Dominant negative ATM mutations in breast cancer families

BACKGROUND: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. METHODS: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. RESULTS: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. CONCLUSION: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.

Weakening of the Gram-negative bacterial outer membrane - A tool for increasing microbiological safety

Gram-negative bacteria are harmful in various surroundings. In the food industy their metabolites are potential cause of spoilage and this group also includes many severe or potential pathogens, such as Salmonella. Due to their ability to produce biofilms Gram-negative bacteria also cause problems in many industrial processes as well as in clinical surroundings. Control of Gram-negative bacteria is hampered by the outer membrane (OM) in the outermost layer of the cells. This layer is an intrinsic barrier for many hydrophobic agents and macromolecules. Permeabilizers are compounds that weaken OM and can thus increase the activity of antimicrobials by facililating entry of hydrophobic compounds and macromolecules into the cell where they can reach their target sites and inhibit or destroy cellular functions. The work described in this thesis shows that lactic acid acts as a permeabilizer and destabilizes the OM of Gram-negative bacteria. In addition, organic acids present in berriers, i.e. malic, sorbic and benzoic acid, were shown to weaken the OM of Gram-negative bacteria. Organic acids can poteniate the antimicrobial activity of other compounds. Microbial colonic degradation products of plant-derived phenolic compounds (3,4-dihydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 3,4-dihydroxyphenylpropionic acid, 4-hydroxyphenylpropionic acid, 3-phenylpropionic acid and 3-hydroxyphenylpropionic acid) efficiently destabilized OM of Salmonella. The studies increase our understanding of the mechanism of action of the classical chelator, ethylenediaminetetra-acetic acid (EDTA). In addition, the results indicate that the biocidic activity of benzalkonium chloride against Pseudomonas can be increased by combined use with polyethylenimine (PEI). In addition to PEI, several other potential permeabilizers, such as succimer, were shown to destabilize the OM of Gram-negative bacteria. Furthermore, combination of the results obtained from various permeability assays (e.g. uptake of a hydrophobic probe, sensitization to hydrophobic antibiotics and detergents, release of lipopolysaccharide (LPS) and LPS-specific fatty acids) with atomic force microscopy (AFM) image results increases our knowledge of the action of permeabilizers.

Negative resistance mode of forced oscillations of a string

A new mode of driven nonlinear vibrations of a stretched string is investigated with reference to conditions of existence, properties, and regions of stability. It is shown that this mode exhibits negative resistance properties at all frequencies and driving force amplitudes. Discovery of this mode helps to fill certain gaps in the theory of forced nonlinear vibrations of strings.

Analysis of two degrees of freedom systems through weighted mean square linearization approach

In this paper a study of the free, forced and self-excited vibrations of non-linear, two degrees of freedom systems is reported. The responses are obtained by linearizing the nonlinear equations using the weighted mean square linearization approach. The scope of this approach, in terms of the type of non-linearities the method can tackle, is also discussed.

Divide-and-Correct Algorithm for Division in a Negative Base

A divide-and-correct algorithm is described for multiple-precision division in the negative base number system. In this algorithm an initial quotient estimate is obtained from suitable segmented operands; this is then corrected by simple rules to arrive at the true quotient.

The letters 1938-1945. The Grunwald's journey from oppression to freedom.

The bulk of the correspondence is between Susanne Sommer's parents, Max and Marga Grunwald, and their sponsors in the United States, Paul and Jean Lewinson. Also included are letters from Susanne Sommer's maternal grandparents prior to their deportation from Berlin in 1942 and from her paternal grandfather prior to and after his deportation from Stettin to a ghetto in Poland. A number of letters by Hugo Grunwald, Susanne Sommer's uncle, joined the British army after his immigration to England, are included as well.

Analysis of two degrees of freedom systems through weighted mean square linearization approach

In this paper a study of the free, forced and self-excited vibrations of non-linear, two degrees of freedom systems is reported. The responses are obtained by linearizing the nonlinear equations using the weighted mean square linearization approach. The scope of this approach, in terms of the type of non-linearities the method can tackle, is also discussed.

Divide-and-Correct Algorithm for Division in a Negative Base

A divide-and-correct algorithm is described for multiple-precision division in the negative base number system. In this algorithm an initial quotient estimate is obtained from suitable segmented operands; this is then corrected by simple rules to arrive at the true quotient.

Negative map of Jewish settlements in Ukraine and Crimea

Digital image

Arithmetic Algorithms in a Negative Base

Algorithms are described for the basic arithmetic operations and square rooting in a negative base. A new operation called polarization that reverses the sign of a number facilitates subtraction, using addition. Some special features of the negative-base arithmetic are also mentioned.

Deterministic Division Algorithm in a Negative Base

Described here is a deterministic division algorithm in a negative-base number system; here, the divisor is mapped into a suitable range by premultiplication, so that the choice of the quotient digit is deterministic.

Negative photocopy of the map of Crimea with marked settlements

Digital image

Contemplating Whitehead's freedom and discipline

This paper extends the previous application of Alfred Whitehead's educational ideas to the domain of enterprise education. In doing so, a unique approach to enterprise education is illustrated that links students to their reality whilst also connecting the curriculum to contemporary entrepreneurship theory. The paper reports upon past cycles of reflective practice related to the developing hic et nunc teaching and learning framework. Two specific findings of note have emerged. First, that student' learning outcomes are enhanced through the oscillating influence of freedom and discipline. However, in the absence of either factor, sub-optimal outcomes are seen to occur. That is, an imbalance between freedom and discipline has resulted in sub-optimal outcomes from either a lack of student interest or an inability to adequately apply acquired knowledge. Where gains have been made, the most obvious process has been through consultation with students. Second, that the students also play an important role in shaping the nature of the learning environments within which they interact. Both findings are of significant importance to all academics charged with the responsibility of developing enterprise education curriculum. The main implication of the paper is that in the absence of sound pedagogical practises, it is possible that enterprise programs may develop a tendency to reinforce past practises. The processes of constructive alignment and criterion-based assessment are argued to offer avenues through which students can influence the educational process. They also provide the educator with a reflective pathway through which continual improvements are constantly possible. This paper provides other academics with a window through which to view the ongoing development of a process that has been recognised nationally for teaching excellence and influenced many fine young entrepreneurs. The paper also draws attention to a set of core educational philosophies that have transferable value to any academic setting. It is noted that the task of developing a learner-centred curriculum for enterprise education has been an entrepreneurial endeavour in itself. Many mistakes have been made and many memorable achievements have been celebrated.

Negative photo map of Jewish settlements in the Krivoy Rog district

Digital image

National media regulations in an age of convergent media: Beyond globalisation, neo-liberalism and internet freedom theories

There is a widely held view that the nation-state has become less central to media and communications policy over the last two decades. As Jan van Cuilenberg and Denis McQuail (2003, p. 181) observed in their overview of trends in communications policy-making, 'the old normative media policies have been challenged and policy-makers are searching for a new communications policy paradigm'. There are characteristically five factors put forward as to why the nation-state has become less central to media in the twenty-first century