Architectural and biochemical expressions of mustard gas keratopathy: preclinical indicators and pathogenic mechanisms

A subset of victims of ocular sulfur mustard (SM) exposure develops an irreversible, idiotypic keratitis with associated secondary pathologies, collectively referred to as mustard gas keratopathy (MGK). MGK involves a progressive corneal degeneration resulting in chronic ocular discomfort and impaired vision for which clinical interventions have typically had poor outcomes. Using a rabbit corneal vapor exposure model, we previously demonstrated a clinical progression with acute and chronic sequelae similar to that observed in human casualties. However, a better understanding of the temporal changes that occur during the biphasic SM injury is crucial to mechanistic understanding and therapeutic development. Here we evaluate the histopathologic, biochemical and ultrastructural expressions of pathogenesis of the chronic SM injury over eight weeks. We confirm that MGK onset exhibits a biphasic trajectory involving corneal surface regeneration over the first two weeks, followed by the rapid development and progressive degeneration of corneal structure. Preclinical markers of corneal dysfunction were identified, including destabilization of the basal corneal epithelium, basement membrane zone abnormalities and stromal deformation. Clinical sequelae of MGK appeared abruptly three weeks after exposure, and included profound anterior edema, recurring corneal erosions, basement membrane disorganization, basal cell necrosis and stromal degeneration. Unlike resolved corneas, MGK corneas exhibited frustrated corneal wound repair, with significantly elevated histopathology scores. Increased lacrimation, disruption of the basement membrane and accumulation of pro-inflammatory mediators in the aqueous humor provide several mechanisms for corneal degeneration. These data suggest that the chronic injury is fundamentally distinct from the acute lesion, involving injury mechanisms that operate on different time scales and in different corneal tissues. Corneal edema appears to be the principal pathology of MGK, in part resulting from persistent necrosis of the basal corneal epithelium and deterioration of the basement membrane. The findings also provide a potential explanation as to why administration of anti-inflammatories transiently delays, but does not prevent, the development of MGK sequelae.     

Evolving concepts of tumor heterogeneity

Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.     

农抗702对植物病原真菌的抑制效果及抑菌机理

为探索农抗702在植物病害生物防治中的实际应用价值及对病原真菌的作用机理,采用生长速率法测定其抑菌谱,并以水稻纹枯病菌为研究对象,测定其作用下菌丝的电解质渗漏、蛋白质、核酸、Mg2+、K+含量的变化,及其对细胞膜麦角甾醇生物合成和水稻纹枯病菌超显微结构的影响.结果表明:农抗702对供试13种病原真菌均有较强的抑制作用,其中对油菜菌核病菌的作用最强,EC50为0.23 μg·mL-1;农抗702作用水稻纹枯病菌菌体后相对电导率增加72.2％;蛋白质、核酸、Mg2+、K+等胞内物质均发生了不同程度的渗漏;细胞麦角甾醇含量降低了92.O％;细胞膜轮廓不清、破损;细胞器严重损伤,有空泡化.抑制麦角甾醇合成、造成真菌细胞膜渗透增加是农抗702抑制真菌的主要机理.     

Evolving concepts of human state dissociation

The concept of state dissociation in humans was made possible only by applying information obtained from basic science animal research studies to the human condition--without which these often dramatic, and treatable conditions would have remained in the mystical, supra-natural, or psychiatric arenas, without appropriate or effective treatment options. Sleep or wakefulness occurring asynchronously in bits and pieces of the brain is a most useful concept. From our standpoint, the basic science work in the function and mechanism of sleep is pertinent, not only adding to our knowledge in these important areas for the sake of knowledge, but also in providing clinicians with important information that is of immense clinical importance. The payoff of such research has been great, and demands that it should be ongoing. The field of sleep research and sleep medicine is in a unique position to foster close interactions between basic scientists and clinicians, the result being basic science answers to clinical questions, and unanswered clinical questions guiding the direction of and reinforcing the basic science research. The clinical conditions discussed above underscore the value of close cooperation among those working at all levels: molecular, cellular, multi-cellular, and clinical. Continued study of state dissociation by both basic scientists and clinicians will undoubtedly identify and explain even more of these fascinating conditions, with important therapeutic implications. The reciprocal benefits of close collaboration between basic scientists and clinicians will continue to be realized.     

Evolving concepts of thyroid hormone action.

The past 25 years have witnessed dramatic changes in our concepts of thyroid hormone action. Progress in this area was made possible by the recognition of the central role of triiodothyronine in mediating thyroid hormone action and the recognition of specific nuclear receptors in target tissues as demonstrated by displacement studies. The cloning of the receptors and receptor variants has enabled investigators to undertake detailed analyses of the biochemical events which underlie the physiological and pathological action of thyroid hormone.     

Modern concepts on the mechanisms of encoding visceral nociceptive stimuli

This paper reviews the existing concepts on the physiology of visceral pain and mechanisms of processing nociceptive stimuli at the level of sensor neurons of surface segments of the spinal dorsal horns. Data on the ion channels and receptors involved in the transduction of the pain signals are discussed.     

Evolving concepts in plant glycolysis: two centuries of progress

Glycolysis, the process responsible for the conversion of monosaccharides to pyruvic acid, is a ubiquitous feature of cellular metabolism and was the first major biochemical pathway to be well characterized. Although the majority of glycolytic enzymes are common to all organisms, the past quarter of a century has revealed that glycolysis in higher plants possesses numerous distinctive features. Research in the nineteenth century established convincingly that plants carry out alcoholic fermentation under anaerobic conditions. In 1878, Wilhelm Pfeffer asserted that a non-oxygen-requiring ‘intramolecular respiration’ was involved in the aerobic respiration of plants. Between 1900 and 1950 it was demonstrated that plants metabolize sugar and starch by a glycolytic pathway broadly similar to that of yeasts and muscle tissue. In 1948, the first purification and characterization of a plant glycolytic enzyme, aldolase, was published by Paul Stumpf. By 1960 the presence of each of the 10 enzymes of glycolysis, presumed at the time to be located in the cytosol, had been confirmed in higher plants. Shortly after 1960 it was shown that the mechanism of glycolytic regulation in plants had features in common with that of animals and yeasts, especially as regards the important role played by the enzyme phosphofructokinase; but important regulatory properties peculiar to plants were soon demonstrated. In the last 30 years, higher-plant glycolysis has been found to exhibit a number of additional characteristics peculiar to plant systems. One conspicuous feature of plant glycolysis, discovered in the 1970s, is the presence of a complete or nearly complete sequence of glycolytic enzymes in plastids, distinct and spatially separated from the glycolytic enzymes located in the cytosol. Plastidic and cytosolic isoenzymes of glycolysis have been shown to differ in their kinetic and regulatory properties, suggesting that the two pathways are independently regulated. Since about 1980 it has become increasingly clear that the cytosolic glycolysis of plants may make use of several enzymes other than the conventional ones found in yeasts, muscle tissue and plant plastids: these enzymes include a pyrophosphate-dependent phosphofructokinase, a non-reversible and nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase, a phosphoenolpyruvate phosphatase (vacuolar location) and a three-enzyme sequence able to produce pyruvate from phosphoenolpyruvate avoiding the pyruvate-kinase step. These non-conventional enzymes may catalyze glycolysis in the plant cytosol especially under conditions of metabolic stress. Experiments on transgenic plants possessing significantly elevated or reduced (reduced to virtually nil in some cases) levels of glycolytic enzymes are currently playing an important part in improving our understanding of the regulation of plant glycolysis; such experiments illustrate an impressive degree of flexibility in the pathway's operation. Plant cells are able to make use of enzymes bypassing or substituting for several of the conventional enzymic steps in the glycolytic pathway; the extent and conditions under which these bypasses operate are the subject of current research. The duplication of the glycolytic pathway in plants and the flexible nature of the pathway have possibly evolved in relation to the crucial biosynthetic role played by plant glycolysis beyond its function in energy generation; both functions must proceed if a plant is to survive under varying and often stressful environmental or nutritional conditions.     

Current concepts of the mechanisms of neurological memory

The modern conceptions on the processes which can participate in the neurological memory formation are stated in the review. The biochemical reactions which can join in genesis of various forms of memory according to the duration (minimum, short-time, relatively limited in time, lifelong) are considered. The data on neuropeptide role as well the possibility of participation of immunological mechanisms in traced processes are under discussion.     

Iron uptake mechanisms of pathogenic bacteria

Abstract: Most of the iron in a mammalian body is complexed with various proteins. Moreover, in response to infection, iron availability is reduced in both extracellular and intracellular compartments. Bacteria need iron for growth and successful bacterial pathogens have therefore evolved to compete successfully for iron in the highly iron-stressed environment of the host's tissues and body fluids. Several strategies have been identified among pathogenic bacteria, including reduction of ferric to ferrous iron, occupation of intracellular niches, utilisation of host iron compounds, and production of siderophores. While direct evidence that high affinity mechanisms for iron acquisition function as bacterial virulence determinants has been provided in only a small number of cases, it is likely that many if not all such systems play a central role in the pathogenesis of infection.     

Lessons from signature-tagged mutagenesis on the infectious mechanisms of pathogenic bacteria

Studies on the genetic basis of bacterial pathogenicity have been undertaken for almost 30 years, but the development of new genetic tools in the past 10 years has considerably increased the number of identified virulence factors. Signature-tagged mutagenesis (STM) is one of the most powerful general genetic approaches, initially developed by David Holden and colleagues in 1995, which has now led to the identification of hundreds of new genes requested for virulence in a broad range of bacterial pathogens. We have chosen to present in this review, the most recent and/or most significant contributions to the understanding of the molecular mechanisms of bacterial pathogenicity among over 40 STM screens published to date. We will first briefly review the principle of the method and its major technical limitations. Then, selected studies will be discussed where genes implicated in various aspects of the infectious process have been identified (including tropism for specific host and/or particular tissues, interactions with host cells, mechanisms of survival and persistence within the host, and the crossing of the blood brain barrier). The examples chosen will cover intracellular as well as extracellular Gram-negative and Gram-positive pathogens.     

Evolving concepts of the epidemiology, diagnosis, and therapy of Mycobacterium tuberculosis infection

Tuberculosis in the United States is evolving in nearly all respects--epidemiology, diagnosis, treatment, and prophylaxis. Today a relatively larger segment of the population has predisposing factors to infection with tuberculosis. There is a greater percentage of people who are elderly, who have immigrated from countries endemic for tuberculosis, or who are immunosuppressed due to medications necessary for other conditions, because of malignancies, or because of infection with HIV. Skin test classifications have been revised to give different meanings to different-sized areas of induration at the injection site for defined populations. More sensitive, more specific, and faster diagnostic laboratory tests for tuberculosis are being developed. Short-course chemotherapy of from six to nine months is now accepted as standard treatment, regardless of exactly which of the proven regimens of antibiotics or accepted lengths of therapy is used. Patient compliance is improved with the shorter courses both for treatment and for prophylaxis. Better compliance with therapy results in better treatment outcomes of infections with Mycobacterium tuberculosis.     

Evolving mechanisms of morphogenesis: on the interplay between differential adhesion and cell differentiation

Differential cell adhesion, mediated by e.g. integrin and cadherins/catenines, plays an important role in morphogenesis and it has been shown that there is intimate cross-talk between their expression and modification, and inter-cellular signalling, cell differentiation, cell growth and apoptosis. In this paper, we introduce and use a formal model to explore the morphogenetic potential of the interplay between these processes. We demonstrate the formation of interesting morphologies. Initiated by cell differentiation, differential cell adhesion leads to a long transient of cell migrations, e.g. engulfing and intercalation of cells and cell layers. This transient can be sustained dynamically by further cell differentiation, and by cell growth/division and cell death which are triggered by the (also long range) forces (stretching and squeezing) generated by the cell adhesion. We study the interrelation between modes of cell differentiation and modes of morphogenesis. We use an evolutionary process to zoom in on gene-regulation networks which lead to cell differentiation. Morphogenesis is not selected for but appears as a side-effect. The evolutionary dynamics shows the hallmarks of evolution on a rugged landscape, including long neutral paths. We show that a combinatorially large set of morphologies occurs in the vicinity of a neutral path which sustains cell differentiation. Thus, an almost linear molecular phylogeny gives rise to mosaic evolution on the morphological level.     

Neural mechanisms for the concepts of difference and similarity

A neurobiophysical mechanism which reacts todifferences in different modalities of a stimulus pattern is suggested. Another mechanism is suggested which reacts tosimilarity. The latter is measured by the number of neurons in common to the two stimulus patterns.     

Virulence mechanisms of Gram-positive plant pathogenic bacteria

Actinobacteria and Firmicutes comprise a group of highly divergent prokaryotes known as Gram-positive bacteria, which are ancestral to Gram-negative bacteria. Comparative genomics is revealing that, though plant virulence genes are frequently located on plasmids or in laterally acquired gene clusters, they are rarely shared with Gram-negative bacterial plant pathogens and among Gram-positive genera. Gram-positive bacterial pathogens utilize a variety of virulence strategies to invade their plant hosts, including the production of phytotoxins to allow intracellular and intercellular replication, production of cytokinins to generate gall tissues for invasion, secretion of proteins to induce cankers and the utilization and manipulation of sap-feeding insects for introduction into the phloem sieve cells. Functional analysis of novel virulence genes utilized by Actinobacteria and Firmicutes is revealing how these ancient prokaryotes manipulate plant, and sometimes insect, metabolic processes for their own benefit.     

Evolving nonapeptide mechanisms of gregariousness and social diversity in birds

Of the major vertebrate taxa, Class Aves is the most extensively studied in relation to the evolution of social systems and behavior, largely because birds exhibit an incomparable balance of tractability, diversity, and cognitive complexity. In addition, like humans, most bird species are socially monogamous, exhibit biparental care, and conduct most of their social interactions through auditory and visual modalities. These qualities make birds attractive as research subjects, and also make them valuable for comparative studies of neuroendocrine mechanisms. This value has become increasingly apparent as more and more evidence shows that social behavior circuits of the basal forebrain and midbrain are deeply conserved (from an evolutionary perspective), and particularly similar in birds and mammals. Among the strongest similarities are the basic structures and functions of avian and mammalian nonapeptide systems, which include mesotocin (MT) and arginine vasotocin (VT) systems in birds, and the homologous oxytocin (OT) and vasopressin (VP) systems, respectively, in mammals. We here summarize these basic properties, and then describe a research program that has leveraged the social diversity of estrildid finches to gain insights into the nonapeptide mechanisms of grouping, a behavioral dimension that is not experimentally tractable in most other taxa. These studies have used five monogamous, biparental finch species that exhibit group sizes ranging from territorial male-female pairs to large flocks containing hundreds or thousands of birds. The results provide novel insights into the history of nonapeptide functions in amniote vertebrates, and yield remarkable clarity on the nonapeptide biology of dinosaurs and ancient mammals. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

The pathogenic mechanisms of Shiga toxin and the Shiga-like toxins

It is now well documented that some enteric bacteria which cause diarrhoeal and/or dysenteric disease produce, at high levels, one or more of a family of protein toxins referred to as Shiga toxin and Shiga-like toxins (SLTs; alternatively called verocytotoxins or VTs). Within the past few years, there have been considerable advancements made in our understanding of the biochemistry and molecular biology of Shiga toxin and SLTs. However, the precise role of the toxins in mediating colonic disease, as well as their contribution to the development of extra-intestinal sequelae (e.g. the haemolytic uraemic syndrome and neurological disorders), remain less clear. In this MicroReview, we will briefly summarize recent progress in Shiga toxin- and SLT-related research and present evidence supporting the concept that these toxins contribute to pathogenesis by directly damaging vascular endothelial cells, thereby disrupting the homeostatic properties of these cells. We will also discuss data which suggest that toxin-mediated damage in the kidney may not be limited to glomerular endothelial cells but may include tubular epithelial cells. Thus, the role of the toxins in renal disease may not be limited to the glomeruli, as was initially hypothesized when the association of infection with toxin-producing strains and the development of acute renal failure was established.     

Unifying concepts and mechanisms in the specificity of plant-enemy interactions

Host ranges are commonly quantified to classify herbivores and plant pathogens as either generalists or specialists. Here, we summarize patterns and mechanisms in the interactions of plants with these enemies along different axes of specificity. We highlight the many dimensions within which plant enemies can specify and consider the underlying ecological, evolutionary and molecular mechanisms. Host resistance traits and enemy effectors emerge as central players determining host utilization and thus host range. Finally, we review approaches to studying the causes and consequences of variation in the specificity of plant-enemy interactions. Knowledge of the molecular mechanisms that determine host range is required to understand host shifts, and evolutionary transitions among specialist and generalist strategies, and to predict potential host ranges of pathogens and herbivores.     

Molecular-genetic mechanisms of antigenic variability of pathogenic bacteria

The literature on the molecular genetic mechanisms for antigenic variability of pathogenic bacteria is reviewed. Ability to antigenic variability in any case discussed is considered to be a pathogenicity factor permitting efficient struggle against the immune system of the host-organism. The molecular basis for such variability is instability of the genome structure, coding for highly immunogenic bacterial proteins.     

高同型半胱氨酸对大鼠神经元的损伤作用及其相关机制的研究

目的:研究同型半胱氨酸(Hcy)对体外培养神经元的损伤作用及其相关机制。方法:用Hcy处理体外培养的海马和皮层神经元,观察神经元的凋亡情况,以及神经元内游离钙浓度改变、DNA损伤和氧化损伤。结果:用250μmol/LHcy作用4h可使神经元凋亡率显著升高,并呈时间依赖性。甲基供体S-腺苷蛋氨酸(SAM)可显著抑制Hcy引起的神经元凋亡。Hcy(250μmol/L)可使神经元内游离钙浓度显著升高;导致神经元的彗星率明显增高;使神经元内MDA的产生增多,但并不影响神经元的总抗氧化能力(T-AOC)。结论:高浓度Hcy可通过神经兴奋作用、DNA损伤和氧化损伤等多方面机制对神经元造成损伤作用,从而诱导神经元发生凋亡。DNA损伤在Hcy导致神经元凋亡的作用中起着关键作用。     

Experimental chemotherapy and concepts related to the cell cycle

Scheduling of chemotherapy is limited by damage to normal tissues, and tolerated schedules are dependent on normal tissue recovery. Most anticancer drugs are more toxic to proliferating cells and the fall and recovery of granulocyte counts after chemotherapy may be explained by the effect of drugs on rapidly proliferating precursor cells in the bone marrow. It is argued that serious toxicity due to myelosuppression most often occurs because of damage to proliferating precursors that may be recognized in bone marrow rather than to stem cells. In contrast, therapy that is aimed at producing cure or long-term remission of tumours must be directed at killing tumour stem cells. The evidence that tumours contain a limited population of cells which can repopulate the tumour after treatment (and are therefore tumour stem cells) is reviewed critically. While there is quite strong evidence for a limited population of target cells, evidence from studies on metastases suggests that the tumour cells which may express this stem cell property may change with time. The stem cell concept has major implications for predictive assays. Although colony-forming assays appear to have a sound biological background for predicting tumour response, technical problems prevent them from being used routinely in patient management. Cells in tumours are known to be heterogeneous and at least three types of heterogeneity may influence tumour response to drug treatment: the development of subclones with differing properties including drug resistance; variation in cellular properties due to differentiation during clonal expansion; and variation in properties due to nutritional status and micro-anatomy. Heterogeneity in drug distribution within solid tumours may occur because of limited drug penetration from blood vessels, and nutrient-deprived cells in solid tumours may be expected to escape the toxicity of some anticancer drugs as well as being resistant to radiation because of hypoxia. This may occur both because nutrient-deprived cells have a low rate of cell proliferation, and also because of poor drug penetration to them. There is a need for improved understanding of the mechanisms that lead to cell death in tumours. If these mechanisms were understood, it might be possible to simulate them by therapeutic manoeuvres. Recent research from our laboratory suggests that the combination of low extracellular pH and hypoxia may be very toxic to cells in nutrient-deprived regions. Drugs which limit the cell's ability to survive in regions of acid pH may provide strategy for therapy of nutrient-deprived cells.