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Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing
Although single base‐pair substitutions in splice junctions constitute at least 10% of all mutations causing human inherited disease, the factors that determine their phenotypic consequences at the RNA level remain to be fully elucidated. Employing a neural network for splice‐site recognition, we performed a meta‐analysis of 478 disease‐associated splicing mutations, in 38 different genes, for which detailed laboratory‐based mRNA phenotype assessment had been performed. Inspection of the ±50‐bp DNA sequence context of the mutations revealed that exon skipping was the preferred phenotype when the immediate vicinity of the affected exon–intron junctions was devoid of alternative splice‐sites. By contrast, in the presence of at least one such motif, cryptic splice‐site utilization, became more prevalent. This association was, however, confined to donor splice‐sites. Outside the obligate dinucleotide, the spatial distribution of pathological mutations was found to differ significantly from that of SNPs. Whereas disease‐associated lesions clustered at positions –1 and +3 to +6 for donor sites and –3 for acceptor sites, SNPs were found to be almost evenly distributed over all sequence positions considered. When all putative missense mutations in the vicinity of splice‐sites were extracted from the Human Gene Mutation Database for the 38 studied genes, a significantly higher proportion of changes at donor sites (37/152; 24.3%) than at acceptor splice‐sites (1/142; 0.7%) was found to reduce the neural network signal emitted by the respective splice‐site. Based upon these findings, we estimate that some 1.6% of disease‐causing missense substitutions in human genes are likely to affect the mRNA splicing phenotype. Taken together, our results are consistent with correct donor splice‐site recognition being a key step in exon recognition. Hum Mutat 28(2), 150–158, 2007. © 2006 Wiley‐Liss, Inc.
Journal Article
DMSO Efficiently Down Regulates Pluripotency Genes in Human Embryonic Stem Cells during Definitive Endoderm Derivation and Increases the Proficiency of Hepatic Differentiation
Definitive endoderm (DE) is one of the three germ layers which during in vivo vertebrate development gives rise to a variety of organs including liver, lungs, thyroid and pancreas; consequently efficient in vitro initiation of stem cell differentiation to DE cells is a prerequisite for successful cellular specification to subsequent DE-derived cell types [1, 2]. In this study we present a novel approach to rapidly and efficiently down regulate pluripotency genes during initiation of differentiation to DE cells by addition of dimethyl sulfoxide (DMSO) to Activin A-based culture medium and report its effects on the downstream differentiation to hepatocyte-like cells.
Human embryonic stem cells (hESC) were differentiated to DE using standard methods in medium supplemented with 100ng/ml of Activin A and compared to cultures where DE specification was additionally enhanced with different concentrations of DMSO. DE cells were subsequently primed to generate hepatic-like cells to investigate whether the addition of DMSO during formation of DE improved subsequent expression of hepatic markers. A combination of flow cytometry, real-time quantitative reverse PCR and immunofluorescence was applied throughout the differentiation process to monitor expression of pluripotency (POUF5/OCT4 & NANOG), definitive endoderm (SOX17, CXCR4 & GATA4) and hepatic (AFP & ALB) genes to generate differentiation stage-specific signatures.
Addition of DMSO to the Activin A-based medium during DE specification resulted in rapid down regulation of the pluripotency genes OCT4 and NANOG, accompanied by an increase expression of the DE genes SOX17, CXCR4 and GATA4. Importantly, the expression level of ALB in DMSO-treated cells was also higher than in cells which were differentiated to the DE stage via standard Activin A treatment.
Journal Article
Lack of Correlation Between Immunohistochemical Expression of SPARC and Invasion in Different Grades of Meningiomas
Background: Grade I meningiomas are generally benign and non-invasive whereas Grade II (atypical) and Grade III (malignant) meningiomas tend to be invasive with a high risk of recurrence. SPARC, secreted protein, acidic and rich in cysteine, is a multifunctional glycoprotein which has been proposed to be a potential diagnostic marker of invasive meningiomas. There has been increased reporting of atypical meningiomas since the current World Health Organization (WHO) included brain invasion as a grading criterion for classification of these particular meningiomas. Materials and Methods: The aim of this study was to re-evaluate any correlation between immunohistochemical expression of SPARC in 34 meningiomas of various grades using the current classification (2016). We had previously classified these cases using the 2002 WHO criteria. Results: There is no correlation between expression of SPARC and invasion in different grades of meningioma. Conclusion: SPARC does not appear to be a good predictor of invasion in meningiomas.
Journal Article
Wolverine and the X-Men. Volume 7
\"Welcome to Hellfire Academy, where there's little chance you'll survive the experience! The most villainous school you've ever seen has its grand opening as a furious Wolverine and Rachel Summers intensify their search for missing Jean Grey School students Glob Herma, Idie, Broo and Quentin Quire. With teachers like Mystique, Sauron, Mondo, Wendigo and Master Pandemonium, there's no limit to the terrible things the kidnapped students can learn. Can Wolverine and the X-Men find them before they're turned into villains? Wolverine corrals the Bamfs into his plans--and the X-Men discover that Krakoa, the island that walks like a man, can fight like one too! And the landscape of the Jean Grey School is redefined when Wolverine and the X-Men face Mystique, Sabretooth and the Hellfire Club!\"--Cover.
BOOK
Human Gene Mutation Database (HGMD®): 2003 update
The Human Gene Mutation Database (HGMD) constitutes a comprehensive core collection of data on germ‐line mutations in nuclear genes underlying or associated with human inherited disease (www.hgmd.org). Data catalogued includes: single base‐pair substitutions in coding, regulatory and splicing‐relevant regions; micro‐deletions and micro‐insertions; indels; triplet repeat expansions as well as gross deletions; insertions; duplications; and complex rearrangements. Each mutation is entered into HGMD only once in order to avoid confusion between recurrent and identical‐by‐descent lesions. By March 2003, the database contained in excess of 39,415 different lesions detected in 1,516 different nuclear genes, with new entries currently accumulating at a rate exceeding 5,000 per annum. Since its inception, HGMD has been expanded to include cDNA reference sequences for more than 87% of listed genes, splice junction sequences, disease‐associated and functional polymorphisms, as well as links to data present in publicly available online locus‐specific mutation databases. Although HGMD has recently entered into a licensing agreement with Celera Genomics (Rockville, MD), mutation data will continue to be made freely available via the Internet. Hum Mutat 21:577–581, 2003. © 2003 Wiley‐Liss, Inc.
Journal Article
Hospital bed capacity and usage across secondary healthcare providers in England during the first wave of the COVID-19 pandemic: a descriptive analysis
ObjectiveIn this study, we describe the pattern of bed occupancy across England during the peak of the first wave of the COVID-19 pandemic.DesignDescriptive survey.SettingAll non-specialist secondary care providers in England from 27 March27to 5 June 2020.ParticipantsAcute (non-specialist) trusts with a type 1 (ie, 24 hours/day, consultant-led) accident and emergency department (n=125), Nightingale (field) hospitals (n=7) and independent sector secondary care providers (n=195).Main outcome measuresTwo thresholds for ‘safe occupancy’ were used: 85% as per the Royal College of Emergency Medicine and 92% as per NHS Improvement.ResultsAt peak availability, there were 2711 additional beds compatible with mechanical ventilation across England, reflecting a 53% increase in capacity, and occupancy never exceeded 62%. A consequence of the repurposing of beds meant that at the trough there were 8.7% (8508) fewer general and acute beds across England, but occupancy never exceeded 72%. The closest to full occupancy of general and acute bed (surge) capacity that any trust in England reached was 99.8% . For beds compatible with mechanical ventilation there were 326 trust-days (3.7%) spent above 85% of surge capacity and 154 trust-days (1.8%) spent above 92%. 23 trusts spent a cumulative 81 days at 100% saturation of their surge ventilator bed capacity (median number of days per trust=1, range: 1–17). However, only three sustainability and transformation partnerships (aggregates of geographically co-located trusts) reached 100% saturation of their mechanical ventilation beds.ConclusionsThroughout the first wave of the pandemic, an adequate supply of all bed types existed at a national level. However, due to an unequal distribution of bed utilisation, many trusts spent a significant period operating above ‘safe-occupancy’ thresholds despite substantial capacity in geographically co-located trusts, a key operational issue to address in preparing for future waves.
Journal Article