Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway.

Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation

MicroRNA-181a Functions as an Oncogene in Gastric Cancer by Targeting Caprin-1

MicroRNA-181a (miRNA-181a) is a multifaceted miRNA implicated in various cellular processes, particularly in cell fate determination and cellular invasion. It is frequently expressed aberrantly in human tumors and shows opposing functions in different types of cancers. In this study, we found that miRNA-181a is overexpressed in Gastric cancer (GC) tissues. Clinical and pathological analyses revealed that the expression of miRNA-181a is correlated with tumor size, lymph node metastasis, distant metastasis, and TNM stage. Kaplan-Meier analysis indicated that overexpression of miRNA-181a is associated with poor overall survival of patients with GC. Moreover, miRNA-181a is overexpressed in GC cells, and downregulation of miRNA-181a induced cell apoptosis and suppressed the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Target prediction and luciferase reporter assay showed that caprin-1 was a direct target of miRNA-181a. Downregulation of caprin-1 expression resulted in a converse change with miRNA-181a in GC. Spearman’s correlation test confirmed that the expression of miRNA-181a expression was inversely correlated with that of caprin-1 in GC cells. Furthermore, the expression of caprin-1 increased after downregulation of miRNA-181a in the GC cells. Caprin-1 siRNA can rescue the oncogenic effect of miRNA-181a on GC cell proliferation, apoptosis, migration, and invasion. These findings suggest that miRNA-181a directly inhibits caprin-1 and promotes GC development. miRNA-181a could be a target for anticancer drug development

Molecular dynamics simulations of structural transformation of perfluorooctane sulfonate (PFOS) at water/rutile interfaces

Concentration and salinity conditions are the dominant environmental factors affecting the behavior of perfluorinated compounds (PFCs) on the surfaces of a variety of solid matrices (suspended particles, sediments, and natural minerals). However, the mechanism has not yet been examined at molecular scales. Here, the structural transformation of perfluorooctane sulfonate (PFOS) at water/rutile interfaces induced by changes of the concentration level of PFOS and salt condition was investigated using molecular dynamics (MD) simulations. At low and intermediate concentrations all PFOS molecules directly interacted with the rutile (110) surface mainly by the sulfonate headgroups through electrostatic attraction, yielding a typical monolayer structure. As the concentration of PFOS increased, the molecules aggregated in a complex multi-layered structure, where an irregular assembling configuration was adsorbed on the monolayer structure by the van der Waals interactions between the perfluoroalkyl chains. When adding CaCl2 to the system, the multi-layered structure changed to a monolayer again, indicating that the addition of CaCl2 enhanced the critical concentration value to yield PFOS multilayer assemblies. The divalent Ca2+ substituted for monovalent K+ as the bridging counterion in PFOS adsorption. MD simulation may trigger wide applications in study of perfluorinated compounds (PFCs) from atomic/molecular scale

A multifactorial analysis of FAP to regulate gastrointestinal cancers progression

BackgroundFibroblast activation protein (FAP) is a cell-surface serine protease that has both dipeptidyl peptidase as well as endopeptidase activities and could cleave substrates at post-proline bond. Previous findings showed that FAP was hard to be detected in normal tissues but significantly up-regulated in remodeling sites like fibrosis, atherosclerosis, arthritis and embryonic tissues. Though increasing evidence has demonstrated the importance of FAP in cancer progression, no multifactorial analysis has been developed to investigate its function in gastrointestinal cancers until now.MethodsBy comprehensive use of datasets from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), scTIME Portal and Human Protein Atlas (HPA), we evaluated the carcinogenesis potential of FAP in gastrointestinal cancers, analyzing the correlation between FAP and poor outcomes, immunology in liver, colon, pancreas as well as stomach cancers. Then liver cancer was selected as example to experimentally validate the pro-tumor and immune regulative role of FAP in gastrointestinal cancers.ResultsFAP was abundantly expressed in gastrointestinal cancers, such as LIHC, COAD, PAAD and STAD. Functional analysis indicated that the highly-expressed FAP in these cancers could affect extracellular matrix organization process and interacted with genes like COL1A1, COL1A2, COL3A1 and POSTN. In addition, it was also observed that FAP was positively correlated to M2 macrophages infiltration across these cancers. To verify these findings in vitro, we used LIHC as example and over-expressed FAP in human hepatic stellate LX2 cells, a main cell type that produce FAP in tumor tissues, and then investigate its role on LIHC cells as well as macrophages. Results showed that the medium from FAP-over-expressed LX2 cells could significantly promote the motility of MHCC97H and SK-Hep1 LIHC cells, increase the invasion of THP-1 macrophages and induce them into pro-tumor M2 phenotype.ConclusionIn summary, we employed bioinformatic tools and experiments to perform a comprehensive analysis about FAP. Up-regulation of FAP in gastrointestinal cancers was primarily expressed in fibroblasts and contributes to tumor cells motility, macrophages infiltration and M2 polarization, revealing the multifactorial role of FAP in gastrointestinal cancers progression

An RX AFE with Programmable BP Filter and Digitization for Ultrasound Harmonic Imaging

This paper presents a front-end integrated circuit for ultrasound (US) harmonic imaging, interfacing to a one-dimensional capacitive micromachined ultrasonic transducer (CMUT). It contains a complete ultrasound receiving chain, from analog front-end (AFE) to gigabit/s data link. A two-stage self-biased inverter-based transimpedance amplifier (TIA) is proposed in this work to improve tradeoffs between power, noise, and linearity at the first stage. To improve harmonic imaging performance, the design is further equipped with a 4th-order highly programmable bandpass filter, which has a tunable bandwidth from 2MHz to 15MHz. An 8bit 80MS/s SAR ADC digitizes the signal, which is further encoded and serialized into an LVDS data link, enabling a reduction in the number of output cables for future systems with multiple ADCs. The design is realized in a 40nm CMOS technology. Electrical measurements show it consumes 2.9mW for the AFE and 2.1mW for the ADC and digital blocks. Its overall dynamic range varies from 61dB to 69dB, depending on the reception bandwidth. The imaging capability of this design is further demonstrated in a US transmission and reception imaging system. The acoustic measurements prove successful ultrasound harmonic acquisition, where the on-chip bandpass filter can improve the lateral resolution by more than 30%

The Impact of the Transmission Pulse Shape in Ultrasound Harmonic Imaging

Suppressing harmonic components in the transmission (TX) pulses is beneficial in ultrasound harmonic imaging (UHI). Compared to bipolar square waves, sinewave pulses can produce less leakage at harmonic frequencies. However, generating a good sinewave or other arbitrary pulse shapes increases the complexity of the TX electronics. As a consequence, 2-level or multi-level square wave pulses are adopted by many ultrasound systems to drive the transducer. This work quantitatively studies the impact of different TX pulse shapes in UHI based on simulations using the k-Wave toolbox. The image quality is evaluated by two metrics: contrast-to-noise ratio and structural similarity based on cyst phantoms. It shows that 8-level square wave pulses achieve comparable image quality compared to sinewave excitations. This study can be a guideline to trade off the design complexity of TX electronics and image quality for UHI

The impact of analog front-end filters on ultrasound harmonic imaging

Ultrasound (US) harmonic imaging has shown advantages in better spatial resolution and contrast compared to classic fundamental imaging, but it suffers from more attenuation due to the increased frequency. To achieve more penetration, high dynamic range (DR) front-end electronics is required to receive the weak harmonic components. Typical US front-ends use a variable gain amplifier (VGA) to compensate part of the required DR, in order to avoid using a highly sensitive analog-to-digital converter (ADC). However, in harmonic imaging, the received signal amplitude is dominated by the fundamental component, thus the VGA is less efficient for these small harmonics. An analog front-end filter can be used before the VGA to mitigate this issue but this has an impact on spatial resolution by changing the dominant frequency component and spatial pulse length of the received signal. In this work, a combined acoustic-and-electronic model is made to understand the impact of the use of an analog front-end filter in US harmonic imaging applications in terms of imaging resolution, contrast, and hardware requirements

A Multicomponent Vaccine Provides Immunity against Local and Systemic Infections by Group A Streptococcus across Serotypes

GAS is among the most common human pathogens and causes a wide variety of diseases, likely more than any other microorganism. The diverse clinical manifestations of GAS may be attributable to its large repertoire of virulence factors that are selectively and synergistically involved in streptococcal pathogenesis. To date, GAS vaccines have not been successful due to multiple serotypes and postinfection sequelae associated with autoimmunity. In this study, five conserved virulence factors that are involved in GAS pathogenesis were used as a combined vaccine. Intranasal immunization with this vaccine induced humoral and cellular immune responses across GAS serotypes and protected against mucosal, systemic, and skin infections. The significance of this work is to demonstrate that the efficacy of GAS vaccines can be achieved by including multiple nonredundant critical virulence factors and inducing local and systemic immunity. The strategy also provides valuable insights for vaccine development against other pathogens.Group A streptococcus (GAS) species are responsible for a broad spectrum of human diseases, ranging from superficial to invasive infections, and are associated with autoimmune disorders. There is no commercial vaccine against GAS. The clinical manifestations of GAS infection may be attributable to the large repertoire of virulence factors used selectively in different types of GAS disease. Here, we selected five molecules, highly conserved among GAS serotypes, and involved in different pathogenic mechanisms, as a multicomponent vaccine, 5CP. Intranasal (i.n.) immunization with 5CP protected mice against both mucosal and systemic GAS infection across serotypes; the protection lasted at least 6 months. Immunization of mice with 5CP constrained skin lesion development and accelerated lesion recovery. Flow cytometry and enzyme-linked immunosorbent assay analyses revealed that 5CP induced Th17 and antibody responses locally and systemically; however, the Th17 response induced by 5CP resolved more quickly than that to GAS when challenge bacteria were cleared, suggesting that 5CP is less likely to cause autoimmune responses. These findings support that immunization through the i.n. route targeting multiple nonredundant virulence factors can induce immunity against different types of GAS disease and represents an alternative strategy for GAS vaccine development, with favorable efficacy, coverage, duration, and safety