Maxima of the QQ-index of non-bipartite C3C_{3}-free graphs

A classic result in extremal graph theory, known as Mantel's theorem, states that every non-bipartite graph of order $n$ with size $m>\lfloor \frac{n^{2}}{4}\rfloor$ contains a triangle. Lin, Ning and Wu [Comb. Probab. Comput. 30 (2021) 258-270] proved a spectral version of Mantel's theorem for given order $n.$ Zhai and Shu [Discrete Math. 345 (2022) 112630] investigated a spectral version for fixed size $m.$ In this paper, we prove $Q$-spectral versions of Mantel's theorem.Comment: 14 pages, 4 figure

GC Gene Polymorphisms and Vitamin D-Binding Protein Levels Are Related to the Risk of Generalized Aggressive Periodontitis

Objective. To explore whether GC (group-specific component) rs17467825, rs4588, and rs7041 polymorphisms are associated with generalized aggressive periodontitis. Methods. This case-control study recruited 372 patients with generalized aggressive periodontitis (group AgP) and 133 periodontal healthy subjects (group HP). GC rs17467825, rs4588, and rs7041 genotypes and plasmatic vitamin D-binding protein (DBP) were measured. Analysis of single SNP and multiple SNPs was performed and relevance between plasmatic DBP and haplotypes was analyzed. Results. GC rs17467825 GG genotype was statistically associated with lower risk for generalized aggressive periodontitis under the recessive model (OR = 0.52, 95% CI: 0.30–0.92, p=0.028). GC rs17467825 and rs4588 had strong linkage disequilibrium with r2≥0.8 and D′≥0.8. Haplotype (GC rs17467825, rs4588) GC was associated with the less risk for generalized aggressive periodontitis (OR = 0.29, 95% CI: 0.09–0.96, p=0.043). In group AgP, individuals with combined genotype (GC rs17467825, rs4588) AG+CA had significantly lower plasmatic DBP level than those with the other two combined genotypes (AG+CA versus AA+CC p=0.007; AG+CA versus GG+AA p=0.026). Conclusions. GC rs17467825 genotype GG and haplotype (GC rs17467825, rs4588) GC are associated with generalized aggressive periodontitis. The association may be acquired through regulating DBP levels. The functions of GC gene and DBP in inflammatory disease need to be further studied

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers

Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of Pten, p53, and Smad4, CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC

Action Real-Time Strategy Gaming Experience Related to Enhanced Capacity of Visual Working Memory

Action real-time strategy gaming (ARSG)—a major genre of action video gaming (AVG)—has both action and strategy elements. ARSG requires attention, visual working memory (VWM), sensorimotor skills, team cooperation, and strategy-making abilities, thus offering promising insights into the learning-induced plasticity. However, it is yet unknown whether the ARSG experience is related to the development of VWM capacity. Using both behavioral and event-related potential (ERP) measurements, this study tested whether ARSG experts had larger VWM capacity than non-experts in a change detection task. The behavioral results showed that ARSG experts had higher accuracy and larger VWM capacity than non-experts. In addition, the ERP results revealed that the difference wave of the contralateral delay activity (CDA) component (size 4–size 2) elicited by experts was significantly larger than that of non-experts, suggesting that the VWM capacity was higher in experts than in non-experts. Thus, the findings suggested that prolonged ARSG experience is correlative with the enhancement of VWM

Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling

[Abstract] Background: Remodeling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown. Methods: Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5ΔCat). Proteomics was applied to study ECM remodeling in left ventricular samples from patients with HF, with a particular focus on the effects of common medications used for the treatment of HF. Results: Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5ΔCat mice, angiotensin II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin β1, filamin A, and connexin 43. Echocardiographic assessment of Adamts5ΔCat mice revealed a reduced ejection fraction and an impaired global longitudinal strain on angiotensin II infusion. Cardiac hypertrophy and collagen deposition were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from patients with ischemic HF (n=65), the use of β-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes. Subsequent experiments in cardiac fibroblasts confirmed that β1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, patients with HF treated with β-blockers had a distinct cardiac ECM profile. Conclusions: Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart and that versican accumulation is associated with impaired cardiac function. A comprehensive characterization of the cardiac ECM in patients with ischemic HF revealed that β-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.Dr Barallobre-Barreiro is a British Heart Foundation Intermediate Fellow (FS/19/33/34328). Drs Mayr and Shah are British Heart Foundation Chair Holders (CH/16/3/32406 and CH/1999001/11735, respectively) and received support from the British Heart Foundation Center for Vascular Regeneration With Edinburgh/Bristol (RM/17/3/33381). Dr Doménech’s work was supported by Project PI16/02049 integrated in the National Plan for Scientific Research, Development and Technological Innovation, 2013–2016, and funded by the ISCIII–General Subdirection of Assessment and Promotion of Research–European Regional Development Fund. Dr Merkely’s work was funded by the National Research, Development and Innovation Fund (NVKP_16-1–2016-0017) and the Thematic Excellence Program of the Ministry for Innovation and Technology (2020-4.1.1.-TKP2020), Hungary. Dr Radovits is supported by the National Research, Development and Innovation Office of Hungary (K134939)British Heart Foundation; FS/19/33/34328British Heart Foundation; CH/16/3/32406British Heart Foundation; CH/1999001/11735British Heart Foundation Center for Vascular Regeneration; RM/17/3/33381Hungría. Ministry for Innovation and Technology; NVKP_16-1–2016-0017Hungría. Ministry for Innovation and Technology; 2020-4.1.1.-TKP2020Hungría. National Research, Development and Innovation Office; K13493