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A variety of challenging conditions are faced by the oral microbiota-from the need for the capacity to catabolize a wide variety of substrates in saliva and the diet to tolerance of major fluctuations in environmental conditions that place considerable stress on the populations diabetes mellitus etiology and pathophysiology best purchase januvia. These can be acquired from the host diet as well as through the action of bacterial enzymes that hydrolyze carbohydrates from host glycoproteins. Lactic acid, a common product of sugar fermentation, is an important substrate for energy generation by other oral bacteria including Veillonella species and A. Many oral bacteria, especially Gram-negative anaerobes, use amino acids as a source of energy. These amino acids are acquired from host proteins through the successive actions of bacterial proteases. In addition, many oral bacteria are unable to synthesize all of the amino acids needed for protein translation and must obtain them from their environment as well. Microorganisms in the multispecies community participate in cross-feeding and cross-metabolism that is important for growth of the participating organisms. Dental plaque as a biofilm and a micro bial community-implications for treatment. Applied and ecological aspects of oxidativestress damage to bacterial spores and to oral microbes. Role of bacterial proteinases in matrix de struction and modulation of host responses. A commensal bacterium promotes virulence of an opportunistic pathogen via crossrespiration. In the 1980s, mechanisms of genetic exchange between oral streptococcal species were described. The isolation of naturally occurring streptococcal plasmids led to the development of new molecular tools for genetic studies. By the late 1980s and 1990s, it was possible to genetically manipulate other oral microorganisms, such as Actinomyces spp. Genetic studies were then extended to strains of Treponema denticola, soon followed by genetic and molecular analyses of Fusobacterium nucleatum and Prevotella intermedia. Indeed, the genomic sequences of over 300 oral bacterial species have now been determined. The application of genetics and molecular biology to studies of the oral microbiota is the topic of this chapter and Chapter 8. Some important terms, as they apply to microorganisms, and more specifically to bacteria, are defined in Table 1; however, it is assumed that the reader has at least a basic understanding of the fundamentals of genetics. The gene also includes noncoding regulatory sequences, such as a promoter and operator. In oral bacteria, the size of bacterial genomes generally falls within the range of 1 to 4 million base pairs (bp). Genetic diversity is dependent on mutations (hatched and black blocks) that yield variants of a given gene, which follow a clonal distribution. Selective pressures that can influence the population distribution include lethal mutations; cells receiving such lethal mutations do not produce progeny. The occurrence of a given genetic variant does not follow a clonal pattern of distribution when transfer is by horizontal transmission. These spontaneous and random mutations, if they occur in an open reading frame, can result in a change in protein amino acid sequence (missense mutations), or early termination of a protein can result from introduction of a stop codon (nonsense mutations). Additionally, point mutations in promoter regions can result in changes in the level of gene expression. Spontaneous rifampin resistance occurs if the binding site amino acid residue is altered due to a single missense point mutation. The double-stranded conjugative plasmid is established in both donor and recipient cells following replication of a second strand. Conjugation is responsible for the transfer of genetic elements between similar microbial species, as well as between organisms as diverse as bacteria and plants. Many Gram-negative bacteria harbor conjugative plasmids known as F (sex factor) plasmids. For these plasmids to be transferred from a donor to a recipient cell, it is necessary that potential donors and recipients come into contact incidentally on a solid surface. In nature, such incidental contact might occur in a biofilm such as dental plaque. Conjugative plasmids are large due to the requirement for genes sufficient to confer all of the properties involved in conjugative transfer. The gene encoding the inhibitor peptide is carried on the conjugative plasmid and functions to ensure that conjugation will not occur between two cells carrying the same conjugative plasmid. These peptide pheromones are highly specific and will only induce conjugation of the cognate plasmid. One of the best characterized of the conjugative transposons is Tn916, which is an 18-kb element first isolated from E. Tn916 possesses a tetM gene, which confers tetracycline resistance to the host bacterium. Conjugative transfer begins with excision of Tn916 from a donor host replicon and formation of a circular intermediate. Relatively little is known about the conjugation process, but regions of Tn916 required for intercellular transposition have been identified. Tn916 is an example of a promiscuous element, as it exhibits a tremendously broad host range. Tn916-like elements have been identified in many genera of oral bacteria, including Streptococcus, Enterococcus, Actinomyces, Bifidobacterium, Fusobacterium, and Veillonella. Natural transformation appears to be widespread in bacteria and common to many oral species, including P. In streptococci, competence develops during the early to late logarithmic phase of growth, and there are considerable differences in the optimal conditions for any specific strain or species.
The figure shows the cell cycle phases (G0 diabetes mellitus zwei januvia 100 mg with amex, G1, G2, S, and M), the location of the G1 restriction point, and the G1/S and G2/M cell cycle checkpoints. G1 restriction point refers to the stage in G1 where the cell is committed to advance further into the cell cycle without requiring any more of the growth signal that initiated cell division. Cells from labile tissues such as the epidermis and the gastrointestinal tract may cycle continuously; stable cells such as hepatocytes are quiescent but can enter the cell cycle; permanent cells such as neurons and cardiac myocytes have lost the capacity to proliferate. These quality control checkpoints ensure that cells with genetic imperfections do not complete replication. Later in the cell cycle, the G2-M restriction point insures that there has been accurate genetic replication before the cell actually divides. If the genetic derangement is too severe to be repaired, cells either undergo apoptosis or enter a nonreplicative state called senescence-primarily through p53-dependent mechanisms (see later). An equally important aspect of cell growth and division is the biosynthesis of the membranes, cytosolic proteins, and organelles necessary to make two daughter cells. Thus as growth factor receptor signaling stimulates cell cycle progression, it also activates events that promote the metabolic changes that support growth. Chief among these is the switch to aerobic glycolysis (with the counter-intuitive reduction in oxidative phosphorylation), also called the Warburg effect. Such replication occurs early in embryogenesis-when stem cell populations are expanding-and under stress conditions, as in bone marrow repopulation after ablative chemotherapy. Although some researchers separate stem cells into multiple different subsets, there are fundamentally only two varieties. They are normally protected within specialized tissue microenvironments called stem cell niches. Such niches have been demonstrated in many organs, most notably the bone marrow, where hematopoietic stem cells characteristically congregate in perivascular niches, and the intestines, where epithelial stem cells are confined to the crypts. Other stem cell niches include the bulge region of hair follicles, the limbus of the cornea, and the subventricular zone in the brain. Adult stem cells have a limited repertoire (lineage potential) of differentiated cells that they can generate. Hematopoietic stem cells continuously replenish all the cellular elements of the blood as they exit the circulation, senesce, or are otherwise consumed. They can be isolated directly from bone marrow, as well as from the peripheral blood after administration of certain colony-stimulating factors that induce their release from bone marrow niches. Although they are overall rare, hematopoietic stem cells can be purified to virtual purity based on cell surface markers. Clinically, these stem cells can be used to repopulate marrows depleted after chemotherapy. Besides hematopoietic stem cells, the bone marrow (and, notably, other tissues such as fat) also contains a population of mesenchymal stem cells. These are multipotent cells that can differentiate into a variety of stromal cells including chondrocytes (cartilage), osteocytes (bone), adipocytes (fat), and myocytes (muscle). Because these cells can be massively expanded and can generate a locally immunosuppressive microenvironment (thus potentially evading rejection), they represent a potential means of manufacturing stromal cellular scaffoldings for tissue regeneration. Stem Cells Stem cells have the dual property of being able to self renew and to give rise to differentiated cells and tissues. During development, totipotent stem cells can give rise to the full range of differentiated tissues; in the mature organism, adult stem cells only have the capacity to replace damaged cells and maintain cell populations within the tissues where they reside. There are also populations of stem cells between these extremes with varying capacities to differentiate into multiple (but limited) cell lineages. Thus depending on the source and stage of development, there are limits on the cell types that a "stem cell" can generate. The dynamic relationship between stem cells and terminally differentiated parenchyma is particularly evident in the continuously dividing epithelium of the skin; stem cells at the basal layer of the epithelium divide and their daughter cells progressively differentiate as they migrate to the upper layers of the epithelium before dying and being shed. Cell numbers can be altered by increased or decreased rates of stem cell input, cell death resulting from apoptosis, or changes in the rates of proliferation or differentiation. The zygote, formed by the union of sperm and egg, divides to form blastocysts, and the inner cell mass of the blastocyst generates the embryo. Regenerative Medicine the burgeoning field of regenerative medicine has been made possible by the ability to identify, isolate, expand, and transplant stem cells. There is, therefore, considerable interest in therapeutic opportunities for restoring tissues that have low intrinsic regenerative capacity, such as myocardium or neurons, to promote healing after myocardial infarction or stroke, respectively. Despite improved ability to purify and expand stem cells, success has, thus far, been limited by difficulties in introducing and functionally integrating replacement cells at sites of damage. This would, in principle, allow new tissues to be generated and transplanted Hair Epidermis Epidermal stem cells Goblet cell Absorptive enterocyte Sebaceous gland Hair follicle bulge Bulge stem cells Enteroendocrine cell Transit amplifying zone Paneth cell Stem cell Dermis A. Bile duct cells and canals of Hering are highlighted here by an immunohistochemical stain for cytokeratin 7. Guillot C, Lecuit T: Mechanics of epithelial tissue homeostasis and morphogenesis, Science 340:1185, 2013. Kaur J, Debnath J: Autophagy at the crossroads of catabolism and anabolism, Nat Rev Mol Cell Biol 16:461, 2015. While not yet in practice, their differentiated progeny could be remarkable therapeutic agents. This survey of selected topics in cell biology will serve as a basis for our later discussions of pathology, and we will refer back to it throughout the book. Students should, however, remember that this summary is intentionally brief, and more information about some of the fascinating topics reviewed here can be readily found in textbooks devoted to cell and molecular biology. Suggested readings Nusse R, Clevers H: Wnt/-catenin signaling, disease, and emerging therapeutic modalities, Cell 169:985, 2017. Perona R: Cell signalling: growth factors and tyrosine kinase receptors, Clin Transl Oncol 8:77, 2011. Jang S, Collin del Hortet A, Soto-Gutierrezy A: Induced pluripotent stem cell-derived endothelial cells: overview, current advances, applications, and future directions, Am J Pathol 189:502, 2019.
Mathis D metabolic diseases list 100 mg januvia with visa, Benoist C: Microbiota and autoimmune disease: the hosted self, Cell Host Microbe 10:297301, 2011. Durandy A, Kracker S, Fischer A: Primary antibody deficiencies, Nat Rev Immunol 13:519533, 2013. Merlini G, Dispenzieri A, Sanchorawala V et al: Systemic immunoglobulin light chain amyloidosis, Nat Rev Dis Primers 4:38, 2018. Dogan A: Amyloidosis: insights from proteomics, Annu Rev Pathol Mech Dis 12:277304, 2017. Even more agonizing than the mortality rate is the emotional and physical suffering inflicted by cancers. Some cancers, such as Hodgkin lymphoma, are curable, whereas others, such as pancreatic adenocarcinoma, are virtually always fatal. The only hope for controlling cancer lies in learning more about its causes and pathogenesis. Fortunately, great strides have been made in understanding its molecular basis, and some good news has emerged: cancer mortality for both men and women in the United States declined during the last decade of the 20th century and has continued its downward course in the 21st century. In this article, we describe the vocabulary of tumor biology and pathology and then review the morphologic characteristics that define neoplasia and allow benign and malignant tumors to be identified and distinguished. Also reviewed is the epidemiology of cancer, which provides a measure of the impact of cancer on human populations as well as clues to its environmental causes, insights that have led to effective prevention campaigns against certain cancers. Building on this foundation, we then discuss the biologic properties of tumors and the molecular basis of carcinogenesis, emphasizing the critical role that genetic alterations play in the development of neoplasia. Finally, we turn to cancer diagnosis, focusing on new technologies that are helping to direct the use of cancer drugs that are targeted at particular molecular lesions. Throughout, we give examples of new analytic methods and therapies that are not only changing our approach to cancer treatment but also providing new insights into cancer pathophysiology. Naming of benign tumors of mesenchymal cells is relatively simple; in general, the suffix "-oma" is attached to the name of the cell type from which the tumor arises. Thus a benign tumor of fibroblast-like cells is called a fibroma, a benign cartilaginous tumor is a chondroma, and so on. The nomenclature of benign epithelial tumors is more complex; some are classified based on their cell of origin, others on their microscopic appearance, and still others on their macroscopic architecture. Adenoma is applied to benign epithelial neoplasms derived from glandular tissues even if the tumor cells fail to form glandular structures. Thus, a benign epithelial neoplasm that arises from renal tubular cells and forms tightly clustered glands and a mass of adrenal cortical cells growing as a solid sheet are both referred to as adenomas. Benign epithelial neoplasms producing fingerlike or warty projections from epithelial surfaces are called papillomas, whereas those that form large cystic masses, such as in the ovary, are referred to as cystadenomas. Some tumors produce papillary projections that protrude into cystic spaces and are called papillary cystadenomas. When a neoplasm-benign or malignant- produces a grossly visible projection above a mucosal surface, for example, into the gastric or colonic lumen, it is termed a polyp. Tumor originally described swelling caused by inflammation, but is now equated with neoplasm. Although physicians know what they mean when they use the term neoplasm, it has been difficult to develop a precise definition. In the modern era, a neoplasm is defined as a genetic disorder of cell growth that is triggered by acquired or less commonly inherited mutations affecting a single cell and its clonal progeny. As discussed later, these causative mutations alter the function of particular genes and give the neoplastic cells a survival and growth advantage, resulting in excessive proliferation that is independent of physiologic growth signals and controls. All tumors are composed of two components: (1) neoplastic cells that constitute the tumor parenchyma and (2) reactive stroma made up of connective tissue, blood vessels, and cells of the adaptive and innate immune system. The classification of tumors and their biologic behavior are based primarily on the parenchymal component, but their growth and spread are critically dependent on their stroma. In others, parenchymal cells stimulate the formation of abundant collagenous stroma, referred to as desmoplasia. Some desmoplastic tumors-for example, some cancers of the female breast-are stony hard or scirrhous. Malignant Tumors Malignant tumors can invade and destroy adjacent structures and spread to distant sites (metastasize). Malignant tumors are collectively referred to as cancers, derived from the Latin word for crab, because they tend to adhere to any part that they seize on in an obstinate manner. Not all cancers pursue a deadly course; some are discovered at early stages Benign Tumors Benign tumors remain localized at their site of origin and are generally amenable to surgical removal. Nomenclature that allow for surgical excision, and others are cured with systemically administered drugs or therapeutic antibodies. The nomenclature of malignant tumors follows essentially the same schema used for benign neoplasms, with certain additions. Malignant tumors arising in solid mesenchymal tissues are usually called sarcomas (Greek sar = fleshy;. In squamous cell carcinoma the tumor cells resemble stratified squamous epithelium, whereas in adenocarcinoma the neoplastic epithelial cells grow in a glandular pattern. Sometimes the tissue or organ of origin can be identified and is added as a descriptor, as in renal cell adenocarcinoma or bronchogenic squamous cell carcinoma. In approximately 2% of cases, cancers are composed of cells of unknown origin and must be designated merely as undifferentiated malignant tumors.