Spindle pole body component 24 homolog potentiates tumor progression via regulation of SRY-box transcription factor 2 in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of human kidney cancer with a high probability of metastasis. To understand the molecular processing essential for ccRCC tumorigenicity, we conducted an integrative in silico analysis of The Cancer Genome Atlas (TCGA) ccRCC dataset and clustered randomly interspersed short palindromic repeats (CRISPR) screening dataset of ccRCC cell lines from Depmap. We identified spindle pole body component 24 homolog (SPC24) as an essential gene for ccRCC cell lines with prognostic significance in the TCGA database. Targeting SPC24 by CRISPR/Cas9-mediated gene knockout attenuated ccRCC proliferation, metastasis, and in vivo tumor growth. Furthermore, we found that SPC24 regulates metastasis genes expression in a SRY-box transcription factor 2 (SOX2)-dependent manner. The anti-proliferative effects of SPC24 knockout were strengthened with SOX2 knockdown. Collectively, our findings suggest SPC24 has a pivotal function in promoting ccRCC progression, providing a new insight for the treatment of ccRCC.

Development of a strategy for the identification of surface proteins in the pathogenic microsporidian Nosema bombycis.

Parasite-host interactions mediated by cell surface proteins have been implicated as a critical step in infections caused by the microsporidian Nosema bombycis. Such cell surface proteins are considered as promising diagnostic markers and targets for drug development. However, little research has specifically addressed surface proteome identification in microsporidia due to technical barriers. Here, a combined strategy was developed to separate and identify the surface proteins of N. bombycis. Briefly, following (1) biotinylation of the spore surface, (2) extraction of total proteins with an optimized method and (3) streptavidin affinity purification of biotinylated proteins, 22 proteins were identified based on LC-MS/MS analysis. Among them, 5 proteins were confirmed to be localized on the surface of N. bombycis. A total of 8 proteins were identified as hypothetical extracellular proteins, whereas 7 other hypothetical proteins had no available function annotation. Furthermore, a protein with a molecular weight of 18·5 kDa was localized on the spore surface by western blotting and immunofluorescence analysis, even though it was predicted to be a nuclear protein by bioinformatics. Collectively, our work provides an effective strategy for isolating microsporidian surface protein components for both drug target identification and further diagnostic research on microsporidian disease control.

Optimization of terminal area arrival flight sorting based on an improved sparrow search algorithm.

At present, airspace congestion and flight delays have become widespread concerns. This study aims to optimize the sequencing of arrival flights in the terminal area of multirunway airports. Considering the constraints of multiple runways, slant intervals and moving flight positions, this article establishes an optimization model for arrival flight sequencing in a multirunway airport terminal area. Accordingly, an improved sparrow search algorithm (ISSA) is proposed based on Chebyshev chaotic mapping, the golden sine strategy, and the variable neighborhood strategy. Through six basic test functions, the ISSA is compared with particle swarm optimization, the whale optimization algorithm, the genetic algorithm, and other algorithms to verify its superiority. Finally, two sets of instance data from Kunming Changshui Airport were used for experiments. The results show that the total delay times (TDTs) of small-scale flights (number of aircraft: 29) and large-scale flights (number of aircraft: 147) are 55.3% and 20.5% lower, respectively, than those of the first-come-first-served algorithm. The superiority of the ISSA designed in this article is verified, and it can significantly reduce the TDTs of arrival flights. It is suitable for optimizing arrival flights during peak hours at most airports. This approach provides theoretical support for optimizing the sorting of flights in terminal areas.

LncRNA INHEG promotes glioma stem cell maintenance and tumorigenicity through regulating rRNA 2'-O-methylation.

Glioblastoma (GBM) ranks among the most lethal of human cancers, containing glioma stem cells (GSCs) that display therapeutic resistance. Here, we report that the lncRNA INHEG is highly expressed in GSCs compared to differentiated glioma cells (DGCs) and promotes GSC self-renewal and tumorigenicity through control of rRNA 2'-O-methylation. INHEG induces the interaction between SUMO2 E3 ligase TAF15 and NOP58, a core component of snoRNP that guides rRNA methylation, to regulate NOP58 sumoylation and accelerate the C/D box snoRNP assembly. INHEG activation enhances rRNA 2'-O-methylation, thereby increasing the expression of oncogenic proteins including EGFR, IGF1R, CDK6 and PDGFRB in glioma cells. Taken together, this study identifies a lncRNA that connects snoRNP-guided rRNA 2'-O-methylation to upregulated protein translation in GSCs, supporting an axis for potential therapeutic targeting of gliomas.

Exosomal lncRNA-Mediated Intercellular Communication Promotes Glioblastoma Chemoresistance.

Standard treatment for glioblastoma (GBM) is surgery followed by radiotherapy and chemotherapy, often with the chemotherapeutic agent temozolomide. However, this treatment is not curative. In this issue, Li and colleagues uncover a novel circuit regulating GBM cell resistance to temozolomide that involves exosome-mediated transfer of the long noncoding RNA (lncRNA) lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence) to microglial cells. The results provide new targets for therapeutics that could help overcome resistance to temozolomide.See related article by Li et al., p. 1383. (3).

Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells.

PTEN is a tumor suppressor that is highly mutated in a variety of human cancers. Recent studies have suggested a link between PTEN loss and deficiency in the non-homologous end-joining (NHEJ) pathway of DNA double strand break (DSB) repair. As a means to achieve synthetic lethality in this context, we tested the effect of 3E10, a cell-penetrating autoantibody that inhibits RAD51, a key factor in the alternative pathway of DSB repair, homology dependent repair (HDR). We report here that treatment of PTEN-deficient glioma cells with 3E10 leads to an accumulation of DNA damage causing decreased proliferation and increased cell death compared to isogenic PTEN proficient controls. Similarly, 3E10 was synthetically lethal to a series of PTEN-deficient, patient-derived primary melanoma cell populations. Further, 3E10 was found to synergize with a small molecule inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein, a DNA damage checkpoint kinase, in both PTEN-deficient glioma cells and primary melanoma cells. These results point to a targeted synthetic lethal strategy to treat PTEN-deficient cancers through a combination designed to disrupt both DNA repair and DNA damage checkpoint signaling.

Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells.

Two classes of azido-modified pyrimidine nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2'-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2'-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5-azido nucleosides leads to the formation of π-aminyl radicals followed by facile conversion to σ-iminyl radicals either via a bimolecular reaction involving intermediate α-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells.

Synthesis, structure, and activity of supramolecular mimics for the active site and arg141 residue of copper, zinc-superoxide dismutase.

Two supramolecular complexes, [Cu(L)(H2O)2(beta-CD)](ClO4)2.10.5H2O.CH3OH (1) and [Cu(L)(H2O)2(beta-GCD)](HClO4)(ClO4)2.10H2O (2) (L = 4-(4'-tert-butyl-benzyl)diethylenetriamine, beta-CD = beta-cyclodextrin, and beta-GCD = mono-6-deoxy-6-guanidinocycloheptaamylose cation), have been synthesized. The structure of 1 has been characterized by X-ray crystallography. The 4-tert-butyl-benzyl of [Cu(L)(H2O)2]2+ moiety in 1 as a guest inserts into the hydrophobic cavity of the beta-CD as a host along the primary hydroxyl side. On the basis of the structure data of 1, complex 2 was modeled, which showed that the distance between the Cu and C atom of the guanidinium is 5.2 A, comparable to the corresponding distance in bovine erythrocyte Cu, Zn-SOD (5.9 A) (SOD = superoxide dismutase). Apparent inclusion stability constants of the host and the guest were measured to be 0.66 (+/-0.01) x 104 and 1.15 (+/-0.03) x 104 M-1 for 1 and 2 respectively. The electronic absorption bands and electronic reflection bands of each complex are almost the same, indicating an identical structure of the complex in aqueous solution and in solid state. The two complexes showed quasi-reversible one-electron Cu(II)/Cu(I) redox waves with redox potentials of -0.345 and -0.338 V for 1 and 2, respectively. Their SOD-like activities (IC50) were measured to be 0.30 +/- 0.01 and 0.17 +/- 0.01 microM by xanthine/xanthine oxidase-NBT assay. The enhanced SOD activity of 2 by approximately 40% compared with 1 suggests that the guanidyl cation in the host of the supramolecular system of 2 can effectively mimic the side chain of Arg141 in the enzyme, which is known to be essential for high SOD activity possibly through steering of the superoxide substrate to and from the active copper ion.

An effective metallohydrolase model with a supramolecular environment: structures, properties, and activities.

A supramolecular inclusion complex, [Zn(L1)(H2O)2(beta-CD)](ClO4)2.9.5 H2O (1) was synthesized and characterized structurally and its first-order active species for hydrolysis of esters, [Zn(L1)(H2O)(OH)(beta-CD)](ClO4) (2), was isolated (L1=4-(4'-tert-butylbenzyl)diethylenetriamine; beta-CD=beta-cyclodextrin). The apparent inclusion stability constant of the host and the guest measured in aqueous solution was (5.91+/-0.03)x10(3) for 1. The measured values of the first- and second-order pK(a) values of coordinated water molecules were 8.20+/-0.08 and 10.44+/-0.08, respectively, and were assigned to water molecules occupying the plane and remaining axial positions in a distorted trigonal bipyramid of the [Zn(L1)(H2O)2(beta-CD)]2+ sphere according to the structural analysis of [Zn(L2)(H2O)}2(mu-OH)](ClO4)3 (3) (L2=4-benzyldiethylenetriamine). p-Nitrophenyl acetate (pNA) hydrolysis catalyzed by 1 at pH 7.5-9.1 and 25.0+/-0.1 degrees C exhibited a first-order reaction with various concentrations of pNA and 1, but the pH profile did not indicate saturated kinetic behavior. Second-order rate constants of 0.59 and 24.0 M(-1) s(-1) were calculated for [Zn(L1)(H2O)(OH)(beta-CD)]+ and [Zn(L1)(OH)2(beta-CD)], respectively; the latter exhibited a potent catalytic activity relative to the reported mononuclear and polynuclear Zn(II) species.