Spatiotemporal regulation of cell migration is crucial for animal development and organogenesis. Compared to spatial signals, little is known about temporal signals and the mechanisms integrating the ...two. In the Caenorhabditis elegans hermaphrodite, the stereotyped migration pattern of two somatic distal tip cells (DTCs) is responsible for shaping the gonad. Guidance receptor UNC-5 is necessary for the dorsalward migration of DTCs. We found that BLMP-1, similar to the mammalian zinc finger transcription repressor Blimp-1/PRDI-BF1, prevents precocious dorsalward turning by inhibiting precocious unc-5 transcription and is only expressed in DTCs before they make the dorsalward turn. Constitutive expression of blmp-1 when BLMP-1 would normally disappear delays unc-5 transcription and causes turn retardation, demonstrating the functional significance of blmp-1 down-regulation. Correct timing of BLMP-1 down-regulation is redundantly regulated by heterochronic genes daf-12, lin-29, and dre-1, which regulate the temporal fates of various tissues. DAF-12, a steroid hormone receptor, and LIN-29, a zinc finger transcription factor, repress blmp-1 transcription, while DRE-1, the F-Box protein of an SCF ubiquitin ligase complex, binds to BLMP-1 and promotes its degradation. We have therefore identified a gene circuit that integrates the temporal and spatial signals and coordinates with overall development of the organism to direct cell migration during organogenesis. The tumor suppressor gene product FBXO11 (human DRE-1 ortholog) also binds to PRDI-BF1 in human cell cultures. Our data suggest evolutionary conservation of these interactions and underscore the importance of DRE-1/FBXO11-mediated BLMP-1/PRDI-BF1 degradation in cellular state transitions during metazoan development.
Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome ...the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.
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•pY211-PCNA is important in maintaining the integrity of replication forks•Inhibition of pY211 leads to biogenesis of cytosolic ssDNA•The cytosolic ssDNA activates the cGAS-STING-cytokine inflammatory pathway•Abrogation of pY211-PCNA induces an anti-tumor immunity mediated by NK cells
Wang et al. show that abrogation of Y211 phosphorylation of PCNA leads to replication fork collapse and cytosolic ssDNA, which triggers the cGAS-STING cascade to release type I interferons from tumor cells. Loss of Y211 phosphorylation results in anti-tumor immunity by NK cells and subsequently the suppression of distant metastasis.
Binding of transcription factors (TFs) promotes the subsequent recruitment of coactivators and preinitiation complexes to initiate eukaryotic transcription, but this time course is usually not ...visualized. It is commonly assumed that recruited factors eventually co-reside in a higher-order structure, allowing distantly bound TFs to activate transcription at core promoters. We use live imaging of endogenously tagged proteins, including the pioneer TF Zelda, the coactivator dBrd4, and RNA polymerase II (RNAPII), to define a cascade of events upstream of transcriptional initiation in early Drosophila embryos. These factors are sequentially and transiently recruited to discrete clusters during activation of non-histone genes. Zelda and the acetyltransferase dCBP nucleate dBrd4 clusters, which then trigger pre-transcriptional clustering of RNAPII. Subsequent transcriptional elongation disperses clusters of dBrd4 and RNAPII. Our results suggest that activation of transcription by eukaryotic TFs involves a succession of distinct biomolecular condensates that culminates in a self-limiting burst of transcription.
Acquisition of chromatin modifications during embryogenesis distinguishes different regions of an initially naïve genome. In many organisms, repetitive DNA is packaged into constitutive ...heterochromatin that is marked by di/trimethylation of histone H3K9 and the associated protein HP1a. These modifications enforce the unique epigenetic properties of heterochromatin. However, in the early
embryo, the heterochromatin lacks these modifications, which appear only later, when rapid embryonic cell cycles slow down at the midblastula transition (MBT). Here we focus on the initial steps restoring heterochromatic modifications in the embryo. We describe the JabbaTrap, a technique for inactivating maternally provided proteins in embryos. Using the JabbaTrap, we reveal a major requirement for the methyltransferase Eggless/SetDB1 in the establishment of heterochromatin. In contrast, other methyltransferases contribute minimally. Live imaging reveals that endogenous Eggless gradually accumulates on chromatin in interphase but then dissociates in mitosis, and its accumulation must restart in the next cell cycle. Cell cycle slowing as the embryo approaches the MBT permits increasing accumulation and action of Eggless at its targets. Experimental manipulation of interphase duration shows that cell cycle speed regulates Eggless. We propose that developmental slowing of the cell cycle times embryonic heterochromatin formation.
The non-fullerene acceptors (NFAs) employed in state-of-art organic photovoltaics (OPVs) often exhibit strong quadrupole moments which can strongly impact on material energetics. Herein, we show that ...changing the orientation of Y6, a prototypical NFA, from face-on to more edge-on by using different processing solvents causes a significant energetic shift of up to 210 meV. The impact of this energetic shift on OPV performance is investigated in both bilayer and bulk-heterojunction (BHJ) devices with PM6 polymer donor. The device electronic bandgap and the rate of non-geminate recombination are found to depend on the Y6 orientation in both bilayer and BHJ devices, attributed to the quadrupole moment-induced band bending. Analogous energetic shifts are also observed in other common polymer/NFA blends, which correlates well with NFA quadrupole moments. This work demonstrates the key impact of NFA quadruple moments and molecular orientation on material energetics and thereby on the efficiency of high-performance OPVs.
Abstract
Malignant brain tumors consist of malignancies originated primarily within the brain and the metastatic lesions disseminated from other organs. In spite of intensive studies, malignant brain ...tumors remain to be a medical challenge. Patient-derived organoid (PDO) can recapitulate the biological features of the primary tumor it was derived from and has emerged as a promising drug-screening model for precision therapy. Here we show a proof-of-concept based on early clinical study entailing the organoids derived from the surgically resected tumors of 26 patients with advanced malignant brain tumors enrolled during December 2020 to October 2021. The tumors included nine glioma patients, one malignant meningioma, one primary lymphoma patient, and 15 brain metastases. The primary tumor sites of the metastases included five from the lungs, three from the breasts, two from the ovaries, two from the colon, one from the testis, one of melanoma origin, and one of chondrosarcoma. Out of the 26 tissues, 13 (50%) organoids were successfully generated with a culture time of about 2 weeks. Among these patients, three were further pursued to have the organoids derived from their tumor tissues tested for the sensitivity to different therapeutic drugs in parallel to their clinical care. Our results showed that the therapeutic effects observed by the organoid models were consistent to the responses of these patients to their treatments. Our study suggests that PDO can recapitulate patient responses in the clinic with high potential of implementation in personalized medicine of malignant brain tumors.
Abstract
An integrative multi-omics database is needed urgently, because focusing only on analysis of one-dimensional data falls far short of providing an understanding of cancer. Previously, we ...presented DriverDB, a cancer driver gene database that applies published bioinformatics algorithms to identify driver genes/mutations. The updated DriverDBv3 database (http://ngs.ym.edu.tw/driverdb) is designed to interpret cancer omics’ sophisticated information with concise data visualization. To offer diverse insights into molecular dysregulation/dysfunction events, we incorporated computational tools to define CNV and methylation drivers. Further, four new features, CNV, Methylation, Survival, and miRNA, allow users to explore the relations from two perspectives in the ‘Cancer’ and ‘Gene’ sections. The ‘Survival’ panel offers not only significant survival genes, but gene pairs synergistic effects determine. A fresh function, ‘Survival Analysis’ in ‘Customized-analysis,’ allows users to investigate the co-occurring events in user-defined gene(s) by mutation status or by expression in a specific patient group. Moreover, we redesigned the web interface and provided interactive figures to interpret cancer omics’ sophisticated information, and also constructed a Summary panel in the ‘Cancer’ and ‘Gene’ sections to visualize the features on multi-omics levels concisely. DriverDBv3 seeks to improve the study of integrative cancer omics data by identifying driver genes and contributes to cancer biology.
Perovskite light-emitting diode (PeLED) has been vigorously developed in recent years. As it has demonstrated good performance on the rigid substrates, the next important direction of PeLED is its ...integration with stretchable components to realize stretchable, responsive device. Here, we describe a facile fabrication of stretchable perovskite light-emissive touch-responsive devices (PeLETDs) by utilizing highly transparent and conductive polyurethane/silver nanowires (PU/AgNWs) as the electrode. Meanwhile, a stretchable tricomposite perovskite emissive layer was developed by blending a small amount of poly(ethylene oxide) (PEO) and poly(vinylpyrrolidone) (PVP) with CsPbBr3. Additionally, a thin PVP layer was introduced at the bottom of the emissive layer. On one hand, it can further improve the morphology of the emissive layer; on the other hand, it can serve as an electron-injection barrier to reduce the high nonradiative recombination at the corresponding interface. Further, to fulfill the responsive function of the fabricated PeLEDs, a poly(ethylene terephthalate) (PET) spacer with a 100 μm thickness was inserted between the top electrode and the emissive layer. A stretchable PeLETD is finally demonstrated to possess a low turn-on voltage of 2 V with a brightness of 380.5 cd m–2 at 7.5 V and can sustain 30% uniaxial strain with a small luminance variation of 24%. More interestingly, our stretchable PeLETD exhibited high stability, which could be well touch responsivity, where the luminance is on/off switched for 300 cycles by repeatedly applying pressure.
Background The development of autoimmune sequelae is one of the characteristic features of drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome; ...however, the incidence of sequelae and prognosis of patients with DRESS are unknown. Objective We sought to investigate the incidence of sequelae, including less well-known sequelae, and long-term prognosis in patients with DRESS/drug-induced hypersensitivity syndrome. Methods A retrospective cohort study was conducted at a medical center in northern Taiwan using a DRESS/drug-induced hypersensitivity syndrome database. Patients who were followed up for at least 1 year were included in the study. Results Nine patients died before interview, whereas 43 patients completed a specially designed questionnaire. The overall cumulative incidence of long-term sequelae was 11.5% (6 of 52 patients). Four patients developed autoimmune diseases, specifically Graves disease (n = 2), type 1 diabetes mellitus (n = 1), and autoimmune hemolytic anemia (n = 1). Alopecia areata was also noted in 1 of the 2 patients with Graves disease. The other 2 patients developed renal failure after visceral involvement and required lifetime hemodialysis. Limitations Our study included a small number of patients. Further, viral studies were not performed. Conclusion The sequelae of DRESS can be divided into 2 major types that appear to occur in different age groups: young patients tend to develop autoimmune diseases, whereas elderly patients are more vulnerable to end-organ failure.
Background Generalized bullous fixed drug eruption (GBFDE), a particular form of fixed drug eruption (FDE), is characterized by widespread blisters and erosions and can be confused with ...Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Objective We sought to analyze specific features of GBFDE and differentiate it from SJS/TEN. Methods We retrospectively studied patients with GBFDE and SJS/TEN during a period of 10 years. GBFDE was defined as typical FDE lesions with blisters involving at least 10% body surface area on at least 3 of 6 different anatomic sites. Clinical presentations; histopathological features; immunohistochemical patterns of cluster-of-differentiation (CD)3, CD4, CD8, CD56, Fas, Fas ligand, granzyme B, perforin, granulysin, and forkhead box P3 (Foxp3); and serum granulysin levels were compared. Results Twenty-three cases of GBFDE were collected. Patients with GBFDE had shorter latent periods, less mucosal involvement, more eosinophil infiltration, and dermal melanophages. Lesional infiltrates in GBFDE had more dermal CD4+ cells including Foxp3+ regulatory T cells, fewer intraepidermal CD56+ cells, and fewer intraepidermal granulysin+ cells. The serum level of granulysin in GBFDE was also significantly lower than in SJS/TEN. Limitations The number of cases in this study is small. Conclusion GBFDE is a distinct disease distinguishable from SJS/TEN by particular features such as granulysin, CD56, and Foxp3 expressions.
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