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  • Role of ciliopathy protein TMEM107 in eye development: insights from a
           mouse model and retinal organoid

    • Authors: Dubaic, M; Peskova, L, Hampl, M, Weissova, K, Celiker, C, Shylo, N. A, Hruba, E, Kavkova, M, Zikmund, T, Weatherbee, S. D, Kaiser, J, Barta, T, Buchtova, M.
      Pages: e202302073 - e202302073
      Abstract: Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary cilia have been linked to human diseases, including retinopathies and ocular defects. Here, we focus on TMEM107, a protein localized to the transition zone of primary cilia. TMEM107 mutations were found in patients with Joubert and Meckel–Gruber syndromes. A mouse model lacking Tmem107 exhibited eye defects such as anophthalmia and microphthalmia, affecting retina differentiation. Tmem107 expression during prenatal mouse development correlated with phenotype occurrence, with enhanced expression in differentiating retina and optic stalk. TMEM107 deficiency in retinal organoids resulted in the loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knocking out TMEM107 in human ARPE-19 cells prevented primary cilia formation and impaired response to Smoothened agonist treatment because of ectopic activation of the SHH pathway. Our data suggest TMEM107 plays a crucial role in early vertebrate eye development and ciliogenesis in the differentiating retina.
      Keywords: Genetics, Gene Therapy & Genetic Disease, Cell Biology, Development
      PubDate: 2023-10-20T09:25:45-07:00
      DOI: 10.26508/lsa.202302073
      Issue No: Vol. 6, No. 12 (2023)
  • The coenzyme A precursor pantethine enhances antitumor immunity in sarcoma

    • Authors: Miallot, R; Millet, V, Roger, A, Fenouil, R, Tardivel, C, Martin, J.-C, Tranchida, F, Shintu, L, Berchard, P, Sousa Lanza, J, Malissen, B, Henri, S, Ugolini, S, Dutour, A, Finetti, P, Bertucci, F, Blay, J.-Y, Galland, F, Naquet, P.
      Pages: e202302200 - e202302200
      Abstract: The tumor microenvironment is a dynamic network of stromal, cancer, and immune cells that interact and compete for resources. We have previously identified the Vanin1 pathway as a tumor suppressor of sarcoma development via vitamin B5 and coenzyme A regeneration. Using an aggressive sarcoma cell line that lacks Vnn1 expression, we showed that the administration of pantethine, a vitamin B5 precursor, attenuates tumor growth in immunocompetent but not nude mice. Pantethine boosts antitumor immunity, including the polarization of myeloid and dendritic cells towards enhanced IFN-driven antigen presentation pathways and improved the development of hypermetabolic effector CD8+ T cells endowed with potential antitumor activity. At later stages of treatment, the effect of pantethine was limited by the development of immune cell exhaustion. Nevertheless, its activity was comparable with that of anti-PD1 treatment in sensitive tumors. In humans, VNN1 expression correlates with improved survival and immune cell infiltration in soft-tissue sarcomas, but not in osteosarcomas. Pantethine could be a potential therapeutic immunoadjuvant for the development of antitumor immunity.
      Keywords: Immunology
      PubDate: 2023-10-13T09:28:52-07:00
      DOI: 10.26508/lsa.202302200
      Issue No: Vol. 6, No. 12 (2023)
  • SBDSR126T rescues survival of sbds-/- zebrafish in a dose-dependent manner
           independently of Tp53

    • Authors: Oyarbide, U; Shah, A. N, Staton, M, Snyderman, M, Sapra, A, Calo, E, Corey, S. J.
      Pages: e202201856 - e202201856
      Abstract: Defects in ribosomal biogenesis profoundly affect organismal development and cellular function, and these ribosomopathies produce a variety of phenotypes. One ribosomopathy, Shwachman–Diamond syndrome (SDS) is characterized by neutropenia, pancreatic exocrine insufficiency, and skeletal anomalies. SDS results from biallelic mutations in SBDS, which encodes a ribosome assembly factor. Some individuals express a missense mutation, SBDSR126T, along with the common K62X mutation. We reported that the sbds-null zebrafish phenocopies much of SDS. We further showed activation of Tp53-dependent pathways before the fish died during the larval stage. Here, we expressed SBDSR126T as a transgene in the sbds–/– background. We showed that one copy of the SBDSR126T transgene permitted the establishment of maternal zygotic sbds-null fish which produced defective embryos with cdkn1a up-regulation, a Tp53 target involved in cell cycle arrest. None survived beyond 3 dpf. However, two copies of the transgene resulted in normal development and lifespan. Surprisingly, neutropenia persisted. The surviving fish displayed suppression of female sex differentiation, a stress response in zebrafish. To evaluate the role of Tp53 in the pathogenesis of sbds–/– fish phenotype, we bred the fish with a DNA binding deficient allele, tp53M214K. Expression of the loss-of-function tp53M214K did not rescue neutropenia or survival in sbds-null zebrafish. Increased expression of cdkn1a was abrogated in the tp53M214K/M214K;sbds–/– fish. We conclude that the amount of SBDSR126T protein is important for development, inactivation of Tp53 fails to rescue neutropenia or survival in the sbds-null background, and cdkn1a up-regulation was dependent on WT tp53. We hypothesize that additional pathways are involved in the pathophysiology of SDS.
      Keywords: Genetics, Gene Therapy & Genetic Disease, Development
      PubDate: 2023-10-10T09:01:26-07:00
      DOI: 10.26508/lsa.202201856
      Issue No: Vol. 6, No. 12 (2023)
  • Identification of biomarkers, pathways, and therapeutic targets for
           EGFR-TKI resistance in NSCLC

    • Authors: Zhu, L; Gao, S, Zhao, X, Wang, Y.
      Pages: e202302110 - e202302110
      Abstract: This study aimed to map the hub genes and potential pathways that might be involved in the molecular pathogenesis of EGFR–TKI resistance in NSCLC. We performed bioinformatics analysis to identify differentially expressed genes, their function, gene interactions, and pathway analysis between EGFR–TKI-sensitive and EGFR–TKI-resistant patient-derived xenotransplantation samples based on Gene Expression Omnibus database. Survival analysis was performed via the GEPIA database (GEO). The relationship between the key gene ITGAM and the therapeutic candidates was retrieved from DGIdb. A total of 1,302 differentially expressed genes were identified based on GEO. The PPI network highlighted 10 potential hub genes. Only ITGAM was linked to poor DSF in NSCLC patients. A total of 10 drugs were predicted to be potential therapeutics for NSCLC with EGFR–TKI resistance. This study indicates the hub genes related to EGFR–TKI resistance in NSCLC through bioinformatics technologies which can improve the understanding of the mechanisms of EGFR–TKI resistance and provide novel insights into therapeutics.
      Keywords: Cancer
      PubDate: 2023-10-10T09:01:26-07:00
      DOI: 10.26508/lsa.202302110
      Issue No: Vol. 6, No. 12 (2023)
  • Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in
           pancreatic cancer

    • Authors: Briseno-Diaz, P; Schnoor, M, Bello-Ramirez, M, Correa-Basurto, J, Rojo-Dominguez, A, Arregui, L, Vega, L, Nunez-Gonzalez, E, Palau-Hernandez, L. A, Parra-Torres, C. G, Garcia Cordova, O. M, Zepeda-Castilla, E, Torices-Escalante, E, Dominguez-Camacho, L, Xoconostle-Cazares, B, Meraz-Rios, M. A, Delfin-Azuara, S, Carrion-Estrada, D. A, Villegas-Sepulveda, N, Hernandez-Rivas, R, Thompson-Bonilla, M. d. R, Vargas, M.
      Pages: e202302019 - e202302019
      Abstract: Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6 complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.
      Keywords: Cancer
      PubDate: 2023-10-09T08:19:34-07:00
      DOI: 10.26508/lsa.202302019
      Issue No: Vol. 6, No. 12 (2023)
  • The highly improved genome of Ixodes scapularis with X and Y

    • Authors: Nuss, A. B; Lomas, J. S, Reyes, J. B, Garcia-Cruz, O, Lei, W, Sharma, A, Pham, M. N, Beniwal, S, Swain, M. L, McVicar, M, Hinne, I. A, Zhang, X, Yim, W. C, Gulia-Nuss, M.
      Pages: e202302109 - e202302109
      Abstract: Ixodes scapularis, the black-legged tick, is the principal vector of the Lyme disease spirochete, Borrelia burgdorferi, and is responsible for most of the ~470,000 estimated Lyme disease cases annually in the USA. Ixodes scapularis can transmit six additional pathogens of human health significance. Because of its medical importance, I. scapularis was the first tick genome to be sequenced and annotated. However, the first assembly, I. scapularis Wikel (IscaW), was highly fragmented because of the technical challenges posed by the long, repetitive genome sequences characteristic of arthropod genomes and the lack of long-read sequencing techniques. Although I. scapularis has emerged as a model for tick research because of the availability of new tools such as embryo injection and CRISPR-Cas9-mediated gene editing yet the lack of chromosome-scale scaffolds has slowed progress in tick biology and the development of tools for their control. Here we combine diverse technologies to produce the I. scapularis Gulia-Nuss (IscGN) genome assembly and gene set. We used DNA from eggs and male and female adult ticks and took advantage of Hi-C, PacBio HiFi sequencing, and Illumina short-read sequencing technologies to produce a chromosome-level assembly. In this work, we present the predicted pseudochromosomes consisting of 13 autosomes and the sex pseudochromosomes: X and Y, and a markedly improved genome annotation compared with the existing assemblies and annotations.
      Keywords: Genomics & Functional Genomics
      PubDate: 2023-10-09T08:19:34-07:00
      DOI: 10.26508/lsa.202302109
      Issue No: Vol. 6, No. 12 (2023)
  • Fn14 promotes myoblast fusion during regenerative myogenesis

    • Authors: Tomaz da Silva, M; Joshi, A. S, Castillo, M. B, Koike, T. E, Roy, A, Gunaratne, P. H, Kumar, A.
      Pages: e202302312 - e202302312
      Abstract: Skeletal muscle regeneration involves coordinated activation of an array of signaling pathways. Fibroblast growth factor–inducible 14 (Fn14) is a bona fide receptor for the TWEAK cytokine. Levels of Fn14 are increased in the skeletal muscle of mice after injury. However, the cell-autonomous role of Fn14 in muscle regeneration remains unknown. Here, we demonstrate that global deletion of the Fn14 receptor in mice attenuates muscle regeneration. Conditional ablation of Fn14 in myoblasts but not in differentiated myofibers of mice inhibits skeletal muscle regeneration. Fn14 promotes myoblast fusion without affecting the levels of myogenic regulatory factors in the regenerating muscle. Fn14 deletion in myoblasts hastens initial differentiation but impairs their fusion. The overexpression of Fn14 in myoblasts results in the formation of myotubes having an increased diameter after induction of differentiation. Ablation of Fn14 also reduces the levels of various components of canonical Wnt and calcium signaling both in vitro and in vivo. Forced activation of Wnt signaling rescues fusion defects in Fn14-deficient myoblast cultures. Collectively, our results demonstrate that Fn14-mediated signaling positively regulates myoblast fusion and skeletal muscle regeneration.
      Keywords: Physiology, Cell Biology, Development
      PubDate: 2023-10-09T08:19:34-07:00
      DOI: 10.26508/lsa.202302312
      Issue No: Vol. 6, No. 12 (2023)
  • Identification of FAM53C as a cytosolic-anchoring inhibitory binding
           protein of the kinase DYRK1A

    • Authors: Miyata, Y; Nishida, E.
      Pages: e202302129 - e202302129
      Abstract: The protein kinase DYRK1A encoded in human chromosome 21 is the major contributor to the multiple symptoms observed in Down syndrome patients. In addition, DYRK1A malfunction is associated with various other neurodevelopmental disorders such as autism spectrum disorder. Here, we identified FAM53C with no hitherto known biological function as a novel suppressive binding partner of DYRK1A. FAM53C is bound to the catalytic protein kinase domain of DYRK1A, whereas DCAF7/WDR68, the major DYRK1A-binding protein, binds to the N-terminal domain of DYRK1A. The binding of FAM53C inhibited autophosphorylation activity of DYRK1A and its kinase activity to an exogenous substrate, MAPT/Tau. FAM53C did not bind directly to DCAF7/WDR68, whereas DYRK1A tethered FAM53C and DCAF7/WDR68 by binding concurrently to both of them, forming a tri-protein complex. DYRK1A possesses an NLS and accumulates in the nucleus when overexpressed in cells. Co-expression of FAM53C induced cytoplasmic re-localization of DYRK1A, revealing the cytoplasmic anchoring function of FAM53C to DYRK1A. Moreover, the binding of FAM53C to DYRK1A suppressed the DYRK1A-dependent nuclear localization of DCAF7/WDR68. All the results show that FAM53C binds to DYRK1A, suppresses its kinase activity, and anchors it in the cytoplasm. In addition, FAM53C is bound to the DYRK1A-related kinase DYRK1B with an Hsp90/Cdc37-independent manner. The results explain for the first time why endogenous DYRK1A is distributed in the cytoplasm in normal brain tissue. FAM53C-dependent regulation of the kinase activity and intracellular localization of DYRK1A may play a significant role in gene expression regulation caused by normal and aberrant levels of DYRK1A.
      Keywords: Molecular Biology, Cell Biology
      PubDate: 2023-10-06T09:14:47-07:00
      DOI: 10.26508/lsa.202302129
      Issue No: Vol. 6, No. 12 (2023)
  • Activation of the JNK/COX-2/HIF-1{alpha} axis promotes M1 macrophage via
           glycolytic shift in HIV-1 infection

    • Authors: Zhang, J; Yuan, Z, Li, X, Wang, F, Wei, X, Kang, Y, Mo, C, Jiang, J, Liang, H, Ye, L.
      Pages: e202302148 - e202302148
      Abstract: Chronic inflammation is recognized as a major risk factor for the severity of HIV infection. Whether metabolism reprogramming of macrophages caused by HIV-1 is related to chronic inflammatory activation, especially M1 polarization of macrophages, is inconclusive. Here, we show that HIV-1 infection induces M1 polarization and enhanced glycolysis in macrophages. Blockade of glycolysis inhibits M1 polarization of macrophages, indicating that HIV-1–induced M1 polarization is supported by enhanced glycolysis. Moreover, we find that this immunometabolic adaptation is dependent on hypoxia-inducible factor 1α (HIF-1α), a strong inducer of glycolysis. HIF-1α–target genes, including HK2, PDK1, and LDHA, are also involved in this process. Further research discovers that COX-2 regulates HIF-1α–dependent glycolysis. However, the elevated expression of COX-2, enhanced glycolysis, and M1 polarization of macrophages could be reversed by inactivation of JNK in the context of HIV-1 infection. Our study mechanistically elucidates that the JNK/COX-2/HIF-1α axis is activated to strengthen glycolysis, thereby promoting M1 polarization in macrophages in HIV-1 infection, providing a new idea for resolving chronic inflammation in clinical AIDS patients.
      Keywords: Immunology, Metabolism
      PubDate: 2023-10-05T09:33:10-07:00
      DOI: 10.26508/lsa.202302148
      Issue No: Vol. 6, No. 12 (2023)
  • Functional plasticity in chromosome-microtubule coupling on the
           evolutionary time scale

    • Authors: Sankaranarayanan, S. R; Polisetty, S. D, Das, K, Dumbrepatil, A, Medina-Pritchard, B, Singleton, M, Jeyaprakash, A. A, Sanyal, K.
      Pages: e202201720 - e202201720
      Abstract: The Dam1 complex is essential for mitotic progression across evolutionarily divergent fungi. Upon analyzing amino acid (aa) sequences of Dad2, a Dam1 complex subunit, we identified a conserved 10-aa–long Dad2 signature sequence (DSS). An arginine residue (R126) in the DSS is essential for viability in Saccharomyces cerevisiae that possesses point centromeres. The corresponding arginine residues are functionally important but not essential for viability in Candida albicans and Cryptococcus neoformans; both carry several kilobases long regional centromeres. The purified recombinant Dam1 complex containing either Dad2DSS or Dad2R126A failed to bind microtubules (MTs) or form any visible rings like the WT complex. Intriguingly, functional analysis revealed that the requirement of the conserved arginine residue for chromosome biorientation and mitotic progression reduced with increasing centromere length. We propose that plasticity of the invariant arginine of Dad2 in organisms with regional centromeres is achieved by conditional elevation of the kinetochore protein(s) to enable multiple kinetochore MTs to bind to each chromosome. The capacity of a chromosome to bind multiple kinetochore MTs may mask the deleterious effects of such lethal mutations.
      Keywords: Molecular Biology, Cell Biology
      PubDate: 2023-10-04T12:01:28-07:00
      DOI: 10.26508/lsa.202201720
      Issue No: Vol. 6, No. 12 (2023)
  • Regulation of alternative splicing and polyadenylation in neurons

    • Authors: Lee, S; Aubee, J. I, Lai, E. C.
      Pages: e202302000 - e202302000
      Abstract: Cell-type–specific gene expression is a fundamental feature of multicellular organisms and is achieved by combinations of regulatory strategies. Although cell-restricted transcription is perhaps the most widely studied mechanism, co-transcriptional and post-transcriptional processes are also central to the spatiotemporal control of gene functions. One general category of expression control involves the generation of multiple transcript isoforms from an individual gene, whose balance and cell specificity are frequently tightly regulated via diverse strategies. The nervous system makes particularly extensive use of cell-specific isoforms, specializing the neural function of genes that are expressed more broadly. Here, we review regulatory strategies and RNA-binding proteins that direct neural-specific isoform processing. These include various classes of alternative splicing and alternative polyadenylation events, both of which broadly diversify the neural transcriptome. Importantly, global alterations of splicing and alternative polyadenylation are characteristic of many neural pathologies, and recent genetic studies demonstrate how misregulation of individual neural isoforms can directly cause mutant phenotypes.
      Keywords: Genetics, Gene Therapy & Genetic Disease, Molecular Biology, Neuroscience
      PubDate: 2023-10-04T12:01:28-07:00
      DOI: 10.26508/lsa.202302000
      Issue No: Vol. 6, No. 12 (2023)
  • Improving lysosomal ferroptosis with NMN administration protects against
           heart failure

    • Authors: Yagi, M; Do, Y, Hirai, H, Miki, K, Toshima, T, Fukahori, Y, Setoyama, D, Abe, C, Nabeshima, Y.-I, Kang, D, Uchiumi, T.
      Pages: e202302116 - e202302116
      Abstract: Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy. Mitochondrial translation defects cause not only mitochondrial dysfunction but also decreased nicotinamide adenine dinucleotide (NAD+) levels, leading to impaired lysosomal acidification and autophagy. In this study, we investigated whether nicotinamide mononucleotide (NMN) administration, which compensates for decreased NAD+ levels, improves heart failure because of mitochondrial dysfunction. NMN administration reduced damaged lysosomes and improved autophagy, thereby reducing heart failure and extending the lifespan in p32cKO mice. We found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide. The ameliorative effects of NMN supplementation were found to strongly affect lysosomal function rather than mitochondrial function, particularly lysosome-mediated ferroptosis. NMN supplementation can improve lysosomal, rather than mitochondrial, function and prevent chronic heart failure.
      Keywords: Molecular Biology
      PubDate: 2023-10-04T12:01:28-07:00
      DOI: 10.26508/lsa.202302116
      Issue No: Vol. 6, No. 12 (2023)
  • FAM111A regulates replication origin activation and cell fitness

    • Authors: Rios-Szwed, D. O; Alvarez, V, Sanchez-Pulido, L, Garcia-Wilson, E, Jiang, H, Bandau, S, Lamond, A, Alabert, C.
      Pages: e202302111 - e202302111
      Abstract: FAM111A is a replisome-associated protein and dominant mutations within its trypsin-like peptidase domain are linked to severe human developmental syndrome, the Kenny–Caffey syndrome. However, FAM111A functions remain unclear. Here, we show that FAM111A facilitates efficient activation of DNA replication origins. Upon hydroxyurea treatment, FAM111A-depleted cells exhibit reduced single-stranded DNA formation and a better survival rate. Unrestrained expression of FAM111A WT and patient mutants causes accumulation of DNA damage and cell death, only when the peptidase domain remains intact. Unrestrained expression of FAM111A WT also causes increased single-stranded DNA formation that relies on S phase entry, FAM111A peptidase activity but not its binding to proliferating cell nuclear antigen. Altogether, these data unveil how FAM111A promotes DNA replication under normal conditions and becomes harmful in a disease context.
      Keywords: Cell Biology
      PubDate: 2023-10-04T08:57:42-07:00
      DOI: 10.26508/lsa.202302111
      Issue No: Vol. 6, No. 12 (2023)
  • MUC13 drives cancer aggressiveness and metastasis through the
           YAP1-dependent pathway

    • Authors: Doxtater, K; Tripathi, M. K, Sekhri, R, Hafeez, B. B, Khan, S, Zafar, N, Behrman, S. W, Yallapu, M. M, Jaggi, M, Chauhan, S. C.
      Pages: e202301975 - e202301975
      Abstract: Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.
      Keywords: Cancer
      PubDate: 2023-10-04T06:02:28-07:00
      DOI: 10.26508/lsa.202301975
      Issue No: Vol. 6, No. 12 (2023)
  • scFseCluster: a feature selection-enhanced clustering for single-cell
           RNA-seq data

    • Authors: Wang, Z; Xie, X, Liu, S, Ji, Z.
      Pages: e202302103 - e202302103
      Abstract: Single-cell RNA sequencing (scRNA-seq) enables researchers to reveal previously unknown cell heterogeneity and functional diversity, which is impossible with bulk RNA sequencing. Clustering approaches are widely used for analyzing scRNA-seq data and identifying cell types and states. In the past few years, various advanced computational strategies emerged. However, the low generalization and high computational cost are the main bottlenecks of existing methods. In this study, we established a novel computational framework, scFseCluster, for scRNA-seq clustering analysis. scFseCluster incorporates a metaheuristic algorithm (Feature Selection based on Quantum Squirrel Search Algorithm) to extract the optimal gene set, which largely guarantees the performance of cell clustering. We conducted simulation experiments in several aspects to verify the performance of the proposed approach. scFseCluster performed very well on eight benchmark scRNA-seq datasets because of the optimal gene sets obtained using the Feature Selection based on Quantum Squirrel Search Algorithm. The comparative study demonstrated the significant advantages of scFseCluster over seven State-of-the-Art algorithms. In addition, our analysis shows that feature selection on high-variable genes can significantly improve clustering performance. In conclusion, our study demonstrates that scFseCluster is a highly versatile tool for enhancing scRNA-seq data clustering analysis.
      Keywords: Systems & Computational Biology
      PubDate: 2023-10-03T10:03:49-07:00
      DOI: 10.26508/lsa.202302103
      Issue No: Vol. 6, No. 12 (2023)
  • Peptide derived from SLAMF1 prevents TLR4-mediated inflammation in vitro
           and in vivo

    • Authors: Nilsen, K. E; Zhang, B, Skjesol, A, Ryan, L, Vagle, H, Boe, M. H, Orning, P, Kim, H, Bakke, S. S, Elamurugan, K, Mestvedt, I. B, Stenvik, J, Husebye, H, Lien, E, Espevik, T, Yurchenko, M.
      Pages: e202302164 - e202302164
      Abstract: Inflammation plays a crucial role in the development and progression of many diseases, and is often caused by dysregulation of signalling from pattern recognition receptors, such as TLRs. Inhibition of key protein–protein interactions is an attractive target for treating inflammation. Recently, we demonstrated that the signalling lymphocyte activation molecule family 1 (SLAMF1) positively regulates signalling downstream of TLR4 and identified the interaction interface between SLAMF1 and the TLR4 adaptor protein TRIF-related adapter molecule (TRAM). Based on these findings, we developed a SLAMF1-derived peptide, P7, which is linked to a cell-penetrating peptide for intracellular delivery. We found that P7 peptide inhibits the expression and secretion of IFNβ and pro-inflammatory cytokines (TNF, IL-1β, IL-6) induced by TLR4, and prevents death in mice subjected to LPS shock. The mechanism of action of P7 peptide is based on interference with several intracellular protein–protein interactions, including TRAM–SLAMF1, TRAM–Rab11FIP2, and TIRAP–MyD88 interactions. Overall, P7 peptide has a unique mode of action and demonstrates high efficacy in inhibiting TLR4-mediated signalling in vitro and in vivo.
      Keywords: Immunology, Microbiology, Virology & Host Pathogen Interaction, Cell Biology
      PubDate: 2023-10-03T10:03:49-07:00
      DOI: 10.26508/lsa.202302164
      Issue No: Vol. 6, No. 12 (2023)
  • Causal links of {alpha}-thalassemia indices and cardiometabolic traits and
           diabetes: MR study

    • Authors: Hsu, L.-A; Wu, S, Teng, M.-S, Ko, Y.-L.
      Pages: e202302204 - e202302204
      Abstract: Our study aimed to investigate if genetic variants around 16p13.3’s HBA1 locus, associated with erythrocyte indices and HbA1c levels, predict α-thalassemia-related erythrocyte indices, cardiometabolic traits, and diabetes risk in Taiwanese individuals. We analyzed Taiwan Biobank data, including whole-genome sequencing from 1,493 participants and genotyping arrays from 129,542 individuals. First, we performed regional association analysis using whole-genome sequencing data to identify genetic variants significantly associated with erythrocyte indices, confirming their linkage disequilibrium with the α0 thalassemia --SEA deletion mutation, a common cause of α-thalassemia in Southeast Asian populations. Deletion mutation sequencing further validated these variants’ association with α-thalassemia. Subsequently, we analyzed genotyping array data, revealing associations between specific genetic variants and cardiometabolic traits, including lipid profiles, HbA1c levels, bilirubin levels, and diabetes risk. Using Mendelian randomization, we established causal relationships between α-thalassemia-related erythrocyte indices and cardiometabolic traits, elucidating their role in diabetes susceptibility. Our findings highlight genetic variants around the α-globin genes as surrogate markers for common α-thalassemia mutations in Taiwan, emphasizing the causal links between α-thalassemia-related erythrocyte indices, cardiometabolic traits, and heightened diabetes risk.
      Keywords: Genetics, Gene Therapy & Genetic Disease, Genomics & Functional Genomics, Medical Research
      PubDate: 2023-10-03T10:03:49-07:00
      DOI: 10.26508/lsa.202302204
      Issue No: Vol. 6, No. 12 (2023)
  • Cost-effective DNA methylation profiling by FML-seq

    • Authors: Foley, J. W; Zhu, S. X, West, R. B.
      Pages: e202302326 - e202302326
      Abstract: Current methods for profiling DNA methylation require costly reagents, sequencing, and labor time. We introduce fragmentation at methylated loci and sequencing (FML-seq), a sequencing library protocol that greatly reduces all these costs. Relative to other techniques tested on the same human cell lines, FML-seq produces similar measurements of absolute and differential cytosine methylation at a fraction of the price. FML-seq enables inexpensive, high-throughput experimental designs for large-scale epigenetics research projects.
      Keywords: Genomics & Functional Genomics, Methods & Resources, Chromatin & Epigenetics
      PubDate: 2023-09-29T08:57:11-07:00
      DOI: 10.26508/lsa.202302326
      Issue No: Vol. 6, No. 12 (2023)
  • TRIM25 targets p300 for degradation

    • Authors: Elabd, S; Pauletto, E, Solozobova, V, Eickhoff, N, Padrao, N, Zwart, W, Blattner, C.
      Pages: e202301980 - e202301980
      Abstract: p300 is an important transcriptional co-factor. By stimulating the transfer of acetyl residues onto histones and several key transcription factors, p300 enhances transcriptional initiation and impacts cellular processes including cell proliferation and cell division. Despite its importance for cellular homeostasis, its regulation is poorly understood. We show that TRIM25, a member of the TRIM protein family, targets p300 for proteasomal degradation. However, despite TRIM25’s RING domain and E3 activity, degradation of p300 by TRIM25 is independent of TRIM25-mediated p300 ubiquitination. Instead, TRIM25 promotes the interaction of p300 with dynein, which ensures a microtubule-dependent transport of p300 to cellular proteasomes. Through mediating p300 degradation, TRIM25 affects p300-dependent gene expression.
      Keywords: Molecular Biology
      PubDate: 2023-09-28T07:40:54-07:00
      DOI: 10.26508/lsa.202301980
      Issue No: Vol. 6, No. 12 (2023)
  • Comparative analysis of bioinformatics tools to characterize SARS-CoV-2
           subgenomic RNAs

    • Authors: Lavezzari, D; Mori, A, Pomari, E, Deiana, M, Fadda, A, Bertoli, L, Sinigaglia, A, Riccetti, S, Barzon, L, Piubelli, C, Delledonne, M, Capobianchi, M. R, Castilletti, C.
      Pages: e202302017 - e202302017
      Abstract: During the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), positive-sense genomic RNA and subgenomic RNAs (sgRNAs) are synthesized by a discontinuous process of transcription characterized by a template switch, regulated by transcription-regulating sequences (TRS). Although poorly known about makeup and dynamics of sgRNAs population and function of its constituents, next-generation sequencing approaches with the help of bioinformatics tools have made a significant contribution to expand the knowledge of sgRNAs in SARS-CoV-2. For this scope to date, Periscope, LeTRS, sgDI-tector, and CORONATATOR have been developed. However, limited number of studies are available to compare the performance of such tools. To this purpose, we compared Periscope, LeTRS, and sgDI-tector in the identification of canonical (c-) and noncanonical (nc-) sgRNA species in the data obtained with the Illumina ARTIC sequencing protocol applied to SARS-CoV-2–infected Caco-2 cells, sampled at different time points. The three software showed a high concordance rate in the identification and in the quantification of c-sgRNA, whereas more differences were observed in nc-sgRNA. Overall, LeTRS and sgDI-tector result to be adequate alternatives to Periscope to analyze Fastq data from sequencing platforms other than Nanopore.
      Keywords: Genomics & Functional Genomics, Microbiology, Virology & Host Pathogen Interaction
      PubDate: 2023-09-25T07:21:28-07:00
      DOI: 10.26508/lsa.202302017
      Issue No: Vol. 6, No. 12 (2023)
  • Two domains of Tim50 coordinate translocation of proteins across the two
           mitochondrial membranes

    • Authors: Genge, M. G; Roy Chowdhury, S, Dohnalek, V, Yunoki, K, Hirashima, T, Endo, T, Dolezal, P, Mokranjac, D.
      Pages: e202302122 - e202302122
      Abstract: Hundreds of mitochondrial proteins with N-terminal presequences are translocated across the outer and inner mitochondrial membranes via the TOM and TIM23 complexes, respectively. How translocation of proteins across two mitochondrial membranes is coordinated is largely unknown. Here, we show that the two domains of Tim50 in the intermembrane space, named core and PBD, both have essential roles in this process. Building upon the surprising observation that the two domains of Tim50 can complement each other in trans, we establish that the core domain contains the main presequence-binding site and serves as the main recruitment point to the TIM23 complex. On the other hand, the PBD plays, directly or indirectly, a critical role in cooperation of the TOM and TIM23 complexes and supports the receptor function of Tim50. Thus, the two domains of Tim50 both have essential but distinct roles and together coordinate translocation of proteins across two mitochondrial membranes.
      Keywords: Cell Biology
      PubDate: 2023-09-25T07:21:28-07:00
      DOI: 10.26508/lsa.202302122
      Issue No: Vol. 6, No. 12 (2023)
  • KCNQ potassium channels modulate Wnt activity in gastro-oesophageal

    • Authors: Shorthouse, D; Zhuang, L, Rahrmann, E. P, Kosmidou, C, Wickham Rahrmann, K, Hall, M, Greenwood, B, Devonshire, G, Gilbertson, R. J, Fitzgerald, R. C, Hall, B. A.
      Pages: e202302124 - e202302124
      Abstract: Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large-scale analysis of 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find KCNQ family genes are mutated in ~30% of patients, and play therapeutically targetable roles in GOA cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of KCNQ3 in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors.
      Keywords: Genomics & Functional Genomics, Systems & Computational Biology, Cancer
      PubDate: 2023-09-25T07:21:28-07:00
      DOI: 10.26508/lsa.202302124
      Issue No: Vol. 6, No. 12 (2023)
  • Themis controls T cell activation, effector functions, and metabolism of
           peripheral CD8+ T cells

    • Authors: Gautam, N; Wojciech, L, Yap, J, Chua, Y. L, Ding, E. M, Sim, D. C, Tan, A. S, Ahl, P. J, Prasad, M, Tung, D. W, Connolly, J. E, Adriani, G, Brzostek, J, Gascoigne, N. R.
      Pages: e202302156 - e202302156
      Abstract: Themis is important in regulating positive selection of thymocytes during T cell development, but its role in peripheral T cells is less understood. Here, we investigated T cell activation and its sequelae using a tamoxifen-mediated, acute Themis deletion mouse model. We find that proliferation, effector functions including anti-tumor killing, and up-regulation of energy metabolism are severely compromised. This study reveals the phenomenon of peripheral adaptation to loss of Themis, by demonstrating direct TCR-induced defects after acute deletion of Themis that were not evident in peripheral T cells chronically deprived of Themis in dLck-Cre deletion model. Peripheral adaptation to long-term loss was compared using chronic versus acute tamoxifen-mediated deletion and with the (chronic) dLck-Cre deletion model. We found that upon chronic tamoxifen-mediated Themis deletion, there was modulation in the gene expression profile for both TCR and cytokine signaling pathways. This profile overlapped with (chronic) dLck-Cre deletion model. Hence, we found that peripheral adaptation induced changes to both TCR and cytokine signaling modules. Our data highlight the importance of Themis in the activation of CD8+ T cells.
      Keywords: Immunology
      PubDate: 2023-09-22T07:33:02-07:00
      DOI: 10.26508/lsa.202302156
      Issue No: Vol. 6, No. 12 (2023)
  • Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T
           effector cell infiltration

    • Authors: Sun, J.-M; Fan, H.-Y, Zhu, Y, Pan, T.-T, Wu, Y.-P, Zhang, D.-Y, Hou, X.-Y.
      Pages: e202301966 - e202301966
      Abstract: MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine-cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R. Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine–chemokine networks.
      Keywords: Cancer
      PubDate: 2023-09-21T07:40:29-07:00
      DOI: 10.26508/lsa.202301966
      Issue No: Vol. 6, No. 12 (2023)
  • Cell-free chromatin immunoprecipitation to detect molecular pathways in
           heart transplantation

    • Authors: Jang, M. K; Markowitz, T. E, Andargie, T. E, Apalara, Z, Kuhn, S, Agbor-Enoh, S.
      Pages: e202302003 - e202302003
      Abstract: Existing monitoring approaches in heart transplantation lack the sensitivity to provide deep molecular assessments to guide management, or require endomyocardial biopsy, an invasive and blind procedure that lacks the precision to reliably obtain biopsy samples from diseased sites. This study examined plasma cell-free DNA chromatin immunoprecipitation sequencing (cfChIP-seq) as a noninvasive proxy to define molecular gene sets and sources of tissue injury in heart transplant patients. In healthy controls and in heart transplant patients, cfChIP-seq reliably detected housekeeping genes. cfChIP-seq identified differential gene signals of relevant immune and nonimmune molecular pathways that were predominantly down-regulated in immunosuppressed heart transplant patients compared with healthy controls. cfChIP-seq also identified cell-free DNA tissue sources. Compared with healthy controls, heart transplant patients demonstrated greater cell-free DNA from tissue types associated with heart transplant complications, including the heart, hematopoietic cells, lungs, liver, and vascular endothelium. cfChIP-seq may therefore be a reliable approach to profile dynamic assessments of molecular pathways and sources of tissue injury in heart transplant patients.
      Keywords: Genomics & Functional Genomics, Molecular Biology, Molecular Diagnostics & Diagnostic Imaging
      PubDate: 2023-09-20T08:33:18-07:00
      DOI: 10.26508/lsa.202302003
      Issue No: Vol. 6, No. 12 (2023)
  • SiR-DNA/SiR-Hoechst-induced chromosome entanglement generates severe
           anaphase bridges and DNA damage

    • Authors: Rajendraprasad, G; Rodriguez-Calado, S, Barisic, M.
      Pages: e202302260 - e202302260
      Abstract: SiR-DNA/SiR–Hoechst is a far-red fluorescent DNA probe that is routinely used for live-cell imaging of cell nuclei in interphase and chromosomes during mitosis. Despite being reported to induce DNA damage, SiR-DNA has been used in more than 300 research articles, covering topics like mitosis, chromatin biology, cancer research, cytoskeletal research, and DNA damage response. Here, we used live-cell imaging to perform a comprehensive analysis of the effects of SiR-DNA on mitosis of four human cell lines (RPE-1, DLD-1, HeLa, and U2OS). We report a dose-, time-, and light-dependent effect of SiR-DNA on chromosome segregation. We found that, upon the exposure to light during imaging, nanomolar concentrations of SiR-DNA induce non-centromeric chromosome entanglement that severely impairs sister chromatid segregation and spindle elongation during anaphase. This causes DNA damage that is passed forward to the following cell cycle, thereby having a detrimental effect on genome integrity. Our findings highlight the drawbacks in using SiR-DNA for investigation of late mitotic events and DNA damage-related topics and urge the use of alternative labeling strategies to study these processes.
      Keywords: Cell Biology
      PubDate: 2023-09-19T07:22:19-07:00
      DOI: 10.26508/lsa.202302260
      Issue No: Vol. 6, No. 12 (2023)
  • RB loss sensitizes cells to replication-associated DNA damage after PARP
           inhibition by trapping

    • Authors: Zamalloa, L. G; Pruitt, M. M, Hermance, N. M, Gali, H, Flynn, R. L, Manning, A. L.
      Pages: e202302067 - e202302067
      Abstract: The retinoblastoma tumor suppressor protein (RB) interacts physically and functionally with a number of epigenetic modifying enzymes to control transcriptional regulation, respond to replication stress, promote DNA damage response and repair, and regulate genome stability. To better understand how disruption of RB function impacts epigenetic regulation of genome stability and determine whether such changes represent exploitable weaknesses of RB-deficient cancer cells, we performed an imaging-based screen to identify epigenetic inhibitors that promote DNA damage and compromise the viability of RB-deficient cells. We found that loss of RB alone leads to high levels of replication-dependent poly-ADP ribosylation (PARylation) and that preventing PARylation by trapping PARP enzymes on chromatin enables RB-deficient cells to progress to mitosis with unresolved replication stress. These defects contribute to high levels of DNA damage and compromised cell viability. We demonstrate this sensitivity is conserved across a panel of drugs that target both PARP1 and PARP2 and can be suppressed by reexpression of the RB protein. Together, these data indicate that drugs that target PARP1 and PARP2 may be clinically relevant for RB-deficient cancers.
      Keywords: Cancer, Cell Biology, Chromatin & Epigenetics
      PubDate: 2023-09-13T10:31:58-07:00
      DOI: 10.26508/lsa.202302067
      Issue No: Vol. 6, No. 12 (2023)
  • Nanoscaled RIM clustering at presynaptic active zones revealed by
           endogenous tagging

    • Authors: Mrestani, A; Dannhäuser, S, Pauli, M, Kollmannsberger, P, Hübsch, M, Morris, L, Langenhan, T, Heckmann, M, Paul, M. M.
      Pages: e202302021 - e202302021
      Abstract: Chemical synaptic transmission involves neurotransmitter release from presynaptic active zones (AZs). The AZ protein Rab-3-interacting molecule (RIM) is important for normal Ca2+-triggered release. However, its precise localization within AZs of the glutamatergic neuromuscular junctions of Drosophila melanogaster remains elusive. We used CRISPR/Cas9-assisted genome engineering of the rim locus to incorporate small epitope tags for targeted super-resolution imaging. A V5-tag, derived from simian virus 5, and an HA-tag, derived from human influenza virus, were N-terminally fused to the RIM Zinc finger. Whereas both variants are expressed in co-localization with the core AZ scaffold Bruchpilot, electrophysiological characterization reveals that AP-evoked synaptic release is disturbed in rimV5–Znf but not in rimHA–Znf. In addition, rimHA–Znf synapses show intact presynaptic homeostatic potentiation. Combining super-resolution localization microscopy and hierarchical clustering, we detect ~10 RIMHA–Znf subclusters with ~13 nm diameter per AZ that are compacted and increased in numbers in presynaptic homeostatic potentiation.
      Keywords: Neuroscience
      PubDate: 2023-09-11T06:24:04-07:00
      DOI: 10.26508/lsa.202302021
      Issue No: Vol. 6, No. 12 (2023)
  • Mitochondrial membrane potential acts as a retrograde signal to regulate
           cell cycle progression

    • Authors: Gorospe, C. M; Carvalho, G, Herrera Curbelo, A, Marchhart, L, Mendes, I. C, Niedzwiecka, K, Wanrooij, P. H.
      Pages: e202302091 - e202302091
      Abstract: Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA–deficient (0) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (m) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both 0 and control cells containing mtDNA. Accordingly, experimentally increasing m was sufficient to restore timely cell cycle progression in 0 cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in 0 cells with a recovered m is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of m as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.
      Keywords: Genetics, Gene Therapy & Genetic Disease, Metabolism, Cell Biology
      PubDate: 2023-09-11T06:24:04-07:00
      DOI: 10.26508/lsa.202302091
      Issue No: Vol. 6, No. 12 (2023)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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