Mathematical and computational modeling in biology at multiple scales

A variety of topics are reviewed in the area of mathematical and computational modeling in biology, covering the range of scales from populations of organisms to electrons in atoms. The use of maximum entropy as an inference tool in the fields of biology and drug discovery is discussed. Mathematical and computational methods and models in the areas of epidemiology, cell physiology and cancer are surveyed. The technique of molecular dynamics is covered, with special attention to force fields for protein simulations and methods for the calculation of solvation free energies. The utility of quantum mechanical methods in biophysical and biochemical modeling is explored. The field of computational enzymology is examined.     

Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease

A point mutation in the Drosophila gene that codes for the major adult isoform of adenine nuclear translocase (ANT) represents a model for human diseases that are associated with ANT insufficiency [stress-sensitive B¹ (sesB¹)]. We characterized the organismal, bioenergetic and molecular phenotype of sesB¹ flies then tested strategies to compensate the mutant phenotype. In addition to developmental delay and mechanical-stress-induced seizures, sesB¹ flies have an impaired response to sound, defective male courtship, female sterility and curtailed lifespan. These phenotypes, excluding the latter two, are shared with the mitoribosomal protein S12 mutant, tko^25t. Mitochondria from sesB¹ adults showed a decreased respiratory control ratio and downregulation of cytochrome oxidase. sesB¹ adults exhibited ATP depletion, lactate accumulation and changes in gene expression that were consistent with a metabolic shift towards glycolysis, characterized by activation of lactate dehydrogenase and anaplerotic pathways. Females also showed downregulation of many genes that are required for oogenesis, and their eggs, although fertilized, failed to develop to the larval stages. The sesB¹ phenotypes of developmental delay and mechanical-stress-induced seizures were alleviated by an altered mitochondrial DNA background. Female sterility was substantially rescued by somatic expression of alternative oxidase (AOX) from the sea squirt Ciona intestinalis, whereas AOX did not alleviate developmental delay. Our findings illustrate the potential of different therapeutic strategies for ANT-linked diseases, based on alleviating metabolic stress.KEY WORDS: Adenine nucleotide translocase, Mitochondrial disease, Mitochondrial biogenesis, Alternative oxidase     

NAMPT-Mediated Salvage Synthesis of NAD+ Controls Morphofunctional Changes of Macrophages

Functional morphodynamic behavior of differentiated macrophages is strongly controlled by actin cytoskeleton rearrangements, a process in which also metabolic cofactors ATP and NAD(H) (i.e. NAD⁺ and NADH) and NADP(H) (i.e. NADP⁺ and NADPH) play an essential role. Whereas the link to intracellular ATP availability has been studied extensively, much less is known about the relationship between actin cytoskeleton dynamics and intracellular redox state and NAD⁺-supply. Here, we focus on the role of nicotinamide phosphoribosyltransferase (NAMPT), found in extracellular form as a cytokine and growth factor, and in intracellular form as one of the key enzymes for the production of NAD⁺ in macrophages. Inhibition of NAD⁺ salvage synthesis by the NAMPT-specific drug FK866 caused a decrease in cytosolic NAD⁺ levels in RAW 264.7 and Maf-DKO macrophages and led to significant downregulation of the glycolytic flux without directly affecting cell viability, proliferation, ATP production capacity or mitochondrial respiratory activity. Concomitant with these differential metabolic changes, the capacity for phagocytic ingestion of particles and also substrate adhesion of macrophages were altered. Depletion of cytoplasmic NAD⁺ induced cell-morphological changes and impaired early adhesion in phagocytosis of zymosan particles as well as spreading performance. Restoration of NAD⁺ levels by NAD⁺, NMN, or NADP⁺ supplementation reversed the inhibitory effects of FK866. We conclude that direct coupling to local, actin-based, cytoskeletal dynamics is an important aspect of NAD⁺’s cytosolic role in the regulation of morphofunctional characteristics of macrophages.     

Weight Loss and Premature Death: The 1946 British Birth Cohort Study

Objective

The relationship between weight loss and mortality has important clinical and public health significance but has proved to be complex. Evidence is mixed and particularly limited on the association between weight loss in mid-life and premature death (i.e. before 65 years of age), a small albeit important segment of total mortality. We aimed to study the association between midlife weight change and mortality accounting for health and lifestyle characteristics, and also considering potential bias due to preexisting chronic diseases and smoking status.

Design

Longitudinal, population-based, ‘the 1946 British’ birth cohort study.

Subjects and Measures

In 2750 men and women, mortality from age 53 through 65 years was analyzed according to categories of measured 10 year weight change between 43 and 53 years. Cox''s hazard ratios (HR) were progressively adjusted for socio-demographic, lifestyle and health characteristics.

Results

Nearly 20% of participants lost weight and over 50% gained 5 kg or more in midlife. There were 164 deaths. Compared to those who gained between 2 and 5 kg, those who lost 5 kg or more had an increased risk of premature death independently of midlife physical activity, socio-economic circumstances and educational attainment. This association was unaltered when highest weight loss (lost more than 15 Kg) (p = 0.04) and early deaths were excluded (p<0.001), but was no longer significant after adjustment for cardiovascular risk factors and health status (HR = 1.8; 95% CI: 0.9 to 3.5).

Conclusion

The inverse association between weight loss in midlife and higher risk of premature death may be explained by vascular risk factors and ill health. In consideration of the burden of premature death, closer monitoring of weight loss in mid-life is warranted.     

Diagnostic Accuracy of the PURE-LAMP Test for Pulmonary Tuberculosis at the County-Level Laboratory in China

Background

Early and effective detection of Mycobacterium tuberculosis (MTB), particularly in smear-negative tuberculosis (TB), is a priority for global TB control. Loop-mediated isothermal amplification with a procedure for ultra rapid DNA extraction (PURE-LAMP) can detect TB in sputum samples rapidly and with high sensitivity and specificity. However, the PURE-LAMP test has not been effectively evaluated, especially in resource-limited laboratories. In this study, we evaluated the performance of the PURE-LAMP test for TB detection in TB suspects from two county-level TB dispensaries in China.

Methodology/Principal Findings

From April 2011 to February 2012, patients with suspected TB were continuously enrolled from two county-level TB laboratories in China. Three sputum samples (spot, night, and morning sputum) were collected from each recruited patient. Detection of MTB by PURE-LAMP was compared to a reference standard L-J culture. The results showed that the sensitivity of the PURE-LAMP test based on spot sputum for MTB detection was 70.67%, while the sensitivity of the PURE-LAMP test based on spot sputum for MTB detection in smear positive and culture positive patients and smear negative and culture positive patients was 92.12% and 53.81%, respectively. The specificity of PURE-LAMP based on spot sputum for MTB detection was 98.32%. The sensitivity and specificity of the PURE-LAMP test based on three sputa combination for MTB detection was 88.80% and 96.86%, respectively. The results also showed that the PURE-LAMP test had a significantly lower contamination rate than did solid culture.

Conclusions/Significance

The study suggested that, in peripheral-level TB laboratories in China, the PURE-LAMP test showed high sensitivity and specificity for TB detection in TB suspects, making it a more effective, rapid, and safe method worthy of broader use in the future.     

Lifecourse Adversity and Physical Performance across Countries among Men and Women Aged 65-74

Background

This study examines the associations between lifecourse adversity and physical performance in old age in different societies of North and South America and Europe.

Methods

We used data from the baseline survey of the International Study of Mobility in Aging, conducted in: Kingston (Canada), Saint-Hyacinthe (Canada), Natal (Brazil), Manizales (Colombia) and Tirana (Albania). The study population was composed of community dwelling people between 65 and 74 years of age, recruiting 200 men and 200 women at each site. Physical Performance was assessed with the Short Physical Performance Battery (SPPB). Economic and social adversity was estimated from childhood adverse events, low education, semi-skilled occupations during adulthood and living alone and insufficient income in old age.

Results

A total of 1995 people were assessed. Low physical performance was associated with childhood social and economic adversity, semi-skilled occupations, living alone and insufficient income. Physical performance was lower in participants living in Colombia, Brazil and Albania than in Canada counterparts, despite adjustment for lifecourse adversity, age and sex.

Conclusions

We show evidence of the early origins of social and economic inequalities in physical performance during old age in distinct populations and for the independent and cumulative disadvantage of low socioeconomic status during adulthood and poverty and living alone in later life.     

In Amnio MRI of Mouse Embryos

Mouse embryo imaging is conventionally carried out on ex vivo embryos excised from the amniotic sac, omitting vital structures and abnormalities external to the body. Here, we present an in amnio MR imaging methodology in which the mouse embryo is retained in the amniotic sac and demonstrate how important embryonic structures can be visualised in 3D with high spatial resolution (100 µm/px). To illustrate the utility of in amnio imaging, we subsequently apply the technique to examine abnormal mouse embryos with abdominal wall defects. Mouse embryos at E17.5 were imaged and compared, including three normal phenotype embryos, an abnormal embryo with a clear exomphalos defect, and one with a suspected gastroschisis phenotype. Embryos were excised from the mother ensuring the amnion remained intact and stereo microscopy was performed. Embryos were next embedded in agarose for 3D, high resolution MRI on a 9.4T scanner. Identification of the abnormal embryo phenotypes was not possible using stereo microscopy or conventional ex vivo MRI. Using in amnio MRI, we determined that the abnormal embryos had an exomphalos phenotype with varying severities. In amnio MRI is ideally suited to investigate the complex relationship between embryo and amnion, together with screening for other abnormalities located outside of the mouse embryo, providing a valuable complement to histology and existing imaging methods available to the phenotyping community.     

Geographic Variation of Failure-to-Rescue in Public Acute Hospitals in New South Wales,Australia

Despite the wide acceptance of Failure-to-Rescue (FTR) as a patient safety indicator (defined as the deaths among surgical patients with treatable complications), no study has explored the geographic variation of FTR in a large health jurisdiction. Our study aimed to explore the spatiotemporal variations of FTR rates across New South Wales (NSW), Australia. We conducted a population-based study using all admitted surgical patients in public acute hospitals during 2002–2009 in NSW, Australia. We developed a spatiotemporal Poisson model using Integrated Nested Laplace Approximation (INLA) methods in a Bayesian framework to obtain area-specific adjusted relative risk. Local Government Area (LGA) was chosen as the areal unit. LGA-aggregated covariates included age, gender, socio-economic and remoteness index scores, distance between patient residential postcode and the treating hospital, and a quadratic time trend. We studied 4,285,494 elective surgical admissions in 82 acute public hospitals over eight years in NSW. Around 14% of patients who developed at least one of the six FTR-related complications (58,590) died during hospitalization. Of 153 LGAs, patients who lived in 31 LGAs, accommodating 48% of NSW patients at risk, were exposed to an excessive adjusted FTR risk (10% to 50%) compared to the state-average. They were mostly located in state''s centre and western Sydney. Thirty LGAs with a lower adjusted FTR risk (10% to 30%), accommodating 8% of patients at risk, were mostly found in the southern parts of NSW and Sydney east and south. There were significant spatiotemporal variations of FTR rates across NSW over an eight-year span. Areas identified with significantly high and low FTR risks provide potential opportunities for policy-makers, clinicians and researchers to learn from the success or failure of adopting the best care for surgical patients and build a self-learning organisation and health system.