A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

MBD4 binds to methylated DNA and acts as a thymine DNA glycosylase in base excision repair. Deficiency of MBD4 in mice enhances mutation at CpG sites and alters apoptosis in response to DNA damage, but does not increase tumorigenesis in mismatch repair-deficient mice. However, in humans, frameshift mutation of MBD4, rather than deletion, is what occurs in up to 43% of microsatellite unstable colon cancers. There is no murine equivalent of this mutation. We now show that recombinant truncated MBD4 (MBD4tru) inhibits glycosylase activities of normal MBD4 or Uracil DNA glycosylase in cell-free assays as a dominant negative effect. Furthermore, overexpression of MBD4tru in Big Blue (lacI)-transfected, MSI human colorectal carcinoma cells doubled mutation frequency, indicating that the modest dominant negative effect on DNA repair can occur in living cells in short-term experiments. Intriguingly, the whole mutation spectrum was increased, not only at CpG sites, suggesting that truncated MBD4 has a more widespread effect on genomic stability. This demonstration of a dominant negative effect may be of significance in tumour progression and acquisition of drug resistance

Predicting functional associations from metabolism using bi-partite network algorithms

<p>Abstract</p> <p>Background</p> <p>Metabolic reconstructions contain detailed information about metabolic enzymes and their reactants and products. These networks can be used to infer functional associations between metabolic enzymes. Many methods are based on the number of metabolites shared by two enzymes, or the shortest path between two enzymes. Metabolite sharing can miss associations between non-consecutive enzymes in a serial pathway, and shortest-path algorithms are sensitive to high-degree metabolites such as water and ATP that create connections between enzymes with little functional similarity.</p> <p>Results</p> <p>We present new, fast methods to infer functional associations in metabolic networks. A local method, the degree-corrected Poisson score, is based only on the metabolites shared by two enzymes, but uses the known metabolite degree distribution. A global method, based on graph diffusion kernels, predicts associations between enzymes that do not share metabolites. Both methods are robust to high-degree metabolites. They out-perform previous methods in predicting shared Gene Ontology (GO) annotations and in predicting experimentally observed synthetic lethal genetic interactions. Including cellular compartment information improves GO annotation predictions but degrades synthetic lethal interaction prediction. These new methods perform nearly as well as computationally demanding methods based on flux balance analysis.</p> <p>Conclusions</p> <p>We present fast, accurate methods to predict functional associations from metabolic networks. Biological significance is demonstrated by identifying enzymes whose strong metabolic correlations are missed by conventional annotations in GO, most often enzymes involved in transport vs. synthesis of the same metabolite or other enzyme pairs that share a metabolite but are separated by conventional pathway boundaries. More generally, the methods described here may be valuable for analyzing other types of networks with long-tailed degree distributions and high-degree hubs.</p

A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

Memory Lower Bounds of Reductions Revisited

In Crypto 2017, Auerbach et al. initiated the study on memory-tight reductions and proved two negative results on the memory-tightness of restricted black-box reductions from multi-challenge security to single-challenge security for signatures and an artificial hash function. In this paper, we revisit the results by Auerbach et al. and show that for a large class of reductions treating multi-challenge security, it is impossible to avoid loss of memory-tightness unless we sacrifice the efficiency of their running-time. Specifically, we show three lower bound results. Firstly, we show a memory lower bound of natural black-box reductions from the multi-challenge unforgeability of unique signatures to any computational assumption. Then we show a lower bound of restricted reductions from multi-challenge security to single-challenge security for a wide class of cryptographic primitives with unique keys in the multi-user setting. Finally, we extend the lower bound result shown by Auerbach et al. treating a hash function to one treating any hash function with a large domain

Diagnostic and preventive service trends in private general practice: 1983-1984 to 1998-1999

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: Aggregate trends have indicated increases in the provision of diagnostic and preventive services but there have been few reports based on their component sub-categories. The aims of this study were to investigate time trends in the provision of sub-categories of diagnostic and preventive services across a 15-year period. Methods: A random sample of Australian dentists was surveyed by mailed questionnaire in 1983-1984, 1988-1989, 1993-1994 and 1998-1999 (response rates 71-75 per cent). Data were weighted to provide representative estimates for the age by sex distribution of private general practitioners in 1983, 1988, 1993 and 1998. Results: Rates per visit were higher, Poisson regression, P<0.05, in 1998-1999 compared to baseline for examinations, radiographs, prophylaxis and topical fluoride. Diagnostic and preventive service rates varied by age of patient: compared to patients aged 65+ years, examinations were higher among children aged <5 years to adults aged 25-44 years, radiographs were lower among children <5 years and 5-11 years but higher among adults aged from 18-24 years to 45-64 years, prophylaxis services were lower among children <5 years but higher among adolescents 12-17 years to adults aged 45-64 years, while topical fluoride was higher among children 5-11 years and adolescents 12-17 years. Conclusions: Examination, radiograph, prophylaxis, and topical fluoride rates increased over the study period. While examination rates increased for both children and adults, and prophylaxis rates increased for adolescents and adults, rates for radiographs and topical fluoride only increased for adults. Agespecific changes in service rates over time indicate the effect of changing oral health status and population demographics on service provision.DS Brennan, AJ Spence

All-sky search for short gravitational-wave bursts in the second Advanced LIGO and Advanced Virgo run

We present the results of a search for short-duration gravitational-wave transients in the data from the second observing run of Advanced LIGO and Advanced Virgo. We search for gravitational-wave transients with a duration of milliseconds to approximately one second in the 32-4096 Hz frequency band with minimal assumptions about the signal properties, thus targeting a wide variety of sources. We also perform a matched-filter search for gravitational-wave transients from cosmic string cusps for which the waveform is well modeled. The unmodeled search detected gravitational waves from several binary black hole mergers which have been identified by previous analyses. No other significant events have been found by either the unmodeled search or the cosmic string search. We thus present the search sensitivities for a variety of signal waveforms and report upper limits on the source rate density as a function of the characteristic frequency of the signal. These upper limits are a factor of 3 lower than the first observing run, with a 50% detection probability for gravitational-wave emissions with energies of ∼10-9 Mc2 at 153 Hz. For the search dedicated to cosmic string cusps we consider several loop distribution models, and present updated constraints from the same search done in the first observing run