bluuebunny/crossref_metadata_2025 huggingface dataset:
Mammalian BLM helicase is critical for integrating multiple pathways of meiotic recombination
Authors: Holloway J. Kim , Morelli Meisha A. , Borst Peter L. , Cohen Paula E.
Published: March 2010

Bloom’s syndrome (BS) is an autosomal recessive disorder characterized by growth retardation, cancer predisposition, and sterility. BS mutated (Blm), the gene mutated in BS patients, is one of five mammalian RecQ helicases. Although BLM has been shown to promote genome stability by assisting in the repair of DNA structures that arise during homologous recombination in somatic cells, less is known about its role in meiotic recombination primarily because of the embryonic lethality associated with Blm deletion. However, the localization of BLM protein on meiotic chromosomes together with evidence from yeast and other organisms implicates a role for BLM helicase in meiotic recombination events, prompting us to explore the meiotic phenotype of mice bearing a conditional mutant allele of Blm. In this study, we show that BLM deficiency does not affect entry into prophase I but causes severe defects in meiotic progression. This is exemplified by improper pairing and synapsis of homologous chromosomes and altered processing of recombination intermediates, resulting in increased chiasmata. Our data provide the first analysis of BLM function in mammalian meiosis and strongly argue that BLM is involved in proper pairing, synapsis, and segregation of homologous chromosomes; however, it is dispensable for the accumulation of recombination intermediates.
Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma
Authors: Gillissen Bernhard , Wendt Jana , Richter Antje , Richter Anja , Müer Annika , Overkamp Tim , Gebhardt Nina , Preissner Robert , Belka Claus , Dörken Bernd , Daniel Peter T.
Published: March 2010

Tumor necrosis factor (α)–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in the majority of tumor cells. Thus, TRAIL-induced cell death entirely depends on the proapoptotic Bcl-2 family member Bax, which is often lost as a result of epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against TRAIL-induced apoptosis. Despite expression of Bak, Bax-deficient cells are resistant to TRAIL-induced apoptosis. In this study, we show that the Bax dependency of TRAIL-induced apoptosis is determined by Mcl-1 but not Bcl-xL. Both are antiapoptotic Bcl-2 family proteins that keep Bak in check. Nevertheless, knockdown of Mcl-1 but not Bcl-xL overcame resistance to TRAIL, CD95/FasL and tumor necrosis factor (α) death receptor ligation in Bax-deficient cells, and enabled TRAIL to activate Bak, indicating that Mcl-1 rather than Bcl-xL is a major target for sensitization of Bax-deficient tumors for death receptor–induced apoptosis via the Bak pathway.
New insights into oxidative folding
Authors: Sevier Carolyn S.
Published: March 2010

The oxidoreductase ERO1 (endoplasmic reticulum [ER] oxidoreductin 1) is thought to be crucial for disulfide bond formation in the ER. In this issue, Zito et al. (2010. J. Cell Biol. doi:10.1083/jcb.200911086) examine the division of labor between the two mammalian isoforms of ERO1 (ERO1-α and -β) in oxidative folding. Their analysis reveals a selective role for ERO1-β in insulin production and a surprisingly minor contribution for either ERO1 isoform on immunoglobulin folding and secretion.
Cancer Precursors
Authors: ROHAN THOMAS E. , HENSON DONALD E. , FRANCO EDUARDO L. , ALBORES-SAAVEDRA JORGE
Published: March 2010

The term “cancer precursor” refers to specific morphologic changes that precede the development of cancer. Knowledge of the etiology of cancer precursors varies considerably by anatomic site. In part, this might reflect the relative inaccessibility of a site to tissue sampling (e.g., ovary and pancreas) and hence the difficulty of detecting and diagnosing precursors at that site. This chapter describes some of the more well studied sites, for which there is substantial knowledge of the histopathology, epidemiology, and natural history.
Genetic Concepts and Methods in Epidemiologic Research
Authors: RISCH NEIL J. , WHITTEMORE ALICE S.
Published: March 2010

Advances in the last thirty years have generated much work for cancer epidemiologists, who must work with geneticists to identify genes that alter cancer risk and then translate the genetic discoveries into risk estimates and cost/benefit analyses that lead to effective strategies for cancer prevention and control. This chapter describes this work as it relates to heritable germline mutations and their roles in cancer susceptibility. It begins by presenting evidence that such mutations are important in specific cancers. It then describes methods for identifying these mutations and discusses how to characterize their effects on risk. The chapter concludes by considering the challenge for the future: how to use information on an individual's genetic susceptibility to prevent cancer occurrence.
Cancer Incidence, Mortality, and Patient Survival in the United States
Authors: RIES LYNN A.G. , DEVESA SUSAN S.
Published: March 2010

This chapter presents current estimates for cancer incidence, mortality, and survival in a large subgroup of the U.S. population based on the results of the Surveillance, Epidemiology, and End Results (SEER) Program. The SEER Program is an ongoing contract-supported program of the National Cancer Institute (NCI) that funds and coordinates the collection of cancer data in population-based cancer registries located throughout the United States. These registries, although not randomly selected, are thought to be reasonably representative of the U.S. population; a number of the registries cover diverse populations of particular epidemiologic interest. The program publishes incidence, mortality, and survival data annually.
Economic Impact of Cancer in the United States
Authors: BROWN MARTIN L. , YABROFF K. ROBIN
Published: March 2010

This chapter discusses the economic impact of cancer in the United States. Three categories of cost domains are identified: direct costs, resulting from the use of resources for medical care; indirect costs, resulting from the loss of economic resources and opportunities associated with disease and treatment; and psychosocial costs, such as pain and suffering. The measurement of health care costs, source of data on the costs of medical care, and approaches to estimating the economic burden of cancer are discussed.
Ionizing Radiation
Authors: BOICE JOHN D.
Published: March 2010

This chapter focuses on the link between exposure to ionizing radiation and cancer. It describes specific studies of exposed populations, touching on strengths and limitations, the need for caution in interpretation, and implications for public health, radiation protection, and carcinogenesis in general.
Obesity and Body Composition
Authors: BALLARD-BARBASH RACHEL , FRIEDENREICH CHRISTINE , SLATTERY MARTHA , THUNE INGER
Published: March 2010

This chapter presents an overview of the state of scientific evidence for the association between obesity-related risk factors and cancer. Data provide convincing evidence of a positive association of overweight and obesity with cancers of the colon (among men), renal cell, postmenopausal breast, endometrium, and probable evidence of a positive association with colon cancer (among women), adenocarcinoma of the esophagus and gastric cardia, and thyroid cancer (among women). On the other hand, the chapter states, epidemiologic studies do not demonstrate an association of weight or BMI with prostate cancer incidence.
Exogenous Hormones
Authors: LACEY JAMES V. , COLDITZ GRAHAM A. , SCHOTTENFELD DAVID
Published: March 2010

This chapter discusses the link between exogenous hormones and cancer. It focuses on estrogen and progesterone effects on tissues of the breast, endometrium, uterine cervix, ovary, and colon. All measures of association (odds ratios (ORs), relative risks (RRs), and hazard ratios (HRs)) for oral contraceptives (OCs) include women who never used OCs as the referent group. Similarly, associations for hormone therapy reflect no menopausal hormone use as the referent group.
Pharmaceuticals Other Than Hormones
Authors: HABEL LAUREL A. , FRIEDMAN GARY D.
Published: March 2010

This chapter discusses the link between therapeutic drugs and cancer. Topics covered include chemical carcinogenesis, drug safety, pharmacoepidemiologic studies, methodologic issues in studies of drugs and cancer, methodologic issues in studies of drugs and cancer, and magnitude of the problem of carcinogenesis due to drugs.
Pleural and Peritoneal Neoplasms
Authors: BOFFETTA PAOLO , STAYNER LESLIE T.
Published: March 2010

This chapter reviews the epidemiology of pleural and peritoneal neoplasms. Topics covered include molecular pathology and genetics, geographic patterns, temporal trends, survival, risk factors, and prevention.
Esophageal Cancer
Authors: BLOT WILLIAM J. , MCLAUGHLIN JOSEPH K. , FRAUMENI JOSEPH F.
Published: March 2010

This chapter reviews the epidemiology of esophageal cancer. It describes the known and suspected causes of esophageal cancer, with emphasis on the differences in risk factors between adenocarcinoma and squamous cell carcinoma of the esophagus. Since treatment successes have been limited and esophageal cancers still are usually fatal, regardless of cell type, epidemiologic patterns may offer clues to prevention.
Stomach Cancer
Authors: SHIBATA ATSUKO , PARSONNET JULIE
Published: March 2010

This chapter reviews the epidemiology of stomach cancer, focusing on adenocarcinoma of the stomach, including that of the gastric cardia and gastoesophageal junction. Topics covered include classification, preneoplasia, demographic patterns, environmental factors, host factors, and preventive measures.
Cancer of the Pancreas
Authors: ANDERSON KRISTIN E. , MACK THOMAS M. , SILVERMAN DEBRA T.
Published: March 2010

Cancer of the pancreas remains a serious medical and public health problem because of difficulties in early diagnosis, aggressive behavior, resistance to therapy, and limited opportunities for prevention. This chapter reviews the epidemiology of pancreatic cancer. Topics covered include classification, diagnosis, incidence, mortality, survival, time trends in the United States, risk factors, host factors, molecular pathogenesis, and prevention.
Biliary Tract Cancer
Authors: HSING ANN W. , RASHID ASIF , DEVESA SUSAN S. , FRAUMENI JOSEPH F.
Published: March 2010

This chapter reviews the epidemiology of biliary tract cancer. Many etiologic leads for biliary tract cancer have come from clinical observations, autopsy series, and descriptive epidemiologic studies. While a significant fraction of these tumors are related to gallstones (cholelithiasis), information on other risk factors is limited, due to the rarity of the tumors, the often rapidly fatal course, and the small number of epidemiologic studies conducted to date. Because the three anatomic categories of biliary tract cancer have distinct epidemiologic patterns and molecular changes, including somatic mutations and loss of heterozygosity (LOH), it has been suggested that the causal factors vary by subsite.
Cancers of the Colon and Rectum
Authors: GIOVANNUCCI EDWARD , WU KANA
Published: March 2010

This chapter reviews the epidemiology of colorectal cancer, focusing on adenocarcinomas, which comprise the vast majority of the cases. The etiologies of colon and rectal cancer overlap, but the differences between the two will be addressed when relevant.
Anal Cancer
Authors: FRISCH MORTEN , MELBYE MADS
Published: March 2010

Variants of invasive squamous carcinoma of the anal canal and perianal skin, referred to collectively as anal cancers, are rare malignancies constituting approximately 2% of all intestinal cancers. of a crude estimate of 35,000–40,000 new anal cancers worldwide, approximately 3,300 cases are diagnosed in the United States each year. This chapter reviews the epidemiology of anal cancer. Topics covered include classification, demographic patterns, lifestyle and environmental factors, host factors, pathogenesis, and preventive measures.
The Leukemias
Authors: LINET MARTHA S. , DEVESA SUSAN S. , MORGAN GARETH J.
Published: March 2010

The leukemias arise from malignant transformation of hematopoietic stem or progenitor cells that originate in the bone marrow, lymph nodes, and/or other lymphoid tissue with immune function. A small pool of stem cells, which persists throughout an individual's lifetime, differentiates to early precursors, then divides into multiple subtypes, and ultimately produces large numbers of end-stage cells of myeloid and lymphoid lineage progeny. Because the effector or end-stage cells of each lineage have a finite lifespan and, therefore, cannot transmit mutations, all leukemias are the consequence of derangements of growth and differentiation of the pluripotential early precursors of myeloid or lymphoid progeny. This chapter discusses the epidemiology of the myeloid and lymphoid leukemias.
Hodgkin Lymphoma
Authors: MUELLER NANCY E. , GRUFFERMAN SEYMOUR
Published: March 2010

Hodgkin lymphoma (HL) is a malignant disease involving the lymph nodes, spleen, and other lymphoid tissue. This chapter reviews the epidemiology of HL. Topics covered include the history of HL, incidence and mortality, classification, demographic patterns, childhood social environment, infectious exposures, occupational and environmental exposures, host factors, and pathogenesis.
Non-Hodgkin Lymphoma
Authors: HARTGE PATRICIA , WANG SOPHIA S. , BRACCI PAIGE M. , DEVESA SUSAN S. , HOLLY ELIZABETH A.
Published: March 2010

Non-Hodgkin lymphomas (NHL) are expected to account for 4.2% of cancer diagnoses and 3.3% of cancer deaths in the United States in 2006. With approximately 58,870 cases diagnosed and 18,840 deaths from NHL expected in 2006, this group of malignancies constitutes a serious public health problem in the United States as it does in most developed countries. This chapter reviews the epidemiology of NHL. Topics covered include classification, molecular characteristics, demographic patterns, and host factors.
Bone Cancer
Authors: MILLER ROBERT W. , BOICE JOHN D. , CURTIS ROCHELLE E.
Published: March 2010

Cancers arising from bone or cartilage account for about 0.5% of all malignant neoplasms in humans. This chapter reviews the epidemiology of bone cancer. Topics covered include demographic patterns, environmental factors, genetic susceptibility, and prevention.
Soft Tissue Sarcoma
Authors: MARIANNE BERWICK
Published: March 2010

Soft tissue sarcoma (STS) is a rare tumor, occurring in approximately 1 to 2 of every 100,000 individuals worldwide, and constitutes about 0.6% of all cancer cases and 0.7% of all cancer deaths. Prognosis is generally poor with a relative survival rate of approximately 67% at five years, with little difference by race. This chapter reviews the epidemiology of STS. Topics covered include classification, demographic patterns, environmental factors, host factors, pathogenesis, and preventive measures.
Breast Cancer
Authors: COLDITZ GRAHAM A. , BAER HEATHER J. , RULLA M. TAMIMI
Published: March 2010

Breast cancer is the most common cancer diagnosis and the second leading cause of cancer death among women in the United States. Over 211,000 women and 1,600 men in the United States are diagnosed with breast cancer each year, and 40,000 Americans die of this disease annually. This chapter reviews the epidemiology of breast cancer. Topics covered include classification, demographic patterns, environmental factors, host factors, pathogenesis, and preventive measures.
Ovarian Cancer
Authors: HANKINSON SUSAN E. , DANFORTH KIM N.
Published: March 2010

Ovarian cancer is the fifth most common cancer among women in the United States, accounting for 4% of cancer diagnoses, or about 25,400 new cases each year. It is also the fifth-leading cause of cancer-related mortality. This chapter reviews the epidemiology of breast cancer. Topics covered include classification, demographic patterns, environmental factors, host factors, pathogenesis, and preventive measures.
Endometrial Cancer
Authors: COOK LINDA S. , WEISS NOEL S. , DOHERTY JENNIFER A. , CHEN CHU
Published: March 2010

Endometrial cancer is a relatively common gynecologic cancer and diagnosis generally occurs after abnormal uterine bleeding or spotting. The overall five-year relative survival following diagnosis is relatively high, varying from roughly 85% in the United States, to 73% in China, 66% in India, and 63% in Eastern Europe. This chapter reviews the epidemiology of endometrial cancer. Topics covered include patterns of incidence and mortality, hormonal risk factors, and preventive measures.
Choriocarcinoma
Authors: PALMER JULIE R. , FELTMATE COLLEEN M.
Published: March 2010

Gestational choriocarcinoma is an extremely rare cancer that occurs in women of childbearing age. The malignancy arises from the trophoblastic epithelium of the placenta, which is formed from embryonic tissue. This chapter reviews the epidemiology of gestational choriocarcinoma. Topics covered include classification, demographic patterns, environmental factors, host factors, pathogenesis, and preventive measures.
Testicular Cancer
Authors: SARMA ARUNA V. , MCLAUGHLIN JULIE C. , SCHOTTENFELD DAVID
Published: March 2010

Cancer of the testis is relatively uncommon in the United States, accounting for approximately 1% of cancers in males. It is most commonly diagnosed in males between the ages of 15 and 44, and occurs more often in white than black men. This chapter reviews the epidemiology of testicular cancer. Topics covered include classification, demographic patterns, environmental factors, pathogenesis, and preventive measures.
Penile Cancer
Authors: WIDEROFF LOUISE , SCHOTTENFELD DAVID
Published: March 2010

Cancer of the penis occurs infrequently in North America and Europe, and generally in populations and cultures that practice neonatal or childhood circumcision. International incidence data indicate that penile cancer is more common in Africa, South America, and some parts of Asia. This chapter reviews the epidemiology of penile cancer. Topics covered include classification, demographic patterns, environmental factors, pathogenesis, and preventive measures.
Nervous System
Authors: PRESTON-MARTIN SUSAN , REEMA MUNIR , REEMA CHAKRABARTI
Published: March 2010

Malignant nervous system (NS) tumors account for 18,300 of new cancer diagnoses each year or 1.4% of all primary incident cancers and for 13,100 or 2.4% of annual cancer deaths. The vast majority of these tumors arise in the central nervous system (CNS), and for this site inclusion of benign tumors doubles the annual incidence. This chapter reviews the epidemiology of tumors in the central nervous system. Topics covered include classification, demographic patterns, environmental factors, host factors, and preventive measures.
Keratinocyte Carcinomas (Basal and Squamous Cell Carcinomas of the Skin)
Authors: KARAGAS MARGARET R. , WEINSTOCK MARTIN A. , NELSON HEATHER H.
Published: March 2010

Cancers arising from keratinocytes or their precursors, which include basal cell carcinoma (BCC) and squamous cell skin carcinoma (SCC) of the skin, are the mostly frequently diagnosed malignancies in fair-skinned populations. These malignancies are commonly referred to as nonmelanoma skin cancers or simply skin cancers. This chapter reviews the epidemiology of keratinocyte carcinomas. Topics covered include demographic patterns, environmental factors, molecular genetic characteristics of tumors, and preventive measures.
Principles and Applications of Cancer Prevention and Control Interventions
Authors: HIATT ROBERT A. , RIMER BARBARA K.
Published: March 2010

This chapter sets forth the principles of cancer prevention and control sciences, with a special emphasis on intervention. It begins with some historical background from which these principles have evolved. It then presents an overview of cancer control interventions and some accomplishments in cancer prevention and control to date. It describes a cancer control research framework that has been useful over the past decade in strategic planning and in directing research and application programs at a national level. Finally, placing the practice of cancer control research within this framework, the chapter highlights where modern cancer prevention and control science is likely to have the largest impact on cancer at both the individual and population levels.
Increasing the Contribution of Epidemiology to the Primary Prevention of Cancer
Authors: ROCKHILL BEVERLY , WEED DOUGLAS
Published: March 2010

This chapters aims to stimulate critical and creative thought about the role that epidemiology can, and should, play in preventing cancer. It presents four suggestions for increasing the contribution that epidemiologists can make to the primary prevention of cancer: that epidemiologists should commit to prevention, and preventive intervention, as central professional goals; be willing to develop the understanding of cancer causation and prevention from a population perspective as well as from an individual perspective; accept uncertainty as the “normal” state and be vigilant about the risk of paralysis that uncertainty brings to action; and broaden the concept of causal inference so that the process is useful for primary prevention.
Principles of Screening
Authors: LEVIN BERNARD , PROROK PHILIP C.
Published: March 2010

This chapter focuses on cancer screening. Screening for cancer provides an alternative approach to cancer control. Cancer screening is defined as the testing of apparently healthy volunteers from the general population for the purpose of separating them into high and low probabilities of having a given cancer. The validity of a screening test, study designs, biases, potential harms of screening, and case studies are discussed.
Molecular mechanisms of crystallization impacting calcium phosphate cements
Authors: Giocondi Jennifer L. , El-Dasher Bassem S. , Nancollas George H. , Orme Christine A.
Published: March 2010

The biomineral calcium hydrogen phosphate dihydrate (CaHPO
4
·2H
2
O), known as brushite, is a malleable material that both grows and dissolves faster than most other calcium minerals, including other calcium phosphate phases, calcium carbonates and calcium oxalates. Within the body, this ready formation and dissolution can play a role in certain diseases, such as kidney stone and plaque formation. However, these same properties, along with brushite’s excellent biocompatibility, can be used to great benefit in making resorbable biomedical cements. To optimize cements, additives are commonly used to control crystallization kinetics and phase transformation. This paper describes the use of
in situ
scanning probe microscopy to investigate the role of several solution parameters and additives in brushite atomic step motion. Surprisingly, this work demonstrates that the activation barrier for phosphate (rather than calcium) incorporation limits growth kinetics and that additives such as magnesium, citrate and bisphosphonates each influence step motion in distinctly different ways. Our findings provide details of how, and where, molecules inhibit or accelerate kinetics. These insights have the potential to aid in designing molecules to target specific steps and to guide synergistic combinations of additives.
Use of unnatural amino acids for design of novel organomodified clays as components of nanocomposite biomaterials
Authors: Katti Kalpana S. , Ambre Avinash H. , Peterka Nicholas , Katti Dinesh R.
Published: March 2010

Sodium montmorillonite (Na-MMT) clay was modified with three different unnatural amino acids in order to design intercalated clay structures that may be used for bone biomaterials applications. Prior work on polymer–clay nanocomposites (PCNs) has indicated the effect of the appropriate choice of modifiers on enhancing properties of PCNs. Our X-ray diffraction results indicate an increase in the
d
-spacing of Na-MMT clay after it was modified with the three unnatural amino acids. Transmission Fourier transform infrared spectroscopy experiments were carried out on the unmodified and modified MMT clay samples to study the molecular interactions between the amino acids used as modifiers and the Na-MMT clay. Cell culture experiments showed that the Na-MMT clay modified with the three amino acids was biocompatible as were the modified clay-incorporated films of chitosan/polygalacturonic acid/hydroxyapatite.
Biomimetic hydroxyapatite-containing composite nanofibrous substrates for bone tissue engineering
Authors: Venugopal J. , Prabhakaran Molamma P. , Zhang Yanzhong , Low Sharon , Choon Aw Tar , Ramakrishna S.
Published: March 2010

The fracture of bones and large bone defects owing to various traumas or natural ageing is a typical type of tissue malfunction. Surgical treatment frequently requires implantation of a temporary or permanent prosthesis, which is still a challenge for orthopaedic surgeons, especially in the case of large bone defects. Mimicking nanotopography of natural extracellular matrix (ECM) is advantageous for the successful regeneration of damaged tissues or organs. Electrospun nanofibre-based synthetic and natural polymer scaffolds are being explored as a scaffold similar to natural ECM for tissue engineering applications. Nanostructured materials are smaller in size falling, in the 1–100 nm range, and have specific properties and functions related to the size of the natural materials (e.g. hydroxyapatite (HA)). The development of nanofibres with nano-HA has enhanced the scope of fabricating scaffolds to mimic the architecture of natural bone tissue. Nanofibrous substrates supporting adhesion, proliferation, differentiation of cells and HA induce the cells to secrete ECM for mineralization to form bone in bone tissue engineering. Our laboratory (NUSNNI, NUS) has been fabricating a variety of synthetic and natural polymer-based nanofibrous substrates and synthesizing HA for blending and spraying on nanofibres for generating artificial ECM for bone tissue regeneration. The present review is intended to direct the reader’s attention to the important subjects of synthetic and natural polymers with HA for bone tissue engineering.
Biomaterials by freeze casting
Authors: Wegst Ulrike G. K. , Schecter Matthew , Donius Amalie E. , Hunger Philipp M.
Published: March 2010

The functional requirements for synthetic tissue substitutes appear deceptively simple: they should provide a porous matrix with interconnecting porosity and surface properties that promote rapid tissue ingrowth; at the same time, they should possess sufficient stiffness, strength and toughness to prevent crushing under physiological loads until full integration and healing are reached. Despite extensive efforts and first encouraging results, current biomaterials for tissue regeneration tend to suffer common limitations: insufficient tissue–material interaction and an inherent lack of strength and toughness associated with porosity. The challenge persists to synthesize materials that mimic both structure and mechanical performance of the natural tissue and permit strong tissue–implant interfaces to be formed. In the case of bone substitute materials, for example, the goal is to engineer high-performance composites with effective properties that, similar to natural mineralized tissue, exceed by orders of magnitude the properties of its constituents. It is still difficult with current technology to emulate in synthetic biomaterials multi-level hierarchical composite structures that are thought to be the origin of the observed mechanical property amplification in biological materials. Freeze casting permits to manufacture such complex, hybrid materials through excellent control of structural and mechanical properties. As a processing technique for the manufacture of biomaterials, freeze casting therefore has great promise.
The role of meiotic drive in hybrid male sterility
Authors: McDermott Shannon R. , Noor Mohamed A. F.
Published: March 2010

Meiotic drive causes the distortion of allelic segregation away from Mendelian expected ratios, often also reducing fecundity and favouring the evolution of drive suppressors. If different species evolve distinct drive-suppressor systems, then hybrid progeny may be sterile as a result of negative interactions of these systems' components. Although the hypothesis that meiotic drive may contribute to hybrid sterility, and thus species formation, fell out of favour early in the 1990s, recent results showing an association between drive and sterility have resurrected this previously controversial idea. Here, we review the different forms of meiotic drive and their possible roles in speciation. We discuss the recent empirical evidence for a link between drive and hybrid male sterility, also suggesting a possible mechanistic explanation for this link in the context of chromatin remodelling. Finally, we revisit the population genetics of drive that allow it to contribute to speciation.
Mutation and the evolution of ageing: from biometrics to system genetics
Authors: Hughes Kimberly A.
Published: March 2010

A notable success for evolutionary genetics during the past century was to generate a coherent, quantitative explanation for an apparent evolutionary paradox: the tendency for multicellular organisms to show declining fitness with age (senescence, often referred to simply as ‘ageing’). This general theory is now widely accepted and explains most of the features of senescence that are observed in natural and laboratory populations, but specific instantiations of that theory have been more controversial. To date, most of the empirical tests of these models have relied on data generated from biometric experiments. Modern population genetics and genomics provide new, and probably more powerful, ways to test ideas that are still controversial more than half a century after the original theory was developed. System-genetic experiments have the potential to address both evolutionary and mechanistic questions about ageing by identifying causal loci and the genetic networks with which they interact. Both the biometrical approaches and the newer approaches are reviewed here, with an emphasis on the challenges and limitations that each method faces.
What drives recombination hotspots to repeat DNA in humans?
Authors: McVean Gil
Published: March 2010

Recombination between homologous, but non-allelic, stretches of DNA such as gene families, segmental duplications and repeat elements is an important source of mutation. In humans, recent studies have identified short DNA motifs that both determine the location of 40 per cent of meiotic cross-over hotspots and are significantly enriched at the breakpoints of recurrent non-allelic homologous recombination (NAHR) syndromes. Unexpectedly, the most highly penetrant form of the motif occurs on the background of an inactive repeat element family (THE1 elements) and the motif also has strong recombinogenic activity on currently active element families including Alu and LINE2 elements. Analysis of genetic variation among members of these repeat families indicates an important role for NAHR in their evolution. Given the potential for double-strand breaks within repeat DNA to cause pathological rearrangement, the association between repeats and hotspots is surprising. Here we consider possible explanations for why selection acting against NAHR has not eliminated hotspots from repeat DNA including mechanistic constraints, possible benefits to repeat DNA from recruiting hotspots and rapid evolution of the recombination machinery. I suggest that rapid evolution of hotspot motifs may, surprisingly, tend to favour sequences present in repeat DNA and outline the data required to differentiate between hypotheses.
Mutations and quantitative genetic variation: lessons fromDrosophila
Authors: Mackay Trudy F. C.
Published: March 2010

A central issue in evolutionary quantitative genetics is to understand how genetic variation for quantitative traits is maintained in natural populations. Estimates of genetic variation and of genetic correlations and pleiotropy among multiple traits, inbreeding depression, mutation rates for fitness and quantitative traits and of the strength and nature of selection are all required to evaluate theoretical models of the maintenance of genetic variation. Studies inDrosophila melanogasterhave shown that a substantial fraction of segregating variation for fitness-related traits inDrosophilais due to rare deleterious alleles maintained by mutation–selection balance, with a smaller but significant fraction attributable to intermediate frequency alleles maintained by alleles with antagonistic pleiotropic effects, and late-age-specific effects. However, the nature of segregating variation for traits under stabilizing selection is less clear and requires more detailed knowledge of the loci, mutation rates, allelic effects and frequencies of molecular polymorphisms affecting variation in suites of pleiotropically connected traits. Recent studies inD. melanogasterhave revealed unexpectedly complex genetic architectures of many quantitative traits, with large numbers of pleiotropic genes and alleles with sex-, environment- and genetic background-specific effects. Future genome wide association analyses of many quantitative traits on a common panel of fully sequencedDrosophilastrains will provide much needed empirical data on the molecular genetic basis of quantitative traits.
The population genetics of mutations: good, bad and indifferent
Authors: Loewe Laurence , Hill William G.
Published: March 2010

Population genetics is fundamental to our understanding of evolution, and mutations are essential raw materials for evolution. In this introduction to more detailed papers that follow, we aim to provide an oversight of the field. We review current knowledge on mutation rates and their harmful and beneficial effects on fitness and then consider theories that predict the fate of individual mutations or the consequences of mutation accumulation for quantitative traits. Many advances in the past built on models that treat the evolution of mutations at each DNA site independently, neglecting linkage of sites on chromosomes and interactions of effects between sites (epistasis). We review work that addresses these limitations, to predict how mutations interfere with each other. An understanding of the population genetics of mutations of individual loci and of traits affected by many loci helps in addressing many fundamental and applied questions: for example, how do organisms adapt to changing environments, how did sex evolve, which DNA sequences are medically important, why do we age, which genetic processes can generate new species or drive endangered species to extinction, and how should policy on levels of potentially harmful mutagens introduced into the environment by humans be determined?
Transposable elements in natural populations ofDrosophila melanogaster
Authors: Lee Yuh Chwen G. , Langley Charles H.
Published: March 2010

Transposable elements (TEs) are families of small DNA sequences found in the genomes of virtually all organisms. The sequences typically encode essential components for the replicative transposition sequences of that TE family. Thus, TEs are simply genomic parasites that inflict detrimental mutations on the fitness of their hosts. Several models have been proposed for the containment of TE copy number in outbreeding host populations such asDrosophila. Surveys of the TEs in genomes from natural populations ofDrosophilahave played a central role in the investigation of TE dynamics. The early surveys indicated that a typical TE insertion is rare in a population, which has been interpreted as evidence that each TE is selected against. The proposed mechanisms of this natural selection are reviewed here. Subsequent and more targeted surveys identify heterogeneity among types of TEs and also highlight the large role of homologous and possibly ectopic crossing over in the dynamics of theDrosophilaTEs. The recent discovery of germline-specific RNA interference via the piwi-interacting RNA pathway opens yet another interesting mechanism that may be critical in containing the copy number of TEs in natural populations ofDrosophila. The expected flood ofDrosophilapopulation genomics is expected to rapidly advance understanding of the dynamics of TEs.
Mutation and the evolution of recombination
Authors: Barton N. H.
Published: March 2010

Under the classical view, selection depends more or less directly on mutation: standing genetic variance is maintained by a balance between selection and mutation, and adaptation is fuelled by new favourable mutations. Recombination is favoured if it breaks negative associations among selected alleles, which interfere with adaptation. Such associations may be generated by negative epistasis, or by random drift (leading to the Hill–Robertson effect). Both deterministic and stochastic explanations depend primarily on the genomic mutation rate,U. This may be large enough to explain high recombination rates in some organisms, but seems unlikely to be so in general. Random drift is a more general source of negative linkage disequilibria, and can cause selection for recombination even in large populations, through the chance loss of new favourable mutations. The rate of species-wide substitutions is much too low to drive this mechanism, but local fluctuations in selection, combined with gene flow, may suffice. These arguments are illustrated by comparing the interaction between good and bad mutations at unlinked loci under the infinitesimal model.
A novel heart‐cell line from brown‐marbled grouper Epinephelus fuscoguttatus and its susceptibility to iridovirus
Authors: Wei Y.‐B. , Fan T.‐J. , Jiang G.‐J. , Xu X.‐H. , Sun A.
Published: March 2010

A novel cell line (bmGH) was established from the heart of brown‐marbled grouper Epinephelus fuscoguttatus and its viral susceptibility was evaluated. The bmGH cells have been subcultured to passage 65 in Dulbecco's modified eagle medium:Ham's nutrient mixture F‐12 (1:1) medium (DMEM/F12) which was further supplemented with foetal bovine serum (FBS), carboxymethyl‐chitosan, basic fibroblast growth factor (bFGF) and insulin‐like growth factor‐I (IGF‐I) at 24° C. The heart cells have a fibroblastic morphology and proliferated to confluence 14 days later. The cells grew at a steady rate during subsequent subculture and had a population doubling time of 40·3 h at passage 60. Karyotype analysis showed that these cells exhibited chromosomal aneuploidy with a modal chromosome number of 48. The results of viral susceptibility characterization revealed that cytopathic effects (CPE) of bmGH cells appeared after infection by two iridoviruses, turbot reddish body iridovirus (TRBIV) and lymphocystis disease virus (LCDV). A large number of TRBIV and LCDV particles were also observed in the infected bmGH cells by electron microscope examination. All of these facts indicate that the bmGH cell line established here may serve as a valuable tool for studies of cell‐virus interactions and has potential applications in fish virus isolation, propagation and vaccine development.
Risk perception and smoking behavior in medically ill smokers: a prospective study
Authors: Borrelli Belinda , Hayes Rashelle B. , Dunsiger Shira , Fava Joseph L.
Published: March 2010

Aims To examine the influence of risk perception on intentions to quit smoking and post‐treatment abstinence.

Design Prospective and longitudinal.

Setting United States.

Participants A total of 237 adult smokers (mean age 56 years) receiving medical care from home health‐care nurses. Participants did not have to want to quit smoking to participate, but received cessation counseling within the context of their medical care.

Measurements Three measures of risk perception were given pre‐ and post‐treatment: perceived vulnerability, optimistic bias and precaution effectiveness. Smoking status was verified biochemically at end of treatment and at 2, 6 and 12 months later.

Findings Principal components analysis supported the theoretical discriminability of the risk perception measures, and intercorrelations provided evidence for concurrent and predictive validity. Elevated risk perception was associated with a variety of socio‐demographic and psychosocial characteristics. Optimistic bias was associated significantly with older age and ethnic minority status. Smokers in pre‐contemplation had lower perceived vulnerability and precaution effectiveness and greater optimistic bias than those in contemplation and preparation. Smokers in preparation had higher perceived vulnerability and lower optimistic bias than those in earlier stages. Change in perceived vulnerability predicted smoking cessation at follow‐up. Optimistic bias predicted a lower likelihood of cessation and precaution effectiveness predicted a greater likelihood of smoking cessation, but only among those with a smoking‐related illness.

Conclusions In patients receiving medical care from home health‐care nurses, change in perceived vulnerability to smoking‐related disease is predictive of smoking cessation. In those with smoking‐related illnesses, optimistic bias predicts continued smoking while precaution effectiveness predicts cessation.
Association between ovocalyxin‐32 gene haplotypes and eggshell quality traits in an F2 intercross between two chicken lines divergently selected for eggshell strength
Authors: Takahashi H. , Sasaki O. , Nirasawa K. , Furukawa T.
Published: March 2010

Broken and cracked eggshells contribute significantly to economic losses in the egg production industry. We previously identified ovocalyxin‐32 as a potential gene influencing eggshell traits, by analysing an intercross between two parent lines developed from the same founder population by a two‐way selection for eggshell strength with non‐destructive deformation (DEF) conducted over 14 generations. We determined the nucleotide sequences of six ovocalyxin‐32 exons in the parent individuals and analysed the association between ovocalyxin‐32 and eggshell traits in the F2 individuals. We identified three haplotypes (W, M and S) of ovocalyxin‐32 in the parent individuals. A mismatch amplification mutation assay was performed to distinguish six diplotype individuals (WW, MM, SS, WM, MS and WS) in the F2 population. The egg weight (EW) of SS‐diplotype individuals was significantly higher than that of WW‐, WM‐ and WS‐diplotypes. Short length of the egg (SLE) of SS‐diplotype individuals was significantly higher than that of WW‐, WM‐ and MS‐diplotypes. Long length of the egg (LLE) of SS‐diplotype individuals was significantly higher than that of WM‐ and WS‐diplotypes. DEF of WW‐diplotype individuals was significantly higher than that of SS‐, WM, MS and WM‐diplotypes. Haplotypic effect analyses showed significant differences between the W‐haplotype and the S‐haplotypes in the EW, SLE, LLE and DEF. The DEF of M‐haplotype was significantly lower than that of W‐ and S‐haplotypes. These results suggest that S‐ and M‐haplotypes are critical for high quality of eggshells in the F2 population. In conclusion, ovocalyxin‐32 is a useful marker of eggshell traits and can be used to develop strategies for improving eggshell traits in commercial layer houses.
Paternity validation and estimation of genotyping error rate for the BovineSNP50 BeadChip
Authors: Weller J. I. , Glick G. , Ezra E. , Zeron Y. , Seroussi E. , Ron M.
Published: March 2010

Incorrect paternity assignment in cattle can have a major effect on rates of genetic gain. Of the 576 Israeli Holstein bulls genotyped by the BovineSNP50 BeadChip, there were 204 bulls for which the father was also genotyped. The results of 38 828 valid single nucleotide polymorphisms (SNPs) were used to validate paternity, determine the genotyping error rates and determine criteria enabling deletion of defective SNPs from further analysis. Based on the criterion of >2% conflicts between the genotype of the putative sire and son, paternity was rejected for seven bulls (3.5%). The remaining bulls had fewer conflicts by one or two orders of magnitude. Excluding these seven bulls, all other discrepancies between sire and son genotypes are assumed to be caused by genotyping mistakes. The frequency of discrepancies was >0.07 for nine SNPs, and >0.025 for 81 SNPs. The overall frequency of discrepancies was reduced from 0.00017 to 0.00010 after deletion of these 81 SNPs, and the total expected fraction of genotyping errors was estimated to be 0.05%. Paternity of bulls that are genotyped for genomic selection may be verified or traced against candidate sires at virtually no additional cost.
Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers
Authors: Butler Kathleen , Teng Renli
Published: March 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The antiplatelet agent clopidogrel is currently the recommended treatment for acute coronary syndrome (ACS).

• Inhibition of platelet aggregation (IPA) with clopidogrel is insufficient, which increases the risk for recurrent ischaemic events. Therefore, there is a need for antiplatelet agents with improved IPA.

• Ticagrelor (AZD6140) is a new antiplatelet agent in clinical development for reduction of thrombotic events in patients with ACS.

WHAT THIS STUDY ADDS

• This study assesses the optimal dosing schedule for ticagrelor in healthy volunteers and compares the degree of IPA with clopidogrel.

• Our findings illustrate that the pharmacokinetics of ticagrelor are predictable and are associated with consistent inhibition of platelet activity.

• IPA with ticagrelor was greater and better sustained at high levels with twice daily ticagrelor than once daily regimens.

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y12 receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single‐blind, placebo‐controlled, ascending dose study. Thirty‐two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day−1, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median tmax 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean Cmax and AUC for ticagrelor and its main metabolite, AR‐C124910XX, increased approximately dose‐proportionately (approximately 2.2‐ to 2.4‐fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with Cmax and AUC(0,t) increasing approximately dose‐proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day−1 was well tolerated.