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12 pages, 1284 KiB  
Communication
Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice
by Franziska Rother, Amishaben R. Parmar, Julia S. Bodenhagen, Letizia Marvaldi, Enno Hartmann and Michael Bader
Genes 2025, 16(6), 690; https://doi.org/10.3390/genes16060690 - 6 Jun 2025
Viewed by 645
Abstract
Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer’s disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and [...] Read more.
Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer’s disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and KPNA4 (also named importin alpha3) could be associated with the development of motor neuron diseases, a condition specifically affecting the neurons projecting from brain to spinal cord or from spinal cord to the muscles. Here we set out to analyze the neuronal function of mice deficient in KPNA3 (Kpna3-KO) or KPNA4 (Kpna4-KO). The motoric abilities and locomotion at different time points in ageing were tested to study the role of these two genes on motor neuron function. While we did not find deficits related to motor neurons in both mouse models, we discovered a hypermotoric phenotype in KPNA4-deficient mice. Attention deficit/hyperactivity disorder (ADHD) is caused by a combination of genetic, environmental and neurobiological factors and a number of genes have been suggested in genome-wide association studies to contribute to ADHD, including KPNA4. Here we provide supportive evidence for KPNA4 as a candidate pathogenic factor in ADHD, by analysing Kpna4-KO mice which show ADHD-like symptoms. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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18 pages, 2580 KiB  
Article
Avermectins Inhibit Replication of Parvovirus B19 by Disrupting the Interaction Between Importin α and Non-Structural Protein 1
by Gualtiero Alvisi, Elisabetta Manaresi, Silvia Pavan, David A. Jans, Kylie M. Wagstaff and Giorgio Gallinella
Viruses 2025, 17(2), 220; https://doi.org/10.3390/v17020220 - 3 Feb 2025
Viewed by 1404
Abstract
Human parvovirus B19 (B19V) is a major human pathogen in which the ssDNA genome is replicated within the nucleus of infected human erythroid progenitor cells (EPCs) through a process involving both cellular and viral proteins, including the non-structural protein (NS)1. We previously characterized [...] Read more.
Human parvovirus B19 (B19V) is a major human pathogen in which the ssDNA genome is replicated within the nucleus of infected human erythroid progenitor cells (EPCs) through a process involving both cellular and viral proteins, including the non-structural protein (NS)1. We previously characterized the interaction between NS1 classical nuclear localization signal (cNLS: GACHAKKPRIT-182) and host cell importin (IMP)α and proposed it as a potential target for antiviral drug development. Here, we further extend on such findings. First, we demonstrate that NS1 nuclear localization is required for viral production since introducing the K177T substitution in a cloned, infectious viral genome resulted in a non-viable virus. Secondly, we demonstrate that the antiparasitic drug ivermectin (IVM), known to inhibit the IMPα/β dependent nuclear import pathway, could impair the NS1-NLS:IMPα interaction and suppress viral replication in UT7/EpoS1 cells in a dose-dependent manner. We also show that a panel of structurally related avermectins (AVMs) can dissociate the NS1-NLS:IMPα complex with half-maximal inhibitory concentrations in the nanomolar range. Among them, Eprinomectin emerged as the most selective inhibitor of B19V replication, with a selectivity index of c. 5.0. However, when tested in EPCs generated from peripheral blood mononuclear cells, which constitute a cellular population close to the natural target cells in bone marrow, the inhibitory effect of IVM and Eprinomectin was demonstrated to a lesser extent, and both compounds exhibited high toxicity, thus highlighting the need for more specific inhibitors of the NS1-NLS:IMPα interaction. Full article
(This article belongs to the Special Issue Advances in Parvovirus Research 2024)
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15 pages, 4704 KiB  
Article
Drosophila Importin Alpha 1 (Dα1) Is Required to Maintain Germline Stem Cells in the Testis Niche
by James Heaney, Jiamin Zhao, Franca Casagranda, Kate L. Loveland, Nicole A. Siddall and Gary R. Hime
Cells 2024, 13(6), 494; https://doi.org/10.3390/cells13060494 - 12 Mar 2024
Viewed by 1745
Abstract
Stem cell maintenance and differentiation can be regulated via the differential activity of transcription factors within stem cells and their progeny. For these factors to be active, they need to be transported from their site of synthesis in the cytoplasm into the nucleus. [...] Read more.
Stem cell maintenance and differentiation can be regulated via the differential activity of transcription factors within stem cells and their progeny. For these factors to be active, they need to be transported from their site of synthesis in the cytoplasm into the nucleus. A tissue-specific requirement for factors involved in nuclear importation is a potential mechanism to regulate stem cell differentiation. We have undertaken a characterization of male sterile importin alpha 1 (Dα1) null alleles in Drosophila and found that Dα1 is required for maintaining germline stem cells (GSCs) in the testis niche. The loss of GSCs can be rescued by ectopic expression of Dα1 within the germline but the animals are still infertile, indicating a second role for Dα1 in spermatogenesis. Expression of a Dα1 dominant negative transgene in GSCs confirmed a functional requirement for Dα1 in GSC maintenance but expression of the transgene in differentiating spermatogonia did not exhibit a phenotype indicating a specific role for Dα1 within GSCs. Our data indicate that Dα1 is utilized as a regulatory protein within GSCs to facilitate nuclear importation of proteins that maintain the stem cell pool. Full article
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17 pages, 4100 KiB  
Review
Viral Targeting of Importin Alpha-Mediated Nuclear Import to Block Innate Immunity
by Olivia A. Vogel, Jade K. Forwood, Daisy W. Leung, Gaya K. Amarasinghe and Christopher F. Basler
Cells 2024, 13(1), 71; https://doi.org/10.3390/cells13010071 - 29 Dec 2023
Cited by 4 | Viewed by 5171
Abstract
Cellular nucleocytoplasmic trafficking is mediated by the importin family of nuclear transport proteins. The well-characterized importin alpha (IMPA) and importin beta (IMPB) nuclear import pathway plays a crucial role in the innate immune response to viral infection by mediating the nuclear import of [...] Read more.
Cellular nucleocytoplasmic trafficking is mediated by the importin family of nuclear transport proteins. The well-characterized importin alpha (IMPA) and importin beta (IMPB) nuclear import pathway plays a crucial role in the innate immune response to viral infection by mediating the nuclear import of transcription factors such as IRF3, NFκB, and STAT1. The nuclear transport of these transcription factors ultimately leads to the upregulation of a wide range of antiviral genes, including IFN and IFN-stimulated genes (ISGs). To replicate efficiently in cells, viruses have developed mechanisms to block these signaling pathways. One strategy to evade host innate immune responses involves blocking the nuclear import of host antiviral transcription factors. By binding IMPA proteins, these viral proteins prevent the nuclear transport of key transcription factors and suppress the induction of antiviral gene expression. In this review, we describe examples of proteins encoded by viruses from several different families that utilize such a competitive inhibition strategy to suppress the induction of antiviral gene expression. Full article
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17 pages, 4046 KiB  
Article
Anti-Cancer Roles of Probiotic-Derived P8 Protein in Colorectal Cancer Cell Line DLD-1
by Byung Chull An, Jun Young Ahn, Daebeom Kwon, Sang Hee Kwak, Jin Young Heo, Seungwoo Kim, Yongku Ryu and Myung Jun Chung
Int. J. Mol. Sci. 2023, 24(12), 9857; https://doi.org/10.3390/ijms24129857 - 7 Jun 2023
Cited by 12 | Viewed by 3114
Abstract
A novel probiotics-derived protein, P8, suppresses the growth of colorectal cancer (CRC). P8 can penetrate the cell membrane via endocytosis and cause cell cycle arrest in DLD-1 cells through down-regulation of CDK1/Cyclin B1. However, neither the protein involved in the endocytosis of P8 [...] Read more.
A novel probiotics-derived protein, P8, suppresses the growth of colorectal cancer (CRC). P8 can penetrate the cell membrane via endocytosis and cause cell cycle arrest in DLD-1 cells through down-regulation of CDK1/Cyclin B1. However, neither the protein involved in the endocytosis of P8 nor the cell cycle arrest targets of P8 are known. We identified two P8-interacting target proteins [importin subunit alpha-4 (KPNA3) and glycogen synthase kinase-3 beta (GSK3β)] using P8 as a bait in pull-down assays of DLD-1 cell lysates. Endocytosed P8 in the cytosol was found to bind specifically to GSK3β, preventing its inactivation by protein kinases AKT/CK1ε/PKA. The subsequent activation of GSK3β led to strong phosphorylation (S33,37/T41) of β-catenin, resulting in its subsequent degradation. P8 in the cytosol was also found to be translocated into the nucleus by KPNA3 and importin. In the nucleus, after its release, P8 binds directly to the intron regions of the GSK3β gene, leading to dysregulation of GSK3β transcription. GSK3β is a key protein kinase in Wnt signaling, which controls cell proliferation during CRC development. P8 can result in a cell cycle arrest morphology in CRC cells, even when they are in the Wnt ON signaling state. Full article
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15 pages, 3659 KiB  
Article
Henipavirus Matrix Protein Employs a Non-Classical Nuclear Localization Signal Binding Mechanism
by Camilla M. Donnelly, Olivia A. Vogel, Megan R. Edwards, Paige E. Taylor, Justin A. Roby, Jade K. Forwood and Christopher F. Basler
Viruses 2023, 15(6), 1302; https://doi.org/10.3390/v15061302 - 31 May 2023
Cited by 4 | Viewed by 3128
Abstract
Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic species from the Henipavirus genus within the paramyxovirus family and are harbored by Pteropus Flying Fox species. Henipaviruses cause severe respiratory disease, neural symptoms, and encephalitis in various animals and humans, with human [...] Read more.
Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic species from the Henipavirus genus within the paramyxovirus family and are harbored by Pteropus Flying Fox species. Henipaviruses cause severe respiratory disease, neural symptoms, and encephalitis in various animals and humans, with human mortality rates exceeding 70% in some NiV outbreaks. The henipavirus matrix protein (M), which drives viral assembly and budding of the virion, also performs non-structural functions as a type I interferon antagonist. Interestingly, M also undergoes nuclear trafficking that mediates critical monoubiquitination for downstream cell sorting, membrane association, and budding processes. Based on the NiV and HeV M X-ray crystal structures and cell-based assays, M possesses a putative monopartite nuclear localization signal (NLS) (residues 82KRKKIR87; NLS1 HeV), positioned on an exposed flexible loop and typical of how many NLSs bind importin alpha (IMPα), and a putative bipartite NLS (244RR-10X-KRK258; NLS2 HeV), positioned within an α-helix that is far less typical. Here, we employed X-ray crystallography to determine the binding interface of these M NLSs and IMPα. The interaction of both NLS peptides with IMPα was established, with NLS1 binding the IMPα major binding site, and NLS2 binding as a non-classical NLS to the minor site. Co-immunoprecipitation (co-IP) and immunofluorescence assays (IFA) confirm the critical role of NLS2, and specifically K258. Additionally, localization studies demonstrated a supportive role for NLS1 in M nuclear localization. These studies provide additional insight into the critical mechanisms of M nucleocytoplasmic transport, the study of which can provide a greater understanding of viral pathogenesis and uncover a potential target for novel therapeutics for henipaviral diseases. Full article
(This article belongs to the Special Issue Henipaviruses: An Ongoing Threat to Livestock and Humans)
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19 pages, 3283 KiB  
Article
In Vitro Investigation of the Interaction of Avian Metapneumovirus and Newcastle Disease Virus with Turkey Respiratory and Reproductive Tissue
by Frederik Bexter, Nancy Rüger, Hicham Sid, Alexandra Herbst, Gülsah Gabriel, Albert Osterhaus and Silke Rautenschlein
Viruses 2023, 15(4), 907; https://doi.org/10.3390/v15040907 - 31 Mar 2023
Cited by 3 | Viewed by 2237
Abstract
In poultry, several respiratory viral infections lead to a drop in egg production associated with high economic losses. While the virus–host interactions at the respiratory epithelium are well studied, less is known about these interactions in the oviduct. To investigate possible differences between [...] Read more.
In poultry, several respiratory viral infections lead to a drop in egg production associated with high economic losses. While the virus–host interactions at the respiratory epithelium are well studied, less is known about these interactions in the oviduct. To investigate possible differences between virus infections at these epithelial structures, we compared the interactions of two important poultry viruses on turkey organ cultures. Two members of the order Mononegavirales, the Avian Metapneumovirus (AMPV) and the Newcastle disease virus (NDV), were selected to conduct the in vitro experiments since these viruses can infect both the trachea and oviduct. In addition, we used different strains of these viruses, a subtype A and a subtype B strain for AMPV and the NDV strains Komarow and Herts’33, to detect possible differences not only between the tissues but also between different viral strains. Turkey tracheal and oviduct organ cultures (TOC and OOC) were prepared to investigate viral replication, antigen localisation, lesion development, and the expression pattern of interferon-λ and importin-α isoforms. All viruses replicated more efficiently in the oviduct than in the tracheal epithelium (p < 0.05). In addition, we observed higher expression levels of both, IFN-λ and importin-α in OOCs compared to TOCs. Our results indicated strain-dependent differences, with the AMPV-B- and Herts’33 strains being more virulent in organ cultures than the AMPV-A- and Komarow strains, based on the higher viral genome loads, more severe histological lesions, and higher upregulation of IFN-λ. Overall, our findings reveal tissue- and virus strain-dependent differences, which may have consequences for disease development in the host tissue and, subsequently, possible treatment strategies. Full article
(This article belongs to the Section Animal Viruses)
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16 pages, 2782 KiB  
Article
Structural Characterization of Porcine Adeno-Associated Virus Capsid Protein with Nuclear Trafficking Protein Importin Alpha Reveals a Bipartite Nuclear Localization Signal
by Mikayla Hoad, Emily M. Cross, Camilla M. Donnelly, Subir Sarker, Justin A. Roby and Jade K. Forwood
Viruses 2023, 15(2), 315; https://doi.org/10.3390/v15020315 - 23 Jan 2023
Cited by 8 | Viewed by 3191
Abstract
Adeno-associated viruses (AAV) are important vectors for gene therapy, and accordingly, many aspects of their cell transduction pathway have been well characterized. However, the specific mechanisms that AAV virions use to enter the host nucleus remain largely unresolved. We therefore aimed to reveal [...] Read more.
Adeno-associated viruses (AAV) are important vectors for gene therapy, and accordingly, many aspects of their cell transduction pathway have been well characterized. However, the specific mechanisms that AAV virions use to enter the host nucleus remain largely unresolved. We therefore aimed to reveal the interactions between the AAV Cap protein and the nuclear transport protein importin alpha (IMPα) at an atomic resolution. Herein we expanded upon our earlier research into the Cap nuclear localization signal (NLS) of a porcine AAV isolate, by examining the influence of upstream basic regions (BRs) towards IMPα binding. Using a high-resolution crystal structure, we identified that the IMPα binding determinants of the porcine AAV Cap comprise a bipartite NLS with an N-terminal BR binding at the minor site of IMPα, and the previously identified NLS motif binding at the major site. Quantitative assays showed a vast difference in binding affinity between the previously determined monopartite NLS, and bipartite NLS described in this study. Our results provide a detailed molecular view of the interaction between AAV capsids and the nuclear import receptor, and support the findings that AAV capsids enter the nucleus by binding the nuclear import adapter IMPα using the classical nuclear localization pathway. Full article
(This article belongs to the Special Issue Viruses of Wildlife: Impact on Human and Animal Health)
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18 pages, 4191 KiB  
Article
Analysis of Ser/Thr Kinase HASPIN-Interacting Proteins in the Spermatids
by Naoko Maeda, Junji Tsuchida, Yoshitake Nishimune and Hiromitsu Tanaka
Int. J. Mol. Sci. 2022, 23(16), 9060; https://doi.org/10.3390/ijms23169060 - 13 Aug 2022
Cited by 3 | Viewed by 2588
Abstract
HASPIN is predominantly expressed in spermatids, and plays an important role in cell division in somatic and meiotic cells through histone H3 phosphorylation. The literature published to date has suggested that HASPIN may play multiple roles in cells. Here, 10 gene products from [...] Read more.
HASPIN is predominantly expressed in spermatids, and plays an important role in cell division in somatic and meiotic cells through histone H3 phosphorylation. The literature published to date has suggested that HASPIN may play multiple roles in cells. Here, 10 gene products from the mouse testis cDNA library that interact with HASPIN were isolated using the two-hybrid system. Among them, CENPJ/CPAP, KPNA6/importin alpha 6, and C1QBP/HABP1 were analyzed in detail for their interactions with HASPIN, with HASPIN phosphorylated C1QBP as the substrate. The results indicated that HASPIN is involved in spermatogenesis through the phosphorylation of C1QBP in spermatids, and also may be involved in the formation of centrosomes. Full article
(This article belongs to the Special Issue Development and Function of the Reproductive System)
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18 pages, 35740 KiB  
Article
Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
by Valeria Inés Segatori, Juan Garona, Lorena Grisel Caligiuri, Juan Bizzotto, Rosario Lavignolle, Ayelén Toro, Pablo Sanchis, Eduardo Spitzer, Alejandro Krolewiecki, Geraldine Gueron and Daniel Fernando Alonso
Viruses 2021, 13(10), 2084; https://doi.org/10.3390/v13102084 - 15 Oct 2021
Cited by 9 | Viewed by 8337
Abstract
Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho [...] Read more.
Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations. Full article
(This article belongs to the Special Issue Towards Host-Centric Antivirals)
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13 pages, 4337 KiB  
Article
Genome-Wide Association Study Reveals a Genomic Region Associated with Mite-Recruitment Phenotypes in the Domesticated Grapevine (Vitis vinifera)
by Erika R. LaPlante, Margaret B. Fleming, Zoë Migicovsky and Marjorie Gail Weber
Genes 2021, 12(7), 1013; https://doi.org/10.3390/genes12071013 - 30 Jun 2021
Cited by 12 | Viewed by 3161
Abstract
Indirect defenses are plant phenotypes that reduce damage by attracting natural enemies of plant pests and pathogens to leaves. Despite their economic and ecological importance, few studies have investigated the genetic underpinnings of indirect defense phenotypes. Here, we present a genome-wide association study [...] Read more.
Indirect defenses are plant phenotypes that reduce damage by attracting natural enemies of plant pests and pathogens to leaves. Despite their economic and ecological importance, few studies have investigated the genetic underpinnings of indirect defense phenotypes. Here, we present a genome-wide association study of five phenotypes previously determined to increase populations of beneficial (fungivorous and predacious) mites on grape leaves (genus Vitis): leaf bristles, leaf hairs, and the size, density, and depth of leaf domatia. Using a common garden genetic panel of 399 V. vinifera cultivars, we tested for genetic associations of these phenotypes using previously obtained genotyping data from the Vitis9kSNP array. We found one single nucleotide polymorphism (SNP) significantly associated with domatia density. This SNP (Chr5:1160194) is near two genes of interest: Importin Alpha Isoform 1 (VIT_205s0077g01440), involved in downy mildew resistance, and GATA Transcription Factor 8 (VIT_205s0077g01450), involved in leaf shape development. Our findings are among the first to examine the genomic regions associated with ecologically important plant traits that facilitate interactions with beneficial mites, and suggest promising candidate genes for breeding and genetic editing to increase naturally occurring predator-based defenses in grapevines. Full article
(This article belongs to the Special Issue Powdery Mildew Resistance Genetics)
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16 pages, 2592 KiB  
Review
The Intrinsically Disordered W Protein Is Multifunctional during Henipavirus Infection, Disrupting Host Signalling Pathways and Nuclear Import
by Sofiya Tsimbalyuk, Emily M. Cross, Mikayla Hoad, Camilla M. Donnelly, Justin A. Roby and Jade K. Forwood
Cells 2020, 9(8), 1913; https://doi.org/10.3390/cells9081913 - 18 Aug 2020
Cited by 15 | Viewed by 4264 | Correction
Abstract
Nipah and Hendra viruses are highly pathogenic, zoonotic henipaviruses that encode proteins that inhibit the host’s innate immune response. The W protein is one of four products encoded from the P gene and binds a number of host proteins to regulate signalling pathways. [...] Read more.
Nipah and Hendra viruses are highly pathogenic, zoonotic henipaviruses that encode proteins that inhibit the host’s innate immune response. The W protein is one of four products encoded from the P gene and binds a number of host proteins to regulate signalling pathways. The W protein is intrinsically disordered, a structural attribute that contributes to its diverse host protein interactions. Here, we review the role of W in innate immune suppression through inhibition of both pattern recognition receptor (PRR) pathways and interferon (IFN)-responsive signalling. PRR stimulation leading to activation of IRF-3 and IFN release is blocked by henipavirus W, and unphosphorylated STAT proteins are sequestered within the nucleus of host cells by W, thereby inhibiting the induction of IFN stimulated genes. We examine the critical role of nuclear transport in multiple functions of W and how specific binding of importin-alpha (Impα) isoforms, and the 14-3-3 group of regulatory proteins suggests further modulation of these processes. Overall, the disordered nature and multiple functions of W warrant further investigation to understand henipavirus pathogenesis and may reveal insights aiding the development of novel therapeutics. Full article
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