CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway.

With its high efficiency for site-specific genome editing and easy manipulation, the clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (CAS9) system has become the most widely used gene editing technology in biomedical research. In addition, significant progress has been made for the clinical development of CRISPR/CAS9 based gene therapies of human diseases, several of which are entering clinical trials. Here we report that CAS9 protein can function as a genome mutator independent of any exogenous guide RNA (gRNA) in human cells, promoting genomic DNA double-stranded break (DSB) damage and genomic instability. CAS9 interacts with the KU86 subunit of the DNA-dependent protein kinase (DNA-PK) complex and disrupts the interaction between KU86 and its kinase subunit, leading to defective DNA-PK-dependent repair of DNA DSB damage via non-homologous end-joining (NHEJ) pathway. XCAS9 is a CAS9 variant with potentially higher fidelity and broader compatibility, and dCAS9 is a CAS9 variant without nuclease activity. We show that XCAS9 and dCAS9 also interact with KU86 and disrupt DNA DSB repair. Considering the critical roles of DNA-PK in maintaining genomic stability and the pleiotropic impact of DNA DSB damage responses on cellular proliferation and survival, our findings caution the interpretation of data involving CRISPR/CAS9-based gene editing and raise serious safety concerns of CRISPR/CAS9 system in clinical application

Stemness factor Sall4 is required for DNA damage response in embryonic stem cells.

Mouse embryonic stem cells (ESCs) are genetically more stable than somatic cells, thereby preventing the passage of genomic abnormalities to their derivatives including germ cells. The underlying mechanisms, however, remain largely unclear. In this paper, we show that the stemness factor Sall4 is required for activating the critical Ataxia Telangiectasia Mutated (ATM)-dependent cellular responses to DNA double-stranded breaks (DSBs) in mouse ESCs and confer their resistance to DSB-induced cytotoxicity. Sall4 is rapidly mobilized to the sites of DSBs after DNA damage. Furthermore, Sall4 interacts with Rad50 and stabilizes the Mre11-Rad50-Nbs1 complex for the efficient recruitment and activation of ATM. Sall4 also interacts with Baf60a, a member of the SWI/SNF (switch/sucrose nonfermentable) ATP-dependent chromatin-remodeling complex, which is responsible for recruiting Sall4 to the site of DNA DSB damage. Our findings provide novel mechanisms to coordinate stemness of ESCs with DNA damage response, ensuring genomic stability during the expansion of ESCs

Comparing the Effects of Distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix Pharmacopuncture With Heart Rate Variability (HRV): A Randomized, Sham-controlled and Double-blind Clinical Trial

AbstractThis study compared the effects of distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix pharmacopuncture on the autonomic nervous system and heart rate variability. The purpose of the trial was to observe the influence distilled Astragali Radix, Wild Ginseng and Rehmannia glutinosa pharmacopuncture have on the autonomic nervous system. 120 healthy male volunteers were divided into four groups, which consisted of three experimental groups and a control group. This study was a randomized, placebo-controlled, double-blind clinical trial. Volunteers in experimental groups were underwent pharmacopuncture at GB21 (Kyonjong), and volunteers in the control group were injected with normal saline at GB21 (Kyonjong). Heart rate variability was measured seven times: before and after injection, every 5 minutes for 30 minutes. The result was distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix pharmacopuncture in healthy adult males tended to activate the autonomic nervous system, particularly the sympathetic nervous system

MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing.

The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC

Analysis of the Thermal Storage Performance of a Radiant Floor Heating System with a PCM

This study first reviewed previous studies on floor heating systems based on the installation of a phase change material (PCM) and the current status of technical developments and found that PCM-based research is still in its infancy. In particular, the improvement of floor heat storage performance in indoor environments by combining a PCM with existing floor structures has not been subject to previous research. Thus, a PCM-based radiant floor heating system that utilizes hot water as a heat source and can be used in conjunction with the widespread wet construction method can be considered novel. This study found the most suitable PCM melting temperature for the proposed PCM-based radiant floor heating system ranged from approximately 35 °C to 45 °C for a floor thickness of 70 mm and a PCM thickness of 10 mm. Mock-up test results, which aimed to assess the performance of the radiant floor heating system with and without the PCM, revealed that the PCM-based room was able to maintain a temperature that was 0.2 °C higher than that of the room without the PCM. This was due to the rise in temperature caused by the PCM’s heat storage capacity and the emission of waste heat that was otherwise lost to the underside of the hot water pipe when the PCM was not present

The roles of NANOG in tumorigenesis

The pluripotency factor Nanog is highly expressed in pluripotent stem cells and certain adult stem cells, but is not expressed in normal adult cells. However, Nanog is frequently overexpressed in human cancers. Here, we discuss the distinct oncogenic roles of Nanog at various stages of tumorigenesis

Comparison of the formula accuracy for calculating multifocal intraocular lens power: a single center retrospective study in Korean patients

Abstract This study evaluated the accuracy of newer formulas (Barrett Universal II, EVO 2.0, Kane, Hoffer QST, and PEARL-DGS) and the Haigis formula in Korean patients with the Alcon TFNT multifocal intraocular lens. In total, 3100 randomly selected eyes of 3100 patients were retrospectively reviewed. After constant optimization, the standard deviation (SD) of the prediction error was assessed for the entire group, and the root mean square error was compared for short and long axial length (AL) subgroup analysis. The Cooke-modified AL (CMAL) was experimentally applied to the Haigis formula. All the newer formulas performed well, but they did not significantly outperform the Haigis formula. In addition, all the newer formulas exhibited significant myopic outcomes (− 0.23 to − 0.29 diopters) in long eyes. Application of the CMAL to the Haigis formula with single constant optimization produced similar behavior and higher correlation with the newer formulas. The CMAL-applied triple-optimized Haigis formula yielded a substantially smaller SD, even superior to the Barrett and Hoffer QST formulas. The AL modification algorithms such as the CMAL used in newer formulas to cope with optical biometry’s overestimation of the AL in long eyes seemed to overcompensate, particularly in the long eyes of the East Asian population

Synergistic Antibacterial Effects of Probiotic Lactic Acid Bacteria with Curcuma longa Rhizome Extract as Synbiotic against Cutibacterium acnes

Acne is a chronic inflammatory skin disease induced by Cutibacterium acnes. Recently, the effects of probiotics, prebiotics and synbiotics have been researched for the treatment of skin diseases in humans. However, the synbiotic effect of probiotics and prebiotic Curcuma longa rhizome extract (CLE) on C. acnes remains ambiguous. Therefore, the aim of this study was to investigate the synergistic antibacterial activities of probiotic lactic acid bacteria (LAB) with CLE as a synbiotic against C. acnes. Agar well diffusion assays were performed to determine the inhibitory effects of each combination of one of five Lactobacillus sp. with CLE as synbiotics against C. acnes KCTC 3314. Among them, the comparison between the average diameters of inhibition zones showed that the synbiotic combination of Lactobacillus acidophilus A001F8 and CLE significantly increased the inhibition zone diameters against C. acnes, compared to the use of Lactobacillus acidophilus A001F8 or CLE alone (p < 0.05). In conclusion, the synbiotics of probiotic LAB and CLE showed synergistic antibacterial effects against C. acnes, suggesting therapeutic potential for this synbiotic combination in the development of cosmetics or medicine against C. acnes

Artificial Action Potential and Ionic Power Device Inspired by Ion Channels and Excitable Cell

Abstract In vivo, the membrane potential of the excitable cell working by ion gradients plays a significant role in bioelectricity generation and nervous system operation. Conventional bioinspired power systems generally have adopted ion gradients, but overlook the functions of ion channels and Donnan effect to generate efficient ion flow in the cell. Here, cell‐inspired ionic power device implementing the Donnan effect using multi‐ions and monovalent ion exchange membranes as artificial ion channels is realized. Different ion‐rich electrolytes on either side of the selective membrane generate the ion gradient potentials with high ionic currents and reduce the osmotic imbalance of the membrane. Based on this device, the artificial neuronal signaling is presented by the mechanical switching system of the ion selectivity like mechanosensitive ion channels in a sensory neuron. Compared with reverse electrodialysis, which requires a low concentration, a high‐power device with ten times the current and 8.5 times the power density is fabricated. This device activates grown muscle cells by increasing power through serial connection like an electric eel, and shows the possibility of an ion‐based artificial nervous system

Brief Report: Immune Microenvironment Determines the Immunogenicity of Induced Pluripotent Stem Cell Derivatives.

International audienceThe breakthrough of induced pluripotent stem cells (iPSCs) has raised the possibility that patient-specific iPSCs can provide autologous cells for cell therapy without the concern for immune rejection. However, the immunogenicity of iPSC-derived cells remains controversial. Using syngeneic C57BL/6 (B6) mouse transplantation model, several studies indicate that B6 iPSC-derived cells exhibit some levels of immunogenicity when transplanted into B6 mice subcutaneously. In contrast, one recent study has concluded that various lineages of B6 iPSC-derived cells exhibit no immunogenicity when transplanted under the kidney capsule of B6 mice. To resolve the controversy concerning this critical issue of iPSC biology, we used the same B6 transplantation model to demonstrate that the immune response toward antigens is dependent on the immune environment of the transplantation site. Immunogenic antigen-expressing B6 embryonic stem cells (ESCs) as well as B6 iPSCs and their terminally differentiated cells survived under the kidney capsule but are immune rejected when transplanted subcutaneously or intramuscularly. The cotransplantation of mature B6 dendritic cells under the kidney capsule leads to immune rejection of B6 iPSC-derived grafts but not B6 ESC-derived grafts, indicating that the lack of detectable immune response to iPSC-derived grafts under the kidney capsule is due to the lack of functional antigen presenting cells