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"Scott, Alexandra"
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The impact of structural variation on human gene expression
Ira Hall, Donald Conrad, the GTEx consortium and colleagues identify 23,602 high-confidence structural variants (SVs) and 24,884
cis
expression quantitative trait loci (eQTLs) across 13 human tissues. They estimate that SVs are the causal variant at 3.5–6.8% of eQTLs and identify 789 SVs predicted to directly alter gene expression, most of which are noncoding variants in regulatory elements.
Structural variants (SVs) are an important source of human genetic diversity, but their contribution to traits, disease and gene regulation remains unclear. We mapped
cis
expression quantitative trait loci (eQTLs) in 13 tissues via joint analysis of SVs, single-nucleotide variants (SNVs) and short insertion/deletion (indel) variants from deep whole-genome sequencing (WGS). We estimated that SVs are causal at 3.5–6.8% of eQTLs—a substantially higher fraction than prior estimates—and that expression-altering SVs have larger effect sizes than do SNVs and indels. We identified 789 putative causal SVs predicted to directly alter gene expression: most (88.3%) were noncoding variants enriched at enhancers and other regulatory elements, and 52 were linked to genome-wide association study loci. We observed a notable abundance of rare high-impact SVs associated with aberrant expression of nearby genes. These results suggest that comprehensive WGS-based SV analyses will increase the power of common- and rare-variant association studies.
Journal Article
Paranoia
\"Director Robert Luketic and screenwriters Jason Dean Hall and Barry Levy team up to adapt author Joseph Finder's novel centering on a tech-savvy twentysomething who becomes a corporate spy for a scheming businessman. Determined to make the most of his new job at Wyatt Telecom, Adam Cassidy (Liam Hemsworth) is horrified when a felonious mistake earns him the wrath of unforgiving CEO Nicholas Wyatt (Gary Oldman). Typically, Wyatt's first response would be to throw a lawbreaking employee under the bus. But this time he's willing to cut a deal: Should Adam agree to infiltrate Wyatt Telecom's chief rival, the CEO will turn a blind eye to his employee's error. In no time Adam is climbing the corporate ladder straight to the top. No one suspects a thing, and Wyatt is gaining a distinct advantage over the competition. Later, upon realizing that his success is a mere illusion and he's become a simple pawn in a much bigger game, Adam hatches an ingenious plan to get out of his situation before it's too late\"--Allmovie.com, viewed August 17, 2018.
DVD
Immortalization and characterization of Schwann cell lines derived from NF1-associated cutaneous neurofibromas
Neurofibromatosis type 1 (NF1) is an autosomal dominant condition in which patients are heterozygous for a disruptive pathogenic variant in the NF1 gene. The most characteristic feature of the condition NF1 is the neurofibroma, a benign, multi-cellular tumor which initiates when a cell of the Schwann cell lineage gains a somatic pathogenic variant of the other NF1 allele. Neurofibromas developing at nerve termini in the skin are termed “cutaneous” neurofibromas (cNFs), while those developing within larger nerves are termed “plexiform.” Most patients develop cNFs beginning in late childhood or early adulthood, continuing throughout life at variable rates. Some patients may develop only a few cNFs, while others suffer from thousands. There are no reliably effective physical or pharmaceutical therapies besides surgical removal. Although these are not life-threatening, they are disfiguring and can interfere with normal life functions. To provide a resource for research, we developed short-term cNF Schwann cell cultures from NF1 patients, from which we subsequently established the first semi-immortalized cNF cell lines through transduction with wild-type human telomerase reverse transcriptase ( hTERT ) and murine cyclin-dependent kinase 4 ( mCdk4 ) genes. Here we present molecular, cellular, and functional characterization of these cell lines, which will be of utility for investigating and developing NF1 cNF therapies.
Journal Article
Correction: Immortalization and characterization of Schwann cell lines derived from NF1-associated cutaneous neurofibromas
[This corrects the article DOI: 10.1371/journal.pone.0340183.].
Journal Article
Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study
Background
Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked
MECP2
gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT.
Methods
Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019.
Results
Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (
P
< 0.001), older age (
P
< 0.001), and mild
MECP2
variants (
P
= 0.002).
Conclusion
Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild
MECP2
variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care.
Trial registration
NCT00299312
and
NCT02738281
Journal Article
Antenatal breast expression in women with diabetes: outcomes from a retrospective cohort study
Background
Women with diabetes are sometimes advised to express breast milk antenatally to prepare for breastfeeding and to store colostrum for infant feeding in preventing or treating hypoglycaemia after the birth. The acceptability, risks and benefits of this practice have not been evaluated. This was aimed to investigate the pattern of antenatal breast expression uptake and its relationship with birth outcomes in women with diabetes.
Methods
This was part of a two year retrospective cohort study of pregnant women with diabetes (type 1, 2 and gestational diabetes) who gave birth during 2001–2003 in Derby Hospitals NHS Foundation Trust (n = 94). The information on the practice of antenatal breastfeeding expression and birth outcomes was collected via self-administered questionnaires and by examining maternity records.
Results
Thirty-seven percent of women (35/94) recalled that they were advised to express antenatally and 17% did (16/94). The mean gestational age at birth for women who hand-expressed was lower than that for those who did not (mean difference (MD) (95% confidence intervals (CI)): -1.2 (−2.4 to 0.04), p = 0.06). A higher proportion of babies from the antenatal expression group were admitted to special care baby units (SCBU) (MD (95% CI): 21% (−3.9 to 46.3).
Conclusions
Less than half the women who stated that they were advised to express, did so. There seems to be an indication that antenatal breast milk expression and lower gestational age at birth are associated. The trend of a higher rate of SCBU admission for babies from the breast milk expression group compared to those who did not express antenatally is of concern. An appropriately-powered randomised controlled trial is needed to determine the safety of this practice and its acceptability to women and health professionals before it can be recommended for implementation in practice.
Journal Article
Integrated genomic analysis of NF1-associated peripheral nerve sheath tumors: an updated biorepository dataset
Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). The Johns Hopkins NF1 biospecimen repository promotes the successful advancement of therapeutic developments for NF1-associated PNST through acquisition and genomic analysis of human tumor specimens. RNA sequencing (RNAseq) and whole exome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. This dataset combines new and previously released samples, offering a comprehensive view of the entire cohort sequenced. As a dedicated effort to systematically bank tumor samples from people with NF1, in collaboration with molecular geneticists and computational biologists, the Johns Hopkins NF1 biospecimen repository offers access to tissue samples and genomic data to promote the advancement of NF1-related tumor biologic insights and therapies.
Journal Article
Ex Vivo Characterization Studies Identify Candidate Therapies for the Individualized Care of NF2-Related Schwannomatosis
Background/Objectives: NF2-related schwannomatosis (NF2-SWN) is a genetic tumor predisposition syndrome of the nervous system caused by pathogenic variants in NF2 encoding the merlin tumor suppressor. Truncating variants in NF2 cause severe phenotypes with higher tumor burden, early mortality, and a lifetime need for multiple surgeries due to lack of medications that control schwannoma growth. Methods: We developed a functional precision medicine (FPM)-inspired workflow to identify drug sensitivities in cells isolated from a pediatric severe NF2-SWN patient’s spinal and peripheral schwannomas. Transcriptomic profiling, high-content drug sensitivity assays, tissue and isolated cell immunostaining, flow cytometry, and capillary-based immunoblotting were used to study the available tissues. Results: Aberrant merlin-dependent pathway expression was conserved between the spinal schwannoma and its cultured primary cells. Drug sensitivity screens in 2- and 3-dimensional formats revealed cytotoxic effects of fimepinostat in primary cells; dasatinib with brigatinib was the most effective cytostatic combination. Ineffective therapies attempted in the patient were also ineffective ex vivo. Conclusions: These data support the idea of using the FPM workflow to improve and individualize the standard of care for severe NF2-SWN patients using surgical samples.
Journal Article
Determining the retrofit viability of Vancouver’s single-detached homes: an expert elicitation
The reduction in energy and emissions from the building sector can come from improved standards for new construction and retrofits to existing buildings. The retrofit viability for single-detached homes in Vancouver, Canada, is examined in terms of the key drivers and barriers involving economic and social forces. Local experts considered the likelihood of retrofits occurring to several archetypal dwellings that were synthesized from local building data and homeowner characteristics. The survey results (n = 56) raised less known but potentially significant issues regarding energy-efficiency retrofits in Vancouver. Domestic fuel switching, from fossil fuel energy services to electricity, is likely the most desirable future mechanism for decarbonizing homes. However, many of the respondents identified that Vancouver’s real estate market has a significant negative influence on retrofitting due to high land values, which results in a high demolition rate of existing homes. Only 46% of responses returned a view that an existing home would remain standing by 2050. In addition, 41% of responses expressed a doubt that the dwelling, whether existing or new, would achieve carbon neutrality by 2050. Both issues confront the City of Vancouver’s current emissions reduction planning, which has targeted near-complete decarbonization of the residential building stock by 2050.Policy relevanceNew construction is expected to account for only 30% of the greenhouse gas emissions reduction in Vancouver’s building sector. The potential for deep retrofits of single detached houses appear to be unlikely due to current real estate market conditions involving several perceived disincentives, e.g. low financial payback, poor knowledge, transaction costs, and the opportunity cost of new construction. If the widespread retrofit of single detached houses is a goal for cities that have high land-to-building value ratios, then the alteration of current market conditions is necessary. A basket of coordinated policy measures can be deployed to counter current market forces and reduce the demolition of existing homes. Such measures could include retrofit and planning codes, energy labelling, innovative finance, and public education.
Journal Article