Antibody-SGM, a Score-Based Generative Model for Antibody Heavy-Chain Design.

Traditional computational methods for antibody design involved random mutagenesis followed by energy function assessment for candidate selection. Recently, diffusion models have garnered considerable attention as cutting-edge generative models, lauded for their remarkable performance. However, these methods often focus solely on the backbone or sequence, resulting in the incomplete depiction of the overall structure and necessitating additional techniques to predict the missing component. This study presents Antibody-SGM, an innovative joint structure-sequence diffusion model that addresses the limitations of existing protein backbone generation models. Unlike previous models, Antibody-SGM successfully integrates sequence-specific attributes and functional properties into the generation process. Our methodology generates full-atom native-like antibody heavy chains by refining the generation to create valid pairs of sequences and structures, starting with random sequences and structural properties. The versatility of our method is demonstrated through various applications, including the design of full-atom antibodies, antigen-specific CDR design, antibody heavy chains optimization, validation with Alphafold3, and the identification of crucial antibody sequences and structural features. Antibody-SGM also optimizes protein function through active inpainting learning, allowing simultaneous sequence and structure optimization. These improvements demonstrate the promise of our strategy for protein engineering and significantly increase the power of protein design models.

Score-based generative modeling for de novo protein design.

The generation of de novo protein structures with predefined functions and properties remains a challenging problem in protein design. Diffusion models, also known as score-based generative models (SGMs), have recently exhibited astounding empirical performance in image synthesis. Here we use image-based representations of protein structure to develop ProteinSGM, a score-based generative model that produces realistic de novo proteins. Through unconditional generation, we show that ProteinSGM can generate native-like protein structures, surpassing the performance of previously reported generative models. We experimentally validate some de novo designs and observe secondary structure compositions consistent with generated backbones. Finally, we apply conditional generation to de novo protein design by formulating it as an image inpainting problem, allowing precise and modular design of protein structure.

A Family-Engaged Educational Program for Atopic Dermatitis: A Seven-Year, Multicenter Experience in Daegu-Gyeongbuk, South Korea.

BACKGROUND: It is important to educate families of pediatric patients with atopic dermatitis (AD) so that they have a correct understanding of AD. OBJECTIVE: The purpose of this study is to introduce, evaluate, and improve our family-engaged educational program. METHODS: Children suffering from AD and their families have participated in a half-day educational program called "AD school" with catchy slogans such as "Enjoy with AD Families!" every year since 2005. Educational lectures were conducted for parents. For children with AD, various entertaining programs were provided. A feedback survey about AD school was administered for the purpose of evaluation. RESULTS: A total of 827 people (376 patients and 451 family members) participated in this program over 7 years. On-site surveys showed a positive response (i.e., "excellent" or "good") for the prick test (95.1%), emollient education (78.4%), educational lecture (97.0%), drawing contest and games (90.2%), and recreation (magic show; 99.0%) respectively. Telephone surveys one year later also elicited a positive response. CONCLUSION: We herein introduce the experience of a half-day, family-engaged educational program for AD. Family-engaged education programs for AD such as this AD school encourage and validate family participation in the treatment of their children's AD.

Possible existence of melanocytes or melanoblasts in human sebaceous glands.

BACKGROUND: Melanocytes are present in both basal epidermis and hair follicles. Melanocyte stem cells have been found in hair follicle bulge. During embryogenesis, the outer cells of the bulge differentiate into the sebaceous gland (SG) and proliferate. OBJECTIVE: To identify and determine the distribution and morphological characteristics of melanocytes in human SGs. METHODS: A total of 171 biopsy specimens of face and scalp were studied. Of these specimens, 103 samples contained SGs. We conducted a retrospective review of slides stained with H&E, F-M, anti-S100, anti-c-kit, anti-HMB-45, anti-CD1a, anti-MITF, and anti-tyrosinase. The presence and distribution of melanocytes in human SGs was also evaluated by electron microscopy. In addition, melanocytes were isolated from SGs for primary culture. RESULTS: S-100-positive cells were observed mainly at the periphery of SGs in 34 of 54 specimens. We did not find F-M-positive and HMB-45-positive cells in SGs. CD1a-positve cells were identified in two specimens. We also found c-kit-, MITF-, and tyrosinase-positive cells in SGs. Electron micrograph showed the presence of melanocytes in the suprabasal portion of SGs. These melanocytes showed fewer melanin-containing granules than the melanocytes of basal epidermis. However, the individually distributed melanosomes in suprabasal melanocytes were larger than those in epidermal melanocytes. Primary culture of melanocytes derived from SGs showed morphologically homogeneous, slender cell bodies with few dendrites. CONCLUSION: Our study confirms the presence of non-melanogenic melanocytes and Langerhans cells in human SGs. In addition, the characteristics of the melanocytes in SGs were found to be different from those of the epidermal melanocytes.

Interleukin-6-induced Twist and N-cadherin enhance melanoma cell metastasis.

Melanoma patients frequently have elevated serum levels of interleukin-6 (IL-6), which is correlated with a poor prognosis. IL-6 activates STAT3 phosphorylation, inducing the transcription of genes that regulate tumor cell proliferation and antiapoptosis. In addition, recent evidence suggests that IL-6 induces the epithelial-to-mesenchymal transition and enhances the invasiveness of tumor cells of epithelial origin. However, it is unknown whether IL-6 affects mesenchymal tumor cells. In this study, we examined the effects of IL-6 on melanoma cells and found that IL-6 can enhance their metastatic potential by regulating the expression of Twist and N-cadherin. First, we confirmed that human melanoma tissues express IL-6 (especially at the lesion site), the IL-6 receptor, N-cadherin, and nuclear Twist. Next, we found that IL-6 induces STAT3 phosphorylation in WM-266-4 human melanoma cells, resulting in transient upregulation of Twist, which is a key regulator of metastasis. Importantly, the expression of N-cadherin, a protein downstream of Twist, was also increased on the cell surface after treatment with IL-6. These cells showed enhanced invasiveness, assessed using an invasion assay, and formed more metastatic nodules in the lungs of NOD-SCID mice after an intravenous injection. Importantly, melanoma cells with knocked-down N-cadherin formed less lung nodules compared with control in the NOD-SCID mouse model. Our data suggest that increased serum IL-6 in cancer patients could increase the invasiveness of melanoma cells and accelerate metastasis. Blocking IL-6 in the melanoma microenvironment may therefore inhibit disease progression.