Multiscale modelling methods in biomechanics

More and more frequently, computational biomechanics deals with problems where the portion of physical reality to be modelled spans over such a large range of spatial and temporal dimensions, that it is impossible to represent it as a single space-time continuum. We are forced to consider multiple space-time continua, each representing the phenomenon of interest at a characteristic space-time scale. Multiscale models describe a complex process across multiple scales, and account for how quantities transform as we move from one scale to another. This review offers a set of definitions for this emerging field, and provides a brief summary of the most recent developments on multiscale modelling in biomechanics. Of all possible perspectives, we chose that of the modelling intent, which vastly affect the nature and the structure of each research activity. To the purpose we organised all papers reviewed in three categories: さcausal confirmationざ, where multiscale models are used as materialisations of the causation theories; さpredictive accuracyざ, where multiscale modelling is aimed to improve the predictive accuracy; and さdetermination of effectざ, where multiscale modelling is used to model how a change at one scale manifest in an effect at another, radically different space-time scale. Consistently with the how the volume of computational biomechanics research is distributed across application targets, we extensively reviewed papers targeting the musculoskeletal and the cardiovascular system, and covered only a few exemplary papers targeting other organ systems. The review shows a research sub-domain still in its infancy, where causal confirmation papers remain the most common

Restoration of IFNγR Subunit Assembly, IFNγ Signaling and Parasite Clearance in Leishmania donovani Infected Macrophages: Role of Membrane Cholesterol

Despite the presence of significant levels of systemic Interferon gamma (IFNγ), the host protective cytokine, Kala-azar patients display high parasite load with downregulated IFNγ signaling in Leishmania donovani (LD) infected macrophages (LD-MØs); the cause of such aberrant phenomenon is unknown. Here we reveal for the first time the mechanistic basis of impaired IFNγ signaling in parasitized murine macrophages. Our study clearly shows that in LD-MØs IFNγ receptor (IFNγR) expression and their ligand-affinity remained unaltered. The intracellular parasites did not pose any generalized defect in LD-MØs as IL-10 mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation remained unaltered with respect to normal. Previously, we showed that LD-MØs are more fluid than normal MØs due to quenching of membrane cholesterol. The decreased rigidity in LD-MØs was not due to parasite derived lipophosphoglycan (LPG) because purified LPG failed to alter fluidity in normal MØs. IFNγR subunit 1 (IFNγR1) and subunit 2 (IFNγR2) colocalize in raft upon IFNγ stimulation of normal MØs, but this was absent in LD-MØs. Oddly enough, such association of IFNγR1 and IFNγR2 could be restored upon liposomal delivery of cholesterol as evident from the fluorescence resonance energy transfer (FRET) experiment and co-immunoprecipitation studies. Furthermore, liposomal cholesterol treatment together with IFNγ allowed reassociation of signaling assembly (phospho-JAK1, JAK2 and STAT1) in LD-MØs, appropriate signaling, and subsequent parasite killing. This effect was cholesterol specific because cholesterol analogue 4-cholestene-3-one failed to restore the response. The presence of cholesterol binding motifs [(L/V)-X1–5-Y-X1–5-(R/K)] in the transmembrane domain of IFNγR1 was also noted. The interaction of peptides representing this motif of IFNγR1 was studied with cholesterol-liposome and analogue-liposome with difference of two orders of magnitude in respective affinity (KD: 4.27×10−9 M versus 2.69×10−7 M). These observations reinforce the importance of cholesterol in the regulation of function of IFNγR1 proteins. This study clearly demonstrates that during its intracellular life-cycle LD perturbs IFNγR1 and IFNγR2 assembly and subsequent ligand driven signaling by quenching MØ membrane cholesterol

A Longitudinal Analysis of Mosquito Net Ownership and Use in an Indigenous Batwa Population after a Targeted Distribution

Major efforts for malaria prevention programs have gone into scaling up ownership and use of insecticidal mosquito nets, particularly in sub-Saharan Africa where the malaria burden is high. Socioeconomic inequities in access to long lasting insecticidal nets (LLINs) are reduced with free distributions of nets. However, the relationship between social factors and retention of nets after a free distribution has been less studied, particularly using a longitudinal approach. Our research aimed to estimate the ownership and use of LLINs, and examine the determinants of LLIN retention, within an Indigenous Batwa population after a free LLIN distribution. Two LLINs were given free of charge to each Batwa household in Kanungu District, Uganda in November 2012. Surveyors collected data on LLIN ownership and use through six cross-sectional surveys pre- and post-distribution. Household retention, within household access, and individual use of LLINs were assessed over an 18-month period. Socioeconomic determinants of household retention of LLINs post-distribution were modelled longitudinally using logistic regression with random effects. Direct house-to-house distribution of free LLINs did not result in sustainable increases in the ownership and use of LLINs. Three months post-distribution, only 73% of households owned at least one LLIN and this period also saw the greatest reduction in ownership compared to other study periods. Eighteen-months post distribution, only a third of households still owned a LLIN. Self-reported age-specific use of LLINs was generally higher for children under five, declined for children aged 6–12, and was highest for older adults aged over 35. In the model, household wealth was a significant predictor of LLIN retention, controlling for time and other variables. This research highlights on-going socioeconomic inequities in access to malaria prevention measures among the Batwa in southwestern Uganda, even after free distribution of LLINs, and provides critical information to inform local malaria programs on possible intervention entry-points to increase access and use among this marginalized population

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease