Autophagy and Coagulation in Liver Cancer and Disorders

The physiological role of autophagy in metabolism of the body involves both protein synthesis and degradation. The autophagy-lysosome and the ubiquitin-proteasome systems are the two major intracellular proteolytic mechanisms. Autophagy in hepatocytes is known to be quite active and contribute to its normal functions and the pathogenesis of liver diseases. The role of autophagy in liver diseases has been widely studied, and growing evidence has now shown that autophagy is involved in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC). However, the role of autophagy in the progression of liver fibrosis and prognosis of human HCC is not well known. Recent studies have demonstrated that tissue factor (TF) combined with coagulation factor VII (FVII) has a pathological role by activating a protease-activated receptor 2 (PAR2) for tumor growth. Autophagy-related LC3A/B-II formation induced by the inhibition of TF/FVII/PAR2 coagulation axis, particularly by FVII knockdown, was selectively mediated by the Atg7 induction. These results are consistent with clinical observations that indicate the important role of FVII activation in regulating autophagy in HCC. In this chapter, we discuss our findings in which FVII promotes growth and progression in HCC through ERK-TSC/mTOR signaling to repress autophagy and may play a pivotal role in conferring cirrhosis and other liver diseases

In vivo sub-femtoliter resolution photoacoustic microscopy with higher frame rates

Microscopy based on non-fluorescent absorption dye staining is widely used in various fields of biomedicine for 400 years. Unlike its fluorescent counterpart, non-fluorescent absorption microscopy lacks proper methodologies to realize its in vivo applications with a sub-femtoliter 3D resolution. Regardless of the most advanced high-resolution photoacoustic microscopy, sub-femtoliter spatial resolution is still unattainable, and the imaging speed is relatively slow. In this paper, based on the two-photon photoacoustic mechanism, we demonstrated a in vivo label free laser-scanning photoacoustic imaging modality featuring high frame rates and sub-femtoliter 3D resolution simultaneously, which stands as a perfect solution to 3D high resolution non-fluorescent absorption microscopy. Furthermore, we first demonstrated in vivo label-free two-photon acoustic microscopy on the observation of non-fluorescent melanin distribution within mouse skin

Observational connection of non-thermal X-ray emission from pulsars with their timing properties and thermal emission

The origin and radiation mechanisms of high energy emissions from pulsars have remained mysterious since their discovery. Here we report, based on a sample of 68 pulsars, observational connection of non-thermal X-ray emissions from pulsars with their timing properties and thermal emissions, which may provide some constraints on theoretical modeling. Besides strong correlations with the spin-down power $\dot{E}$ and the magnetic field strength at the light cylinder $B_{\rm lc}$, the non-thermal X-ray luminosity in 0.5 - 8 keV, $L_{\rm p}$, represented by the power-law component in the spectral model, is found to be strongly correlated with the highest possible electric field strength in the polar gap, $E_{\rm pc}$, of the pulsar. The spectral power index $\Gamma_{\rm p}$ of that power-law component is also found, for the first time in the literature, to strongly correlate with $\dot{E}$, $B_{\rm lc}$ and $E_{\rm pc}$, thanks to the large sample. In addition, we found that $L_{\rm p}$ can be well described by $L_{\rm p}\propto T^{5.96\pm 0.64}R^{2.24\pm 0.18}$, where $T$ and $R$ are the surface temperature and the emitting-region radius of the surface thermal emission, represented by the black-body component in the spectral model. $\Gamma_{\rm p}$, on the other hand, can be well described only when timing variables are included, and the relation is $\Gamma_{\rm p} = \log(T^{-5.8\pm 1.93}R^{-2.29\pm 0.85}P^{-1.19\pm 0.88}\dot{P}^{0.94\pm 0.44})$ plus a constant. These relations strongly suggest the existence of connections between surface thermal emission and electron-positron pair production in pulsar magnetospheres.Comment: 13 pages, 11 figures, accepted by MNRA

Role of pirenoxine in the effects of catalin on in vitro ultraviolet-induced lens protein turbidity and selenite-induced cataractogenesis in vivo

Purpose: In this study, we investigated the biochemical pharmacology of pirenoxine (PRX) and catalin under in vitro selenite/calcium- and ultraviolet (UV)-induced lens protein turbidity challenges. The systemic effects of catalin were determined using a selenite-induced cataractogenesis rat model. Methods: In vitro cataractogenesis assay systems (including UVB/C photo-oxidation of lens crystallins, calpain-induced proteolysis, and selenite/calcium-induced turbidity of lens crystallin solutions) were used to screen the activity of PRX and catalin eye drop solutions. Turbidity was identified as the optical density measured using spectroscopy at 405 nm. We also determined the in vivo effects of catalin on cataract severity in a selenite-induced cataract rat model. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS–PAGE) was applied to analyze the integrity of crystallin samples. Results: PRX at 1,000 μM significantly delayed UVC-induced turbidity formation compared to controls after 4 h of UVC exposure (p<0.05), but not in groups incubated with PRX concentrations of <1,000 μM. Results were further confirmed by SDS–PAGE. The absolute γ-crystallin turbidity induced by 4 h of UVC exposure was ameliorated in the presence of catalin equivalent to 1~100 μM PRX in a concentration-dependent manner. Samples with catalin-formulated vehicle only (CataV) and those containing PRX equivalent to 100 μM had a similar protective effect after 4 h of UVC exposure compared to the controls (p<0.05). PRX at 0.03, 0.1, and 0.3 μM significantly delayed 10 mM selenite- and calcium-induced turbidity formation compared to controls on days 0~4 (p<0.05). Catalin (equivalent to 32, 80, and 100 μM PRX) had an initial protective effect against selenite-induced lens protein turbidity on day 1 (p<0.05). Subcutaneous pretreatment with catalin (5 mg/kg) also statistically decreased the mean cataract scores in selenite-induced cataract rats on post-induction day 3 compared to the controls (1.3±0.2 versus 2.4±0.4; p<0.05). However, catalin (equivalent to up to 100 μM PRX) did not inhibit calpain-induced proteolysis activated by calcium, and neither did 100 μM PRX. Conclusions: PRX at micromolar levels ameliorated selenite- and calcium-induced lens protein turbidity but required millimolar levels to protect against UVC irradiation. The observed inhibition of UVC-induced turbidity of lens crystallins by catalin at micromolar concentrations may have been a result of the catalin-formulated vehicle. Transient protection by catalin against selenite-induced turbidity of crystallin solutions in vitro was supported by the ameliorated cataract scores in the early stage of cataractogenesis in vivo by subcutaneously administered catalin. PRX could not inhibit calpain-induced proteolysis activated by calcium or catalin itself, and may be detrimental to crystallins under UVB exposure. Further studies on formulation modifications of catalin and recommended doses of PRX to optimize clinical efficacy by cataract type are warranted

Borders of Cis-Regulatory DNA Sequences Preferentially Harbor the Divergent Transcription Factor Binding Motifs in the Human Genome

Changes in cis-regulatory DNA sequences and transcription factor (TF) repertoires provide major sources of phenotypic diversity that shape the evolution of gene regulation in eukaryotes. The DNA-binding specificities of TFs may be diversified or produce new variants in different eukaryotic species. However, it is currently unclear how various levels of divergence in TF DNA-binding specificities or motifs became introduced into the cis-regulatory DNA regions of the genome over evolutionary time. Here, we first estimated the evolutionary divergence levels of TF binding motifs and quantified their occurrence at DNase I-hypersensitive sites. Results from our in silico motif scan and experimentally derived chromatin immunoprecipitation (TF-ChIP) show that the divergent motifs tend to be introduced in the edges of cis-regulatory regions, which is probably accompanied by the expansion of the accessible core of promoter-associated regulatory elements during evolution. We also find that the genes neighboring the expanded cis-regulatory regions with the most divergent motifs are associated with functions like development and morphogenesis. Accordingly, we propose that the accumulation of divergent motifs in the edges of cis-regulatory regions provides a functional mechanism for the evolution of divergent regulatory circuits

Instantaneous 3D EEG Signal Analysis Based on Empirical Mode Decomposition and the Hilbert–Huang Transform Applied to Depth of Anaesthesia

Depth of anaesthesia (DoA) is an important measure for assessing the degree to which the central nervous system of a patient is depressed by a general anaesthetic agent, depending on the potency and concentration with which anaesthesia is administered during surgery. We can monitor the DoA by observing the patient’s electroencephalography (EEG) signals during the surgical procedure. Typically high frequency EEG signals indicates the patient is conscious, while low frequency signals mean the patient is in a general anaesthetic state. If the anaesthetist is able to observe the instantaneous frequency changes of the patient’s EEG signals during surgery this can help to better regulate and monitor DoA, reducing surgical and post-operative risks. This paper describes an approach towards the development of a 3D real-time visualization application which can show the instantaneous frequency and instantaneous amplitude of EEG simultaneously by using empirical mode decomposition (EMD) and the Hilbert–Huang transform (HHT). HHT uses the EMD method to decompose a signal into so-called intrinsic mode functions (IMFs). The Hilbert spectral analysis method is then used to obtain instantaneous frequency data. The HHT provides a new method of analyzing non-stationary and nonlinear time series data. We investigate this approach by analyzing EEG data collected from patients undergoing surgical procedures. The results show that the EEG differences between three distinct surgical stages computed by using sample entropy (SampEn) are consistent with the expected differences between these stages based on the bispectral index (BIS), which has been shown to be quantifiable measure of the effect of anaesthetics on the central nervous system. Also, the proposed filtering approach is more effective compared to the standard filtering method in filtering out signal noise resulting in more consistent results than those provided by the BIS. The proposed approach is therefore able to distinguish between key operational stages related to DoA, which is consistent with the clinical observations. SampEn can also be viewed as a useful index for evaluating and monitoring the DoA of a patient when used in combination with this approach

miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions

MicroRNAs (miRNAs) are small non-coding RNA molecules capable of negatively regulating gene expression to control many cellular mechanisms. The miRTarBase database (http://mirtarbase.mbc.nctu.edu.tw/) provides the most current and comprehensive information of experimentally validated miRNA-target interactions. The database was launched in 2010 with data sources for >100 published studies in the identification of miRNA targets, molecular networks of miRNA targets and systems biology, and the current release (2013, version 4) includes significant expansions and enhancements over the initial release (2010, version 1). This article reports the current status of and recent improvements to the database, including (i) a 14-fold increase to miRNA-target interaction entries, (ii) a miRNA-target network, (iii) expression profile of miRNA and its target gene, (iv) miRNA target-associated diseases and (v) additional utilities including an upgrade reminder and an error reporting/user feedback system

Memory Impairment and Plasma BDNF Correlates of the BDNF Val66Met Polymorphism in Patients With Bipolar II Disorder

Studies suggest that a functional polymorphism of brain-derived neurotrophic factor (BDNF), polymorphism BDNF Val66Met affects cognitive functions, however, the effect is unclear in bipolar II (BD-II) disorder. We used the Wechsler Memory Scale-third edition (WMS-III), the presence of the BDNF Val66Met polymorphism, and plasma concentrations of BDNF to investigate the association between memory impairment and BDNF in BD-II disorder. We assessed the memory functions of 228 BD-II patients and 135 healthy controls (HCs). BD-II patients had significantly lower scores on five of the eight WMS-III subscales. In addition to education, the BDNF polymorphism were associated with the following subscales of WMS-III, auditory delayed memory, auditory delayed recognition memory and general memory scores in BD-II patients, but not in HC. Moreover, BD-II patients with the Val-homozygote scored significantly higher on the visual immediate memory subscale than did those with the Met/Met and Val/Met polymorphisms. The significantly positive effect of the Val-homozygote did not have a significantly positive effect on memory in the HC group, however. We found no significant association between BDNF polymorphisms and plasma concentrations of BDNF. The plasma BDNF was more likely to be associated with clinical characteristics than it was with memory indices in the BD-II group. The impaired memory function in BD-II patients might be dependent upon the association between the BDNF Val66Met polymorphism and peripheral BDNF levels

Integration, Launch, and First Results from IDEASSat/INSPIRESat-2 - A 3U CubeSat for Ionospheric Physics and Multi-National Capacity Building

The Ionospheric Dynamics and Attitude Subsystem Satellite (IDEASSat) is a 3U CubeSat carrying a Compact Ionospheric Probe (CIP) to detect ionospheric irregularities that can impact the usability and accuracy of global satellite navigation systems (GNSS), as well as satellite and terrestrial over the horizon communications. The spacecraft was developed by National Central University (NCU) in Taiwan, with additional development and operational support from partners in the International Satellite Program in Science and Education (INSPIRE) consortium. The spacecraft system needed to accommodate these mission objectives required three axis attitude control, dual band communications capable of supporting both tracking, telemetry and command (TT&C) and science data downlink, as well as flight software and ground systems capable of supporting the autonomous operation and short contact times inherent to a low Earth orbit mission developed on a limited university budget with funding agency-imposed constraints. As the first spacecraft developed at NCU, lessons learned during the development, integration, and operation of IDEASSat have proven to be crucial to the objective of developing a sustainable small satellite program. IDEASSat was launched successfully on January 24, 2021 aboard the SpaceX Falcon 9 Transporter 1 flight. and successfully began operations, demonstrating power, thermal, and structural margins, as well as validation of uplink and downlink communications functionality, and autonomous operation. A serious anomaly occurred after 22 days on orbit when communication with the spacecraft were abruptly lost. Communication was re-established after 1.5 months for sufficient time to downlink stored flight data, which allowed the cause of the blackout to be identified to a high level of confidence and precision. In this paper, we will report on experiences and anomalies encountered during the final flight model integration and delivery, commissioning, and operations. The agile support from the international amateur radio community and INSPIRE partners were extremely helpful in this process, especially during the initial commissioning phase following launch. It is hoped that the lessons learned reported here will be helpful for other university teams working to develop spaceflight capacity