Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.     

Spin Effects in Collisions of Electrons with Atoms and Molecules

IntroductionThedynamicsofelectron-atomandelectron-moleculecollisionshasbeenthefocusofmuchinterestinthepastbecauseofitsrelevanceingasdischargesandplasmas,includinggaslasers,orastrophysicalproblemsofpracticalinterest.Avarietyofinvestigationshavebeenperformedtostudysuchprocessesinsomedetail.Moresophisticatedexperimentalmethodsincludepolarization-correlationmeasurementstoobtaingeneralizedSTUparameters,spinasymmetrieswithpolarizedtargets(alsosuperelasticscatteringfromlaserexcitedtarget),opticalpar…     

Differential water permeability and regulation of three aquaporin 4 isoforms

Aquaporin 4 (AQP4) is expressed in the perivascular glial endfeet and is an important pathway for water during formation and resolution of brain edema. In this study, we examined the functional properties and relative unit water permeability of three functional isoforms of AQP4 expressed in the brain (M1, M23, Mz). The M23 isoform gave rise to square arrays when expressed in Xenopus laevis oocytes. The relative unit water permeability differed significantly between the isoforms in the order of M1 > Mz > M23. None of the three isoforms were permeable to small osmolytes nor were they affected by changes in external K⁺ concentration. Upon protein kinase C (PKC) activation, oocytes expressing the three isoforms demonstrated rapid reduction of water permeability, which correlated with AQP4 internalization. The M23 isoform was more sensitive to PKC regulation than the longer isoforms and was internalized significantly faster. Our results suggest a specific role for square array formation.     

Collaboration,interdisciplinarity, and the epistemology of contemporary science

Over the last decades, science has grown increasingly collaborative and interdisciplinary and has come to depart in important ways from the classical analyses of the development of science that were developed by historically inclined philosophers of science half a century ago. In this paper, I shall provide a new account of the structure and development of contemporary science based on analyses of, first, cognitive resources and their relations to domains, and second of the distribution of cognitive resources among collaborators and the epistemic dependence that this distribution implies. On this background I shall describe different ideal types of research activities and analyze how they differ. Finally, analyzing values that drive science towards different kinds of research activities, I shall sketch the main mechanisms underlying the perceived tension between disciplines and interdisciplinarity and argue for a redefinition of accountability and quality control for interdisciplinary and collaborative science.     

Large scale preparation of calf liver nuclei by continuous flow centrifugation

Summary Large scale purification and preparation of calf liver nuclei was accomplished by high speed centrifugation of a fraction enriched in nuclei (nuclear homogenate) through 1.8 M sucrose by means of a Beckman CF-32 Ti continuous flow rotor. In comparison with methods involving the use of conventional high capacity rotors, larger volumes of homogenate could be processed. This method was used to prepare nuclei from calf liver for the preparation of DNA-dependent RNA polymerases. The use of continuous flow ultracentrifugation avoids time-consuming manipulations, thus allowing handling of large quantities of tissue.Acknowledgments. The authors wish to thank Professor J. Brachet for his interest and fruitful discussion. They also thank Ms J. Gilder for secretarial assistance.     

Categorization, anomalies and the discovery of nuclear fission

The characteristics of scientific revolutions and by the same token the question of which events in the history of science deserve the name of revolutionary are controversial themes in the philosophy of science. An issue of disagreement is the question of whether or not events in which only parts of a paradigm are overthrown can truly be called a revolution, or if this term is to be reserved for the developments in which a wholesale replacement of ideas takes place. In this paper Kuhn's latest attempt to state a principle for distinguishing revolutionary developments will be reviewed, and it will be argued that certain developments entailing only partial replacements of the paradigm can be called revolutionary. The discovery of fission will serve as case study to illustrate this idea.     

Sophisticated sperm allocation in male fowl

When a female is sexually promiscuous, the ejaculates of different males compete for the fertilization of her eggs; the more sperm a male inseminates into a female, the more likely he is to fertilize her eggs. Because sperm production is limited and costly, theory predicts that males will strategically allocate sperm (1) according to female promiscuity, (2) saving some for copulations with new females, and (3) to females producing more and/or better offspring. Whether males allocate sperm in all of these ways is not known, particularly in birds where the collection of natural ejaculates only recently became possible. Here we demonstrate male sperm allocation of unprecedented sophistication in the fowl Gallus gallus. Males show status-dependent sperm investment in females according to the level of female promiscuity; they progressively reduce sperm investment in a particular female but, on encountering a new female, instantaneously increase their sperm investment; and they preferentially allocate sperm to females with large sexual ornaments signalling superior maternal investment. Our results indicate that female promiscuity leads to the evolution of sophisticated male sexual behaviour.     

Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis

Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor alpha chain (IL7Ralpha), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Ralpha and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.     

Genome-wide association analysis identifies three new breast cancer susceptibility loci

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ～8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ～70,000 cases and ～68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.