Although mouse models exist for many immune-based diseases, the clinical translation remains challenging. Most basic and translational studies utilize only a single inbred mouse strain. However, basal and diseased immune states in humans show vast inter-individual variability. Here, focusing on macrophage responses to lipopolysaccharide (LPS), we use the hybrid mouse diversity panel (HMDP) of 83 inbred strains as a surrogate for human natural immune variation. Since conventional bioinformatics fail to analyse a population spectrum, we highlight how gene signatures for LPS responsiveness can be derived based on an Interleukin-12β and arginase expression ratio. Compared to published signatures, these gene markers are more robust to identify susceptibility or resilience to several macrophage-related disorders in humans, including survival prediction across many tumours. This study highlights natural activation diversity as a disease-relevant dimension in macrophage biology, and suggests the HMDP as a viable tool to increase translatability of mouse data to clinical settings.

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Background: Studies have shown that higher body mass index (BMI) is associated with improved prognosis in heart failure (HF), and this is often termed the obesity paradox.Hypothesis: Analysis of body composition may reveal that muscle mass rather than adipose tissue accounts for the obesity paradox.Methods: Bioelectrical impedance analysis of body composition in 359 outpatients with HF was performed using an In Body 520 body composition scale (Biospace Inc., California). Body fat and lean mass were indexed by height (m 2 ). The cohort was stratified by median fat and lean mass indexed by height. Results:The mean age of patients studied was 56 AE 14; mean left ventricular ejection fraction was 38 AE 16%. Patients with higher indexed body fat mass had improved 5-year survival over patients with lower indexed body fat mass (90.2% vs 80.1%, P = 0.008). There was also improved survival in patients with high vs low indexed lean body mass (89.3% vs 80.9%, P = 0.036). On multivariable analysis, higher indexed body fat mass, but not lean body mass, was independently associated with improved survival (HR 0.89, per kg/m 2 increase in indexed body fat mass, P = 0.044); however, this was attenuated after adjustment for diabetes. The combination of low lean with low-fat mass was independently associated with poor prognosis.Conclusions: Our data suggest that higher fat mass-and to a lesser extent higher lean mass-is associated with improved outcomes in HF. Further investigations of specific components of body composition and outcomes in HF are warranted.

The neurodegeneration in colchicine induced AD rats (cAD) is mediated by cox-2 linked neuroinflammation. The importance of ROS in the inflammatory process in cAD has not been identified, which may be deciphered by blocking oxidative stress in this model by a well-known anti-oxidant vitamin C. Therefore, the present study was designed to investigate the role of vitamin C on colchicine induced oxidative stress linked neuroinflammation mediated neurodegeneration and memory impairments along with peripheral immune responses in cAD. The impairments of working and reference memory were associated with neuroinflammation and neurodegeneration in the hippocampus of cAD. Administration of vitamin C (200 and 400 mg/kg BW) in cAD resulted in recovery of memory impairments, with prevention of neurodegeneration and neuroinflammation in the hippocampus. The neuroinflammation in the hippocampus also influenced the peripheral immune responses and inflammation in the serum of cAD and all of these parameters were also recovered at 200 and 400 mg dose of vitamin C. However, cAD treated with 600 mg dose did not recover but resulted in increase of memory impairments, neurodegeneration and neuroinflammation in hippocampus along with alteration of peripheral immune responses in comparison to cAD of the present study. Therefore, the present study showed that ROS played an important role in the colchicine induced neuroinflammation linked neurodegeneration and memory impairments along with alteration of peripheral immune responses. It also appears from the results that vitamin C at lower doses showed anti-oxidant effect and at higher dose resulted in pro-oxidant effects in cAD.