Sequence of Biosynthesis of the Components of the Polyene Macrolides Candidin and Candihexin: Macrolide Aglycones as Intracellular Components

A sequential formation of the single components of the polyene macrolide candidin complex (heptaene) has been found. In addition to the three components occurring in the candidin complex at the end of the fermentation, two other "early" all-trans heptaene components have been characterized. They exist only during the phase of active biosynthesis of candidin. Two of the components of the polyene macrolide candihexin complex (hexaene) that have been described as lacking amino sugar were the only intracellular (mycelium-associated) components observed under conditions in which no extracellular polyene remained attached to the producing cell. The results indicate that glycosylation of the macrolide ring takes place during the secretion process.     

Receptors, rafts, and microvesicles in thrombosis and inflammation

Hemostasis at sites of blood vessel injury and its pathologic counterpart, thrombosis, involve a complex interplay between several blood elements: soluble proteins of the blood coagulation system, blood cells (most prominently platelets) and cell fragments, and elements of the vessel wall (endothelial cells and, at sites of injury, the exposed matrix and deeper cellular components). In this review, we focus on ways in which specialized membrane microdomains known as lipid rafts are involved in various phases of hemostasis and thrombosis.     

Cellular pathophysiology of ischemic acute kidney injury

Ischemic kidney injury often occurs in the context of multiple organ failure and sepsis. Here, we review the major components of this dynamic process, which involves hemodynamic alterations, inflammation, and endothelial and epithelial cell injury, followed by repair that can be adaptive and restore epithelial integrity or maladaptive, leading to chronic kidney disease. Better understanding of the cellular pathophysiological processes underlying kidney injury and repair will hopefully result in the design of more targeted therapies to prevent the injury, hasten repair, and minimize chronic progressive kidney disease.     

The role of inflammation in vascular injury and repair

Summary.  Inflammation plays a critical role in the vascular response to injury. In particular, mechanical injury using techniques such as balloon angioplasty and stenting results in complex inflammatory reactions which influence proliferation of vessel wall constituents such as endothelial cells, smooth muscle cells, and extracellular matrix proteins. Inflammatory cells are recruited to the injured vessel wall initially as a reparative mechanism; however, these same imflammatory processes are also pivotal in the development of restenotic lesions. Leukocytes serve as the primary inflammatory cells but we now know that platelets produce a number of important inflammatory mediators. This review describes the mechanisms that regulate endothelial cell migration, smooth muscle cell activation, and extracellular matrix protein production, all of which are key components in the inflammatory response to vascular injury.     

Biological mediators of acute inflammation

Inflammation may be defined as the normal response of living tissue to injury or infection. It is important to emphasize two components of this definition. First, that inflammation is a normal response and, as such, is expected to occur when tissue is damaged. Indeed, if injured tissue did not exhibit signs of inflammation this would be considered abnormal. Secondly, inflammation occurs in living tissue, hence the need for an adequate blood supply to the tissues in order for an inflammatory response to be exhibited. The inflammatory response may be triggered by mechanical injury, chemical toxins, invasion by microorganisms, and hypersensitivity reactions. Three major events occur during the inflammatory response: the blood supply to the affected area is increased substantially, capillary permeability is increased, and leucocytes migrate from the capillary vessels into the surrounding interstitial spaces to the site of inflammation or injury. The inflammatory response represents a complex biological and biochemical process involving cells of the immune system and a plethora of biological mediators. Cell-to-cell communication molecules known collectively as cytokines play an extremely important role in mediating the process of inflammation. An extensive exposition of this complex phenomenon is beyond the scope of this article. Rather, the author provides a review of inflammation, an overview of the role of certain biological mediators in inflammation, and a discussion of the implications of certain biological response modifiers in clinical practice.     

间充质干细胞-支架复合体修复膝关节半月板损伤

背景：半月板损伤常规治疗手段效果并不显著,随着组织工程学的进展,间充质干细胞-支架复合体有望应用于此方面的治疗。 目的：对间充质干细胞-支架技术治疗半月板损伤的相关研究进行综述,为后续研究和临床应用提供参考。 方法：第一、二作者共同检索PubMed、中国期刊全文数据库（CNKI）、维普数据库和万方数据库1980至2013年有关间充质干细胞-支架复合体修复半月板损伤的文献,英文检索词为“mesenchymal stem cel ,meniscus injury,tissue engineering,scaffold,stent”,中文检索词为“间充质干细胞,半月板损伤,组织工程”。同一领域文献选择近期发表或发表在权威杂志的文章,排除Meta分析及重复性研究。共检索到文献282篇,根据纳入标准选取59篇文献进行综述。 结果与结论：目前很多研究表明间充质干细胞可在体外或体内被诱导分化为软骨细胞,间充质-支架复合体对半月板损伤有明显疗效。虽然此技术仍处于探索阶段,但其具有取材方便,无抗原性,有生命力等优点,在治疗半月板损伤方面有着广阔的应用前景。     

The Joint Commission complex organization survey process and its impact on hospital-based home care and hospice providers

The October and November 2004 HHN Accreditation Strategies columns addressed the new Joint Commission on Accreditation of Healthcare Organizations (Joint Commission) home care and hospice survey process describing in detail components of each survey activity. This column builds on the foundation laid in the two columns and focuses on survey process nuances for complex organizations, specifically pertaining to hospital-based agencies and hospices. Therefore, all discussion and examples in this column will pertain to home health agencies and hospices that are a department of a hospital seeking Joint Commission accreditation.     

The inflammatory macrophage: a story of Jekyll and Hyde

Recent investigations have highlighted new roles for the macrophage (Mphi) in the biology of inflammation. Selective depletion of Mphis from inflamed sites has confirmed their predominant role in immune-mediated damage. The components of this injury have been dissected. Mphis mediate death of stromal, parenchymal and other immune cells by engaging the death programme, resulting in apoptosis. In addition, Mphis induce destruction of matrix and extracellular structures both directly and indirectly by inducing stromal cells to release matrix metalloproteinases. However, there is another side to the inflammatory Mphi. Evidence is provided that Mphis at the same sites possess the ability to aid cell proliferation, secrete and stabilize new matrix components and induce resident cells to secrete matrix components themselves. Mphi phagocytosis of apoptotic cells brings about a change from the cell-killing matrix-degrading cell to the matrix-generating cell-proliferating tissue-healing cell. Just as both Mphi types are necessary at the inflamed site, the right balance of these two populations is required for healing and resolution. Evidence of excessive inflammation as a manifestation of impaired phagocytosis of apoptotic cells emphasizes that defects in the transition from one Mphi type to another may account for the uncontrolled excessive inflammation seen in disease. Recent insights into the mechanisms by which apoptotic cells signal the change of function to the Mphi offer the prospect of novel targets for manipulation of Mphis in the inflamed tissue.     

In vitro development of engineered muscle using a scaffold based on the pressure‐activated microsyringe (PAM) technique

The development of new human skeletal muscle tissue is an alternative approach to the replacement of tissue after severe damage, for example in the case of traumatic injury, where surgical reconstruction is often needed following major loss of natural tissue. Treatment to date has involved the transfer of muscle tissue from other sites, resulting in a functional loss and volume deficiency of donor sites. Approaches that seek to eliminate these problems include the relatively new solution of skeletal muscle engineering. Here there are two main components to consider: (a) the cells with their regenerative potential; and (b) the polymeric structure onto which cells are seeded and where they must perform their activities. In this paper we describe well‐defined two‐ and three‐dimensional polymeric structures able to drive the myoblast process of adhesion, proliferation and differentiation. We examine a series of polymers and protein adhesions with which to functionalize the structures, and cell‐seeding methods, with a view to defining the optimal protocol for engineering skeletal muscle tissue. All polymer samples were tested for their mechanical and biological properties, to support the validity of our results in the real context of muscle tissue engineering. Copyright © 2014 John Wiley & Sons, Ltd.     

Predominant role for C5b-9 in renal ischemia/reperfusion injury

Previous work has indicated that complement is a mediator of ischemia/reperfusion (I/R) injury. To investigate the components of complement responsible for this effect, we examined a model of renal I/R injury in C3-, C4-, C5-, and C6-deficient mice. We occluded the renal arteries and veins (40-58 minutes) and, after reperfusion (0-72 hours), assessed renal structural and functional injury. C3-, C5-, and C6-deficient mice were protected from renal I/R injury, whereas C4-deficient mice were not protected. C6-deficient mice treated with antibody to block C5a generation showed no additional protection from I/R injury. Reconstitution with C6 alone restored the I/R injury in C6-deficient mice. Tubular epithelial cells were the main structures damaged by complement-mediated attack, and, in contrast, the renal vessels were spared. Neutrophil infiltration and myeloperoxidase activity were reduced in C-deficient mouse kidney, but by a similar extent in C3-deficient and C6-deficient mice. We conclude that the membrane attack complex of complement (in which C5 and C6 participate) may account for the effect of complement on mouse renal I/R injury. Neither C5a-mediated neutrophil infiltration nor the classic pathway, in which C4 participates, appears to contribute to I/R injury in this model. By contrast with other organs, such as the heart, the primary effect of complement in the ischemic area is on the parenchymal cell rather than the vascular endothelial cell. The membrane attack complex of complement is a potential target for prevention of I/R injury in this model.     

MMP-9、HIF-1和SIRT1在急性肺损伤中的研究进展

基质金属蛋白酶-9(matrix metalloproteinase,MMP-9)9是MMPs家族成员之一,参与炎症、血管形成和肿瘤侵袭转移等病理生理过程.低氧诱导因子-1(hypoxia-inducible factor,HIF-1)是具有转录活性的核蛋白,由功能亚基HIF-1α和结构亚基HIF-1β组成的异源二聚体,它在缺血坏死后新生血管的形成和低氧诱导的细胞凋亡过程当中起着非常关键的作用.沉默信息调节因子2相关酶1(silent information regulator2-related enzymes 1,Sirtuin 1,SIRT1)是一种烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucletide,NAD)依赖性的去乙酰化酶,属于Sirtuin蛋白家族成员之一,参与衰老、细胞死亡和肿瘤发生等病理生理过程.本文就MMP-9、HIF-1和SIRT1在急性肺损伤中所起作用的最新研究进展作一综述.     

Enabling stem cell therapies through synthetic stem cell–niche engineering

Enabling stem cell–targeted therapies requires an understanding of how to create local microenvironments (niches) that stimulate endogenous stem cells or serve as a platform to receive and guide the integration of transplanted stem cells and their derivatives. In vivo, the stem cell niche is a complex and dynamic unit. Although components of the in vivo niche continue to be described for many stem cell systems, how these components interact to modulate stem cell fate is only beginning to be understood. Using the HSC niche as a model, we discuss here microscale engineering strategies capable of systematically examining and reconstructing individual niche components. Synthetic stem cell–niche engineering may form a new foundation for regenerative therapies.     

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.     

The three R's of lung health and disease: repair, remodeling, and regeneration

All tissues and organs can be classified according to their ability to repair and regenerate during adult homeostasis and after injury. Some exhibit a high rate of constant cell turnover, while others, such as the lung, exhibit only low-level cell regeneration during normal adult homeostasis but have the ability to rapidly regenerate new cells after injury. Lung regeneration likely involves both activation of progenitor cells as well as cell replacement through proliferation of remaining undamaged cells. The pathways and factors that control this process and its role in disease are only now being explored. In this Review, we will discuss the connection between pathways required for lung development and how the lung responds to injury and disease, with a particular emphasis on recent studies describing the role for the epithelium in repair and regeneration.     

mTORC2功能及其在血液肿瘤中作用的研究进展

哺乳动物雷帕霉素靶蛋白复合体(mammalian target of rapamycin complex,mTORC)是细胞生长、存活、代谢的重要调控中心,它对维持生命有机体的正常生理活动和内稳态的平衡有着重要作用。mTORC根据其蛋白组份可分为mTORC1和mTORC2。mTORC2的主要组成蛋白有mTOR、Rictor、mLST8、Deptor、mSin1、Protor和Hsp70。mTORC2通过作用于Akt,PKCα和SGK1等来调控多项生命活动,如胚胎发育,细胞骨架重建,细胞迁移,蛋白质翻译和修饰等。mTOR信号通路异常已被证实与肿瘤相关,同时发现多种肿瘤发生与mTORC2及其异常调节信号通路相关。因此,对mTORC2组成、功能以及参与的信号通路的研究,可能为进一步研制其相关的靶向抑制药物乃至肿瘤治疗提供新思路。本综述将介绍mTORC2的组成结构、功能、参与的信号通路,及其在血液肿瘤中作用的研究进展。     

Biomaterial design strategies to address obstacles in craniomaxillofacial bone repair

Biomaterial design to repair craniomaxillofacial defects has largely focused on promoting bone regeneration, while there are many additional factors that influence this process. The bone microenvironment is complex, with various mechanical property differences between cortical and cancellous bone, a unique porous architecture, and multiple cell types that must maintain homeostasis. This complex environment includes a vascular architecture to deliver cells and nutrients, osteoblasts which form new bone, osteoclasts which resorb excess bone, and upon injury, inflammatory cells and bacteria which can lead to failure to repair. To create biomaterials able to regenerate these large missing portions of bone on par with autograft materials, design of these materials must include methods to overcome multiple obstacles to effective, efficient bone regeneration. These obstacles include infection and biofilm formation on the biomaterial surface, fibrous tissue formation resulting from ill-fitting implants or persistent inflammation, non-bone tissue formation such as cartilage from improper biomaterial signals to cells, and voids in bone infill or lengthy implant degradation times. Novel biomaterial designs may provide approaches to effectively induce osteogenesis and new bone formation, include design motifs that facilitate surgical handling, intraoperative modification and promote conformal fitting within complex defect geometries, induce a pro-healing immune response, and prevent bacterial infection. In this review, we discuss the bone injury microenvironment and methods of biomaterial design to overcome these obstacles, which if unaddressed, may result in failure of the implant to regenerate host bone.

There exist many challenges in the process of regenerating craniomaxillofacial bone defects, thus biomaterials must be designed to overcome these.     

Acute wounds: an overview of the physiological healing process

When an injury occurs and the skin is damaged, the process of tissue repair begins immediately, but some wounds can take up to two years or more to heal completely. Healing is usually categorised into stages to aid understanding of the complex physiological processes that are occurring. However, it is a continuous process and different parts of a wound may be at different stages of healing at any one time.     

Thrombus formation in vivo

To examine thrombus formation in a living mouse, new technologies involving intravital videomicroscopy have been applied to the analysis of vascular windows to directly visualize arterioles and venules. After vessel wall injury in the microcirculation, thrombus development can be imaged in real time. These systems have been used to explore the role of platelets, blood coagulation proteins, endothelium, and the vessel wall during thrombus formation. The study of biochemistry and cell biology in a living animal offers new understanding of physiology and pathology in complex biologic systems.     

Pathophysiology and implications for treatment of acute respiratory distress syndrome

Acute respiratory distress syndrome is a complex group of signs and symptoms caused by direct or indirect lung injury. In spite of decades of research, it is still associated with a high mortality rate. Pathogenesis of this disease is related to alveolar endothelial and epithelial cell injury and associated release and sequestration of inflammatory mediators and cells, including cytokines and neutrophils, respectively. Pharmacologic interventions have been largely unsuccessful, and ventilation strategies to support oxygenation while limiting ventilator associated lung injury have not demonstrated any significant reductions in the mortality rate. However, novel therapies are in development, based on the knowledge of the pathologic processes of acute respiratory distress syndrome. In this article an overview of the disease process and mediator involvement is presented, followed by a review of pharmacologic and ventilation treatments currently in use or under study.