Cutaneous ischemia-reperfusion injury is exacerbated by IL-36 receptor antagonist deficiency.

BACKGROUND: Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear. OBJECTIVES: We investigated the role of IL36Ra in cutaneous I/R injury. METHODS: We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined. RESULTS: IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-ß, IL-1ß, IL-6 and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1ß, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1ß showed significantly increased CXCL1, TNF-α, IL-6, IL-36ß and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn-/- mice. CONCLUSIONS: This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

Isolated autosomal recessive woolly hair/hypotrichosis: genetics, pathogenesis and therapies.

Isolated autosomal recessive woolly hair/hypotrichosis (ARWH) is a rare hereditary hair disease characterized by tightly curled sparse hair at birth or in early infancy. Patients with ARWH consist of genetically heterogeneous groups. Woolly hair autosomal recessive 1 (ARWH1) (MIM #278150), woolly hair autosomal recessive 2 (ARWH2) (MIM #604379) and woolly hair autosomal recessive 3 (ARWH3) (MIM #616760) are caused by mutations in LPAR6, LIPH and KRT25, respectively. In addition, nonsense variants in C3ORF52 (*611956) were identified in ARWH patients. The frequencies of the mutations in the causative genes in ARWH patients are thought to differ by ethnicity and country/geographical area. Large numbers of ARWH families with LIPH mutations have been described only in populations from Japan, Pakistan and the Volga-Ural region of Russia. In that region of Russia, most ARWH families have an extremely prevalent founder mutation, the deletion of exon 4, in LIPH. In the Pakistani population, 47.2% of ARWH families had the disease due to LIPH mutations and 52.8% of them carried LPAR6 mutations. The prevalent, recurrent LIPH mutation c.659_660delTA (p.Ile220Argfs*29) was found in more than half of Pakistani ARWH families with LIPH mutations. Most Japanese ARWH families (98.7%) harbour LIPH mutations, including the two highly prevalent, recurrent LIPH mutations c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn). In ARWH patients whose disease was due to LIPH, LPAR6 or C3ORF52 mutations, the loss of function of LIPH, LPAR6 or C3ORF52 leads to reduced LIPH-LPA-LPAR6 signalling, resulting in the decreased transactivation of EGFR signalling and the phenotype of underdeveloped hairs. Our recent prospective interventional study suggests that topical minoxidil might be a promising treatment for ARWH due to LIPH mutations, although sufficiently effective treatments have not been established for ARWH yet.

Imperceptible magnetic sensor matrix system integrated with organic driver and amplifier circuits.

Artificial electronic skins (e-skins) comprise an integrated matrix of flexible devices arranged on a soft, reconfigurable surface. These sensors must perceive physical interaction spaces between external objects and robots or humans. Among various types of sensors, flexible magnetic sensors and the matrix configuration are preferable for such position sensing. However, sensor matrices must efficiently map the magnetic field with real-time encoding of the positions and motions of magnetic objects. This paper reports an ultrathin magnetic sensor matrix system comprising a 2 × 4 array of magnetoresistance sensors, a bootstrap organic shift register driving the sensor matrix, and organic signal amplifiers integrated within a single imperceptible platform. The system demonstrates high magnetic sensitivity owing to the use of organic amplifiers. Moreover, the shift register enabled real-time mapping of 2D magnetic field distribution.

Numerical study on spindle positioning using phase field method.

A method of numerical simulation of cell division using phase fields is presented. The cell division plane is obtained as a result of the spindle position and orientation considered with the spatial distribution of the activated cortical force generators and the dividing cell shape. To exemplify the application of the proposed method, numerical simulations of the development of cysts and early embryos are performed. The numerical results demonstrate that the activated cortical force generators that are localized at the lateral cortices of the epithelial cells lead to the formation of a single central lumen. It is additionally shown that the linear distribution of the activated cortical force generators along the animal-vegetal axis of a spherical cell engenders a similar cell proliferation of the divided embryo generated by the 32 cell period in a sea cucumber.