NUT midline carcinoma as a primary lung tumor treated with anlotinib combined with palliative radiotherapy: a case report

Background NUT (nuclear protein in testis) midline carcinoma (NMC) is a rapidly progressive tumor arising from midline structures. Recent cases have reported that the poor prognosis with a median survival of 6.7 months and a 2 years overall survival of 19% due to limited treatment. Based on the effect of arotinib on inhibiting tumor growth and angiogenesis. We present one patient case treated with anlotinib and radiotherapy. Case presentation Here, we describe a 33-year old patient who complained of cough and chest pain and was diagnosed as a pulmonary NMC through CT scan, FISH and immunohistochemistry. In addition, we initially demonstrated that anlotinib combined with palliative radiotherapy could significantly prevent the tumor growth in a pulmonary NMC. Conclusion The report indicated that anlotinib combined with palliative radiotherapy could inhibit the tumor progression in a pulmonary NMC, which may provide a combined therapy to pulmonary NMC in the future.

NnABI4-Mediated ABA Regulation of Starch Biosynthesis in Lotus (Nelumbo nucifera Gaertn)

Starch is an important component in lotus. ABA is an important plant hormone, which plays a very crucial role in regulating plant starch synthesis. Using ‘MRH’ as experimental materials, the leaves were sprayed with exogenous ABA before the rhizome expansion. The results showed that stomatal conductance and transpiration rate decreased while net photosynthetic rate increased. The total starch content of the underground rhizome of lotus increased significantly. Meanwhile, qPCR results showed that the relative expression levels of NnSS1, NnSBE1 and NnABI4 were all upregulated after ABA treatment. Then, yeast one-hybrid and dual luciferase assay suggested that NnABI4 protein can promote the expression of NnSS1 by directly binding to its promoter. In addition, subcellular localization results showed that NnABI4 encodes a nuclear protein, and NnSS1 protein was located in the chloroplast. Finally, these results indicate that ABA induced the upregulated expression of NnABI4, and NnABI4 promoted the expression of NnSS1 and thus enhanced starch accumulation in lotus rhizomes. This will provide a theoretical basis for studying the molecular mechanism of ABA regulating starch synthesis in plant.

Importance of the Q/N-rich Segment for Protein Stability and Activity of Endogenous Mouse TDP-43

TAR DNA-binding protein 43 kDa (TDP-43), a nuclear protein, plays an important role in the molecular pathogenesis of amyotrophic lateral sclerosis (ALS). TDP-43 aggregation and translocation out of the nucleus are crucial factors in ALS. TDP-43 aggregation results from its resistance to degradation, to which the long-disordered C-terminal region (CTR) is thought to contribute. The CTR has two Gly, aromatic, and Ser-rich (GaroS) segments and an amyloidogenic core divided into a hydrophobic patch and a Gln/Asn (Q/N)-rich segment. Although TDP-43 lacking the CTR is known to be unstable, as observed in knock-in mice, it is unclear which of these segments contributes to the stability of TDP-43. Here, we generated 12 mouse lines lacking the various sub-regions of CTR by genome editing and compared the protein stability, activity, and subcellular localization of TDP-43. We demonstrated the functional diversity of the four segments of CTR, finding that the presence of Q/N-rich segment greatly restored the protein stability and activity of TDP-43. In addition, we found that the second GaroS deletion did not affect protein stability and mouse development.

Chromosome clustering in mitosis by the nuclear protein Ki-67

Ki-67 is highly expressed in proliferating cells, a characteristic that made the protein a very important proliferation marker widely used in the clinic. However, the molecular functions and properties of Ki-67 remained quite obscure for a long time. Only recently important discoveries have shed some light on its function and shown that Ki-67 has a major role in the formation of mitotic chromosome periphery compartment, it is associated with protein phosphatase one (PP1) and regulates chromatin function in interphase and mitosis. In this review, we discuss the role of Ki-67 during cell division. Specifically, we focus on the importance of Ki-67 in chromosome individualisation at mitotic entry (prometaphase) and its contribution to chromosome clustering and nuclear remodelling during mitotic exit.

Inner Nuclear Protein Matrin-3 Coordinates Hematopoietic Cell Transcription and Differentiation By Stabilizing Chromatin Architecture

The nucleus is spatially organized by chromosome and interchromatin functional components. Global reorganization of chromatin interactions and compartmentalization occurring during differentiation requires proper chromosome positioning, but the involvement of nuclear components in this process remains largely underexplored. In particular, blood cell development exemplifies a coordinated process accompanied by dramatic chromatin reorganization, thereby providing a model in which to interrogate chromatin dynamics during differentiation. Here, we show that an abundant inner nuclear protein Matrin-3 (Matr3) plays a critical role in the maintenance of chromatin structure and has a broad effect on erythroid cell differentiation by coordinating gene expression. First, we deleted the entire gene body by CRISPR/Cas9 in mouse erythroleukemia (MEL) cells. The Matr3 knockout (KO) cells proliferate normally and exhibit morphological changes on differentiation suggestive of accelerated maturation. Consistently, erythroid-specific genes were expressed at a higher level in MEL Matr3 KO cells than in parental cells. The consequences of Matr3 deletion were also determined in G1ER cells, in which differentiation is conditional on activation of GATA-1. To assess the global impact of Matr3 loss on erythroid cell maturation, we measured global RNA expression changes. Erythroid-specific genes were expressed at a much higher level upon differentiation of Matr3 KO cells. Differentiation is typically accompanied by specific changes in nuclear architecture. Using super-resolution microscopy, we observed that heterochromatin protein 1α (HP1α) was more dispersed and irregular in appearance in Matr3 KO cells, suggesting that Matr3 loss alters morphological boundaries of heterochromatin. Analysis of the interactions between different regions of chromatin identifies topologically associating domains and classifies the genome into two compartments (A and B). The A and B compartments correspond to the structures and characteristics of known euchromatin and heterochromatin, respectively. We next explored global chromatin structure using a high-throughput chromosome conformation capture (Hi-C) assay. In Matr3 KO cells, insulation at the domain boundaries was reduced, and the compartment strengths between the B compartments became stronger, while those between A-type domains were reduced. Remarkably, we found that these changes in cells lacking Matr3 were similar to changes in chromatin contact during differentiation. To access the genomic features at a higher resolution, we performed the assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq). Notably, the newly opened regions in Matr3 KO, as compared to parental, cells were enriched for GATA motifs, which are generally more accessible in differentiated erythroid cells. Architectural proteins function cooperatively to organize chromatin. Using affinity purification followed by mass spectrometry and immunoblotting, we found that Matr3 interacts with proteins involved in chromatin remodeling, such as CTCF and cohesin. To identify whether Matr3 loss alters chromatin occupancy of its interacting partners, we performed ChIP-seq for CTCF and the core cohesin component Rad21. In the absence of Matr3, occupancy of CTCF and Rad21 was perturbed in a subset of genomic regions. Moreover, destabilization of CTCF and cohesin binding correlated with altered transcription and accelerated erythroid differentiation. Most sites with disrupted CTCF and Rad21 binding during differentiation were also sensitive to the absence of the scaffold protein Matr3. Our data demonstrate that the nucleoplasmic protein Matr3 stabilizes the binding of the architectural proteins (CTCF and cohesin) to chromatin and serves to maintain chromatin structure. We speculate that Matr3 negatively regulates cell fate transitions by maintaining cellular state through fine-tuning the binding of CTCF/cohesin to chromatin and associated 3D interactions. Our work reveals a previously unrecognized role of Matr3 in chromatin organization and responses to developmental cues. Disclosures No relevant conflicts of interest to declare.

Inner nuclear protein Matrin-3 coordinates cell differentiation by stabilizing chromatin architecture

Precise control of gene expression during differentiation relies on the interplay of chromatin and nuclear structure. Despite an established contribution of nuclear membrane proteins to developmental gene regulation, little is known regarding the role of inner nuclear proteins. Here we demonstrate that loss of the nuclear scaffolding protein Matrin-3 (Matr3) in erythroid cells leads to morphological and gene expression changes characteristic of accelerated maturation, as well as broad alterations in chromatin organization similar to those accompanying differentiation. Matr3 protein interacts with CTCF and the cohesin complex, and its loss perturbs their occupancy at a subset of sites. Destabilization of CTCF and cohesin binding correlates with altered transcription and accelerated differentiation. This association is conserved in embryonic stem cells. Our findings indicate Matr3 negatively affects cell fate transitions and demonstrate that a critical inner nuclear protein impacts occupancy of architectural factors, culminating in broad effects on chromatin organization and cell differentiation.

Differential expression of THYN1 in cancer of the vulva.

In these brief notes we document work using published microarray data (1, 2) to pioneer integrative transcriptome analysis comparing vulvar carcinoma to its tissue of origin, the vulva. We report the differential expression of thymocyte nuclear protein 1, encoded by THYN1, in cancer of the vulva. THYN1 may be of pertinence to understanding transformation and disease progression in vulvar cancer (3).

Monophyletic blowflies revealed by phylogenomics

Background Blowflies are ubiquitous insects, often shiny and metallic, and the larvae of many species provide important ecosystem services (e.g., recycling carrion) and are used in forensics and debridement therapy. Yet, the taxon has repeatedly been recovered to be para- or polyphyletic, and the lack of a well-corroborated phylogeny has prevented a robust classification. Results We here resolve the relationships between the different blowfly subclades by including all recognized subfamilies in a phylogenomic analysis using 2221 single-copy nuclear protein-coding genes of Diptera. Maximum likelihood (ML), maximum parsimony (MP), and coalescent-based phylogeny reconstructions all support the same relationships for the full data set. Based on this backbone phylogeny, blowflies are redefined as the most inclusive monophylum within the superfamily Oestroidea not containing Mesembrinellidae, Mystacinobiidae, Oestridae, Polleniidae, Sarcophagidae, Tachinidae, and Ulurumyiidae. The constituent subfamilies are re-classified as Ameniinae (including the Helicoboscinae, syn. nov.), Bengaliinae, Calliphorinae (including Aphyssurinae, syn. nov., Melanomyinae, syn. nov., and Toxotarsinae, syn. nov.), Chrysomyinae, Luciliinae, Phumosiinae, Rhiniinae stat. rev., and Rhinophorinae stat. rev. Metallic coloration in the adult is shown to be widespread but does not emerge as the most likely ground plan feature. Conclusions Our study provides the first phylogeny of oestroid calyptrates including all blowfly subfamilies. This allows settling a long-lasting controversy in Diptera by redefining blowflies as a well-supported monophylum, and blowfly classification is adjusted accordingly. The archetypical blowfly trait of carrion-feeding maggots most likely evolved twice, and the metallic color may not belong to the blowfly ground plan.