The evolutionary trajectory of mitochondrial carrier family during metazoan evolution

BACKGROUND: Exploring metabolic evolution is a way to understand metabolic complexity. The substrate transport of mitochondrial carrier family (MCF) influences direct metabolic activities, making it possible to understand indirectly metabolic evolution from the evolution of substrate transport of MCF. However, the evolutionary study of substrate transport of MCF does not mean that all the concrete structures of mitochondrial carriers (MCs) must first be gained. RESULTS: Here we studied the alternation of MCF structure and potential correlated functions of MCF during metazoan evolution. The data analysis indicates that the types of substrates transported by MCF as a whole were maintained during metazoan evolution. However, the size of the substrates transported by members of MCs continuously diminished during the evolutionary process. We have found that the ratio of hydrophobic amino acids at specific helix-helix interfaces increases significantly during vertebrate evolution. Amino acid's spatial positioning and the calculating of packing values both indicate the increase in the number of hydrophobic amino acids would lead to a more "tight" structure of the TR domain, which is in agreement with the trend of diminishing size of substrates transported by MCs. In addition, there was a significant increase in the number of carriers of MCF during vertebrate evolution. CONCLUSIONS: We propose that the more "tight" TR structure generated by the increase of the hydrophobic amino acids at specific helix-helix interfaces during vertebrate evolution enhances the substrate selectivity of MCF, reflecting the evolutionary trajectory of MCF during metazoan evolution

RNase P Ribozymes Inhibit the Replication of Human Cytomegalovirus by Targeting Essential Viral Capsid Proteins.

An engineered RNase P-based ribozyme variant, which was generated using the in vitro selection procedure, was used to target the overlapping mRNA region of two proteins essential for human cytomegalovirus (HCMV) replication: capsid assembly protein (AP) and protease (PR). In vitro studies showed that the generated variant, V718-A, cleaved the target AP mRNA sequence efficiently and its activity was about 60-fold higher than that of wild type ribozyme M1-A. Furthermore, we observed a reduction of 98%-99% in AP/PR expression and an inhibition of 50,000 fold in viral growth in cells with V718-A, while a 75% reduction in AP/PR expression and a 500-fold inhibition in viral growth was found in cells with M1-A. Examination of the antiviral effects of the generated ribozyme on the HCMV replication cycle suggested that viral DNA encapsidation was inhibited and as a consequence, viral capsid assembly was blocked when the expression of AP and PR was inhibited by the ribozyme. Thus, our study indicates that the generated ribozyme variant is highly effective in inhibiting HCMV gene expression and blocking viral replication, and suggests that engineered RNase P ribozyme can be potentially developed as a promising gene-targeting agent for anti-HCMV therapy

Changes in endotracheal tube cuff pressure during laparoscopic surgery in head-up or head-down position

BACKGROUND: The abdominal insufflation and surgical positioning in the laparoscopic surgery have been reported to result in an increase of airway pressure. However, associated effects on changes of endotracheal tube cuff pressure are not well established. METHODS: 70 patients undergoing elective laparoscopic colorectal tumor resection (head-down position, n = 38) and laparoscopic cholecystecomy (head-up position, n = 32) were enrolled and were compared to 15 patients undergoing elective open abdominal surgery. Changes of cuff and airway pressures before and after abdominal insufflation in supine position and after head-down or head-up positioning were analysed and compared. RESULTS: There was no significant cuff and airway pressure changes during the first fifteen minutes in open abdominal surgery. After insufflation, the cuff pressure increased from 26 ± 3 to 32 ± 6 and 27 ± 3 to 33 ± 5 cmH(2)O in patients receiving laparoscopic cholecystecomy and laparoscopic colorectal tumor resection respectively (both p < 0.001). The head-down tilt further increased cuff pressure from 33 ± 5 to 35 ± 5 cmH(2)O (p < 0.001). There six patients undergoing colorectal tumor resection (18.8%) and eight patients undergoing cholecystecomy (21.1%) had a total increase of cuff pressure more than 10 cm H(2)O (18.8%). There was no significant correlation between increase of cuff pressure and either the patient's body mass index or the common range of intra-abdominal pressure (10-15 mmHg) used in laparoscopic surgery. CONCLUSIONS: An increase of endotracheal tube cuff pressure may occur during laparoscopic surgery especially in the head-down position

Salmonella produce microRNA-like RNA fragment Sal-1 in the infected cells to facilitate intracellular survival.

Salmonella have developed a sophisticated machinery to evade immune clearance and promote survival in the infected cells. Previous studies were mostly focused on either bacteria itself or host cells, the interaction mechanism of host-pathogen awaits further exploration. In the present study, we show that Salmonella can exploit mammalian cell non-classical microRNA processing machinery to further process bacterial small non-coding RNAs into microRNA-like fragments. Sal-1, one such fragment with the highest copy number in the infected cells, is derived from Salmonella 5-leader of the ribosomal RNA transcript and has a stem structure-containing precursor. Processing of Sal-1 precursors to mature Sal-1 is dependent on host cell Argonaute 2 (AGO2) but not Dicer. Functionally, depleting cellular Sal-1 strongly renders the Salmonella bacteria less resistant to the host defenses both in vitro and in vivo. In conclusion, we demonstrate a novel strategy for Salmonella evading the host immune clearance, in which Salmonella produce microRNA-like functional RNA fragments to establish a microenvironment facilitating bacterial survival

Ludwigia octovalvis extract improves glycemic control and memory performance in diabetic mice

Ethnopharmacological relevance Ludwigia octovalvis (Jacq.) P.H. Raven (Onagraceae) extracts have historically been consumed as a healthful drink for treating various conditions, including edema, nephritis, hypotension and diabetes. Aim of the study We have previously shown that Ludwigia octovalvis extract (LOE) can significantly extend lifespan and improve age-related memory deficits in Drosophila melanogaster through activating AMP-activated protein kinase (AMPK). Since AMPK has become a critical target for treating diabetes, we herein investigate the anti-hyperglycemic potential of LOE. Materials and methods Differentiated C2C12 muscle cells, HepG2 hepatocellular cells, streptozotocin (STZ)-induced diabetic mice and high fat diet (HFD)-induced diabetic mice were used to investigate the anti-hyperglycemic potential of LOE. The open field test and novel object recognition test were used to evaluate spontaneous motor activity and memory performance of HFD-induced diabetic mice. Results In differentiated C2C12 muscle cells and HepG2 hepatocellular cells, treatments with LOE and its active component (β-sitosterol) induced significant AMPK phosphorylation. LOE also enhanced uptake of a fluorescent glucose derivative (2-NBDG) and inhibited glucose production in these cells. The beneficial effects of LOE were completely abolished when an AMPK inhibitor, dorsomorphin, was added to the culture system, suggesting that LOE requires AMPK activation for its action in vitro. In streptozotocin (STZ)-induced diabetic mice, we found that both LOE and β-sitosterol induced an anti-hyperglycemic effect comparable to that of metformin, a drug that is commonly prescribed to treat diabetes. Moreover, LOE also improved glycemic control and memory performance of mice fed a HFD. Conclusions These results indicate that LOE is a potent anti-diabetic intervention that may have potential for future clinical applications

Virtuoso: Massive Multilingual Speech-Text Joint Semi-Supervised Learning for Text-To-Speech

This paper proposes Virtuoso, a massively multilingual speech-text joint semi-supervised learning framework for text-to-speech synthesis (TTS) models. Existing multilingual TTS typically supports tens of languages, which are a small fraction of the thousands of languages in the world. One difficulty to scale multilingual TTS to hundreds of languages is collecting high-quality speech-text paired data in low-resource languages. This study extends Maestro, a speech-text joint pretraining framework for automatic speech recognition (ASR), to speech generation tasks. To train a TTS model from various types of speech and text data, different training schemes are designed to handle supervised (paired TTS and ASR data) and unsupervised (untranscribed speech and unspoken text) datasets. Experimental evaluation shows that 1) multilingual TTS models trained on Virtuoso can achieve significantly better naturalness and intelligibility than baseline ones in seen languages, and 2) they can synthesize reasonably intelligible and naturally sounding speech for unseen languages where no high-quality paired TTS data is available.Comment: Submitted to ICASSP 202

MicroRNA-223 Delivered by Platelet-Derived Microvesicles Promotes Lung Cancer Cell Invasion via Targeting Tumor Suppressor EPB41L3

Background: Patients with hematogenous metastatic lung cancer displayed significantly increased platelet count and aggregation compared to lung cancer patients without hematogenous metastasis. The mechanism underlying the correlation between the lung cancer hematogenous metastasis and platelet activation remains unknown. Results: In the present study, we explored the role of microRNA-223 (miR-223) derived from platelets in modulating lung cancer cell invasion. Our results demonstrated that platelets from NSCLC patients contain higher level of miR-223 than that from healthy subjects. The concentration of miR-223 in the platelet-secreted microvesicles (P-MVs) from NSCLC patients was also increased compared to that from healthy subjects. Incubation of human lung cancer A549 cells with P-MVs resulted in rapid delivery of miR-223 into A549 cells, in which platelet miR-223 targeted EPB41L3 and thus promoted A549 cell invasion. The effect of P-MVs on reducing EPB41L3 in A549 cells but promoting tumor cell invasion could be largely abolished by depletion of miR-223 via transfection with miR-223 antagomir. The role of EPB41L3 in inhibiting A549 cell invasion was further validated by directly downregulating EPB41L3 via transfecting cells with EPB41L3 siRNA or miR-223 mimic. Conclusions: Our study demonstrates for the first time that platelet-secreted miR-223 via P-MVs can promote lung cancer cell invasion via targeting tumor suppressor EPB41L3