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1.
SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.
Maraschi, A, Gumina, V, Dragotto, J, Colombrita, C, Mompeán, M, Buratti, E, Silani, V, Feligioni, M, Ratti, A
Molecular neurobiology. 2021;(11):5682-5702
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Abstract
The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106-110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.
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2.
Stem cell plasticity and regenerative potential regulation through Ca2+-mediated mitochondrial nuclear crosstalk.
Paliwal, S, Fiumera, HL, Mohanty, S
Mitochondrion. 2021;:1-14
Abstract
The multi-lineage differentiation potential is one of the prominent mechanisms through which stem cells can repair damaged tissues. The regenerative potential of stem cells is the manifestation of several changes at the structural and molecular levels in stem cells that are regulated through intricate mitochondrial-nuclear interactions maintained by Ca2+ ion signaling. Despite the exhilarating evidences strengthening the versatile and indispensible role of Ca2+ in regulating mitochondrial-nuclear interactions, the extensive details of signaling mechanisms remains largely unexplored. In this review we have discussed the effect of Ca2+ ion mediated mitochondrial-nuclear interactions participating in stem plasticity and its regenerative potential.
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3.
Unraveling the multifaceted nature of the nuclear function of mTOR.
Torres, AS, Holz, MK
Biochimica et biophysica acta. Molecular cell research. 2021;(2):118907
Abstract
Positioned at the axis between the cell and its environment, mTOR directs a wide range of cellular activity in response to nutrients, growth factors, and stress. Our understanding of the role of mTOR is evolving beyond the spatial confines of the cytosol, and its role in the nucleus becoming ever more apparent. In this review, we will address various studies that explore the role of nuclear mTOR (nmTOR) in specific cellular programs and how these pathways influence one another. To understand the emerging roles of nuclear mTOR, we discuss data and propose plausible mechanisms to offer novel ideas, hypotheses, and future research directions.
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4.
Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: Epidemiology and Long-Term Outcomes in a Strictly Defined Cohort.
Chung, R, Guan, H, Ponchiardi, C, Cerda, S, Marwaha, N, Yilmaz, OH, Pinjic, E, McAneny, D, Lee, SL, Drake, FT
Thyroid : official journal of the American Thyroid Association. 2021;(1):68-75
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Abstract
Background: A subset of encapsulated/circumscribed follicular variant of papillary thyroid carcinoma (FVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016 to reduce overtreatment of a low-risk tumor. Study objectives were to describe the epidemiology and long-term outcomes of NIFTP in a high-volume, urban, tertiary referral center. Methods: Among patients enrolled in the Boston Medical Center (BMC) Thyroid Cancer Registry, 110 cases of FVPTC underwent index thyroid surgery at BMC between 2000 and 2016. Historically, BMC pathologists assess all malignant nodules using sections ≤0.3 cm with evaluation of the entire nodule and capsule. After review of pathology reports to identify potential NIFTPs, slides were rereviewed using criteria established by the NIFTP Working Group in 2016 and 2018. We evaluated interobserver reliability using Cohen's Kappa coefficient. Results: Among 110 FVPTCs, 15 (13%) met NIFTP criteria; 11 women and 4 men, age range 31-64 (mean 47.5) years. Mean tumor diameter was 1.7 cm (compared with 2.2 cm for FVPTC). Among NIFTP cases, there were no lymph node metastases, distant metastases, or tumor recurrences. All NIFTP cases were American Thyroid Association (ATA) low risk compared with only 68% of FVPTC (p = 0.011). Among FVPTCs, 14% had positive lymph nodes at index operation. Four patients (4%) had distant metastases. Mean follow-up time was 46 and 69 months for FVPTC and NIFTP, respectively. Among FVPTCs with an excellent response to therapy (2015 ATA guidelines), there were no recurrences. Just over half (n = 8) of patients with NIFTP received postoperative radioactive iodine (RAI) therapy. Concordance between pathologists was high for ruling out NIFTP (75%), but only 36% for ruling in NIFTP. Overall, for NIFTP designation, Cohen's Kappa was 0.39, which is considered fair. Conclusions: Although this is a relatively small cohort, all NIFTP specimens underwent updated pathology review consistent with current guidelines; mean follow-up was nearly 6 years. NIFTP represents a small fraction of the total papillary neoplasia diagnosed at this tertiary referral center (2.3%). None of the NIFTP cohort experienced an adverse oncologic event, and there were no regional or distant metastases. Over 50% of patients with NIFTP received RAI. Thus, the NIFTP reclassification may substantially reduce the number of patients who require adjuvant therapies, such as completion surgery or RAI.
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5.
Advancing organelle genome transformation and editing for crop improvement.
Li, S, Chang, L, Zhang, J
Plant communications. 2021;(2):100141
Abstract
Plant cells contain three organelles that harbor DNA: the nucleus, plastids, and mitochondria. Plastid transformation has emerged as an attractive platform for the generation of transgenic plants, also referred to as transplastomic plants. Plastid genomes have been genetically engineered to improve crop yield, nutritional quality, and resistance to abiotic and biotic stresses, as well as for recombinant protein production. Despite many promising proof-of-concept applications, transplastomic plants have not been commercialized to date. Sequence-specific nuclease technologies are widely used to precisely modify nuclear genomes, but these tools have not been applied to edit organelle genomes because the efficient homologous recombination system in plastids facilitates plastid genome editing. Unlike plastid transformation, successful genetic transformation of higher plant mitochondrial genome transformation was tested in several research group, but not successful to date. However, stepwise progress has been made in modifying mitochondrial genes and their transcripts, thus enabling the study of their functions. Here, we provide an overview of advances in organelle transformation and genome editing for crop improvement, and we discuss the bottlenecks and future development of these technologies.
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A novel nuclear localization region in SIPA1 determines protein nuclear distribution and epirubicin-sensitivity of breast cancer cells.
Ma, Y, Weng, J, Wang, N, Zhang, Y, Minato, N, Su, L
International journal of biological macromolecules. 2021;:718-728
Abstract
Signal-induced proliferation-associated protein 1 (SIPA1) is highly expressed and mainly located in the nucleus in some breast cancer cell lines and clinical tumor tissues. Previous study revealed that nuclear localization of SIPA1 is functionally involved in breast cancer metastasis in the lymphatic gland. In the current study, we identified a non-typical region (140-179aa) of SIPA1 as a novel nuclear localization region (NLR) which is crucial for translocating the proteins into the nucleus in HEK293 cells and breast cancer cells. This region contained one basic amino acid, His160, and had no common features of typical nuclear localization signals. In addition, overexpressing SIPA1 without NLR could suppress breast cancer cell proliferation but could not promote cell migration in MCF7 cells. Furthermore, we found that a high expression of SIPA1 upregulated the expression of ABCB1, encoding multi-drug resistance protein MDR1, and promoted the resistance to epirubicin in breast cancer cells, while this effect was largely abolished in the cells with the expression of NLR-deleted SIPA1. This study overall, identified a nuclear localization-dependent region determining the nuclear distribution of SIPA1 and its regulation on epirubicin-sensitivity in breast cancer cells, which could be a potential drug target to facilitate the development of breast cancer chemotherapy.
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Frequent blood flow restricted training not to failure and to failure induces similar gains in myonuclei and muscle mass.
Bjørnsen, T, Wernbom, M, Paulsen, G, Berntsen, S, Brankovic, R, Stålesen, H, Sundnes, J, Raastad, T
Scandinavian journal of medicine & science in sports. 2021;(7):1420-1439
Abstract
The purpose of the present study was to compare the effects of short-term high-frequency failure vs non-failure blood flow-restricted resistance exercise (BFRRE) on changes in satellite cells (SCs), myonuclei, muscle size, and strength. Seventeen untrained men performed four sets of BFRRE to failure (Failure) with one leg and not to failure (Non-failure; 30-15-15-15 repetitions) with the other leg using knee-extensions at 20% of one repetition maximum (1RM). Fourteen sessions were distributed over two 5-day blocks, separated by a 10-day rest period. Muscle samples obtained before, at mid-training, and 10-day post-intervention (Post10) were analyzed for muscle fiber area (MFA), myonuclei, and SC. Muscle size and echo intensity of m.rectus femoris (RF) and m.vastus lateralis (VL) were measured by ultrasonography, and knee extension strength with 1RM and maximal isometric contraction (MVC) up until Post24. Both protocols increased myonuclear numbers in type-1 (12%-17%) and type-2 fibers (20%-23%), and SC in type-1 (92%-134%) and type-2 fibers (23%-48%) at Post10 (p < 0.05). RF and VL size increased by 5%-10% in both legs at Post10 to Post24, whereas the MFA of type-1 fibers in Failure was decreased at Post10 (-10 ± 16%; p = 0.02). Echo intensity increased by ~20% in both legs during Block1 (p < 0.001) and was ~8 to 11% below baseline at Post24 (p = 0.001-0.002). MVC and 1RM decreased by 5%-10% after Block1, but increased in both legs by 6%-11% at Post24 (p < 0.05). In conclusion, both short-term high-frequency failure and non-failure BFRRE induced increases in SCs, in myonuclei content, muscle size, and strength, concomitant with decreased echo intensity. Intriguingly, the responses were delayed and peaked 10-24 days after the training intervention. Our findings may shed light on the mechanisms involved in resistance exercise-induced overreaching and supercompensation.
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Recapitulation of selective nuclear import and export with a perfectly repeated 12mer GLFG peptide.
Ng, SC, Güttler, T, Görlich, D
Nature communications. 2021;(1):4047
Abstract
The permeability barrier of nuclear pore complexes (NPCs) controls nucleocytoplasmic transport. It retains inert macromolecules while allowing facilitated passage of importins and exportins, which in turn shuttle cargo into or out of cell nuclei. The barrier can be described as a condensed phase assembled from cohesive FG repeat domains. NPCs contain several distinct FG domains, each comprising variable repeats. Nevertheless, we now found that sequence heterogeneity is no fundamental requirement for barrier function. Instead, we succeeded in engineering a perfectly repeated 12mer GLFG peptide that self-assembles into a barrier of exquisite transport selectivity and fast transport kinetics. This barrier recapitulates RanGTPase-controlled importin- and exportin-mediated cargo transport and thus represents an ultimately simplified experimental model system. An alternative proline-free sequence forms an amyloid FG phase. Finally, we discovered that FG phases stain bright with 'DNA-specific' DAPI/ Hoechst probes, and that such dyes allow for a photo-induced block of nuclear transport.
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Prognostic Impact of Membranous/Nuclear Epidermal Growth Factor Receptor Localization in Clear Cell Renal Cell Carcinoma.
Muroni, MR, Ribback, S, Sotgiu, G, Kroeger, N, Saderi, L, Angius, A, Cossu-Rocca, P, De Miglio, MR
International journal of molecular sciences. 2021;(16)
Abstract
EGFR is overexpressed in the majority of clear cell renal cell carcinomas (CCRCCs). Although EGFR deregulation was found to be of great significance in CCRCC biology, the EGFR overexpression is not associated with EGFR-targeted therapy responsiveness. Moreover, the prognostic role of EGFR expression remains controversial. In the present study, we evaluated the role played by EGFR overexpression in CCRCC and its prognostic significance associated with different immunohistochemical localization patterns. In our study, the Total Score (TS) related to membranous-cytoplasmic EGFR expression showed a significant correlation with grade, pathologic stage (pT), and Stage, Size, Grade, and Necrosis (SSIGN) score, and a negative correlation with nuclear EGFR expression. No significant correlations were shown between nuclear EGFR and clinic-pathological features. Additionally, a correlation between SGLT1 expression levels and pT was described. Multivariate analysis identifies pT and SSIGN score as independent prognostic factors for CCRCC. A significantly increased survival rate was found in the case of positive expression of nuclear EGFR and SGLT1. Based on our findings, SGLT1 and nuclear EGFR overexpression defines a subgroup of CCRCC patients with good prognosis. Membranous-cytoplasmic EGFR expression was shown to be a poor prognostic factor and could define a CCRCC subgroup with poor prognosis that should be responsive to anti-EGFR therapies.
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10.
Pathological findings of the retrospective diagnosis of NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) in 84 cases from Turkey and systematic review.
Turan, G, Özkara, SK
Annals of diagnostic pathology. 2021;:151764
Abstract
AIM: The terminology of "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was introduced in 2016; and estimated to cause significant effects in the clinical management of thyroid nodules. The aim of our study is to review our cases that were previously diagnosed as non-invasive encapsulated follicular variant PTC (NI/E-FVPTC) which are compatible with NIFTP and to correlate their follow-up. METHOD All thyroidectomy cases evaluated in the last 15 years were screened, and possible NIFTP cases were determined among patients with NI/E-FVPTC and they were re-examined microscopically. Revised histopathological criteria were used for the retrospective diagnosis of NIFTP. Histopathological findings were correlated to follow up information. RESULTS Totally 2138 cases had been previously diagnosed with PTC; 481 (22.5%) of them were FVPTC. After microscopic reevaluation of potential NIFTP cases, 84 cases (3.9%) received final diagnosis of NIFTP. 78.6% of NIFTP patients were female (F/M: 66/18); mean age was 49.0, tumor diameter was 22.7 mm and follow-up time was 66.4 months. 17.9% of NIFTP cases were multifocal and 13.1% were bilateral. No recurrence, lymph node involvement or distant metastasis was detected in any of the patients who were followed up. The mean age of the patients who had total thyroidectomy and received RAI was significantly higher than those who did not. CONCLUSION Although conservative treatment of NIFTP with lobectomy is recommended, age of the patients has been continuing to be the most important determinant for the clinicians to decide on total thyroidectomy and RAI ablation therapy at our institution.