Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of kidney cysts leading to kidney failure in adulthood. Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment. Here, we demonstrate that treatment with mTOR inhibitors result in the removal of negative feedback loops and up-regulates pro-proliferative phosphatidylinositol 3-kinase (PI3K)-Akt and PI3K-extracellular signal-regulated kinase (ERK) signaling in rat and mouse PKD models. Dual mTOR/PI3K inhibition with NVP-BEZ235 abrogated these pro-proliferative signals and normalized kidney morphology and function by blocking proliferation and fibrosis. Our findings suggest that multi-target PI3K/mTOR inhibition may represent a potential treatment for ADPKD

Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices (LVADs) in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery not only of contractile function.We herein review the current knowledge on the effects of volume-unloading the left ventricle via different methods of heterotopic heart transplantation in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under reloaded conditions.While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced remodeling of the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients

DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks.

Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA D

Reconstructing Visual Stimulus Images from EEG Signals Based on Deep Visual Representation Model

Reconstructing visual stimulus images is a significant task in neural decoding, and up to now, most studies consider the functional magnetic resonance imaging (fMRI) as the signal source. However, the fMRI-based image reconstruction methods are difficult to widely applied because of the complexity and high cost of the acquisition equipments. Considering the advantages of low cost and easy portability of the electroencephalogram (EEG) acquisition equipments, we propose a novel image reconstruction method based on EEG signals in this paper. Firstly, to satisfy the high recognizability of visual stimulus images in fast switching manner, we build a visual stimuli image dataset, and obtain the EEG dataset by a corresponding EEG signals collection experiment. Secondly, the deep visual representation model(DVRM) consisting of a primary encoder and a subordinate decoder is proposed to reconstruct visual stimuli. The encoder is designed based on the residual-in-residual dense blocks to learn the distribution characteristics between EEG signals and visual stimulus images, while the decoder is designed based on the deep neural network to reconstruct the visual stimulus image from the learned deep visual representation. The DVRM can fit the deep and multiview visual features of human natural state and make the reconstructed images more precise. Finally, we evaluate the DVRM in the quality of the generated images on our EEG dataset. The results show that the DVRM have good performance in the task of learning deep visual representation from EEG signals and generating reconstructed images that are realistic and highly resemble the original images

Up-Regulation of the Cardiac Lipid Metabolism at the Onset of Heart Failure

Chronic pressure overload and atherosclerosis are primary etiologic factors for cardiac hypertrophy and failure. However, mechanisms underlying the transition from hypertrophy to heart failure are incompletely understood. We analyzed the development of heart failure in mice with chronic pressure overload induced by aortic constriction and compared the results with aged apolipoprotein E-deficient mice suffering from advanced atherosclerosis. We combined cardiac function analysis by echocardiography and invasive hemodynamics with a comprehensive microarray gene expression study (GSE25765-8). The microarray data showed that the onset of heart failure induced by pressure overload or advanced atherosclerosis was accompanied by a strong up-regulation of key lipid metabolizing enzymes involved in fat synthesis, storage and oxidation. Cardiac lipid overload may be involved in the progression of heart failure by enhancing cardiomyocyte death. Up-regulation of the cardiac lipid metabolism was related to oxygen and ATP depletion of failing hearts because anti-ischemic treatment with ranolazine normalized the cardiac lipid metabolism and improved cardiac function. Vice versa, inhibition of cellular respiration and ATP generation by mild thiol-blocking with cystamine triggered the cardiac lipid metabolism and caused signs of heart failure. Cardiac tissue specimens of patients with heart failure also showed high protein levels of key fat metabolizing enzymes as well as lipid accumulation. Taken together, our data strongly indicate that up-regulation of the cardiac lipid metabolism and myocardial lipid overload are underlying the development of heart failure

Towards Multi-modality Fusion and Prototype-based Feature Refinement for Clinically Significant Prostate Cancer Classification in Transrectal Ultrasound

Prostate cancer is a highly prevalent cancer and ranks as the second leading cause of cancer-related deaths in men globally. Recently, the utilization of multi-modality transrectal ultrasound (TRUS) has gained significant traction as a valuable technique for guiding prostate biopsies. In this study, we propose a novel learning framework for clinically significant prostate cancer (csPCa) classification using multi-modality TRUS. The proposed framework employs two separate 3D ResNet-50 to extract distinctive features from B-mode and shear wave elastography (SWE). Additionally, an attention module is incorporated to effectively refine B-mode features and aggregate the extracted features from both modalities. Furthermore, we utilize few shot segmentation task to enhance the capacity of classification encoder. Due to the limited availability of csPCa masks, a prototype correction module is employed to extract representative prototypes of csPCa. The performance of the framework is assessed on a large-scale dataset consisting of 512 TRUS videos with biopsy-proved prostate cancer. The results demonstrate the strong capability in accurately identifying csPCa, achieving an area under the curve (AUC) of 0.86. Moreover, the framework generates visual class activation mapping (CAM), which can serve as valuable assistance for localizing csPCa. These CAM images may offer valuable guidance during TRUS-guided targeted biopsies, enhancing the efficacy of the biopsy procedure.The code is available at https://github.com/2313595986/SmileCode

Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy

BACKGROUND: Bone marrow mesenchymal stem cells (BMMSCs) and bone marrow mononuclear cells (BMMNCs) are both used to treat spastic cerebral palsy. However, the differences in therapeutic effect remain unknown. METHODS: A total of 105 patients with spastic cerebral palsy were enrolled and randomly assigned to three groups: the BMMSC group, the BMMNC group and the control group. Patients in both transplantation groups received four intrathecal cell injections. Patients in the control group received Bobath therapy. The gross motor function measure (GMFM) and the fine motor function measure (FMFM) were used to evaluate the therapeutic efficacy before transplantation and 3, 6, and 12 months after transplantation. RESULTS: Three months after cell transplantation, scores in the A dimension of GMFM and the A and C dimensions of FMFM scores in the BMMSC group are all higher than those of the BMMNC and the control groups (P < 0.05). Six months after cell transplantation, scores in the A, B dimensions of GMFM and the A, B, C, D, and E dimensions of FMFM scores in the BMMSC group are higher than those of the BMMNC and the control groups (P < 0.05). Twelve months after cell transplantation, scores in the A, B, and C dimensions of GMFM and the A, B, C, D, and E dimensions of FMFM scores in the BMMSC group are all higher than those of the BMMNC and the control groups (P < 0.05). No obvious adverse effects were investigated during follow-up. CONCLUSIONS: BMMSC transplantation for the treatment of cerebral palsy is safe and feasible, and can improve gross motor and fine motor function significantly. In addition, compared with BMMNC, the motor function of children improved significantly in terms of gross motor and fine motor functions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-017-1149-0) contains supplementary material, which is available to authorized users

Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling.

Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under "reloaded" conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients

De-Pinning Transition of Bubble Phases in a High Landau Level

While in the lowest Landau level the electron-electron interaction leads to the formation of the Wigner crystal, in higher Landau levels a solid phase with multiple electrons in a lattice site of crystal was predicted, which was called the bubble phase. Reentrant integer quantum Hall states are believed to be the insulating bubble phase pinned by disorder. We carry out nonlinear transport measurements on the reentrant states and study the de-pinning of the bubble phase, which is complementary to previous microwave measurements and provides unique information. In this study, conductivity is directly measured with Corbino geometry. Based on the threshold electric field of de-pinning, a phase diagram of the reentrant state is mapped. We discuss an interaction-driven topological phase transition between the integer quantum Hall state and the reentrant integer quantum Hall state.Comment: 11 pages, 3 figure

Research on the dynamic characteristics of the electromagnetic repulsion mechanism of a self-driving fault current limiter

A fault self-driven current limiter is proposed in the paper, which uses a special fault current direct-driven electromagnetic repulsion mechanism to realize the first half-wave of the fault current over the zero point into the current-limiting reactance. The paper analyzes the working principle of the self-driven electromagnetic repulsion mechanism, establishes the equivalent model of the mechanism, and simulates the dynamic characteristics of the electromagnetic repulsion mechanism through the calculation of the double-layer iterative algorithm in time and space. The LC oscillation loop test platform is built, and the stroke–time curve of the prototype is measured. In the test, the prototype is driven by a 3 kA current, and the first half-wave stroke (FHWS) is 3.55 mm past the zero point, which is consistent with the simulation and test results. The effects of structural parameters such as the radius, thickness, and number of turns of the self-driven electromagnetic repulsion mechanism on the dynamic characteristics of the electromagnetic repulsion mechanism are investigated, and it is found that the first half-wave stroke can be significantly improved by increasing the number of turns and outer diameter of the coil. The optimum height of the dynamic repulsion coil is approximately 3 mm