utilizing-functional-genomics-screening-to-identify-potentially-novel

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures

The identification of functional driver events in cancer is central to furthering our understanding of cancer biology and indispensable for the discovery ...

The Institute of Cancer Research

Bulk chondritic meteorites and terrestrial planets show a monotonic depletion in moderately volatile and volatile elements relative to the Sun's photosphere and CI carbonaceous chondrites. Although volatile depletion was the most fundamental chemical process affecting the inner solar nebula, debate continues as to its cause. Carbonaceous chondrites are the most primitive rocks available to us, and fine-grained, volatile-rich matrix is the most primitive component in these rocks. Several volatile depletion models posit a pristine matrix, with uniform CI-like chemistry across the different chondrite groups. To understand the nature of volatile fractionation, we studied minor and trace element abundances in fine-grained matrices of a variety of carbonaceous chondrites. We find that matrix trace element abundances are characteristic for a given chondrite group; they are depleted relative to CI chondrites, but are enriched relative to bulk compositions of their parent meteorites, particularly in volatile siderophile and chalcophile elements. This enrichment produces a highly nonmonotonic trace element pattern that requires a complementary depletion in chondrule compositions to achieve a monotonic bulk. We infer that carbonaceous chondrite matrices are not pristine: they formed from a material reservoir that was already depleted in volatile and moderately volatile elements. Additional thermal processing occurred during chondrule formation, with exchange of volatile siderophile and chalcophile elements between chondrules and matrix. This chemical complementarity shows that these chondritic components formed in the same nebula region.

Volatile fractionation in the early solar system and chondrule/matrix complementarity.

Recent data, and modelling of the interaction between asteroids and the atmosphere, has defined a complete size-frequency distribution for terrestrial impactors, from meteorite-sized objects up to kilometre-sized asteroids, for both the upper atmosphere and the Earth's surface. Although there remain significant uncertainties in the incidence of specific size-fractions of impactors, these estimates allow us to constrain the threat posed by impacts to human populations. It is clear that impacts remain a significant natural hazard, but uniquely, they are a threat that we can accurately predict, and take steps to avoid.

The impact rate on Earth.

Commonly viewed solely as agents of destruction, asteroid and comet impact events can also have a beneficial influence on processes from the molecular to the evolutionary scale. On the heavily bombarded early Earth, impacts might have delivered and caused the synthesis of prebiotic compounds that eventually led to life. At the organismal and ecosystem level, impact events can provide new habitats through the shock processing of target materials and by enhancing water availability, such as within intracrater lakes. At the evolutionary level, by destroying entire groups of organisms, impacts might have been instrumental in enabling the rise of new groups, such as the dinosaurs and mammals. Here, we synthesize the emerging literature on the beneficial effects of impacts to provide a novel perspective on these extraterrestrial agents of biological change.

The evolutionary and ecological benefits of asteroid and comet impacts.

Astronomy. Small-scale observations tell a cosmological story.

Triangulated observations of fireballs allow us to determine orbits and fall positions for meteorites. The great majority of basaltic meteorites are derived from the asteroid 4 Vesta. We report on a recent fall that has orbital properties and an oxygen isotope composition that suggest a distinct parent body. Although its orbit was almost entirely contained within Earth's orbit, modeling indicates that it originated from the innermost main belt. Because the meteorite parent body would likely be classified as a V-type asteroid, V-type precursors for basaltic meteorites unrelated to Vesta may reside in the inner main belt. This starting location is in agreement with predictions of a planetesimal evolution model that postulates the formation of differentiated asteroids in the terrestrial planet region, with surviving fragments concentrated in the innermost main belt.

An anomalous basaltic meteorite from the innermost main belt.

Group CBT is a cost-effective option for persistent back pain.

Autosomal-recessive exfoliative ichthyosis presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of nonerythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Using whole-genome homozygosity mapping, candidate-gene analysis and deep sequencing, we have identified loss-of-function mutations in the gene for protease inhibitor cystatin A (CSTA) as the underlying genetic cause of exfoliative ichthyosis. We found two homozygous mutations, a splice-site and a nonsense mutation, in two consanguineous families of Bedouin and Turkish origin. Electron microscopy of skin biopsies from affected individuals revealed that the level of detachment occurs in the basal and lower suprabasal layers. In addition, in vitro modeling suggests that in the absence of cystatin A protein, there is a cell-cell adhesion defect in human keratinocytes that is particularly prominent when cells are subject to mechanical stress. We show here evidence of a key role for a protease inhibitor in epidermal adhesion within the lower layers of the human epidermis.

Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion.

Targeted sequence capture and high-throughput sequencing in the molecular diagnosis of ichthyosis and other skin diseases.

Harequin ichthyosis is a severe autosomal recessive ichthyosis of congenital onset caused by biallelic mutations in the ABCA12 gene. We report two neonates of Indian origin with harlequin ichthyosis. The parents were retrospectively found to have novel mutations in ABCA12 gene after neonatal demise, which helped in providing prenatal diagnosis in subsequent pregnancies.

Article	Year
Volatile fractionation in the early solar system and chondrule/matrix complementarity. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 16174733	2005
The impact rate on Earth. Philosophical transactions. Series A, Mathematical, physical, and engineering sciences\| PubMed ID: 16286291	2005
The evolutionary and ecological benefits of asteroid and comet impacts. Trends in ecology & evolution\| PubMed ID: 16701365	2005
Astronomy. Small-scale observations tell a cosmological story. Science (New York, N.Y.)\| PubMed ID: 18388282	2008
An anomalous basaltic meteorite from the innermost main belt. Science (New York, N.Y.)\| PubMed ID: 19762639	2009
Group CBT is a cost-effective option for persistent back pain. The Practitioner\| PubMed ID: 20486479	2010
Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion. American journal of human genetics\| PubMed ID: 21944047	2011
Targeted sequence capture and high-throughput sequencing in the molecular diagnosis of ichthyosis and other skin diseases. The Journal of investigative dermatology\| PubMed ID: 22992804	2013
Novel ABCA12 mutations in harlequin ichthyosis: a journey from photo diagnosis to prenatal diagnosis. Gene\| PubMed ID: 25479012	2015

Philip Bland

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