We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c.1061C>T ...(p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies.
Abstract The quantification of urban impervious area has important implications for the design and management of urban water and environmental infrastructure systems. This study proposes a deep ...learning model to classify 15‐cm aerial imagery of urban landscapes, coupled with a vector‐oriented post‐classification processing algorithm for automatically retrieving canopy‐covered impervious surfaces. In a case study in Corpus Christi, TX, deep learning classification covered an area of approximately 312 km 2 (or 14.86 billion 0.15‐m pixels), and the post‐classification effort led to the retrieval of over 4 km 2 (or 0.18 billion pixels) of additional impervious area. The results also suggest the underestimation of urban impervious area by existing methods that cannot consider the canopy‐covered impervious surfaces. By improving the identification and quantification of various impervious surfaces at the city scale, this study could directly benefit a variety of environmental and infrastructure management practices and enhance the reliability and accuracy of processed‐based models for urban hydrology and water infrastructure.
Abstract
Background
VRE are prevalent among patients in ICUs. Non-typeable vanA VRE, due to loss of one of the genes used for MLST (pstS), have increased in Australia, suggestive of a new, ...hospital-acquired lineage.
Objectives
To understand the significance of this lineage and its transmission using WGS of strains isolated from patients in ICUs across New South Wales, Australia.
Methods
A total of 240 Enterococcus faecium isolates collected between February and May 2016, and identified by conventional PCR as vanA positive, were sequenced. Isolates originated from 12 ICUs in New South Wales, grouped according to six local health districts, and represented both rectal screening swab (n = 229) and clinical (n = 11) isolates.
Results
ST analysis revealed the absence of the pstS gene in 84.2% (202 of 240) of vanA isolates. Two different non-typeable STs were present based on different allelic backbone patterns. Loss of the pstS gene appeared to be the result of multiple recombination events across this region. Evidence for pstS-negative lineage spread across all six local health districts was observed suggestive of inter-hospital transmission. In addition, multiple outbreaks were detected, some of which were protracted and lasted for the duration of the study.
Conclusions
These findings confirmed the evolution, emergence and dissemination of non-typeable vanA E. faecium. This study has highlighted the utility of WGS when attempting to describe accurately the hospital-based pathogen epidemiology, which in turn will continue to inform optimal infection control measures necessary to halt the spread of this important nosocomial organism.
Protein phosphorylation plays a crucial role in the signal transduction pathways that regulate gene expression, metabolism, cell adhesion, and cell survival in response to oxidative stress. In this ...study, we have used hydrogen peroxide treatment of H9C2 rat cardiomyocytes as a model of oxidative stress in heart ischemia–reperfusion injury. We show that oxidative stress induces a robust tyrosine phosphorylation of multiple proteins in this cell type. A phosphoproteomics approach using anti-phosphotyrosine affinity purification and LC–MS/MS was then used to identify the protein targets of this stress-induced phosphorylation. Twenty-three tyrosine-phosphorylated proteins were identified, with the majority known to be associated with cell–cell junctions, the actin cytoskeleton, and cell adhesion. This suggested that oxidative stress may have a profound effect on intercellular connections and the cytoskeleton to affect cell adhesion, morphology, and survival. Importantly, Src kinase was shown to be a major upstream regulator of these events. Immunofluorescence studies, fluorescence-activated cell sorting, and cell-based assays were used to demonstrate oxidative stress-induced modification of cell adhesion structures and the cytoskeleton, induced de-adhesion, and increased apoptosis, which were reversed by treatment with the Src kinase inhibitor PP1. These data demonstrate the critical role of Src kinase in oxidative stress-induced phosphorylation and cell damage in cardiomyocytes and suggest that targeting this kinase may be an effective strategy for preventing ischemia–reperfusion injury in the heart.
Epithelial ovarian cancer (EOC) is still considered the most lethal gynecological malignancy and improved early detection of ovarian cancer is crucial to improving patient prognoses. To address this ...need, we tested whether candidate EOC biomarkers can be identified using three‐dimensional (3D) in vitro models. We quantified changes in the abundance of secreted proteins in a 3D genetic model of early‐stage EOC, generated by expressing CMYC and KRASG12V in TERT‐immortalized normal ovarian epithelial cells. Cellular proteins were labeled in live cells using stable isotopic amino acid analogues, and secreted proteins identified and quantified using liquid chromatography‐tandem mass spectrometry. Thirty‐seven and 55 proteins were differentially expressed by CMYC and CMYC+KRASG12V expressing cells respectively (p < 0.05; >2‐fold). We evaluated expression of the top candidate biomarkers in ∼210 primary EOCs: CHI3L1 and FKBP4 are both expressed by >96% of primary EOCs, and FASN and API5 are expressed by 86 and 75% of cases. High expression of CHI3L1 and FKBP4 was associated with worse patient survival (p = 0.042 and p = 0.002, respectively). Expression of LGALS3BP was positively associated with recurrence (p = 0.0001) and suboptimal debulking (p = 0.018) suggesting that these proteins may be novel prognostic biomarkers. Furthermore, within early stage tumours (I/II), high expression of API5, CHI3L1 and FASN was associated with high tumour grade (p = 3 × 10−4, p = 0.016, p = 0.010, respectively). We show in vitro cell biology models of early‐stage cancer development can be used to identify novel candidate biomarkers for disease, and report the identification of proteins that represent novel potential candidate diagnostic and prognostic biomarkers for this highly lethal disease.
What's new?
Early detection of epithelial ovarian cancer (EOC) remains a substantial clinical challenge. The authors built a 3D in vitro model of early stage EOC by expressing known oncogenes in immortalized primary ovarian epithelial cells. They then quantified changes in abundance of secreted proteins using mass spectrometry at the earliest stages of neoplastic transformation. Candidate biomarkers were followed in >200 primary EOCs, and three (API5, CHI3L1, FASN) were associated with high tumor grade in early‐stage EOCs, validating the in vitro approach to in vivo biomarkers for this deadly cancer.
•Chlamydia pecorum is a common but under-recognised cause of disease in livestock.•Joint and central nervous system infections are the most economically significant.•Sub-clinical infections may also ...have major impacts on on-farm productivity.•Different strains are associated with disease versus asymptomatic colonisation.•Chlamydia serology lacks sensitivity and is difficult to interpret by clinicians.
There is a growing recognition that infections of livestock by the obligate intracellular bacterium, Chlamydia pecorum, are more widespread than was previously thought. A range of diseases have been associated with this pathogen, with the most important manifestations including infectious arthritis, infertility, enteritis, reduced growth rates, mastitis, and pneumonia. C. pecorum infections have also been associated with sub-clinical disease, highlighting our lack of knowledge about its true economic impact on livestock producers.
Diagnosis of C. pecorum infection is based on clinical findings, serology and histopathology, which are not necessarily implemented in subclinical or early stages of infection, thus potentially contributing to under-diagnosis and under-reporting of infections associated with this bacterium. Recent molecular epidemiology studies have revealed that C. pecorum is genetically diverse and that there may be an association between certain strains and disease in sheep and cattle. Antimicrobial treatment of affected animals has questionable efficacy, justifying development of chlamydia vaccines for livestock. This review summarises current knowledge of the prevalence and impact of C. pecorum infections in sheep and cattle and provides an update on attempts to improve detection, management and treatment of infections by this important obligate intracellular pathogen.
Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have ...not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.
In a large, cluster-randomized trial involving women giving vaginal birth, a multicomponent intervention lowered the risk of severe PPH, laparotomy for bleeding, or maternal death from bleeding by ...60%.
Measurement of barometric efficiency (BE) from open monitoring wells or loading efficiency (LE) from formation pore pressures provides valuable information about the hydraulic properties and ...confinement of a formation. Drained compressibility (
α
) can be calculated from LE (or BE) in confined and semi-confined formations and used to calculate specific storage (
S
s
).
S
s
and
α
are important for predicting the effects of groundwater extraction and therefore for sustainable extraction management. However, in low hydraulic conductivity (
K
) formations or large diameter monitoring wells, time lags caused by well storage may be so long that BE cannot be properly assessed in open monitoring wells in confined or unconfined settings. This study demonstrates the use of packers to reduce monitoring-well time lags and enable reliable assessments of LE. In one example from a confined, high-
K
formation, estimates of BE in the open monitoring well were in good agreement with shut-in LE estimates. In a second example, from a low-
K
confining clay layer, BE could not be adequately assessed in the open monitoring well due to time lag. Sealing the monitoring well with a packer reduced the time lag sufficiently that a reliable assessment of LE could be made from a 24-day monitoring period. The shut-in response confirmed confined conditions at the well screen and provided confidence in the assessment of hydraulic parameters. A short (time-lag-dependent) period of high-frequency shut-in monitoring can therefore enhance understanding of hydrogeological systems and potentially provide hydraulic parameters to improve conceptual/numerical groundwater models.