A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System

The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.Singapore. Ministry of Education (Grant T208B3109)Singapore. Agency for Science, Technology and Research (BMRC 08/1/21/19/574)Singapore-MIT Alliance (Computational and Systems Biology Flagship Project)Swedish Research Counci

Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity

Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2)

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Not AvailableEconomic loss due to Enterocytozoon hepatopenaei (EHP), white spot syndrome virus (WSSV) infections and other diseases to Penaeus vannamei farming in India was estimated through a questionnaire-based survey of shrimp farms in major shrimp farming states of India during 2018–2019. The survey covered an area of 7259 ha of shrimp farming in 23 coastal districts based on multistage stratified sampling (n = 909). Probability of disease occurrence (PDO) was calculated to estimate the economic loss due to diseases. Double log regression was employed to examine the relationship between economic loss with production, stocking density, culture period, average body weight, survival, FCR and incidence of disease. Loss of production (t ha 1crop 1) was highest in infections due to WSSV (2.58 ± 0.32), followed by EHP (1.80 ± 0.24), mixed infections of EHP and WSSV (1.89 ± 0.53), vibriosis (0.97 ± 0.42), running mortality syndrome (1.1 ± 0.39) and other diseases (1.72 ± 0.36). Although WSSV caused the highest loss of production (t ha 1 crop 1), EHP with a 17% probability of occurrence,accounted for a production loss of 0.77 M tons, with a corresponding revenue loss of Rs. 3977 crores (US$567.62 M). Although the probability of occurrence of WSSV was estimated (25$ 238.33 M). National loss of revenue due to EHP was higher primarily because, in Andhra Pradesh, primary shrimp farming state had the PDO of 22% for EHP against 8% for WSSV. The total employment loss due to diseases was estimated to be 1.65 M man-days worth US$7.07 M. The study revealed that the overall probability of infectious disease occurrence in the country was at 49$ 1.02 B. Economic loss due to shrimp diseases in Indian shrimp farming warrants prioritized implementation of better management practices (BMP) and biosecurity protocols along with policy interventions to reduce the direct and indirect losses.Not Availabl

βCaMKII controls the direction of plasticity at parallel fiber–Purkinje cell synapses

We found that beta CaMKII, the predominant CaMKII isoform of the cerebellum, is important for controlling the direction of plasticity at the parallel fiber-Purkinje cell synapse; a protocol that induced synaptic depression in wild-type mice resulted in synaptic potentiation in Camk2b knockout mice and vice versa. These findings provide us with unique experimental insight into the mechanisms that transduce graded calcium signals into either synaptic depression or potentiation