 years with no history of cardiovascular disease (CVD) at baseline. To estimate the association between baseline IDL-P concentrations and 5-year progression of carotid atherosclerosis, indicated by atherosclerotic plaque progression and changes in total plaque area (TPA), multivariable-adjusted regression was employed. RESULTS: During the 5-year follow-up period, 45.8% of participants developed new plaques. Baseline IDL-P concentrations were significantly associated with the progression of carotid atherosclerosis. Participants in the highest quartile of IDL-P concentrations exhibited 1.36-fold (95% confidence interval [CI]: 1.09-1.68) increased progression of carotid plaque and 1.67-fold (95% CI: 1.04-2.69) higher TPA than those in the lowest quartile. These relationships were independent of baseline concentrations of low-density lipoprotein particles and very-low-density lipoprotein particles and their subclasses. CONCLUSIONS: Elevated IDL-P concentrations were independently associated with the progression of carotid atherosclerosis, suggesting that IDL-P is a novel risk factor for the development of atherosclerosis.

Group 2 Innate Lymphoid Cells Protect Mice from Abdominal Aortic Aneurysm Formation via IL5 and Eosinophils.

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/fl Il7rCre/+ mice or induced ILC2 depletion in Icosfl-DTR-fl/+ Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild-type (WT) mice, but not ILC2 from Il5-/- mice induces EOS differentiation in bone-marrow cells from Rorafl/fl Il7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5-/- and Il13-/- mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5-/- mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5-/- ILC2 slows AAA growth in Rorafl/fl Il7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.

Eosinophils protect pressure overload- and ß-adrenoreceptor agonist-induced cardiac hypertrophy.

AIMS: Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy. METHODS AND RESULTS: A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and ß-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient ΔdblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. ΔdblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type (WT) mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In ΔdblGATA and WT mice, administration of ECP mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-ß signalling and fibrotic protein synthesis. The use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-ß signalling. CONCLUSION: Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of ECPs in this human CVD.

Group 2 innate lymphoid cells protect mouse heart from myocardial infarction injury via interleukin 5, eosinophils, and dendritic cells.

AIMS: Group 2 innate lymphoid cells (ILC2s) regulate adaptive and innate immunities. In mouse heart, production of myocardial infarction (MI) increased ILC2 accumulation, suggesting a role for ILC2 in cardiac dysfunction post-MI. METHODS AND RESULTS: We produced MI in ILC2-deficeint Rorafl/flIl7rCre/+ mice and in Icosfl-DTR-fl/+Cd4Cre/+ mice that allowed diphtheria toxin-induced ILC2 depletion. Genetic or induced deficiency of ILC2 in mice exacerbated cardiac dysfunction post-MI injury along with increased myocardial accumulation of neutrophils, CD11b+Ly6Chi monocytes, and CD4+ T cells but deficiency of eosinophils (EOS) and dendritic cells (DC). Post-MI hearts from genetic and induced ILC2-deficient mice contained many more apoptotic cells than those of control mice, and Rorafl/flIl7rCre/+ mice showed thinner and larger infarcts and more collagen-I depositions than the Il7rCre/+ mice only at early time points post-MI. Mechanistic studies revealed elevated blood IL5 in Il7rCre/+ mice at 1, 7, and 28 days post-MI. Such increase was blunted in Rorafl/flIl7rCre/+ mice. Administration of recombinant IL5 reversed EOS losses in Rorafl/flIl7rCre/+ mice, but IL5 did not correct the DC loss in these mice. Adoptive transfer of ILC2, EOS, or DC from wild-type mice, but not ILC2 from Il5-/- mice improved post-MI cardiac functions in Rorafl/flIl7rCre/+ recipient mice. EOS are known to protect cardiomyocytes from apoptosis. Here we showed that DC acted like EOS in blocking cardiomyocyte apoptosis. Yet, ILC2 or IL5 alone did not directly affect cardiomyocyte apoptosis or TGF-ß (transforming growth factor-ß)-induced cardiac fibroblast Smad signalling. CONCLUSION: This study revealed an indirect cardiac reparative role of ILC2 in post-MI hearts via the IL5, EOS, and DC mechanism.

The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and notch signaling in the somite segmentation clock.

Periodic formation of somites is controlled by the segmentation clock, where the oscillator Hes7 regulates cyclic expression of the Notch modulator Lunatic fringe. Here, we show that Hes7 also regulates cyclic expression of the Fgf signaling inhibitor Dusp4 and links Notch and Fgf oscillations in phase. Strikingly, inactivation of Notch signaling abolishes the propagation but allows the initiation of Hes7 oscillation. By contrast, transient inactivation of Fgf signaling abolishes the initiation, whereas sustained inactivation abolishes both the initiation and propagation of Hes7 oscillation. We thus propose that Hes7 oscillation is initiated by Fgf signaling and propagated/maintained anteriorly by Notch signaling.

Global Trends in the Epidemiology and Management of Dyslipidemia.

Dyslipidemia, especially a circulating non-optimal level of cholesterol, is one of the most important risk factors for atherosclerotic cardiovascular disease (ASCVD), which accounts for the most deaths worldwide. Maintaining a healthy level of blood cholesterol is an important prevention strategy for ASCVD, through lifestyle intervention or cholesterol-lowering therapy. Over the past three decades, the epidemiology and management of dyslipidemia has changed greatly in many countries. Therefore, it is necessary to understand the current epidemiologic features of dyslipidemia and challenges from a global perspective.