Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood-brain barrier disruption.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

Diel rhythms and sex differences in the locomotor activity of hawkmoths.

Circadian patterns of activity are considered ubiquitous and adaptive, and are often invoked as a mechanism for temporal niche partitioning. Yet, comparisons of rhythmic behavior in related animal species are uncommon. This is particularly true of Lepidoptera (butterflies and moths), in which studies of whole-animal patterns of behavior are far outweighed by examinations of tissue-specific molecular clocks. Here, we used a comparative approach to examine the circadian patterns of flight behavior in Manduca sexta and Hyles lineata [two distantly related species of hawkmoth (Sphingidae)]. By filming isolated, individual animals, we were able to examine rhythmic locomotor (flight) activity at the species level, as well as at the level of the individual sexes, and in the absence of interference from social interaction. Our results confirmed classic descriptions of strictly nocturnal behavior in M. sexta and demonstrated a dramatically different activity pattern in H. lineata Furthermore, we showed distinct species and sex-specific differences in the maintenance of the endogenous rhythm under conditions of constant darkness. In both species, female activity peaked in advance of males whereas male activity coincided with periods of female sexual receptivity. This suggests a role for circadian patterns of locomotor activity in synchronizing periods of sexual receptivity between the sexes.

Aspergillus fumigatus-Secreted Alkaline Protease 1 Mediates Airways Hyperresponsiveness in Severe Asthma.

The hallmark features of allergic asthma are type 2 (eosinophilic) inflammation and airways hyperresponsiveness (AHR). Although these features often comanifest in mouse lungs in vivo, we demonstrate in this study that the serine protease Alp1 from the ubiquitous mold and allergen, Aspergillus fumigatus, can induce AHR in mice unable to generate eosinophilic inflammation. Strikingly, Alp1 induced AHR in mice devoid of protease-activated receptor 2/F2 trypsin-like receptor 1 (PAR2/F2RL1), a receptor expressed in lung epithelium that is critical for allergic responses to protease-containing allergens. Instead, using precision-cut lung slices and human airway smooth muscle cells, we demonstrate that Alp1 directly increased contractile force. Taken together, these findings suggest that Alp1 induces bronchoconstriction through mechanisms that are largely independent of allergic inflammation and point to a new target for direct intervention of fungal-associated asthma.