40 research outputs found

    Quantifying Drug-Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model.

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    Haematological toxicity associated with cancer therapeutics is monitored by changes in blood cell count, and their primary effect is on proliferative progenitors in the bone marrow. Using observations in rat bone marrow and blood, we characterize a mathematical model that comprises cell proliferation and differentiation of the full haematopoietic phylogeny, with interacting feedback loops between lineages in homeostasis as well as following carboplatin exposure. We accurately predicted the temporal dynamics of several mature cell types related to carboplatin-induced bone marrow toxicity and identified novel insights into haematopoiesis. Our model confirms a significant degree of plasticity within bone marrow cells, with the number and type of both early progenitors and circulating cells affecting cell balance, via feedback mechanisms, through fate decisions of the multipotent progenitors. We also demonstrated cross-species translation of our predictions to patients, applying the same core model structure and considering differences in drug-dependent and physiology-dependent parameters

    Impact Factor: outdated artefact or stepping-stone to journal certification?

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    A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

    Mental disorders as risk factors: assessing the evidence for the Global Burden of Disease Study

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    Background: Mental disorders are associated with a considerable burden of disease as well as being risk factors for other health outcomes. The new Global Burden of Disease (GBD) Study will make estimates for both the disability and mortality directly associated with mental disorders, as well as the burden attributable to other health outcomes. Herein we discuss the process by which health outcomes in which mental disorders are risk factors are selected for inclusion in the GBD Study. We make suggestions for future research to strengthen the body of evidence for mental disorders as risk factors

    The scale, governance, and sustainability of central places in pre-Hispanic Mesoamerica

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    Examinations of the variation and relative successes or failures of past large-scale societies have long involved attempts to reconcile efforts at generalization and the identification of specific factors with explanatory value for regional trajectories. Although historical particulars are critical to understanding individual cases, there are both scholarly and policy rationales for drawing broader implications regarding the growing corpus of cross-cultural data germane to understanding variability in the constitution of human societies, past and present. Archaeologists have recently highlighted how successes and failures in communal-resource management can be studied over the long term through the material record to both engage and enhance transdisciplinary research on cooperation and collective action. In this article we consider frameworks that have been traditionally employed in studies of the rise, diversity, and fall of preindustrial urban aggregations. We suggest that a comparative theoretical perspective that foregrounds collective-action problems, unaligned individual and group interests, and the social mechanisms that promote or hamper cooperation advances our understanding of variability in these early cooperative arrangements. We apply such a perspective to an examination of pre-Hispanic Mesoamerican urban centers to demonstrate tendencies for more collective systems to be larger and longer lasting than less collective ones, likely reflecting greater sustainability in the face of the ecological and cultural perturbations specific to the region and era.Accepted manuscrip

    Mitochondrial physiology

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    As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

    Stroke genetics informs drug discovery and risk prediction across ancestries

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    Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

    Of mice and men: molecular genetics of congenital heart disease

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