Inherited ichthyosis comprises a series of heterogeneous dermal conditions; it mainly manifests as widespread hyperkeratosis, xerosis and scaling of the skin. At times, overlapping symptoms require differential diagnosis between ichthyosis and several other similar disorders. The present study reports seven patients with confirmed or suspected to be associated with ichthyosis by conducting a thorough clinical and genetic investigation. Genetic testing was conducted using whole‑exome sequencing, with Sanger sequencing as the validation method. The MEGA7 program was used to analyze the conservation of amino acid residues affected by the detected missense variants. The enrolled patients exhibited ichthyosis‑like but distinct clinical manifestations. Genetic analysis identified diagnostic variations in the FLG, STS, KRT10 and SERPINB7 genes and clarified the carrying status of each variant in the respective family members. The two residues affected by the detected missense variants remained conserved across multiple species. Of note, the two variants, namely STS: c.452C>T(p.P151L) and c.647_650del(p.L216fs) are novel. In conclusion, a clear genetic differential diagnosis was made for the enrolled ichthyosis‑associated patients; the study findings also extended the mutation spectrum of ichthyosis and provided solid evidence for the counseling of the affected families.

Stem cell differentiation requires dramatic changes in gene expression and global remodeling of chromatin architecture. How and when chromatin remodels relative to the transcriptional, behavioral, and morphological changes during differentiation remain unclear, particularly in an intact tissue context. Here, we develop a quantitative pipeline which leverages fluorescently-tagged histones and longitudinal imaging to track large-scale chromatin compaction changes within individual cells in a live mouse. Applying this pipeline to epidermal stem cells, we reveal that cell-to-cell chromatin compaction heterogeneity within the stem cell compartment emerges independent of cell cycle status, and instead is reflective of differentiation status. Chromatin compaction state gradually transitions over days as differentiating cells exit the stem cell compartment. Moreover, establishing live imaging of Keratin-10 (K10) nascent RNA, which marks the onset of stem cell differentiation, we find that Keratin-10 transcription is highly dynamic and largely precedes the global chromatin compaction changes associated with differentiation. Together, these analyses reveal that stem cell differentiation involves dynamic transcriptional states and gradual chromatin rearrangement.

A 3-months old Chinese shar-pei puppy with ichthyosis was investigated. The dog showed generalized scaling, alopecia and footpad lesions. Histopathological examinations demonstrated a non-epidermolytic hyperkeratosis. The parents of the affected puppy did not show any skin lesions. A trio whole genome sequencing analysis identified a heterozygous de novo 3 bp deletion in the KRT1 gene in the affected dog. This variant, NM_001003392.1:c.567_569del, is predicted to delete a single asparagine from the conserved coil 1A motif within the rod domain of KRT1, NP_001003392.1:p.(Asn190del). Immunohistochemistry demonstrated normal levels of KRT1 expression in the epidermis and follicular epithelia. This might indicate that the variant possibly interferes with keratin dimerization or another function of KRT1. Missense variants affecting the homologous asparagine residue of the human KRT1 cause epidermolytic hyperkeratosis. Histologically, the investigated Chinese shar-pei showed a non-epidermolytic ichthyosis. The finding of a de novo variant in an excellent functional candidate gene strongly suggests that KRT1:p.Asn190del caused the ichthyosis phenotype in the affected Chinese shar-pei. To the best of our knowledge, this is the first description of a KRT1-related non-epidermolytic ichthyosis in domestic animals.

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.

Background and aims: Patients with systemic lupus erythematosus (SLE) have a significantly higher incidence of atherosclerosis than the general population. Studies on atherosclerosis prediction models specific for SLE patients are very limited. This study aimed to build a risk prediction model for atherosclerosis in SLE. Methods: RNA sequencing was performed on 67 SLE patients. Subsequently, differential expression analysis was carried out on 19 pairs of age-matched SLE patients with (AT group) or without (Non-AT group) atherosclerosis using peripheral venous blood. We used logistic least absolute shrinkage and selection operator regression to select variables among differentially expressed (DE) genes and clinical features and utilized backward stepwise logistic regression to build an atherosclerosis risk prediction model with all 67 patients. The performance of the prediction model was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses. Results: The 67 patients had a median age of 42.7 (Q1-Q3: 36.6-51.2) years, and 20 (29.9%) had atherosclerosis. A total of 106 DE genes were identified between the age-matched AT and Non-AT groups. Pathway analyses revealed that the AT group had upregulated atherosclerosis signaling, oxidative phosphorylation, and interleukin (IL)-17-related pathways but downregulated T cell and B cell receptor signaling. Keratin 10, age, and hyperlipidemia were selected as variables for the risk prediction model. The AUC and Hosmer-Lemeshow test p-value of the model were 0.922 and 0.666, respectively, suggesting a relatively high discrimination and calibration performance. The prediction model had a higher net benefit in the decision curve analysis than that when predicting with age or hyperlipidemia only. Conclusions: We built an atherosclerotic risk prediction model with one gene and two clinical factors. This model may greatly assist clinicians to identify SLE patients with atherosclerosis, especially asymptomatic atherosclerosis.

This pilot study was aimed at comparing TLR7/TLR9 expression, cytoskeletal arrangement, and cell proliferation by indirect immunofluorescence in parallel lesional and non lesional skin samples of guttate psoriasis (PG) and psoriasis vulgaris (PV) in five male patients for each group (n=10). TLR7 expression was detected throughout all the epidermal compartment in PV samples, while in PG skin was restricted to the granular layer. TLR9 was present in the granular layer of non lesional skin and in the suprabasal layers of PV/PG lesional skin. Cell proliferation was localized in all the epidermal layers in lesional PG and PV, consistently with the immunopositivity for the \"psoriatic keratin\" K16. In the suprabasal layers of lesional PG and PV skin, a similar K17 expression was detected and K10 exhibited a patchy distribution. The present results suggest that TLR7 expression can be considered an intrinsic and differential histomorphological feature of PV.

Despite the progress in chronic wound treatment, antibacterial cutaneous scaffold with high efficiency in wound healing is still the hot spot in the field. In present study, a functionalized silk fibroin (SF) cutaneous scaffold incorporated with natural medicine usnic acid (UA) is investigated, in which UA is used as an antibacterial and wound-healing reagent. Via electrospinning, UA-SF mixture is fabricated into UA-SF composite scaffold (USCS), which is composed of uniform nanofibers with average diameters of around 360 ± 10 nm. The interwoven nanofibers form mesh structure providing sufficient moisture permeability for scaffold. With methanol treatment, USCS presents improved mechanical properties and stability to protease XIV. In the presence of USCS, the growth rate of both Gram-positive and Gram-negative bacteria, including Staphylococcus aureus, Streptococci pyogenes, Escherichia coli, and Pseudomonas aeruginosa, is significantly inhibited in plate culture and suspension assays. In a cutaneous excisional mouse wound model, USCS presents a significant increase of wound closure rate, compared with pure SF scaffold and commercial dressing, Tegaderm Hydrocolloid 3M . The histological assessments further prove that USCS can enhance re-epithelialization, vascularization, and collagen deposition in wound site to promote the wound-healing process, which indicates the potential application of USCS in chronic wound treatment.

Atopic Dermatitis is an inflammatory skin disease associated with broad defects in skin barrier function caused by increased levels of type-2 cytokines (IL-4 and IL-13) that repress keratinocyte (KC) differentiation. Although crucial in mediating allergic disease, the mechanisms for gene repression induced by type-2 cytokines remain unclear. In this study, we determined that gene repression requires the master regulator of the epidermal differentiation program, p63. We found that type-2 cytokine-mediated inhibition of the expression of genes involved in early KC differentiation, including keratin 1, keratin 10, and DSC-1, is reversed by p63 blockade. Type-2 cytokines, through p63, also regulate additional genes involved in KC differentiation, including CHAC-1, STC2, and CALML5. The regulation of the expression of these genes is ablated by p63 small interfering RNA as well. In addition, we found that IL-4 and IL-13 and Staphylococcus aureus lipoteichoic acid work in combination through p63 to further suppress the early KC differentiation program. Finally, we found that IL-4 and IL-13 also inhibit the activity of Notch, a transcription factor required to induce early KC differentiation. In conclusion, type-2 cytokine-mediated gene repression and blockade of KC differentiation are multifactorial, involving pathways that converge on transcription factors critical for epidermal development, p63 and Notch.

Adult-onset inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon cutaneous disease compared to childhood-onset ILVEN. The typical histopathologic features are alternating parakeratosis and orthokeratosis with an absent granular layer underneath parakeratosis, in contrast to a thickened granular layer below the foci of orthokeratosis in psoriasiform epidermal hyperplasia. Herein, we present a 49-year-old woman with typical clinical and histopathologic characteristics of adult-onset ILVEN, including linear arrangement of thick scaly papules and plaques localized on the medial side of her right leg, ankle, and foot. Immunohistochemical studies included involucrin, Ki-67, and keratin-10. Compared to the staining pattern in psoriasis, the expression of involucrin in this case was of lower intensity and localized to upper epidermal layers with relatively less extensive staining beneath regions of parakeratosis as compared to orthokeratosis; Ki-67 showed lower basal layer proliferative activity; and keratin-10 showed a greater intensity of staining within suprabasal epidermis.

Psoriasis is one of the most common chronic inflammatory skin diseases, it is characterized by hyperproliferation of keratinocytes and infiltration of inflammatory cells. Several in vitro studies have reported that interleukin (IL)‑22 is involved in excessive proliferation and abnormal differentiation of human keratinocytes. However, the association between IL‑22 and CCAAT enhancer binding protein α (C/EBPα) in the pathogenesis of psoriasis remains unclear. Therefore, the present study aimed to investigate the association between IL‑22 and C/EBPα, and the effects of IL‑22 on the proliferation and differentiation of keratinocytes. Keratinocytes were treated with different concentrations of IL‑22 (30, 60 and 90 ng/ml) and subsequently cells were collected at different time intervals. The expression levels of the key molecules of the mitogen‑activated protein kinase (MAPK) signaling pathway were detected using western blot analysis. In addition, the effect of IL‑22 on the proliferation rate of keratinocytes and the mRNA expression levels of C/EBPα were determined using a Cell Counting Kit‑8 assay and reverse transcription‑quantitative PCR, respectively. Furthermore, keratinocytes were transfected with C/EBPα small interfering (si)RNA or control using Lipofectamine® 2000. The results revealed that IL‑22 significantly induced the proliferation of keratinocytes and the expression of phosphorylated (p)‑JNK, p‑ERK and p‑p38 (P<0.05). Additionally, IL‑22 significantly inhibited the differentiation of keratinocytes, and the mRNA and protein expression of C/EBPα (P<0.05). Furthermore, downregulation of C/EBPα increased the proliferation rate of keratinocytes and reduced the expression levels of cytokeratin 10 and involucrin. Therefore, these results suggested that the effect of IL‑22 on the proliferation and differentiation of keratinocytes may be mediated via the regulation of the MAPK signaling pathway and the expression of C/EBPα.