SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1 cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction.

3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model -like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC.

A mouse SWATH-mass spectrometry reference spectral library enables deconvolution of species-specific proteomic alterations in human tumour xenografts.

SWATH-mass spectrometry (MS) enables accurate and reproducible proteomic profiling in multiple model organisms including the mouse. Here, we present a comprehensive mouse reference spectral library (MouseRefSWATH) that permits quantification of up to 10,597 proteins (62.2% of the mouse proteome) by SWATH-MS.

regulates cell state and activity of embryonic mouse mammary progenitor cells.

Embryonic mammary cells are a unique population comprised of undifferentiated, highly plastic progenitor cells that create normal mammary tissues. The mammary gland continues to develop after birth from descendants of embryonic mammary cells. Here, we establish cell lines from mouse mammary organs, immediately after they formed during prenatal development, to facilitate studies of primitive mammary cells, which are difficult to isolate in sufficient quantities for use in functional experiments.

SWATH mass spectrometry as a tool for quantitative profiling of the matrisome.

Proteomic analysis of extracellular matrix (ECM) and ECM-associated proteins, collectively known as the matrisome, is a challenging task due to the inherent complexity and insolubility of these proteins. Here we present sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH MS) as a tool for the quantitative analysis of matrisomal proteins in both non-enriched and ECM enriched tissue without the need for prior fractionation. Utilising a spectral library containing 201 matrisomal proteins, we compared the performance and reproducibility of SWATH MS over conventional data-dependent analysis mass spectrometry (DDA MS) in unfractionated murine lung and liver.

Corrigendum: Probing the early stages of shock-induced chondritic meteorite formation at the mesoscale.

This corrects the article DOI: 10.1038/srep45206.

Giant convecting mud balls of the early solar system.

Carbonaceous asteroids may have been the precursors to the terrestrial planets, yet despite their importance, numerous attempts to model their early solar system geological history have not converged on a solution. The assumption has been that hydrothermal alteration was occurring in rocky asteroids with material properties similar to meteorites. However, these bodies would have accreted as a high-porosity aggregate of igneous clasts (chondrules) and fine-grained primordial dust, with ice filling much of the pore space.

SOX11 promotes invasive growth and ductal carcinoma in situ progression.

Here, we show that SOX11, an embryonic mammary marker that is normally silent in postnatal breast cells, is expressed in many oestrogen receptor-negative preinvasive ductal carcinoma in situ (DCIS) lesions. Mature mammary epithelial cells engineered to express SOX11 showed alterations in progenitor cell populations, including an expanded basal-like population with increased aldehyde dehydrogenase (ALDH) activity, and increased mammosphere-forming capacity. DCIS.

Probing the early stages of shock-induced chondritic meteorite formation at the mesoscale.

Chondritic meteorites are fragments of asteroids, the building blocks of planets, that retain a record of primordial processes. Important in their early evolution was impact-driven lithification, where a porous mixture of millimetre-scale chondrule inclusions and sub-micrometre dust was compacted into rock. In this Article, the shock compression of analogue precursor chondrite material was probed using state of the art dynamic X-ray radiography.

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 of the next generation of novel drug targets. It is becoming apparent that more complex models of cancer are required to fully appreciate the contributing factors that drive tumorigenesis in vivo and increase the efficacy of novel therapies that make the transition from pre-clinical models to clinical trials. Here we present a methodology for generating uniform and reproducible tumor spheroids that can be subjected to siRNA functional screening.

Novel ABCA12 mutations in harlequin ichthyosis: a journey from photo diagnosis to prenatal diagnosis.

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.

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

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.

An anomalous basaltic meteorite from the innermost main belt.

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.

The evolutionary and ecological benefits of asteroid and comet impacts.

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.

The impact rate on Earth.

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.

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

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.