117 research outputs found
Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation
Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation
Variation in helper effort among cooperatively breeding bird species is consistent with Hamilton's Rule.
Investment by helpers in cooperative breeding systems is extremely variable among species, but this variation is currently unexplained. Inclusive fitness theory predicts that, all else being equal, cooperative investment should correlate positively with the relatedness of helpers to the recipients of their care. We test this prediction in a comparative analysis of helper investment in 36 cooperatively breeding bird species. We show that species-specific helper contributions to cooperative brood care increase as the mean relatedness between helpers and recipients increases. Helper contributions are also related to the sex ratio of helpers, but neither group size nor the proportion of nests with helpers influence helper effort. Our findings support the hypothesis that variation in helping behaviour among cooperatively breeding birds is consistent with Hamilton's rule, indicating a key role for kin selection in the evolution of cooperative investment in social birds
The Role of Imported Cases and Favorable Meteorological Conditions in the Onset of Dengue Epidemics
Dengue/dengue hemorrhagic fever is the world's most widely spread mosquito-borne arboviral disease and threatens more than two-thirds of the world's population. Cases are mainly distributed in tropical and subtropical areas in accordance with vector habitats for Aedes aegypti and Ae. albopictus. However, the role of imported cases and favorable meteorological conditions has not yet been quantitatively assessed. This study verified the correlation between the occurrence of indigenous dengue and imported cases in the context of weather variables (temperature, rainfall, relative humidity, etc.) for different time lags in southern Taiwan. Our findings imply that imported cases have a role in igniting indigenous outbreaks, in non-endemics areas, when favorable weather conditions are present. This relationship becomes insignificant in the late phase of local dengue epidemics. Therefore, early detection and case management of imported cases through timely surveillance and rapid laboratory-diagnosis may avert large scale epidemics of dengue/dengue hemorrhagic fever. An early-warning surveillance system integrating meteorological data will be an invaluable tool for successful prevention and control of dengue, particularly in non-endemic countries
The impact of corporate social responsibility disclosure on financial performance : evidence from the GCC Islamic banking sector.
This paper examines the relationship between corporate social responsibility (CSR) and financial performance for Islamic banks in the Gulf Cooperation Council (GCC) region over the period 2000â2014 by generating CSR-related data through disclosure analysis of the annual reports of the sampled banks. The findings of this study indicate that there is a significant positive relationship between CSR disclosure and the financial performance of Islamic banks in the GCC countries. The results also show a positive relationship between CSR disclosure and the future financial performance of GCC Islamic banks, potentially indicating that current CSR activities carried out by Islamic banks in the GCC could have a long-term impact on their financial performance. Furthermore, despite demonstrating a significant positive relationship between the composite measure of the CSR disclosure index and financial performance, the findings show no statistically significant relationship between the individual dimensions of the CSR disclosure index and the current financial performance measure except for âmission and visionâ and âproducts and servicesâ. Similarly, the empirical results detect a positive significant association only between âmission and visionâ dimension and future financial performance of the examined banks
Patientsâ views of treatment focused genetic testing (TFGT): some lessons for the mainstreaming of BRCA1 and BRCA2 testing
This paper explores patients' views and experiences of undergoing treatment-focused BRCA1 and BRCA2 genetic testing (TFGT), either offered following triaging to clinical genetics (breast cancer) or as part of a mainstreamed care pathway in oncology (ovarian cancer). Drawing on 26 in-depth interviews with patients with breast or ovarian cancer who had undergone TFGT, this retrospective study examines patients' views of genetic testing at this point in their care pathway, focusing on issues, such as initial response to the offer of testing, motivations for undergoing testing, and views on care pathways. Patients were amenable to the incorporation of TFGT at an early stage in their cancer care irrespective of (any) prior anticipation of having a genetic test or family history. While patients were glad to have been offered TFGT as part of their care, some questioned the logic of the test's timing in relation to their cancer treatment. Crucially, patients appeared unable to disentangle the treatment role of TFGT from its preventative function for self and other family members, suggesting that some may undergo TFGT to obtain information for others rather than for self
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic
variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary
arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial
hypertension. These GWAS used data from four international case-control studies across 11744 individuals with
European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and
the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching
genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants
at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and
tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.
Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55â2·08], p=5·13Ă10â
Âčâ”) and a second locus in
HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42â1·71],
p=7·65Ă10â
ÂČâ°) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus
had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25â1·48],
p=1·69Ă10â
ÂčÂČ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene
regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined
haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The
HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in
patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI
12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02â8·05]), despite similar baseline disease severity.
Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in
HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more
common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed
to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA
typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA,
ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and
RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR
Does the newly observed inflammatory syndrome in children demonstrate a link between uncontrolled neutrophil extracellular traps formation and COVID-19?
Construction of a Pseudomonas aeruginosa genomic DNA library.
International audienceAlthough the completion and annotation of the entire genomic DNA sequence of Pseudomonas aeruginosa PAO1 strain has been carried out, an important number of genes are still of unknown function and many genetic elements involved in various regulatory pathways like small RNA are still unrevealed. One of the strategies to identify gene function or genetic elements is the construction and utilization of DNA genomic library. Here, we describe the construction a P. aeruginosa DNA genomic library
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