Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4-NOTCH-CLDN5 pathway and is vulnerable to neonatal hyperoxia.

The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental vascularization is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia in premature infants can disrupt the development and functions of cerebral blood vessels and lead to long-term cognitive impairment. However, its role in cerebral vascular development and the impact of postnatal hyperoxia on DLL4 expression in mouse brain EC have not been explored. We determined the DLL4 expression pattern and its downstream signalling gene expression in brain EC using Dll4+/+ and Dll4+/LacZ mice. We also performed in vitro studies using human brain microvascular endothelial cells. Finally, we determined Dll4 and Cldn5 expression in mouse brain EC exposed to postnatal hyperoxia. DLL4 is expressed in various cell types, with EC being the predominant one in immature brains. Moreover, DLL4 deficiency leads to persistent abnormalities in brain microvasculature and increased vascular permeability both in vivo and in vitro. We have identified that DLL4 insufficiency compromises endothelial integrity through the NOTCH-NICD-RBPJ-CLDN5 pathway, resulting in the downregulation of the tight junction protein claudin 5 (CLDN5). Finally, exposure to neonatal hyperoxia reduces DLL4 and CLDN5 expression in developing mouse brain EC. We reveal that DLL4 is indispensable for brain vascular development and maintaining the blood-brain barrier's function and is repressed by neonatal hyperoxia. We speculate that reduced DLL4 signalling in brain EC may contribute to the impaired brain development observed in neonates exposed to hyperoxia. KEY POINTS: The role of delta like 4 (DLL4), a Notch ligand in vascular endothelial cells, in brain vascular development and functions remains unknown. We demonstrate that DLL4 is expressed at a high level during postnatal brain development in immature brains and DLL4 insufficiency leads to abnormal cerebral vasculature and increases vascular permeability both in vivo and in vitro. We identify that DLL4  regulates endothelial integrity through NOTCH-NICD-RBPJ-CLDN5 signalling. Dll4 and Cldn5 expression are decreased in mouse brain endothelial cells exposed to postnatal hyperoxia.

NK-like CD8 T Cell: One Potential Evolutionary Continuum between Adaptive Memory and Innate Immunity.

CD8 T cells are crucial adaptive immune cells with cytotoxicity to fight against pathogens or abnormal self-cells via major histocompatibility complex class I-dependent priming pathways. The composition of the memory CD8 T cell pool is influenced by various factors. Physiological aging, chronic viral infection, and autoimmune diseases promote the accumulation of CD8 T cells with highly differentiated memory phenotypes. Accumulating studies have shown that some of these memory CD8 T cells also exhibit innate-like cytotoxicity and upregulate the expression of receptors associated with natural killer (NK) cells. Further analysis shows that these NK-like CD8 T cells have transcriptional profiles of both NK and CD8 T cells, suggesting the transformation of CD8 T cells into NK cells. However, the specific induction mechanism underlying NK-like transformation and the implications of this process for CD8 T cells are still unclear. This review aimed to deduce the possible differentiation model of NK-like CD8 T cells, summarize the functions of major NK cell receptors expressed on these cells and provide a new perspective for exploring the role of these CD8 T cells in health and disease.

The SARS-CoV-2 E protein induces Toll-like receptor 2-mediated neonatal lung injury in a model of COVID-19 viremia that is rescued by the glucocorticoid ciclesonide.

SARS-CoV-2 viremia is associated with increased acute lung injury (ALI) and mortality in children and adults. The mechanisms by which viral components in the circulation mediate ALI in COVID-19 remain unclear. We tested the hypothesis that the SARS-CoV-2 envelope (E) protein induces Toll-like receptor (TLR)-mediated ALI and lung remodeling in a model of neonatal COVID-19. Neonatal C57BL6 mice given intraperitoneal E protein injections revealed a dose-dependent increase in lung cytokines [interleukin 6 (Il6), tumor necrosis factor (Tnfα), and interleukin 1 beta (Il1ß)] and canonical proinflammatory TLR signaling. Systemic E protein induced endothelial immune activation, immune cell influx, and TGFß signaling and lung matrix remodeling inhibited alveolarization in the developing lung. E protein-mediated ALI and transforming growth factor beta (TGFß) signaling was repressed in Tlr2-/-, but not Tlr4-/- mice. A single dose of intraperitoneal E protein injection induced chronic alveolar remodeling as evidenced by a decrease in radial alveolar counts and increase in mean linear intercepts. Ciclesonide, a synthetic glucocorticoid, inhibited E protein-induced proinflammatory TLR signaling and ALI. In vitro, E protein-mediated inflammation and cell death were TLR2-dependent in human primary neonatal lung endothelial cells and were rescued by ciclesonide. This study provides insight into the pathogenesis of ALI and alveolar remodeling with SARS-CoV-2 viremia in children, whereas revealing the efficacy of steroids.NEW & NOTEWORTHY We reveal that the envelope protein of SARS-CoV-2 mediates acute lung injury (ALI) and alveolar remodeling through Toll-like receptor activation, which is rescued by the glucocorticoid, ciclesonide.

Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia.

Hyperoxia disrupts lung development in mice and causes bronchopulmonary dysplasia (BPD) in neonates. To investigate sex-dependent molecular and cellular programming involved in hyperoxia, we surveyed the mouse lung using single cell RNA sequencing (scRNA-seq), and validated our findings in human neonatal lung cells in vitro. Hyperoxia-induced inflammation in alveolar type (AT) 2 cells gave rise to damage-associated transient progenitors (DATPs). It also induced a new subpopulation of AT1 cells with reduced expression of growth factors normally secreted by AT1 cells, but increased mitochondrial gene expression. Female alveolar epithelial cells had less EMT and pulmonary fibrosis signaling in hyperoxia. In the endothelium, expansion of Car4+ EC (Cap2) was seen in hyperoxia along with an emergent subpopulation of Cap2 with repressed VEGF signaling. This regenerative response was increased in females exposed to hyperoxia. Mesenchymal cells had inflammatory signatures in hyperoxia, with a new distal interstitial fibroblast subcluster characterized by repressed lipid biosynthesis and a transcriptomic signature resembling myofibroblasts. Hyperoxia-induced gene expression signatures in human neonatal fibroblasts and alveolar epithelial cells in vitro resembled mouse scRNA-seq data. These findings suggest that neonatal exposure to hyperoxia programs distinct sex-specific stem cell progenitor and cellular reparative responses that underpin lung remodeling in BPD.

Infiltrating myeloid cell-derived properdin markedly promotes microglia-mediated neuroinflammation after ischemic stroke.

BACKGROUND: Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with microglia. Properdin, which is typically secreted by immune cells such as neutrophils, monocytes, and T cells, has been found to possess damage-associated molecular patterns (DAMPs) properties and can perform functions unrelated to the complement pathway. However, the role of properdin in modulating microglia-mediated post-stroke neuroinflammation remains unclear. METHODS: Global and conditional (myeloid-specific) properdin-knockout mice were subjected to transient middle cerebral artery occlusion (tMCAO). Histopathological and behavioral tests were performed to assess ischemic brain injury in mice. Single-cell RNA sequencing and immunofluorescence staining were applied to explore the source and the expression level of properdin. The transcriptomic profile of properdin-activated primary microglia was depicted by transcriptome sequencing. Lentivirus was used for macrophage-inducible C-type lectin (Mincle) silencing in microglia. Conditioned medium from primary microglia was administered to primary cortex neurons to determine the neurotoxicity of microglia. A series of cellular and molecular biological techniques were used to evaluate the proinflammatory response, neuronal death, protein-protein interactions, and related signaling pathways, etc. RESULTS: The level of properdin was significantly increased, and brain-infiltrating neutrophils and macrophages were the main sources of properdin in the ischemic brain. Global and conditional myeloid knockout of properdin attenuated microglial overactivation and inflammatory responses at the acute stage of tMCAO in mice. Accordingly, treatment with recombinant properdin enhanced the production of proinflammatory cytokines and augmented microglia-potentiated neuronal death in primary culture. Mechanistically, recombinant properdin served as a novel ligand that activated Mincle receptors on microglia and downstream pathways to drive primary microglia-induced inflammatory responses. Intriguingly, properdin can directly bind to the microglial Mincle receptor to exert the above effects, while Mincle knockdown limits properdin-mediated microglial inflammation. CONCLUSION: Properdin is a new medium by which infiltrating peripheral myeloid cells communicate with microglia, further activate microglia, and exacerbate brain injury in the ischemic brain, suggesting that targeted disruption of the interaction between properdin and Mincle on microglia or inhibition of their downstream signaling may improve the prognosis of ischemic stroke.

Endoplasmic reticulum stress in T cell-mediated diseases.

T cells synthesize a large number of proteins during their development, activation, and differentiation. The build-up of misfolded and unfolded proteins in the endoplasmic reticulum, however, causes endoplasmic reticulum (ER) stress. Thus, T cells can maintain ER homeostasis via endoplasmic reticulum-associated degradation, unfolded protein response, and autophagy. In T cell-mediated diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, type 1 diabetes and vitiligo, ER stress caused by changes in the internal microenvironment can cause disease progression by affecting T cell homeostasis. This review discusses ER stress in T cell formation, activation, differentiation, and T cell-mediated illnesses, and may offer new perspectives on the involvement of T cells in autoimmune disorders and cancer.

Topological plasmons in stacked graphene nanoribbons.

In this Letter, we theoretically study the topological plasmons in Su-Schrieffer-Heeger (SSH) model-based graphene nanoribbon (GNR) layers. We find that for the one-dimensional (1D) stacked case, only two topological modes with the field localized in the top or bottom layer are predicted to exist by the Zak phase. When we further expand the stacked 1D GNR layers to two-dimensional (2D) arrays in the in-plane direction, the topology is then characterized by the 2D Zak phase, which predicts the emergence of three kinds of topological modes: topological edge, surface, and corner modes. For a 2D ribbon array with Nx × Ny units, there are 4(Ny - 1), 4(Nx - 1), and 4 topological edge, surface, and corner modes, and the field is highly localized at the edge/surface/corner ribbons. This work offers a platform to realize topological modes in GNRs and could be important for the design of topological photonic devices such as lasers and sensors.

Dual-mode tunable absorber based on quasi-bound states in the continuum.

In this Letter, we propose a novel, to the best of our knowledge, dual-mode tunable absorber that utilizes quasi-bound states in the continuum (q-BIC) based on the periodically arranged silicon cylinders tetramer. By introducing asymmetry perturbation through manipulating the diameters of diagonal cylinders in the all-dielectric structure, the symmetry-protected BIC (SP-BIC) transforms into q-BIC, leading to the emergence of one transmission and one reflection Fano-like resonant mode. The relationship between the quality factor of each mode and the asymmetry parameter α is analyzed, revealing an exponential dependence with an exponent of -1.75, i.e., Q ∝ α-1.75. To explain the underlying physics, multipole decomposition analysis and Aleksandra's theory are applied. Subsequently, a monolayer graphene is introduced to the all-dielectric structure to demonstrate the application of the dual-mode tunable absorber. When the critical coupling condition is satisfied, each mode can achieve the theoretical maximum absorption, demonstrating the distinctive capability of our proposed absorber for tuning and efficient light absorption. This research provides valuable insights into light-matter interactions and opens up possibilities for optical modulation and the development of graphene-based devices.

Cation Substitution and Size Effects in Ca2ZnSb2 and Yb2MnSb2: Crystal and Electronic Structures and Thermoelectric Properties.

Zintl compounds often feature complex structural fragments and small band gaps, favoring promising thermoelectric properties. In this work, a new phase Ca2ZnSb2 is synthesized and characterized to be a LiGaGe-type structure. It is isotypic to Yb2MnSb2 with half vacancies at transition metal sites and undergoes a phase transition to Ca9Zn4+xSb9 after annealing. Interestingly, Ca2ZnSb2 and Yb2MnSb2 are amenable to diverse doping mechanisms at different sites. Here, by substituting smaller Li on cation sites, two novel layered compounds Ca1.84(1)Li0.16(1)Zn0.84(1)Sb2 and Yb1.82(1)Li0.18(1)Mn0.96(1)Sb2 with the P63/mmc space group are discovered, which can be viewed as derivatives of LiGaGe type. Despite having lower occupancy, the structural stability is improved compared with the prototype compounds owing to the reduced interlayered distances. Besides, the band structure analyses demonstrate that the bands near the Fermi level are mainly governed by the interlayered interaction. Due to the highly disordered structure, Yb1.82Li0.18Mn0.96Sb2 features ultralow thermal conductivity from 0.79 to 0.47 W·m-1·K-1 among the testing range; in addition, a remarkable Seebeck coefficient of 270.77 µV·K-1 at 723 K is observed. The discovery of the Ca2ZnSb2 phase enriches the 2-1-2 map, and the size effect induced by cations provides new ideas for material designing.

Transurethral columnar balloon dilation of the prostate combined with holmium laser incision for bladder neck contracture in day-surgery mode.

The study aimed to investigate the clinical effect of transurethral columnar balloon dilation of the prostate combined with holmium laser in the treatment of bladder neck contracture (BNC). This retrospective study included 41 patients with BNC, who had been treated with transurethral columnar balloon dilation and holmium laser in our hospital from June 2020 to June 2022. Admission, operation, and discharge of all the patients were completed in 24 h. The patients' satisfaction, postoperative complications, and chronic pain after operation were followed up. Clinical parameters, such as International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), quality of life (QoL), and post-void residual volume (PVR) in pre-operation, 1 month and 6 months after operation were recorded. All patients underwent the operations successfully. Six patients experienced urge incontinence and one patient experienced recurrence of BNC after 12 months. At 1 month and 6 months after the operation, IPSS, QoL, PVR, and Qmax of the patients were significantly better than those before the operation (P < 0.05). Transurethral columnar balloon dilation of the prostate combined with holmium laser can effectively treat BNC with simple performance and satisfactory clinical effects. It is a minimally invasive treatment that can be conducted by simple day surgery.

Angiopoietin-1 protects against endotoxin-induced neonatal lung injury and alveolar simplification in mice.

BACKGROUND: Sepsis in premature newborns is a risk factor for bronchopulmonary dysplasia (BPD), but underlying mechanisms of lung injury remain unclear. Aberrant expression of endothelial cell (EC) angiopoietin 2 (ANGPT2) disrupts angiopoietin 1 (ANGPT1)/TIE2-mediated endothelial quiescence, and is implicated in sepsis-induced acute respiratory distress syndrome in adults. We hypothesized that recombinant ANGPT1 will mitigate sepsis-induced ANGPT2 expression, inflammation, acute lung injury (ALI), and alveolar remodeling in the saccular lung. METHODS: Effects of recombinant ANGPT1 on lipopolysaccharide (LPS)-induced endothelial inflammation were evaluated in human pulmonary microvascular endothelial cells (HPMEC). ALI and long-term alveolar remodeling were assessed in newborn mice exposed to intraperitoneal LPS and recombinant ANGPT1 pretreatment. RESULTS: LPS dephosphorylated EC TIE2 in association with increased ANGPT2 in vivo and in vitro. ANGPT1 suppressed LPS and ANGPT2-induced EC inflammation in HPMEC. Neonatal mice treated with LPS had increased lung cytokine expression, neutrophilic influx, and cellular apoptosis. ANGPT1 pre-treatment suppressed LPS-induced lung Toll-like receptor signaling, inflammation, and ALI. LPS-induced acute increases in metalloproteinase 9 expression and elastic fiber breaks, as well as a long-term decrease in radial alveolar counts, were mitigated by ANGPT1. CONCLUSIONS: In an experimental model of sepsis-induced BPD, ANGPT1 preserved endothelial quiescence, inhibited ALI, and suppressed alveolar simplification. IMPACT: Key message: Angiopoietin 1 inhibits LPS-induced neonatal lung injury and alveolar remodeling. Additions to existing literature: Demonstrates dysregulation of angiopoietin-TIE2 axis is important for sepsis- induced acute lung injury and alveolar simplification in experimental BPD. Establishes recombinant Angiopoietin 1 as an anti-inflammatory therapy in BPD. IMPACT: Angiopoietin 1-based interventions may represent novel therapies for mitigating sepsis-induced lung injury and BPD in premature infants.

Influence of Trichomonas vaginalis macrophage migration inhibitory factor on the proliferation activity of prostate epithelial cell line and its preliminary mechanism.

Currently, the pathogenesis of prostate diseases is still under investigation, but it is generally clinically recognized to be related to the imbalance of prostate cell viability. Trichomonas vaginalis macrophage migration inhibitory factor (TvMIF) has been reported to induce the proliferation and invasion of prostate cancer cells, but for normal PECs, the relationship between them has not been reliably confirmed. Therefore, this research aims to determine the influence of macrophage TvMIF on prostate epithelial cells (PECs) and its preliminary mechanism. The activity of RWPE-1 human normal prostate epithelial cells, the inflammatory response state, the expression of miR-451, and the effect of miR-451 on RWPE-1 were detected after TvMIF intervention. We found that TvMIF can enhance RWPE-1 cell proliferation and activate inflammatory factors by suppressing miR-451, thus taking part in the development and proliferation of diseases such as prostatic hyperplasia and prostatitis.

Zr-Doped h-BN Monolayer: A High-Sensitivity Atmospheric Pollutant-Monitoring Sensor.

In the post-epidemic era, industrial production has gradually recovered, and the attendant air pollution problem has attracted much attention. In this study, the Zr-doped h-BN monolayer (Zr-BN) is proposed as a new gas sensor for air pollution. Based on density functional theory (DFT), we calculated and compared the adsorption energies (Eads), geometric parameters, the shortest distance between gas and substrate (dsub/gas), density of states (DOS), electron localization function (ELF), charge density difference (CDD), band structure, band gap energy change rate (ΔEg), and sensitivity (S) of Zr-BN adsorption systems (SO2F2, SOF2, SO2, NO, and CO2 adsorption systems). The results show that Zr-BN had strong adsorption and high sensitivity to the above-mentioned polluted gases, and the sensitivity was in the order of SOF2 > SO2F2 > CO2 > SO2 > NO. Therefore, this study provides a theoretical basis for the preparation of Zr-BN gas sensors and provides new ideas and methods for the development of other gas sensors.

As-Doped h-BN Monolayer: A High Sensitivity and Short Recovery Time SF6 Decomposition Gas Sensor.

SF6 is a common insulating medium of gas-insulated switchgear (GIS). However, it is inevitable that SF6 will be decomposed due to partial discharge (PD) in GIS, which will cause hidden dangers to the safe and stable operation of equipment. Based on the DFT method, the two-dimensional nano-composite As-doped h-BN (As-BN) monolayer was proposed. By modeling and calculating, the ability of an As-BN monolayer as a specific sensor for SO2F2 (compared with an H2O adsorption system and CO2 adsorption system) was evaluated by parameters such as the binding energy (Eb), adsorption energy (Eads), transfer charge (ΔQ), geometric structure parameters, the total density of states (TDOS), band structure, charge difference density (CDD), electron localization function (ELF), sensitivity (S), and recovery time (τ). The results showed that an As-BN monolayer showed strong adsorption specificity, high sensitivity, and short recovery time for SO2F2 gas molecules. Therefore, the As-BN monolayer sensor has great application potential in the detection of SF6 decomposition gases.

Regulation of thymic T regulatory cell differentiation by TECs in health and disease.

The thymus produces self-limiting and self-tolerant T cells through the interaction between thymocytes and thymus epithelial cells (TECs), thereby generating central immune tolerance. The TECs are composed of cortical and medullary thymic epithelial cells, which regulate the positive and negative selection of T cells, respectively. During the process of negative selection, thymocytes with self-reactive ability are deleted or differentiated into regulatory T cells (Tregs). Tregs are a subset of suppressor T cells that are important for maintaining immune homeostasis. The differentiation and development of Tregs depend on the development of TECs and other underlying molecular mechanisms. Tregs regulated by thymic epithelial cells are closely related to human health and are significant in autoimmune diseases, thymoma and pregnancy. In this review, we summarize the current molecular and transcriptional regulatory mechanisms by which TECs affect the development and function of thymic Tregs. We also review the pathophysiological models of thymic epithelial cells regulating thymic Tregs in human diseases and specific physiological conditions.

A phase I/II clinical trial on the efficacy and safety of NKT cells combined with gefitinib for advanced EGFR-mutated non-small-cell lung cancer.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. METHODS: The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. DISCUSSION: Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. TRIAL REGISTRATION: This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .

Room-Temperature Ferromagnetism in Mg1-xMn2+xAs2 with Layered Structure.

A series of Mg/Mn mixed intermetallic compounds Mg1-xMn2+xAs2 (x = 0.17, 0.48, 0.69) were synthesized by using metal flux reactions. Single-crystal X-ray diffraction measurements indicated that CaAl2Si2-type phases with Mn and Mg atoms located on the cation sites (Wickoff site: 1a) were obtained. The special structure of these Mg1-xMn2+xAs2 compounds corresponded to unique magnetic behavior, which led to increased divergence between zero-field-cooling (ZFC) and field-cooling magnetic susceptibilities with decreasing temperature. The small magnetic hysteresis loop measured at 300 K for Mg0.31(2)Mn2.69As2 revealed its room-temperature ferromagnetism, and its ZFC exchange bias behavior at low temperatures indicated the existence of both ferromagnetic (FM) and antiferromagnetic (AFM) interactions. Spin-polarized density functional theory calculations were also performed to verify the magnetic ground state, and these were consistent with the experimental results.

Sr9Mg4.45(1)Bi9 and Sr9Mg4.42(1)Sb9: Mg-Containing Zintl Phases with Low Thermal Conductivity.

Zintl phases with nominal 9-4-9 formulas are very interesting for their potential applications as thermoelectric materials. However, the formation of such phases usually requires divalent transition metals, for example, Zn, Mn, and Cd, which are covalently bonded to the pnictogen atoms. In this report, for the first time, two Mg-containing compounds with such structures as Sr9Mg4.45(1)Bi9 and Sr9Mg4.42(1)Sb9 were synthesized and their structures were determined by the single-crystal X-ray diffraction method. Both title compounds crystallize in the orthorhombic space group Pnma and are isostructural with Ca9Mn4.41(1)Sb9, which features complex polyanion structures compared to the classical 9-4-9 phases. For Sr9Mg4.45(1)Bi9, its low thermal conductivity, combined with its high electrical conductivity and moderate Seebeck coefficient, leads to a decent figure of merit of 0.57 at 773 K, which obviously prevails in the unoptimized 9-4-9 phases. The discovery of such Mg-containing 9-4-9 phases is very significant, as the discovery not only enriches the structure map of the well-known 9-4-9 family but also provides very valuable thermoelectric candidates surely deserving of more in-depth investigation.

ITGB2 (Integrin ß2) Immunomodulatory Gene Variants in Premature Infants With Necrotizing Enterocolitis.

ABSTRACT: Aberrant toll-like receptor (TLR) activation is central to necrotizing enterocolitis (NEC) pathogenesis. ß2 integrins regulate TLR signaling, and integrin ß2 (ITGB2) deficiency causes TLR hyperresponsiveness. To test the hypothesis that ITGB2 genetic variants modulate NEC susceptibility, we sequenced the exonic ITGB2 locus to compare the prevalence of deleterious variants among 221 preterm infants with and without NEC. ITGB2 variants were not associated with NEC in our entire cohort (NEC [9/56] versus controls [16/165], P = 0.19) or in extremely low birthweight infants (ELBW, controls [7.9%] versus NEC [18.2%]; P = 0.11) but were increased compared to the populace (4.5%, gnomad.broadinstitute.org). Combined annotation-dependent depletion -predicted deleterious ITGB2 variants increased proportionately with increasing NEC severity in ELBW infants (controls [6.7%] versus medical NEC [16.7%] versus surgical NEC [19%] (P = 0.03). Although ITGB2 variants were not associated with NEC in our preterm cohort, subgroup analysis showed a trend towards enrichment with NEC severity in ELBW infants.

Dual inhibition of EGFR and IL-6-STAT3 signalling by miR-146b: a potential targeted therapy for epithelial ovarian cancer.

Epidermal growth factor receptor (EGFR) signalling and the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) are aberrantly activated in ovarian cancer. However, inhibition of EGFR signalling in ovarian cancer patients resulted in a disappointing clinical benefit. In this study, we found that EGFR could activate IL-6-STAT3 pathway in ovarian cancer cells. However, we also demonstrated that EGFR knockdown could increase STAT3 phosphorylation in HO8910 and OVCAR-3 ovarian cancer cells. Interestingly, we further demonstrated that the non-coding RNA miR-146b could simultaneously block both the EGFR and IL-6-STAT3 pathways. Finally, our data demonstrated that miR-146b overexpression resulted in a greater suppression of cell migration than STAT3 pathway inhibition alone.These results suggest a complex and heterogeneous role of EGFR in ovarian cancer. Combined blockade of EGFR and IL-6-STAT3 pathways by miR-146b might be a strategy for improving the clinical benefit of targeting the EGFR pathway in ovarian cancer patients in the future.