Middle East respiratory syndrome coronavirus (MERS-CoV), a new coronavirus that has been causing severe and fatal acute respiratory illnesses in humans since its outbreak in 2012, has raised public fear worldwide. The development of prophylactics and therapeutics is urgently needed to prevent and control MERS-CoV infections. In this study, a bacterium (Lactococcus lactis)-like particle (BLP) vaccine displaying the MERS-CoV receptor-binding domain (RBD) was developed, and gram-positive enhancer matrix (GEM) particles were used as substrates to externally bind to the MERS-CoV RBD through a protein anchor (PA). The designs included different numbers of lysin motif (LysM) repeats in the PAs linked by linkers (RBD-linker-PA2 (RLP2), RBD-linker-PA3 (RLP3) and RBD-PA3 (RP3)), and three LysM repeats and a linker in the fusion proteins increased the binding activity to the RBD. The specific immune responses were tested by intranasally immunizing mice with RLP3-GEM with or without the adjuvant GEL01. The results showed that GEL01-adjuvanted RLP3-GEM increased the systemic humoral, cellular and local mucosal immune responses in the mouse model, especially in the intestinal tract. The above results indicate that the MERS-CoV BLP product has the potential to be developed into a promising mucosal candidate vaccine to protect against MERS-CoV infections.

Background: Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention. Methods: We assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomaldominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

cells among half of the cohort, which would be expected for a common unifying origin.Differential gene expression analysis revealed T cells with shared TCRs to be enriched for central memory markers, including CD69, SELL (CD62L) and the Th2-skewing transcription factor JunB (Figure 1b). By contrast, T cells with unique TCRs were more Th1 polarized, as reflected by their expression of STAT1, CX3CR1, GNLY, LGALS1, S100A9 and S100A10. Module scores using well-defined gene sets for Th1, Th2 and central memory phenotypes supported this transcriptional dichotomy (Figure 1c). In addition, protein expression measured by AbSeq revealed that shared TCRs were chronically antigen experienced with an amplified expression of LAG3 and TIM3, 5 which are enriched among cutaneous neoplastic T cells and promote tumorigenesis (Figure 1d). These findings collectively demonstrate that TCR usage phenotypically segregates S ezary cells based on distinct origins in their pathogenesis.Immune dysregulation induced by staphylococcal toxins has been reported to drive the Th2 cytokine production that is characteristic of SS. 2,4 We found that this phenotype was reproduced among S ezary cells with a shared toxinresponsive TCR, supporting the hypothesis that infectious agents influence this neoplastic process. On the other hand, these findings may also reflect inherent VDJ recombination biases that occur during thymocyte development, as TRBV20-1*01 and other staphylococcal toxin-responsive TCRs have been reported to be preferentially utilized by T cells among healthy individuals as well as patients with CTCL. 6 The presence of a Th2 profile among malignant cells could represent one carcinogenic pathway whereby the nuclear accumulation of the NLRP3 inflammasome promotes a positive Th2 feedback loop that bolsters cellular proliferation and resistance to apoptosis. 7 Interestingly, antibodymediated blockade of programmed death-1 enriched among S ezary cells blunts Th2 cytokine production but reciprocally and paradoxically unleashes their proliferation potential, 8 suggesting the Th2 cytokine profile may be a by-product rather than a primary instigator of disease progression.The high frequency of the Th2 cytokine profile observed among patients with SS may reflect the ubiquitous nature by which S. aureus is recovered from patients with CTCL. CTCL affects an older population with a naturally impaired skin barrier that fosters S. aureus overgrowth. Nevertheless, other factors also contribute to the pathogenesis of CTCL, as S. aureus is only identified in a subset of patients, and the contextual role of S. aureus as a natural commensal or pathogenic strain is difficult to dissociate. If S. aureus promotes the classic Th2 phenotype, these findings may help identify patients who respond to targeted Th2 depletion with the anti-CCR4 therapy mogamulizumab. Future studies aimed at unravelling the role of S. aureus in instigating CTCL may be pivotal for developing targeted therapies.