Two macrophages, osteoclasts and microglia: from development to pleiotropy

Tissue-resident macrophages are highly specialized to their tissue-specific microenvironments,activated by various inflammatory signals and modulated by genetic and environmental factors.Osteoclasts and microglia are distinct tissue-resident cells of the macrophage lineage in bone and brain that are responsible for pathological changes in osteoporosis and Alzheimer’s disease(AD),respectively.Osteoporosis is more frequently observed in individuals with AD compared to the prevalence in general population.Diagnosis of AD is often delayed until underlying pathophysiological changes progress and cause irreversible damages in structure and function of brain.As such earlier diagnosis and intervention of individuals at higher risk would be indispensable to modify clinical courses.Pleiotropy is the phenomenon that a genetic variant affects multiple traits and the genetic correlation between two traits could suggest a shared molecular mechanism.In this review,we discuss that the Pyk2-mediated actin polymerization pathway in osteoclasts and microglia in bone and brain,respectively,is the horizontal pleiotropic mediator of shared risk factors for osteoporosis and AD.

Computational prediction and validation of specific EmbR binding site on PknH

Tuberculosis drug resistance continues to threaten global health but the underline molecular mechanisms are not clear.Ethambutol(EMB),one of the well-known first-line drugs in tuberculosis treatment is,unfortunately,not free from drug resistance problems.Genomic studies have shown that some genetic mutations in Mycobacterium tuberculosis(Mtb)EmbR,and EmbC/A/B genes cause EMB resistance.EmbR-PknH pair controls embC/A/B operon,which encodes EmbC/A/B genes,and EMB interacts with EmbA/B proteins.However,the EmbR binding site on PknH was unknown.We conducted molecular simulation on the EmbR-peptides binding structures and discovered phosphorylated PknH 273-280(N′-HEALS^(P)DPD-C′)makesβstrand with the EmbR FHA domain,asβ-MoRF(MoRF;molecular recognition feature)does at its binding site.Hydrogen bond number analysis also supported the peptides’β-MoRF forming activity at the EmbR FHA domain.Also,we discovered that previously known phosphorylation residues might have their chronological order according to the phosphorylation status.The discovery validated that Mtb PknH 273-280(N′-HEALSDPD-C′)has reliable EmbR binding affinity.This approach is revolutionary in the computer-aided drug discovery field,because it is the first trial to discover the protein-protein interaction site,and find binding partner in nature from this site.

Relatedness of the incidence decay with exponential adjustment(IDEA)model,“Farr's law”and SIR compartmental difference equation models

Mathematical models are often regarded as recent innovations in the description and analysis of infectious disease outbreaks and epidemics,but simple mathematical expressions have been in use for projection of epidemic trajectories for more than a century.We recently introduced a single equation model(the incidence decay with exponential adjustment,or IDEA model)that can be used for short-term epidemiological forecasting.In the mid-19th century,Dr.William Farr made the observation that epidemic events rise and fall in a roughly symmetrical pattern that can be approximated by a bell-shaped curve.He noticed that this time-evolution behavior could be captured by a single mathematical formula(“Farr's law”)that could be used for epidemic forecasting.We show here that the IDEA model follows Farr's law,and show that for intuitive assumptions,Farr's Law can be derived from the IDEA model.Moreover,we show that both mathematical approaches,Farr's Law and the IDEA model,resemble solutions of a susceptible-infectious-removed(SIR)compartmental differential-equation model in an asymptotic limit,where the changes of disease transmission respond to control measures,and not only to the depletion of susceptible individuals.This suggests that the concept of the reproduction number eR 0T was implicitly captured in Farr's(pre-microbial era)work,and also suggests that control of epidemics,whether via behavior change or intervention,is as integral to the natural history of epidemics as is the dynamics of disease transmission.