84 research outputs found

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    Finishing the euchromatic sequence of the human genome

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    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

    Molecular basis of USP7 inhibition by selective small-molecule inhibitors

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    Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

    Evaluation of An Intervention Designed to Help Divorced Parents Forgive Their Ex-Spouse

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    This study evaluated a 1-day workshop combined with postintervention journal writing designed to help divorced parents forgive their ex-spouse. Participants (N=99) were randomly assigned to a workshop with gratitude journal condition (WG), the same workshop with daily events journal condition (WDE), or a wait-list comparison condition (WAIT). Participants completed measures of forgiveness, well-being, and parenting at pretest, posttest (i.e., after the workshop but prior to journaling), and 1-month follow-up (i.e., after the journaling). Consistent with hypotheses, forgiveness of an ex-spouse and dispositional forgiveness were positively related to coparenting, and forgiveness of an ex-spouse was related to better mental health. Participants assigned to WG improved more on situational and dispositional forgiveness as compared to other conditions. Contrary to hypotheses, participants in WG and WDE did not improve over time more than WAIT participants on mental health or parenting measures

    The Survival of <i>Pinus ponderosa</i> Saplings Subjected to Increasing Levels of Fire Behavior and Impacts on Post-Fire Growth

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    Improved predictions of tree species mortality and growth metrics following fires are important to assess fire impacts on forest succession, and ultimately forest growth and yield. Recent studies have shown that North American conifers exhibit a &#8216;toxicological dose-response&#8217; relationship between fire behavior and the resultant mortality or recovery of the trees. Prior studies have not been conclusive due to potential pseudo-replication in the experimental design and time-limited observations. We explored whether dose-response relationships are observed in ponderosa pine (Pinus ponderosa) saplings exposed to surface fires of increasing fire behavior (as quantified by Fire Radiative Energy&#8212;FRE). We confirmed equivalent dose-response relationships to the prior studies that were focused on other conifer species. The post-fire growth in the saplings that survived the fires decreased with increasing FRE dosages, while the percentage mortality in the sapling dosage groups increased with the amount of FRE applied. Furthermore, as with lodgepole pine (Pinus contorta), a low FRE dosage could be applied that did not yield mortality in any of the replicates (r = 10). These results suggest that land management agencies could use planned burns to reduce fire hazard while still maintaining a crop of young saplings. Incorporation of these results into earth-system models and growth and yield models could help reduce uncertainties associated with the impacts of fire on timber growth, forest resilience, carbon dynamics, and ecosystem economics
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