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"James, Marianne"
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How money works : the facts visually explained
A guide to key financial concepts relies on bold, clear infographics to easily explain economics and finances.
Book
The NF1 Tumor Suppressor Critically Regulates TSC2 and mTOR
Loss-of-function mutations in the NF1 tumor suppressor gene underlie the familial cancer syndrome neurofibromatosis type I (NF1). The NF1-encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (RasGAP). Accordingly, deregulation of Ras is thought to contribute to NF1 development. However, the critical effector pathways involved in disease pathogenesis are still unknown. We show here that the mTOR pathway is tightly regulated by neurofibromin. mTOR is constitutively activated in both NF1-deficient primary cells and human tumors in the absence of growth factors. This aberrant activation depends on Ras and PI3 kinase, and is mediated by the phosphorylation and inactivation of the TSC2-encoded protein tuberin by AKT. Importantly, tumor cell lines derived from NF1 patients, and a genetically engineered cell system that requires Nf1-deficiency for transformation, are highly sensitive to the mTOR inhibitor rapamycin. Furthermore, while we show that the activation of endogenous Ras leads to constitutive mTOR signaling in this disease state, we also demonstrate that in normal cells Ras is differentially required for mTOR signaling in response to various growth factors. Thus, these findings identify the NF1 tumor suppressor as an indispensable regulator of TSC2 and mTOR. Furthermore, our results also demonstrate that Ras plays a critical role in the activation of mTOR in both normal and tumorigenic settings. Finally, these data suggest that rapamycin, or its derivatives, may represent a viable therapy for NF1.
Journal Article
How money works : the facts visually explained
A guide to key financial concepts relies on bold, clear infographics to easily explain economics and finances.
Book
Mediator Subunit Med28 Is Essential for Mouse Peri-Implantation Development and Pluripotency
The multi-subunit mammalian Mediator complex acts as an integrator of transcriptional regulation by RNA Polymerase II, and has emerged as a master coordinator of development and cell fate determination. We previously identified the Mediator subunit, MED28, as a cytosolic binding partner of merlin, the Neurofibromatosis 2 (NF2) tumor suppressor, and thus MED28 is distinct in having a cytosolic role as an NF2 interacting protein as well as a nuclear role as a Mediator complex subunit. Although limited in vitro studies have been performed on MED28, its in vivo function remains unknown. Employing a knockout mouse model, we describe for the first time the requirement for Med28 in the developing mouse embryo. Med28-deficiency causes peri-implantation lethality resulting from the loss of pluripotency of the inner cell mass accompanied by reduced expression of key pluripotency transcription factors Oct4 and Nanog. Further, overexpression of Med28 in mouse embryonic fibroblasts enhances the efficiency of their reprogramming to pluripotency. Cre-mediated inactivation of Med28 in induced pluripotent stem cells shows that Med28 is required for their survival. Intriguingly, heterozygous loss of Med28 results in differentiation of induced pluripotent stem cells into extraembryonic trophectoderm and primitive endoderm lineages. Our findings document the essential role of Med28 in the developing embryo as well as in acquisition and maintenance of pluripotency during reprogramming.
Journal Article
Human pluripotent stem cell modeling of alveolar type 2 cell dysfunction caused by ABCA3 mutations
Mutations in ATP-binding cassette A3 (ABCA3), a phospholipid transporter critical for surfactant homeostasis in pulmonary alveolar type II epithelial cells (AEC2s), are the most common genetic causes of childhood interstitial lung disease (chILD). Treatments for patients with pathological variants of ABCA3 mutations are limited, in part due to a lack of understanding of disease pathogenesis resulting from an inability to access primary AEC2s from affected children. Here, we report the generation of AEC2s from affected patient induced pluripotent stem cells (iPSCs) carrying homozygous versions of multiple ABCA3 mutations. We generated syngeneic CRISPR/Cas9 gene-corrected and uncorrected iPSCs and ABCA3-mutant knockin ABCA3:GFP fusion reporter lines for in vitro disease modeling. We observed an expected decreased capacity for surfactant secretion in ABCA3-mutant iPSC-derived AEC2s (iAEC2s), but we also found an unexpected epithelial-intrinsic aberrant phenotype in mutant iAEC2s, presenting as diminished progenitor potential, increased NFκB signaling, and the production of pro-inflammatory cytokines. The ABCA3:GFP fusion reporter permitted mutant-specific, quantifiable characterization of lamellar body size and ABCA3 protein trafficking, functional features that are perturbed depending on ABCA3 mutation type. Our disease model provides a platform for understanding ABCA3 mutation-mediated mechanisms of alveolar epithelial cell dysfunction that may trigger chILD pathogenesis.
Journal Article
Heterogeneity in the abundance and distribution of Ixodes ricinus and Borrelia burgdorferi (sensu lato) in Scotland: implications for risk prediction
Background
Cases of Lyme borreliosis, a vector-borne zoonosis caused by bacteria in the
Borrelia burgdorferi
(
sensu lato
) species group, have increased in recent years in Europe. Knowledge of environmental factors associated with abundance of the tick vector
Ixodes ricinus
and the pathogen
B. burgdorferi
(
s.l
.) is of interest to understand responses to environmental changes, predict variation in risk and to inform management interventions.
Methods
Nineteen woodland sites across Scotland were surveyed in 2012 for
B. burgdorferi
(
s.l.
) infection in questing
I. ricinus
nymphs (
n
= 200 per site), deer abundance and vegetation. Climatic factors were extracted for each site. Six additional sites were surveyed for questing nymphs in both 2012 and 2013 (
n
= 200 per site and year) to test for variation in
B. burgdorferi
(
s.l
.) prevalence between years.
Results
The mean prevalence of
B. burgdorferi
(
s.l
.) across 19 sites was 1.7% (95% CI: 1.4–2.2%; range 0–6%), all four genospecies known to be present in the UK were detected:
B. garinii
,
B. afzelii
,
B. burgdorferi
(
sensu stricto
) and
B. valaisiana
. A higher prevalence of
B. burgdorferi
(
s.l
.), higher densities of nymphs and higher densities of infected nymphs were found at sites with warmer climates, estimated with growing degree-days. No association between infection prevalence in nymphs and woodland type (semi-natural mixed
vs
coniferous) or deer density was found. At six sites sampled in 2012 and 2013, there was a significant increase in
B. afzelli
prevalence at two sites and a decrease in
B. garinii
prevalence at one site.
Conclusions
This study highlights challenges for the prediction of risk of Lyme borreliosis, reflecting the sensitivity of both pathogen and vector ecology to habitat, host and climatic factors. Significant changes in the prevalence of individual genospecies at sites monitored across time are likely to be due to variability in the host community composition between years. Our results indicate the importance of monitoring dynamic variables such as reservoir host populations as well as climate and habitat factors over multiple years, to identify environmental factors associated with Lyme borreliosis risk.
Journal Article
Adaptive and neutral genetic differentiation among Scottish and endangered Irish red grouse (Lagopus lagopus scotica)
Studying patterns of intra-specific genetic variation among populations allows for a better understanding of population structure and local adaptation. However, those patterns may differ according to the genetic markers applied, as neutral genetic markers reflect demographic processes and random genetic drift, whereas adaptive markers also carry the footprint of selection. In combination, neutral and adaptive genetic markers permit to assess the relative roles of drift and selection in shaping population structure. Among the best understood adaptive genetic loci are the genes of the major histocompatibility complex (MHC). We here study variation and differentiation at neutral SNP markers and MHC class II genes in red grouse (Lagopus lagopus scotica) from Ireland and Scotland. Irish red grouse populations are fragmented and drastically declining, but red grouse are abundant in Scotland. We find evidence for positive selection acting on the MHC genes and variation in MHC gene copy numbers among Irish individuals. Furthermore, there was significant population differentiation among red grouse from Ireland and Scotland at the neutral SNP markers (FST = 0.084) and the MHC-BLB genes (FST: BLB1 = 0.116, BLB2 = 0.090, BLB3 = 0.104). Differentiation at the MHC-BLB1 was significantly higher than at the neutral SNP markers, suggesting that selection plays an important role in shaping MHC variation, in addition to genetic drift. We speculate that the observed differentiation pattern might be due to local adaptation to different parasite regimes. These findings have strong conservation implications and we advise against the introduction of Scottish red grouse to supplement Irish populations.
Journal Article
SUSTAINABILITY AND INTEGRATED REPORTING: OPPORTUNITIES AND STRATEGIES FOR SMALL AND MIDSIZE COMPANIES
Sustainability, the responsible utilization and preservation of resources, represents a trend embraced by companies of all sizes. Sustainability practices include a multitude of efforts with the goal of preserving resources for future generations while satisfying current needs. Many organizations communicate their sustainability efforts to stakeholders via company websites, promotional materials, and as part of product packaging. In addition, increasingly, companies formally report their sustainability efforts to stakeholders. However, reporting typically is voluntary and the level and quality of the disclosures vary significantly among companies. To support this globally growing trend, guidelines for reporting sustainability efforts to stakeholder have been developed, with the Global Reporting Initiative (GRI) providing the most frequently utilized reporting guidelines. Companies typically report on sustainability separately from their financial results; this may change in the future. Efforts to develop a framework for reporting companies' sustainability efforts with their financial results have emerged. This is referred to as \"integrated reporting\" or the integrated \"triple bottom line,\" which stands for \"profit, people, and planet.\" Integrated reporting may provide significant benefits for small and midsize companies and may, in the long-run, enhance a company 's economic success. This study provides insights regarding the current trend toward sustainability reporting and the current status of global sustainability and integrated reporting guidelines; it also explores opportunities that arise for small and midsize entities considering adopting an integrated reporting approach, and provides strategies for successfully integrating sustainability reporting with companies' financial results. [PUBLICATION ABSTRACT]
Journal Article
PRIVATE COMPANY FINANCIAL REPORTING - STRATEGIES FOR SMALL AND MIDSIZE COMPANIES
For decades, small and midsize private companies have requested financial reporting standards that are more compatible with the needs of their financial statement users. The continually increasing complexity and volume of U.S. Generally Accepted Accounting Principles (GAAP) has led to a steadily increasing burden for those private companies that apply U.S. GAAP. With the likely implementation of International Financial Reporting Standards (IFRS) by U.S. public companies on the horizon, private company financial reporting standards finally may become a reality. This is a very significant development for the approximately 28 million private companies and especially those that are small or midsize. Standards tailored to private companies may be more relevant to financial statement users, less complex, and less costly to apply. However, managers of small and midsize companies should consider potential challenges that may arise and consider their impact in light of their company 's short-term and long-term strategic plans. This study addresses financial reporting from the perspective of private companies. The study presents information about current significant developments regarding private company financial reporting standards and explores the impact that the availability of such standards may have on private companies. The study also focuses on key strategic decisions that private companies need to consider when assessing the benefits and challenges that the use of private company standards may entail. [PUBLICATION ABSTRACT]
Journal Article
Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas
Background
Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the
NF2
locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas.
Methods
We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH).
Results
Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the
NF2
tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors.
Conclusion
Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.
Journal Article