Search

In this paper, we establish a Moser-Trudinger type inequality with a special degenerate potential V. Specifically, we demonstrate that for any potentials V (x) satisfying the conditions (V 1) and (V 2) , the following inequality MT (V , α , p) ≔ sup u ∈ E , ‖ u ‖ ≤ 1 ⁡ ∫ R n Φ (α n (1 + α ‖ u ‖ p n) 1 n − 1 u n n − 1 ) d x < ∞ holds if α < λ 1 (V) ; where E is the usual weighted Sobolev space associated to the potential V , the norm ‖ u ‖ n : = ∫ R n | ∇ u | n + V (x) | u | n d x , and λ 1 (V) is the first Dirichlet eigenvalue of the corresponding operator − Δ + V. The potential conditions are as follows. (V 1) 0 ≤ m = inf x ∈ R n ⁡ V (x) < sup x ∈ R n ⁡ V (x) = lim | x | → ∞ ⁡ V (x) = M ≤ ∞. (V 2) V is radially symmetric, non-decreasing. Besides, we also prove that for any potentials V (x) satisfying the condition (V 1) merely and for p = n , the previous inequality is still valid. In addition, this inequality is sharp in the sense that if p > n and α ≥ λ 1 (V) , there holds MT (V , α , p) = ∞. Meanwhile, if α > λ 1 (V) , then MT (V , α , n) = ∞. Furthermore, via a subtle blow-up analysis, we also prove the existence of an extremal function for the inequality above when α is sufficiently small. [ABSTRACT FROM AUTHOR]

Rationale The major role of a transverse-tubular (TT) network in a cardiac cell is to facilitate effective excitation-contraction coupling and signaling. The TT network structures are heterogeneous within a single cell, and vary between different types of cells and species. They are also remodeled in cardiac diseases. However, how different TT network structures predispose cardiac cells to arrhythmogenesis remains to be revealed. Objective To systematically investigate the roles of TT network structure and the underlying mechanisms in the genesis of intracellular calcium (Ca 2 + ) alternans and triggered activity (TA). Methods and results Based on recent experimental observations, different TT network structures, including uniformly and non-uniformly random TT distributions, were modeled in a cardiac cell model consisting of a three-dimensional network of Ca 2 + release units (CRUs). Our simulations showed that both Ca 2 + alternans and Ca 2 + wave-mediated TA were promoted when the fraction of orphaned CRUs was in an intermediate range, but suppressed in cells exhibiting either well-organized TT networks or low TT densities. Ca 2 + alternans and TA could be promoted by low TT densities when the cells were small or the CRU coupling was strong. Both alternans and TA occurred more easily in uniformly random TT networks than in non-uniformly random TT networks. Subcellular spatially discordant Ca 2 + alternans was promoted by non-uniformly random TT networks but suppressed by increasing CRU coupling strength. These mechanistic insights provide a holistic understanding of the effects of TT network structure on the susceptibility to arrhythmogenesis. Conclusions The TT network plays important roles in promoting Ca 2 + alternans and TA, and different TT network structures may predispose cardiac cells differently to arrhythmogenesis. [ABSTRACT FROM AUTHOR]

In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the effects of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in “orphaned” RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down-regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF. [ABSTRACT FROM AUTHOR]

Phospholamban (PLB) inhibits the activity of cardiac sarcoplasmic reticulum (SR) Ca 2 + -ATPase (SERCA2a). Phosphorylation of PLB during sympathetic activation reverses SERCA2a inhibition, increasing SR Ca 2 + uptake. However, sympathetic activation also modulates multiple other intracellular targets in ventricular myocytes (VMs), making it impossible to determine the specific effects of the reversal of PLB inhibition on the spontaneous SR Ca 2 + release. Therefore, it remains unclear how PLB regulates rhythmic activity in VMs. Here, we used the Fab fragment of 2D12, a monoclonal anti-PLB antibody, to test how acute reversal of PLB inhibition affects the spontaneous SR Ca 2 + release in normal VMs. Ca 2 + sparks and spontaneous Ca 2 + waves (SCWs) were recorded in the line-scan mode of confocal microscopy using the Ca 2 + fluorescent dye Fluo-4 in isolated permeabilized mouse VMs. Fab, which reverses PLB inhibition, significantly increased the frequency, amplitude, and spatial/temporal spread of Ca 2 + sparks in VMs exposed to 50 nM free [Ca 2 + ]. At physiological diastolic free [Ca 2 + ] (100–200 nM), Fab facilitated the formation of whole-cell propagating SCWs. At higher free [Ca 2 + ], Fab increased the frequency and velocity, but decreased the decay time of the SCWs. cAMP had little additional effect on the frequency or morphology of Ca 2 + sparks or SCWs after Fab addition. These findings were complemented by computer simulations. In conclusion, acute reversal of PLB inhibition alone significantly increased the spontaneous SR Ca 2 + release, leading to the facilitation and organization of whole-cell propagating SCWs in normal VMs. PLB thus plays a key role in subcellular Ca 2 + dynamics and rhythmic activity of VMs. [ABSTRACT FROM AUTHOR]

Gliomas are the major type of primary brain tumors. Accumulating research has demonstrated that tubulin is connected with the development and malignant progression of tumors. TUBA1C is a subtype of α-tubulin and is linked to prognosis in multiple cancers. In this study, the prognosis-related gene TUBA1C in glioma was identified and analyzed by bioinformatic approaches such as Kaplan–Meier (KM) survival time analysis, univariate and multivariate Cox analysis, receiver operating characteristic (ROC) analysis and functional enrichment analysis. Based on the above analyses, we found that glioma tissues had significantly higher expression of TUBA1C than normal brain tissues, and high expression of TUBA1C has worse prognosis in glioma. Gene set enrichment analysis (GSEA) revealed the signaling pathways related to the cell cycle. Furthermore, knockdown of TUBA1C also inhibited proliferation and migration and caused apoptosis and G2/M phase arrest in glioma cells. This study demonstrated that high TUBA1C expression correlated with poor outcomes in glioma patients and that knocking down TUBA1C suppressed glioma cell proliferation via cell cycle arrest. In addition, TUBA1C might be a therapeutic biomarker for gliomas. • Identified TUBA1C gene based on CGGA database using bioinformatics. • First revealed of TUBA1C correlated with poor prognosis in glioma patients. • TUBA1C might be a therapeutic biomarker for gliomas. • Indicated that TUBA1C promoted glioma cell proliferation via regulated of cell cycle. [ABSTRACT FROM AUTHOR]

TSP50, a testis-specific gene encoding a serine protease-like protein, was specifically expressed in the spermatocytes of testes but abnormally activated and expressed in many different kinds of cancers. Here, we aimed to analyze the expression of TSP50 in mouse embryo and its function in early embryonic development. Firstly, the distribution of TSP50 in oocytes and embryonic development was characterized by immunofluorescence, RT-PCR and western blotting, and the results showed that TSP50 was detected at all studied stages with a dynamic expression pattern. When overexpressed TSP50 in zygotes by microinjection, the zygotes development was highly accelerated. On the contrary, knocking down TSP50 expression by RNA interference greatly retarded the zygote development. Furthermore, TSP50 expression at embryonic day 6.5 (E6.5), day 8.5 (E8.5) and day 10.5 (E10.5) were increasingly enhanced, However, the expression of TSP50 decreased gradually in the development and differentiation of cardiac myocyte from E12.5 to postnatal (P0). Additionally, we found that TSP50 expression was decreased during cardiac myocyte differentiation of P19 cells. Overexpression of TSP50 could decrease the expression of GATA-4, and knockdown of TSP50 markedly increase the expression of GATA-4. Taken together, our data indicate that TSP50 may play an important role during the process of mouse embryonic development as well as myocardial cell differentiation. [ABSTRACT FROM AUTHOR]

Previously, we showed that activation of the spinal CXCL9, 10/CXCR3 pathway mediated bone cancer pain (BCP) in rats. However, the cellular mechanism involved is poorly understood. Here, we found that the activated CXCR3 was co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non-peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion. The inoculation of Walker-256 mammary gland carcinoma cells into the rat’s tibia induced a time-dependent phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2) in the spinal cord, and CXCR3 was necessary for the phosphorylation of Akt and ERK 1/2. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 prevented or reversed the mechanical allodynia in BCP rats. Furthermore, there was cross-activation between PI3K/Akt and Raf/MEK/ERK pathway under the BCP condition. Our results demonstrated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt and ERK 1/2 kinase, and also indicated a crosstalk between PI3K/Akt and Raf/MEK/ERK signaling pathways under the BCP condition. [ABSTRACT FROM AUTHOR]

Abstract: Fusions of patient-derived dendritic cells (DCs) and autologous tumor cells induce T-cell responses against autologous tumors in animal models and human clinical trials. These fusion cells require patient-derived tumor cells, which are not, however, always available. Here we fused autologous DCs from patients with hepatocellular carcinoma (HCC) to an allogeneic HCC cell line (HepG2). These fusion cells co-expressed tumor-associated antigens (TAAs) and DC-derived costimulatory and MHC molecules. Both CD4+ and CD8+ T cells were activated by the fusion cells. Cytotoxic T lymphocytes (CTLs) induced by the fusion cells were able to kill autologous HCC by HLA-A2- and/or HLA-A24-restricted mechanisms. CTL activity against shared TAAs indicates that the presence of alloantigens does not prevent the development of CTLs with activity against autologous HCC cells. These fusion cells may have applications in anti-tumor immunotherapy through cross-priming against shared tumor antigens and may provide a platform for adoptive immunotherapy. [Copyright &y& Elsevier]

Eco-tourism is rapidly developing in giant panda nature reserves in China, and is considered a popular tool for biodiversity conservation and the welfare of local communities. However, there is lack of empirical evidence on whether eco-tourism promotes the conservation behavior of local communities members, who live around nature reserves. To this end, this study constructed a framework to measure households' forest conservation activities, and conducted a questionnaire survey in 12 giant panda nature reserves in Sichuan Province, China. A total of 686 valid samples were obtained. A logit model was used to confirm whether income from community-based ecotourism (CBET) could enhance households' conservation behavior. The results show that households prefer three types of conservation practices, and CBET could significantly improve the income of households engaged in it. Income from CBET has motivated local households to participate in conservation activities; however, but the effects are different. In all three conservation activities, income from CBET has shown significant effects on promoting forest maintenance and protection activities, but not on reforestation ones. The results of this research could help us better understand the relationship between CBET and local households' conservation behavior. It also provides information for policymakers seeking for the best way to balance conservation and development. [Display omitted] • Community based ecotourism (CBET) has developed fast in giant panda nature reserve. • A total of 686 valid samples was collected in 12 giant panda nature reserves in Sichuan province according to a questionnaire survey. • A Logit model was employed to confirm whether the income from CBET could enhance the conservation behavior. • Income from CBET have motivated local households' participation in conservation activities, but the effects are different. [ABSTRACT FROM AUTHOR]