39 research outputs found
Outcomes following oesophagectomy in patients with oesophageal cancer: a secondary analysis of the ICNARC Case Mix Programme Database
Get PDFIntroduction: This report describes the case mix and outcomes of patients with oesophageal cancer admitted to adult critical care units following elective oesophageal surgery in England, Wales and Northern Ireland.
Methods: Admissions to critical care following elective oesophageal surgery for malignancy were identified using data from the Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme Database. Information on admissions between December 1995 and September 2007 were extracted and the association between in-hospital mortality and patient characteristics on admission to critical care was assessed using multiple logistic regression analysis. The performance of three prognostic models (Simplified Acute Physiology Score (SAPS) II, Acute Physiology and Chronic Health Evaluation (APACHE) II and the ICNARC physiology score) was also evaluated.
Results: Between 1995 and 2007, there were 7227 admissions to 181 critical care units following oesophageal surgery for malignancy. Overall mortality in critical care was 4.4% and in-hospital mortality was 11%, although both declined steadily over time. Eight hundred and seventy-three (12.2%) patients were readmitted to critical care, most commonly for respiratory complications (49%) and surgical complications (25%). Readmitted patients had a critical care unit mortality of 24.7% and in-hospital mortality of 33.9%. Overall in-hospital mortality was associated with patient age, and various physiological measurements on admission to critical care (partial pressure of arterial oxygen (PaO2):fraction of inspired oxygen (FiO2) ratio, lowest arterial pH, mechanical ventilation, serum albumin, urea and creatinine). The three prognostic models evaluated performed poorly in measures of discrimination, calibration and goodness of fit.
Conclusions: Surgery for oesophageal malignancy continues to be associated with significant morbidity and mortality. Age and organ dysfunction in the early postoperative period are associated with an increased risk of death. Postoperative serum albumin is confirmed as an additional prognostic factor. More work is required to determine how this knowledge may improve clinical management
An evolutionary ratchet leading to loss of elongation factors in eukaryotes
Get PDFBackground
The GTPase eEF1A is the eukaryotic factor responsible for the essential, universal function of aminoacyl-tRNA delivery to the ribosome. Surprisingly, eEF1A is not universally present in eukaryotes, being replaced by the paralog EFL independently in multiple lineages. The driving force behind this unusually frequent replacement is poorly understood.
Results
Through sequence searching of genomic and EST databases, we find a striking association of eEF1A replacement by EFL and loss of eEF1A’s guanine exchange factor, eEF1Bα, suggesting that EFL is able to spontaneously recharge with GTP. Sequence conservation and homology modeling analyses indicate several sequence regions that may be responsible for EFL’s lack of requirement for eEF1Bα.
Conclusions
We propose that the unusual pattern of eEF1A, eEF1Bα and EFL presence and absence can be explained by a ratchet-like process: if either eEF1A or eEF1Bα diverges beyond functionality in the presence of EFL, the system is unable to return to the ancestral, eEF1A:eEFBα-driven state
A framework to identify epigenome and transcription factor crosstalk
Get PDFWhile changes in chromatin are integral to transcriptional reprogramming during cellular differentiation, it is currently unclear how chromatin modifications are targeted to specific loci. To systematically identify transcription factors (TFs) that can direct chromatin changes during cell fate decisions, we model the genome-wide dynamics of chromatin marks in terms of computationally predicted TF binding sites. By applying this computational approach to a time course of Polycomb-mediated H3K27me3 marks during neuronal differentiation of murine stem cells, we identify several motifs that likely regulate dynamics of this chromatin mark. Among these, the motifs bound by REST and by the SNAIL family of TFs are predicted to transiently recruit H3K27me3 in neuronal progenitors. We validate these predictions experimentally and show that absence of REST indeed causes loss of H3K27me3 at target promoters in trans, specifically at the neuronal progenitor state. Moreover, using targeted transgenic insertion, we show that promoter fragments containing REST or SNAIL binding sites are sufficient to recruit H3K27me3 in cis, while deletion of these sites results in loss of H3K27me3. These findings illustrate that the occurrence of TF binding sites can determine chromatin dynamics. Local determination of Polycomb activity by Rest and Snail motifs exemplifies such TF based regulation of chromatin. Furthermore, our results show that key TFs can be identified ab initio through computational modeling of epigenome datasets using a modeling approach that we make readily accessible
The small-subunit processome is a ribosome assembly intermediate
Get PDFThe small-subunit (SSU) processome is a large ribonucleoprotein required for the biogenesis of the 18S rRNA and likely corresponds to the terminal knobs visualized by electron microscopy on the 5' end of nascent rRNAs. The original purification of the SSU processome of Saccharomyces cerevisiae resulted in the identification of 28 proteins. Here, we characterize 12 additional protein components, including five small-ribosomal-subunit proteins (Rps4, Rps6, Rps7, Rps9, and Rps14) that had previously been copurified. Our multiple criteria for including a component as a bona fide SSU processome component included coimmunoprecipitation with Mpp10 (an SSU processome component), the U3 snoRNA, and the anticipated pre-rRNAs. Importantly, the association of specific ribosomal proteins with the SSU processome suggests that the SSU processome has roles in both pre-rRNA processing and ribosome assembly. These ribosomal proteins may be analogous to the primary or secondary RNA binding proteins first described in bacterial in vitro ribosome assembly maps. In addition to the ribosomal proteins and based on the same experimental approach, we found seven other proteins (Utp18, Noc4, Utp20, Utp21, Utp22, Emg1, and Krr1) to be bona fide SSU processome proteins
Growth Oriented Macroeconomic Policies for Small Islands Economies: Lessons from Singapore
Get PDFMost small island economies or ?microstates? have distinctly different characteristics from larger developing economies. They are more open and vulnerable to external and environmental shocks, resulting in high output volatility. Most of them also suffer from locational disadvantages. Although a few small island economies have succeeded in generating sustained rapid growth and reducing poverty, most have dismal growth performance, resulting in high unemployment and poverty. Although macroeconomic policies play an important role in growth and poverty reduction, there has been very little work on the issue for small island economies or microstates. Most work follows the conventional framework and finds no or very little effectiveness of macroeconomic policies in stabilization. They also concentrate on short-run macroeconomic management with a focus almost entirely on either price stability or external balance. The presumption is that price stability and external balance are prerequisite for sustained rapid growth. This paper aims to provide a critical survey of the extant literature on macroeconomic policies for small island economies in light of the available evidence on their growth performance. Given the high output volatility and its impact on poverty, this paper will argue for a balance between price and output stabilization goals of macroeconomic policy mix. Drawing on the highly successful experience of Singapore, it will also outline a framework for growth promoting, pro-poor macroeconomic policies for small island economies/microstates.Caribbean, Pacific Islands, fiscal policy, small open economies
QoS in Node-disjoint Routing for Ad Hoc Networks
No full textPhDA mobile ad hoc network (MANET) is a collection of mobile nodes that
can communicate with each other without using any fixed infrastructure.
It is necessary for MANETs to have efficient routing protocol and quality
of service (QoS) mechanism to support multimedia applications such as
video and voice.
Node-Disjoint Multipath Routing Protocol (NDMR) is a practical protocol
in MANETs: it reduces routing overhead dramatically and achieves
multiple node-disjoint routing paths.
Because QoS support in MANETs is important as best-effort routing is
not efficient for supporting multimedia applications, this thesis presents a
novel approach to provide that support.
In this thesis NDMR is enhanced to provide a QoS enabled NDMR that
decreases the transmission delay between source and destination nodes.
A multi-rate mechanism is also implemented in the new protocol so that
the NDMR QoS can minimise the overall delays. It is shown that these
approaches lead to significant performance gains. A modification to
NDMR is also proposed to overcome some of the limitations of the
original
The HY5-PIF regulatory module coordinates light and temperature control of photosynthetic gene transcription
Get PDFThe ability to interpret daily and seasonal alterations in light and temperature signals is essential for plant survival. This is particularly important during seedling establishment when the phytochrome photoreceptors activate photosynthetic pigment production for photoautotrophic growth. Phytochromes accomplish this partly through the suppression of PHYTOCHROME INTERACTING FACTORS (PIFs), negative regulators of chlorophyll and carotenoid biosynthesis. While the bZIP transcription factor LONG HYPOCOTYL 5 (HY5), a potent PIF antagonist, promotes photosynthetic pigment accumulation in response to light. Here we demonstrate that by directly targeting a common promoter cis-element (G-box), HY5 and PIFs form a dynamic activation-suppression transcriptional module responsive to light and temperature cues. This antagonistic regulatory module provides a simple, direct mechanism through which environmental change can redirect transcriptional control of genes required for photosynthesis and photoprotection. In the regulation of photopigment biosynthesis genes, HY5 and PIFs do not operate alone, but with the circadian clock. However, sudden changes in light or temperature conditions can trigger changes in HY5 and PIFs abundance that adjust the expression of common target genes to optimise photosynthetic performance and growth.</p
Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer
Get PDFIntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years
Intellectual property laws and Islam in Malaysia.
No full textPhDThis study is undertaken on the premise that Islam and Islamic law is to be taken into
serious consideration in any future legislative reform of laws in Malaysia. Islam being
the religion of the country and the strong religious sentiment of the Muslims (who
form the majority in Malaysia) cannot be overlooked or dismissed lightly by the
legislators in Malaysia. Reformation of intellectual property laws is timely, as we are
now approaching to the dateline set by GATF-Trips agreement which aim is to
improve our standard of intellectual property protection. This study seeks to analyze
and evaluate the current legislation pertaining to intellectual property in Malaysia in
terms of the philosophy and rules governing the existence, ownership and exercise of
these rights and their consistency and inconsistency with Islam and Islamic law. The
main objective of this study is to prove that a coherent and logical conceptual
framework of ownership of intellectual property can be derived from an Islamic
perspective which not only offers the basis of rights but also defines the scope of
these rights. From the point of ownership of rights, support can be obtained from the
normative framework of property rights within the traditional classification of 'mal'
(property) and 'haqq al-milkiyyah' (ownership rights) under Islamic law. From the
point of exercise of rights, the exact scope can be defined from the analysis of
fundamental concepts which have been developed by Muslim jurists. It has been
established that Islam and Islamic law offers a sound and systematic paradigm, which
in deeper analysis, can satisfy both our current obligations under international
treatises, as well as our responsibility to practise our religion to the fullest
Validation of extracorporeal membrane oxygenation mortality prediction and severity of illness scores in an international COVID-19 cohort
No full textBackground: Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is a lifesaving support modality for severe respiratory failure, but its resource-intensive nature led to significant controversy surrounding its use during the COVID-19 pandemic. We report the performance of several ECMO mortality prediction and severity of illness scores at discriminating survival in a large COVID-19 V-V ECMO cohort. Methods: We validated ECMOnet, PRESET (PREdiction of Survival on ECMO Therapy-Score), Roch, SOFA (Sequential Organ Failure Assessment), APACHE II (acute physiology and chronic health evaluation), 4C (Coronavirus Clinical Characterisation Consortium), and CURB-65 (Confusion, Urea nitrogen, Respiratory Rate, Blood Pressure, age >65 years) scores on the ISARIC (International Severe Acute Respiratory and emerging Infection Consortium) database. We report discrimination via Area Under the Receiver Operative Curve (AUROC) and Area under the Precision Recall Curve (AURPC) and calibration via Brier score. Results: We included 1147 patients and scores were calculated on patients with sufficient variables. ECMO mortality scores had AUROC (0.58–0.62), AUPRC (0.62–0.74), and Brier score (0.286–0.303). Roch score had the highest accuracy (AUROC 0.62), precision (AUPRC 0.74) yet worst calibration (Brier score of 0.3) despite being calculated on the fewest patients (144). Severity of illness scores had AUROC (0.52–0.57), AURPC (0.59–0.64), and Brier Score (0.265–0.471). APACHE II had the highest accuracy (AUROC 0.58), precision (AUPRC 0.64), and best calibration (Brier score 0.26). Conclusion: Within a large international multicenter COVID-19 cohort, the evaluated ECMO mortality prediction and severity of illness scores demonstrated inconsistent discrimination and calibration highlighting the need for better clinically applicable decision support tools
