Despite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, ...comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.
Background PDZ-binding kinase/T-lymphokine-activated killer cell-derived protein kinase (PBK/TOPK) is a potential prognostic indicator for patients with breast cancer. The objective of the present ...study was to explore the relationship between PBK/TOPK expression and clinicopathological indicators as well as the survival of patients with breast cancer. Methods Immunohistochemical staining was used to detect the expression of PBK/TOPK in 202 cases of breast cancer tissues. The relationship between PBK/TOPK and clinicopathological parameters was evaluated using Spearman's rank-order correlation. The difference in PBK/TOPK expression among different molecular types was analyzed with the chi-square test. Kaplan-Meier analysis was used to create a survival curve and the log rank test was used to analyze the overall survival (OS) and disease-free survival (DFS). Prognostic correlation was assessed using univariate and multivariate Cox regression analyses. Results Among 202 breast cancer samples, PBK/TOPK was expressed ("+" and "++") in 182 samples (90.1%). In addition, the histological grade, TNM stages, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 were positively associated with PBK/TOPK expression. With regard to the molecular type, the expression of PBK/TOPK is different. The expression level of PBK/TOPK was negatively correlated with both the OS and DFS of breast cancer patients. The difference in the above results is meaningful (P < 0.05). Conclusions PBK/TOPK is overexpressed in breast cancer, and the expression is closely related to the clinicopathological characteristics of the disease. Breast cancer patients with high expression of PBK/TOPK have a poor prognosis. Therefore, healthcare providers can optimize breast cancer management using this indicator. Keywords: PBK/TOPK, Overexpressed, Breast cancer, Prognosis
Non-cryogenic protein structures determined at ambient temperature may disclose significant information about protein activity. Chloride-pumping rhodopsin (ClR) exhibits a trend to hyperactivity ...induced by a change in the photoreaction rate because of a gradual decrease in temperature. Here, to track the structural changes that explain the differences in CIR activity resulting from these temperature changes, we used serial femtosecond crystallography (SFX) with an X-ray free electron laser (XFEL) to determine the non-cryogenic structure of ClR at a resolution of 1.85 Å, and compared this structure with a cryogenic ClR structure obtained with synchrotron X-ray crystallography. The XFEL-derived ClR structure revealed that the all-trans retinal (ATR) region and positions of two coordinated chloride ions slightly differed from those of the synchrotron-derived structure. Moreover, the XFEL structure enabled identification of one additional water molecule forming a hydrogen bond network with a chloride ion. Analysis of the channel cavity and a difference distance matrix plot (DDMP) clearly revealed additional structural differences. B-factor information obtained from the non-cryogenic structure supported a motility change on the residual main and side chains as well as of chloride and water molecules because of temperature effects. Our results indicate that non-cryogenic structures and time-resolved XFEL experiments could contribute to a better understanding of the chloride-pumping mechanism of ClR and other ion pumps.
Text-based speech editors expedite the process of editing speech recordings by permitting editing via intuitive cut, copy, and paste operations on a speech transcript. A major drawback of current ...systems, however, is that edited recordings often sound unnatural because of prosody mismatches around edited regions. In our work, we propose a new context-aware method for more natural sounding text-based editing of speech. To do so, we 1) use a series of neural networks to generate salient prosody features that are dependent on the prosody of speech surrounding the edit and amenable to fine-grained user control 2) use the generated features to control a standard pitch-shift and time-stretch method and 3) apply a denoising neural network to remove artifacts induced by the signal manipulation to yield a high-fidelity result. We evaluate our approach using a subjective listening test, provide a detailed comparative analysis, and conclude several interesting insights.
State-of-the art voice conversion methods re-synthesize voice from spectral representations such as MFCCs and STRAIGHT, thereby introducing muffled artifacts. We propose a method that circumvents ...this concern using concatenative synthesis coupled with exemplar-based unit selection. Given parallel speech from source and target speakers as well as a new query from the source, our method stitches together pieces of the target voice. It optimizes for three goals: matching the query, using long consecutive segments, and smooth transitions between the segments. To achieve these goals, we perform unit selection at the frame level and introduce triphone-based preselection that greatly reduces computation and enforces selection of long, contiguous pieces. Our experiments show that the proposed method has better quality than baseline methods, while preserving high individuality.
Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular ...mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression.
HIV-1 integrase (HIV-1 IN) is an enzyme produced by the HIV-1 virus that integrates genetic material of the virus into the DNA of infected human cells. HIV-1 IN acts as a key component of the ...Retroviral Pre-Integration Complex (PIC). Protein dynamics could play an important role during the catalysis of HIV-1 IN; however, this process has not yet been fully elucidated. X-ray free electron laser (XFEL) together with nuclear magnetic resonance (NMR) could provide information regarding the dynamics during this catalysis reaction. Here, we report the non-cryogenic crystal structure of HIV-1 IN catalytic core domain at 2.5 Å using microcrystals in XFELs. Compared to the cryogenic structure at 2.1 Å using conventional synchrotron crystallography, there was a good agreement between the two structures, except for a catalytic triad formed by Asp64, Asp116, and Glu152 (DDE) and the lens epithelium-derived growth factor binding sites. The helix III region of the 140-153 residues near the active site and the DDE triad show a higher dynamic profile in the non-cryogenic structure, which is comparable to dynamics data obtained from NMR spectroscopy in solution state.
The dark brown anaerobic digestion piggery effluent (ADPE) with a large amount of ammonium generally needs high dilution before microalgae cultivation due to its inhibiting effects on algal growth. ...Due to the strong decolorization of fungi by degrading organic compounds in wastewater, the process-optimization integrated strategy of fungal decolorization of ADPE and subsequent microalgae cultivation with ammonium-tolerant strain may be a more reliable procedure to reduce the dilution ratio and enhance algal biomass production, and nutrient removal from ADPE. This study determined a suitable fungal strain for ADPE decolorization, which was isolated and screened from a local biogas plant, and identified using 26s rRNA gene sequence analysis. Subsequently, ADPE was pretreated by fungal decolorization to make low-diluted ADPE suitable for the algal growth, and conditions of microalgae cultivation were optimized to achieve maximum algal yield and nutrient removal from the pretreated ADPE. The results showed one promising locally isolated fungal strain, Nanchang University-27, which was selected out of three candidates and identified as Lichtheimia ornata, presenting a high decolorization to ADPE through fungal pretreatment. Five-fold low-diluted ADPE pretreated by L. ornata was the most suitable medium for the algal growth at an initial concentration of ammonium nitrogen of 380 mg L−1 in all dilution treatments. Initial optical density of 0.3 and pH of 9.0 were optimal culture conditions for the algal strain to provide the maximum algal yield (optical density = 2.1) and nutrient removal (88%, 58%, 65%, and 77% for the removal rates of ammonium nitrogen, total nitrogen, total phosphorus, and chemical oxygen demand, respectively) from the pretreated ADPE. This study demonstrated that fungal decolorization and subsequent microalgae cultivation could be a promising approach to algal biomass production and nutrient removal from ADPE.
Underwater explosion seriously affects the combat performance and vitality of submarines. In order to improve the blast resistance of stiffened double cylindrical shells, a new type of stiffened ...style that replaces the traditional T-shaped stiffeners with circular tube stiffeners, namely O-shaped stiffeners are studied. A series of comparative underwater explosion tests are carried out on two scaled stiffened double cylindrical shells with O and T-shaped stiffeners. Based on the tests, more detailed numerical simulations are made to explore the influence of the structure parameters on the shock performance of the whole structure. It is shown that the O-shaped stiffeners show more superior crushing performance than T-shaped ones when the large plastic deformation appears on the shells. As the plastic deformation of the T-shaped stiffeners is dominated by harmonic buckling while that of the O-shaped stiffeners is dominated by the flattening deformation of circular tubes, the latter can produce greater plastic deformation and absorb more shock energy to reduce the internal energy of pressure hull and thin hull. The shock response spectrums measuring at pressure hull can also be significantly attenuated at high frequency band. Therefore, the O-shaped stiffeners may be more effective sacrificial connected structures in the submarine.
•Circular tube is proposed as the stiffener of double cylindrical shells to improve the blast resistance.•Comparative non-contact underwater explosion tests are carried out on the stiffened double cylindrical shells.•The circular tube stiffeners are effective sacrificial connected structures to protect the inner and outer hull.
PDF
