17 research outputs found
Finishing the euchromatic sequence of the human genome
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
Effects of Long-Term Surfing on Bone Health in Mature-Aged Males
Low mechanical loading aquatic activities such as swimming and scuba diving have identified decreased bone mineral density (BMD); however, the effects of long-term surfing on bone health remains uninvestigated. This was a cross-sectional observational study with two groups: surfers (n = 11) with 40 years surfing experience and age and gender-matched sedentary controls (n = 10). Data collected included physical activity questionnaires, biomarkers, BMD, bone mineral content and body composition. Surfers demonstrated a significantly (p < 0.05) higher mean BMD in the arms (+18.8%), trunk (+26.1%), ribs (+27.2%), spine (+39.5%), and lumbar spine (+22.8%). Surfers also exhibited a significantly (p < 0.05) higher BMC in the arms, trunk, ribs, spine and pelvis. Surfers also had a significantly higher (p = .046) lean muscle mass in their arms (+16.8%). Our results indicate long-term participation in surfing is beneficial to bone health and maybe an ideal physical activity for middle-aged aquatic enthusiasts
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The host phylogeny determines viral infectivity and replication across<i>Staphylococcus</i>host species
Genetic similarity between eukaryotic host species is an important determinant of the outcome of virus host shifts, where a pathogen infects a novel host species. However, it is less clear if this is the case for prokaryotes where anti-virus defences can be transmitted by horizontal gene transfer and evolve rapidly. Understanding the patterns and determinants of cross-species transmissions may provide insights into the processes underlying pathogen emergence. Here, we measure the susceptibility of 64 strains of Staphylococcus bacteria (48 strains of S. aureus and 16 non- aureus species) to the bacteriophage ISP, which is currently under investigation for use in phage therapy. Using three methods – plaque assays, optical density (OD) assays, and quantitative (q)PCR – we find that the host phylogeny explains a large proportion of the variation in susceptibility to ISP across the host panel. These patterns were consistent in models of only S. aureus strains and models with a single representative from each Staphylococcus species, suggesting that these phylogenetic effects are conserved both within and among host species. We find positive correlations between susceptibility assessed using a binary measure of plaque assay, OD, and qPCR, but not between the continuous component of plaque assay and any other method, suggesting that plaque assays alone may be inadequate to assess host range. Together, our results demonstrate the ability of bacterial host evolutionary relatedness to explain differences in susceptibility to phage infection, with implications for the development of ISP both as a phage therapy treatment and as an experimental system for the study of virus host shifts
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The host phylogeny determines viral infectivity and replication across Staphylococcus host species.
Funder: Medical Research Council and the Raymond and Beverly Sackler FundVirus host shifts, where a virus transmits to and infects a novel host species, are a major source of emerging infectious disease. Genetic similarity between eukaryotic host species has been shown to be an important determinant of the outcome of virus host shifts, but it is unclear if this is the case for prokaryotes where anti-virus defences can be transmitted by horizontal gene transfer and evolve rapidly. Here, we measure the susceptibility of 64 strains of Staphylococcaceae bacteria (48 strains of Staphylococcus aureus and 16 non-S. aureus species spanning 2 genera) to the bacteriophage ISP, which is currently under investigation for use in phage therapy. Using three methods-plaque assays, optical density (OD) assays, and quantitative (q)PCR-we find that the host phylogeny explains a large proportion of the variation in susceptibility to ISP across the host panel. These patterns were consistent in models of only S. aureus strains and models with a single representative from each Staphylococcaceae species, suggesting that these phylogenetic effects are conserved both within and among host species. We find positive correlations between susceptibility assessed using OD and qPCR and variable correlations between plaque assays and either OD or qPCR, suggesting that plaque assays alone may be inadequate to assess host range. Furthermore, we demonstrate that the phylogenetic relationships between bacterial hosts can generally be used to predict the susceptibility of bacterial strains to phage infection when the susceptibility of closely related hosts is known, although this approach produced large prediction errors in multiple strains where phylogeny was uninformative. Together, our results demonstrate the ability of bacterial host evolutionary relatedness to explain differences in susceptibility to phage infection, with implications for the development of ISP both as a phage therapy treatment and as an experimental system for the study of virus host shifts
The host phylogeny determines viral infectivity and replication across Staphylococcus host species.
Virus host shifts, where a virus transmits to and infects a novel host species, are a major source of emerging infectious disease. Genetic similarity between eukaryotic host species has been shown to be an important determinant of the outcome of virus host shifts, but it is unclear if this is the case for prokaryotes where anti-virus defences can be transmitted by horizontal gene transfer and evolve rapidly. Here, we measure the susceptibility of 64 strains of Staphylococcaceae bacteria (48 strains of Staphylococcus aureus and 16 non-S. aureus species spanning 2 genera) to the bacteriophage ISP, which is currently under investigation for use in phage therapy. Using three methods-plaque assays, optical density (OD) assays, and quantitative (q)PCR-we find that the host phylogeny explains a large proportion of the variation in susceptibility to ISP across the host panel. These patterns were consistent in models of only S. aureus strains and models with a single representative from each Staphylococcaceae species, suggesting that these phylogenetic effects are conserved both within and among host species. We find positive correlations between susceptibility assessed using OD and qPCR and variable correlations between plaque assays and either OD or qPCR, suggesting that plaque assays alone may be inadequate to assess host range. Furthermore, we demonstrate that the phylogenetic relationships between bacterial hosts can generally be used to predict the susceptibility of bacterial strains to phage infection when the susceptibility of closely related hosts is known, although this approach produced large prediction errors in multiple strains where phylogeny was uninformative. Together, our results demonstrate the ability of bacterial host evolutionary relatedness to explain differences in susceptibility to phage infection, with implications for the development of ISP both as a phage therapy treatment and as an experimental system for the study of virus host shifts
Identification and Characterization of Dual Inhibitors of the USP25/ 28 Deubiquitinating Enzyme Subfamily
The
ubiquitin proteasome system is widely postulated to be a new
and important field of drug discovery for the future, with the ubiquitin
specific proteases (USPs) representing one of the more attractive
target classes within the area. Many USPs have been linked to critical
axes for therapeutic intervention, and the finding that USP28 is required
for c-Myc stability suggests that USP28 inhibition may represent a
novel approach to targeting this so far undruggable oncogene. Here,
we describe the discovery of the first reported inhibitors of USP28,
which we demonstrate are able to bind to and inhibit USP28, and while
displaying a dual activity against the closest homologue USP25, these
inhibitors show a high degree of selectivity over other deubiquitinases
(DUBs). The utility of these compounds as valuable probes to investigate
and further explore cellular DUB biology is highlighted by the demonstration
of target engagement against both USP25 and USP28 in cells. Furthermore,
we demonstrate that these inhibitors are able to elicit modulation
of both the total levels and the half-life of the c-Myc oncoprotein
in cells and also induce apoptosis and loss of cell viability in a
range of cancer cell lines. We however observed a narrow therapeutic
index compared to a panel of tissue-matched normal cell lines. Thus,
it is hoped that these probes and data presented herein will further
advance our understanding of the biology and tractability of DUBs
as potential future therapeutic targets
Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells
A collaborative
high throughput screen of 1.35 million compounds
against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification
of a novel series of inhibitors. Elucidation of the bound ligand crystal
structure showed that the inhibitors exhibited a novel binding mode
in a previously identified allosteric site of IDH1 (R132H). This information
guided the optimization of the series yielding submicromolar enzyme
inhibitors with promising cellular activity. Encouragingly, one compound
from this series was found to induce myeloid differentiation in primary
human IDH1 R132H AML cells <i>in vitro</i>
Development of a Series of Pyrrolopyridone MAT2A Inhibitors
The
optimization of an allosteric fragment, discovered by differential
scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed.
The structure-based drug discovery approach, aided by relative binding
free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic
properties. This tool showed a selective antiproliferative effect
on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro
and in vivo, providing further evidence to support the utility of
MAT2a inhibitors as potential anticancer therapies for MTAP-deficient
tumors
Development of a Series of Pyrrolopyridone MAT2A Inhibitors
The
optimization of an allosteric fragment, discovered by differential
scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed.
The structure-based drug discovery approach, aided by relative binding
free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic
properties. This tool showed a selective antiproliferative effect
on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro
and in vivo, providing further evidence to support the utility of
MAT2a inhibitors as potential anticancer therapies for MTAP-deficient
tumors