Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

Heterotopic ossification(HO),true bone formation in soft tissue,is closely associated with abnormal injury/immune responses.We hypothesized that a key underlying mechanism of HO might be injury-induced dysregulation of immune checkpoint proteins(ICs).We found that the earliest stages of HO are characterized by enhanced infiltration of polarized macrophages into sites of minor injuries in an animal model of HO.The non-specific immune suppressants,Rapamycin and Ebselen,prevented HO providing evidence of the central role of the immune responses.We examined the expression pattern of ICs and found that they are dysregulated in HO lesions.More importantly,loss of function of inhibitory ICs(including PD1,PD-L1,and CD152)markedly inhibited HO,whereas loss of function of stimulatory ICs(including CD40L and OX-40L)facilitated HO.These findings suggest that IC inhibitors may provide a therapeutic approach to prevent or limit the extent of HO.

Plastering mud around the entrance hole affects the estimation of threat levels from nest predators in Eurasian Nuthatches

Background:For cavity-nesting birds,the nest entrance plays an important role in preventing predators from accessing nests.Several species of nuthatches use mud to narrow the entrance of cavities.In theory,the smaller the entrance hole size,the more effective it is against predators;however,few studies have tested whether narrowing the entrance hole size can affect the estimation of threat levels from nest predators in cavity-nesting birds.Methods:Using dummy experiments,we tested whether Eurasian Nuthatches(Sitta europaea,narrow the entrance hole of cavities)and Cinereous Tits(Parus cinereus,do not narrow the entrance hole,as a control)perform different nest defence behaviours against Common Chipmunks(Tamias sibiricus,small nest predator)and Red Squirrels(Sciurus vulgaris,larger nest predator).Results:Both nuthatches and tits exhibited stronger response behaviours(high dummy response scores)against chipmunks than against squirrels.Compared with tits,nuthatches exhibited more aggressive behaviours to chipmunks,but their responses to squirrels were similar.Conclusions:Nest defence behaviours of nuthatches to chipmunks differed from tits,and the results suggested that nuthatches might estimate threat levels of nest predators according to their narrowed entrance-hole size.

Melanin precursors mediated adaption to temperature changes in fungus and animal via inhibition of lipid-mediated ferroptosis

The discovery of biological activities of natural products plays a vital part in drug development.The mechanism by which organisms respond to temperature changes via biosynthesis of natural products remained largely cryptic.A thermophilic fungus under cold stress turned black and accumulated a polyketide metabolite 1 and lipid mass.Deficiency in 1 caused melanin loss and accumulated extra lipid mass,unexpectedly leading to seriously damaged mitochondria diagnostic for ferroptosis.Further analysis revealed that lipid mass induced by cold stress intensively increased ferroptosis risk and 1 functioned as cell wall reinforcer against mass lipid accumulation and as reactive oxygen species scavenger against lipid peroxidation.We also found that melanin in mice lowered lipid level but enhanced animal resistance to cold stress.Treatment with melanin precursors significantly increased mouse cell survival rate under cold stress.Our results unveiled a metabolite-lipid-ferroptosis-cold relationship,which provided mechanistic insights into the functions of most common metabolites and into diseases related to cold stress.These findings opened a perspective for developing anti-cold and anti-ferroptosis therapeutics and agents.

Multiple olfactory pathways contribute to the lure process of Caenorhabditis elegans by pathogenic bacteria

Chemosensation is indispensable for the survival of Caenorhabditis elegans to discriminate food and pathogenic bacteria in their living environment. Food-like odors emitted by the pathogen Bacillus nematocida B16 for trapping its hosts and an olfactory signaling pathway responsible to sense the attractant 2-heptanone were identified in our previous study. Here, we further explore how the worms recognize the attractive molecules indole and 2-ethyl hexanol, which have different chemical properties and modest nematode-luring ability. We show that the chemotaxis toward indole and 2-ethyl hexanol requires the G protein-coupled receptors encoded by str-193 on AWC and str-7 on AWA. In a further genetic screen for downstream effectors in olfactory signaling cascades, the Gα subunit GSA-1, guanylyl cyclase ODR-1 and DAF-11 and the c GMP-gated channel TAX-2/TAX-4 were found to be necessary for indole sensation, whereas the TRPV channels OSM-9/OCR-2 and the PLC pathway activated by GPA-6 are responsible for the detection of 2-ethyl hexanol. Altogether, our current work further clarifies the distinct olfactory signaling pathways through which C. elegans senses different chemicals and is lured by B. nematocida B16, improving our comprehensive understanding of the mechanisms by which bacterial pathogens effectively infect their hosts.