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

High circulating CD39+ regulatory T cells predict poor survival for sepsis patients

SummaryBackgroundSepsis encompasses two phases, the ‘hyper’-reactive phase and the ‘hypo’-reactive phase. The initial inflammatory stage is quickly counterbalanced by an anti-inflammatory response, which compromises the immune system, leading to immune suppression. Regulatory T cells (Tregs) have been implicated in the pathogenesis of sepsis by inducing immunosuppression; however, the role of CD39+ Tregs in the process of sepsis is uncertain. This study investigated the dynamic levels of CD39+ Tregs and their phenotypic change in sepsis.MethodsFourteen patients with systemic inflammatory response syndrome (SIRS), 42 patients with sepsis, and 14 healthy controls were enrolled. Sequential blood samples were used to analyze the numbers of CD39+ Tregs and their phenotypic changes. Survival at 28 days was used to evaluate the capacity of CD39+ Treg levels to predict mortality in sepsis patients.ResultsSepsis patients displayed a high percentage (3.13%, 1.46%, and 0.35%, respectively) and mean fluorescence intensity (MFI) (59.65, 29.7, and 24.3, respectively) of CD39+ Tregs compared with SIRS patients and healthy subjects. High-level expression of CD39+ Tregs was correlated with the severity of sepsis, which was reflected by the sepsis-related organ failure assessment score (r=0.322 and r=0.31, respectively). In addition, the expression of CD39+ Tregs was associated with survival of sepsis patients (p<0.01). By receiver-operating characteristic (ROC) curve analysis, the percentage and MFI of CD39+ Tregs showed similar sensitivities and specificities to predict mortality (74.2% and 85.1%, and 73.9% and 84.1%, respectively). Using Kaplan–Meier curves to assess the impact of CD39+ Tregs percentage and MFI on overall survival, we found that a high CD39+ Tregs percentage (p<0.001; >4.1%) and MFI (p<0.001; >49.2) were significantly associated with mortality. Phenotypically, CD39+ Tregs from sepsis patients showed high expression of CD38 and PD-1 (p<0.01 and p<0.01 respectively).ConclusionsIncreased expression of CD39+ Tregs was associated with a poor prognosis for sepsis patients, which suggests that CD39+ Treg levels could be used as a biomarker to predict the outcome of sepsis patients

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice

Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI)1–6. Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders7, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a ‘senolytic’ pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type– and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents

Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function

Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A Generic Compliance Modeling Method for Two-Axis Elliptical-Arc-Filleted Flexure Hinges

As a kind of important flexible joint, two-axis flexure hinges can realize in-plane and out-of-plane motions and can be used for constructing flexure-based spatial compliant mechanisms. The paper introduces a common two-axis elliptical-arc-filleted flexure hinge that is generated by two different elliptical-arc-filleted cutout profiles and that provides some new hinge types. The analytical compliance equations of both half-segments of the two-axis elliptical-arc flexure hinges are firstly formulated, and then, based on a generic compliance modeling method of a flexure serial chain, the closed-form compliance and precision matrices of two-axis elliptical-arc-filleted flexure hinges are established and validated by the finite element method. Some numerical simulations are conducted to compare the effect of different design geometric parameters on the performance of the two-axis flexure hinges

Application of tip-bendable ureteral access sheath in flexible ureteroscopic lithotripsy: an initial experience of 224 cases

Abstract Introduction During the last decades, the advent of flexible ureteroscopic lithotripsy has revolutionized the management of upper urinary tract stones. We designed a patented tip-bendable ureteral access sheath to facilitate stone clearance. Our current study reported our initial experience of 224 cases. Materials and methods The study is a descriptive, retrospective analysis. The initial 224 cases, operated consecutively by one surgeon during 16 months, were reviewed. The novel tip-bendable ureteral access sheath was applied in the procedure. Demographics, laboratory tests, and peri- and postoperative findings (operation duration, stone-free rate (SFR), utilization of flexible instruments and complications) were analyzed. Resutls The median age of the patients was 56 years and the mean stones size was 2.3 ± 1.3 cm. There were 63 cases of upper ureteral stone, 93cases of renal stone and 68 cases of ureteral-renal stones. The mean operative time was 69.2 ± 65.2 min. The immediate stone-free rate was 76.8% and the 1 month post-operative stone-free rate was 97.3%. Most cases(95.5%)were success in single session. Two patient experienced post-operative fever. There was no unplanned readmission. The frequency of post-operative complications was estimated at 0.89% (Clavien I). Conclusion Flexible ureteroscopic lithotripsy with tip-bendable ureteral access sheath is a safe and effective procedure, which can achieve excellent stone clearance

Preparation and characterization of double macromolecular network (DMMN) hydrogels based on hyaluronan and high molecular weight poly(ethylene glycol)

Abundant research efforts have been devoted to meet the demands for high-strength hydrogels in biomedical applications. Double-network (DN) hydrogels and homogeneous hydrogels are two typical samples. In this study, a novel ultra-strong and resilient double macromolecular network (DMMN) hydrogel system has been developed via a two-step sequential cross-linking process using hyaluronan (HA) and high molecular weight poly(ethylene glycol) (PEG) for the first and second network, respectively. A lower concentration of the HA precursor solution and a higher concentration of the PEG precursor solution as well as a higher molecular weight of the PEG precursor are beneficial to produce high-strength DMMN gels. Dynamic light scattering measurements demonstrate that DMMN gels possess the more evenly distributed polymer networks; the distinctive double and relatively evenly distributed networks of the DMMN gel make it combine the current DN and homogeneous network strategies for preparing robust hydrogels. The optimized DMMN gel is capable of sustaining up to 50 MPa of compressive stress. Besides, DMMN gels exhibit excellent cytocompatibility. This study expands the DN principle in designing and fabricating high-strength hydrogels with biocompatible macromolecules that show a promising prospect for biomedical applications.Published versio

Lower Expression of SPRY4 Predicts a Poor Prognosis and Regulates Cell Proliferation in Colorectal Cancer

Background/Aims: Colorectal cancer (CRC) is the third most common type of cancer worldwide. Sprouty proteins are modulators of mitogeninduced signal transduction processes and therefore can influence the process of cancerogenesis. The encoded protein of Sprouty homolog 4 (SPRY4) is associated with various human cancers. However, its biological role and clinical significance in CRC development and progression are unknown. Methods: The aim of this study was to evaluate the expression and biological role of SPRY4 in colorectal cancer. qRT-PCR was performed to investigate the expression of SPRY4 in tumor tissues and corresponding non tumor colorectal tissues from 70 patients. The effect of SPRY4 on proliferation was evaluated by MTT and colony formation assays. CRC cells transfected with SPRY4 were injected into nude mice to study the effect of SPRY4 on tumorigenesis in vivo. Results: The lower expression of SPRY4 was remarkably correlated with deep tumor invasion and advanced TNM stage. Multivariate analyses revealed that SPRY4 expression served as an independent predictor for overall survival. Using 5-aza treatment, we also observed that SPRY4 expression can be affected by DNA methylation. Further experiments revealed that overexpressed SPRY4 significantly inhibited CRC cell proliferation both in vitro and in vivo. Conclusion: Our study demonstrated that SPRY4 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that SPRY4 may be a potential diagnostic and prognostic target in patients with colorectal cancer