Single-Cell Network-Based Drug Repositioning for Discovery of Therapies against Anti-Tumour Necrosis Factor-Resistant Crohns Disease.

Primary and secondary non-response affects approximately 50% of patients with Crohns disease treated with anti-tumour necrosis factor (TNF) monoclonal antibodies. To date, very little single cell research exists regarding drug repurposing in Crohns disease. We aimed to elucidate the cellular phenomena underlying resistance to anti-TNF therapy in patients with Crohns disease and to identify potential drug candidates for these patients. Single-cell transcriptome analyses were performed using data (GSE134809) from the Gene Expression Omnibus and Library of Integrated Network-Based Cellular Signatures L1000 Project. Data aligned to the Genome Reference Consortium Human Build 38 reference genome using the Cell Ranger software were processed using the Seurat package. To capture significant functional terms, gene ontology functional enrichment analysis was performed on the marker genes. For biological analysis, 93,893 cells were retained (median 20,163 genes). Through marker genes, seven major cell lineages were identified: B-cells, T-cells, natural killer cells, monocytes, endothelial cells, epithelial cells, and tissue stem cells. In the anti-TNF-resistant samples, the top 10 differentially expressed genes were HLA-DQB-1, IGHG1, RPS23, RPL7A, ARID5B, LTB, STAT1, NAMPT, COTL1, ISG20, IGHA1, IGKC, and JCHAIN, which were robustly distributed in all cell lineages, mainly in B-cells. Through molecular function analyses, we found that the biological functions of both monocyte and T-cell groups mainly involved immune-mediated functions. According to multi-cluster drug repurposing prediction, vorinostat is the top drug candidate for patients with anti-TNF-refractory Crohns disease. Differences in cell populations and immune-related activity within tissues may influence the responsiveness of Crohns disease to anti-TNF agents. Vorinostat may serve as a promising novel therapy for anti-TNF-resistant Crohns disease

Pathogenicity of a Sclerotia-Forming Fungus, Sclerotinia trifoliorum BWC98-105, to Burcucumber (Sicyos angulatus)

Burcucumber (Sicyos angluatus) is a representative ecosystem-disturbing plant in Korea and currently widely spread throughout the country. A sclerotia-forming fungus with moderate host selectivity, Sclerotinia trifoliorum BWC98-105, was tested in the laboratory, green house and natural habitat for its pathogenicity to burcucumber. When mycelial culture fragment was inoculated to burcucumber seedlings under the green house condition, mycelial growth was observed in the following day, and then resulted in the onset of wilting from 5 days after inoculation (DAI). Its characteristic sclerotia as a sign was observed from 7 DAI, and thus plants turned into dark-brown color at the bottom of stem of burcucumber that was eventually blighted at 14 DAI. Similar visible symptoms were observed in natural habitat. Based on the results of showing typical blight symptom to burcucumber and the sign of sclerotia, we report S. trifoliorum BWC98-105 causing stem blight against burcucumber. Its globular pellet was considered of having quite potential as a bioherbicide to control burcucumber in Korea

KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics.

Pancreatic cancer (PC), one of the most aggressive and life-threatening human malignancies, is known for its resistance to cytotoxic therapies. This is increasingly ascribed to the subpopulation of undifferentiated cells, known as pancreatic cancer stem cells (PCSCs), which display greater evolutionary fitness than other tumor cells to evade the cytotoxic effects of chemotherapy. PCSCs are crucial for tumor relapse as they possess stem cell-like features that are characterized by self-renewal and differentiation. However, the molecular mechanisms that maintain the unique characteristics of PCSCs are poorly understood. Here, we identify the histone methyltransferase KMT2A as a physical binding partner of an RNA polymerase-associated PHF5A-PHF14-HMG20A-RAI1 protein subcomplex and an epigenetic regulator of PCSC properties and functions. Targeting the protein subcomplex in PCSCs with a KMT2A-WDR5 inhibitor attenuates their self-renewal capacity, cell viability, and in vivo tumorigenicity

A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer.

Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ~10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients mutations would improve patients outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer

Facile Microfluidic Fabrication of 3D hydrogel SERS Substrate with High Reusability and Reproducibility via Programmable Maskless Flow Microlithography

In the field of surface???enhanced Raman scattering (SERS), advances in nanotechnology and surface chemistry have contributed to fabricating the metal substrates with highly sophisticated architectures and strong binding affinity to target molecules which enhanced the sensitivity to target molecules. However, the elaborate yet complicated steps for the synthesis, patterning, and surface modification of metal substrates have often resulted in compromising the reliability, reproducibility, and reusability as SERS substrates. Here, a fully programmable and automated digital maskless flow microlithography process that spatiotemporally controls the fluid flow, UV irradiation, and the shape and location of SERS polymer matrix is provided to fabricate a reliable, reproducible, and reusable hydrogel???based 3D SERS substrate. The SERS substrates are located inside the microfluidic device in the form of disk???shaped hydrogels. By rationally designing the functional group chemistry of the hydrogel microposts, Ag nanoparticles are homogeneously synthesized in situ, a target molecule is amplified by 25???fold inside the microposts, and an enhancement factor as high as 2.4 ?? 108 is observed. Furthermore, a highly reusable multitarget sensing capability is demonstrated by a sequential analysis of multiple analytes without the trace of former analytes via the intermittent washing step

Dynamic multimodal holograms of conjugated organogels via dithering mask lithography

Polymeric materials have been used to realize optical systems that, through periodic variations of their structural or optical properties, interact with light-generating holographic signals. Complex holographic systems can also be dynamically controlled through exposure to external stimuli, yet they usually contain only a single type of holographic mode. Here, we report a conjugated organogel that reversibly displays three modes of holograms in a single architecture. Using dithering mask lithography, we realized two-dimensional patterns with varying cross-linking densities on a conjugated polydiacetylene. In protic solvents, the organogel contracts anisotropically to develop optical and structural heterogeneities along the third dimension, displaying holograms in the form of three-dimensional full parallax signals, both in fluorescence and bright-field microscopy imaging. In aprotic solvents, these heterogeneities diminish as organogels expand, recovering the two-dimensional periodicity to display a third hologram mode based on iridescent structural colours. Our study presents a next-generation hologram manufacturing method for multilevel encryption technologies. Periodic patterns with varying cross-linking densities are realized in conjugated polydiacetylene films, creating multiple holographic images-all dynamically responsive to exposure to various solvents-simultaneously in the same polymeric structures