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Mortalin [also known as heat shock protein family A (HSP70) member 9 (HSPA9) or glucose-regulated protein 75 (GRP75)] is a mitochondrial molecular chaperone that is often up-regulated and mislocalized in tumors with abnormal activation of the kinases MEK and ERK. Here, we found that mortalin depletion was selectively lethal to tumor and immortalized normal cells expressing the mutant kinase B-RafV600E or the chimeric protein ΔRaf-1:ER and that MEK-ERK-sensitive regulation of the peptide-binding domain in mortalin was critical to cell survival or death. Proteomics screening identified adenine nucleotide translocase 3 (ANT3) as a previously unknown mortalin substrate and cell survival/death effector. Mechanistically, increased MEK-ERK signaling activity and mortalin function converged opposingly on the regulation of mitochondrial permeability. Specifically, whereas MEK-ERK activity increased mitochondrial permeability by promoting the interaction between ANT3 and the peptidyl-prolyl isomerase cyclophilin D (CypD), mortalin decreased mitochondrial permeability by inhibiting this interaction. Hence, mortalin depletion increased mitochondrial permeability in MEK-ERK-deregulated cells to an extent that triggered cell death. HSP70 inhibitor derivatives that effectively inhibited mortalin suppressed the proliferation of B-RafV600E tumor cells in culture and in vivo, including their B-Raf inhibitor-resistant progenies. These findings suggest that targeting mortalin has potential as a selective therapeutic strategy in B-Raf-mutant or MEK-ERK-driven tumors.

Objective To investigate the potential effects of long non-coding RNA (lncRNA) MINCR on lipopolysaccharide (LPS)-induced human alveolar epithelial cell line A549 damage and inflammation through targeted regulation of miR-223. Methods A549 cells were randomly divided into control group, LPS group, LPS+transfection group(Si NC group, Si MINCR group, miR-223 NC group, miR-223 mimic group, Si NC+miR-223 NC group, Si NC+miR-223 antagomir group, Si MINCR+miR-223 NC group, and Si MINCR+miR-223 antagomir group). RT-qPCR was performed to determine the expression levels of MINCR and miR-223; Flow cytometry was performed to determine the rate of apoptosis; ELISA was performed to determine the levels of serum tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6); Bioinformatics prediction and dual luciferase reporter gene assay were performed to verify the targeting relationship of MINCR and miR-223; Western blot was performed to test the expression levels of activated caspase-3 (cleaved caspase-3) and B-cell lymphoma-2(Bcl-2) proteins in the cells. Results There was a targeting relationship between MINCR and miR-223. Compared with the control group, the apoptosis rate, the level of TNF-α and IL-6, and the expression of MINCR, cleaved caspase-3 proteins in the LPS group were significantly increased (PPPPPPPConclusions Silencing the expression of lncRNA MINCR may target the activation of miR-223 expression, inhibit cell apoptosis and inflammation, and reduce LPS-induced damage of alveolar epithelial cells.

In this paper, we study the following singularly perturbed biharmonic Choquard equation: ε4Δ2u+V(x)u=εμ−41|x|μ∗F(u)f(u)inℝ4,$$ {\varepsilon}&#x0005E;4{\Delta}&#x0005E;2u&#x0002B;V(x)u&#x0003D;{\varepsilon}&#x0005E;{\mu -4}\left(\frac{1}{{\left&#x0007C;x\right&#x0007C;}&#x0005E;{\mu }}\ast F(u)\right)f(u)\kern0.30em \mathrm{in}\kern0.4em {\mathrm{\mathbb{R}}}&#x0005E;4, $$ where ε>0$$ \varepsilon >0 $$ is a parameter, 0<μ<4$$ 0<\mu <4 $$, ∗ is the convolution product in ℝ4$$ {\mathrm{\mathbb{R}}}&#x0005E;4 $$, and V(x)$$ V(x) $$ is a continuous real function. F(u)$$ F(u) $$ is the primitive function of f(u)$$ f(u) $$, and f$$ f $$ has critical exponential growth in the sense of the Adams inequality. By using variational methods, we establish the existence of ground state solutions when ε>0$$ \varepsilon >0 $$ small enough. [ABSTRACT FROM AUTHOR]

To gain deeper insights into the genomic characteristics of Limosilactobacillus reuteri (L. reuteri) YLR001 and uncover its probiotic properties, in the current study, a comprehensive analysis of its whole genome was conducted, explicitly exploring the genetic variations associated with different host organisms. The genome of YLR001 consisted of a circular 2,242,943 bp chromosome with a GC content of 38.84%, along with three circular plasmids (24,864, 38, 926, and 132,625 bp). Among the 2183 protein-coding sequences (CDSs), the specific genes associated with genetic adaptation and stress resistance were identified. We predicted the function of COG protein genes and analyzed the KEGG pathways. Comparative genome analysis revealed that the pan-genome contained 5207 gene families, including 475 core gene families and 941 strain-specific genes. Phylogenetic analysis revealed distinct host specificity among 20 strains of L. reuteri, highlighting substantial genetic diversity across different hosts. This study enhanced our comprehension of the genetic diversity of L. reuteri YLR001, demonstrated its potential probiotic characteristics, and established more solid groundwork for future applications. [ABSTRACT FROM AUTHOR]

The evolution process of the North China Craton has been discussed by many scholars; however, the frame for the timing of the Trans-North China Block has not been fully agreed upon. Related research has mostly focused on the northern and southern sections of the Trans-North China Block, and in-depth studies on intrusive rocks in the central region are lacking. In this study, we conduct a systematic study of the petrography, the whole-rock geochemistry, and the zircon U–Pb dating for the beschtauite intrusion, located in the Mengjiaping area of the Southern Taihang Mountains. Our results demonstrate that the dyke intrusion is mainly composed of beschtauite. Laser ablation inductively coupled plasma mass spectrometry zircon U–Pb dating shows that the beschtauite intrusion occurred at ∼1,880 ± 69 Ma. The beschtauite belongs to I-type granite, Arc tholeiite series, and Cale-alkaline series, with low total alkali, low potassium, and high aluminum. They are also enriched in large-ion lithophile elements, relatively depleted in high-field strength elements, and low total rare-earth elements. Based on the abovementioned data, it is suggested that the magmas for the beschtauite intrusion were metasomatized by oceanic slab subduction in the Late Paleoproterozoic. The formation time of the North China Craton basement should be set to after 1,880 Ma.