Search Results (3,323)

Porcine epidemic diarrhea virus (PEDV) continues to undergo genetic evolution and remains a major etiological agent of enteric disease in swine, causing significant economic losses worldwide. This study investigated the molecular epidemiology and genetic characteristics of PEDV circulating in Chongqing, China, between 2022 and 2024. A total of 296 diarrheic piglet samples collected from nine regions were screened using RT-qPCR, of which 48.31% (143/296) tested positive for PEDV. A subset of positive samples was subjected to S gene amplification and sequencing, yielding 15 complete sequences. Phylogenetic analysis revealed that all sequenced strains clustered within the G2c lineage and showed high nucleotide similarity (93.37–94.09%) to the classical CV777 strain. Recombination analysis indicated potential recombination events among field strains involving S-INDEL and G2b-like parental lineages, although these findings are based on a limited number of sequences. Sequence analysis identified multiple amino acid substitutions within the COE antigenic region, while other neutralizing epitopes (SS2, SS6, and 2C10) remained largely conserved. In addition, variation in predicted N-glycosylation sites was observed among some strains. Structural modelling suggested that these changes may influence spike protein conformation and antigenic properties; however, these interpretations are based on in silico analysis and require experimental validation. Overall, the findings indicate ongoing genetic evolution of PEDV in Chongqing and suggest circulation of G2c-associated variants in diarrheic piglets. However, given the limited and non-random nature of sequencing, these results may not fully represent the broader viral population. Continued large-scale molecular surveillance and functional studies are needed to better understand PEDV evolution and to support the development of improved control strategies and vaccines. Full article

Marine sponges represent a rich source of lectins with diverse biological activities and biotechnological potential. In this study, we report the purification and comprehensive biochemical and structural characterization of a lectin (CspL) from the marine sponge Cinachyrella sp. and evaluate its effects on bacterial agglutination, planktonic bacterial growth, and biofilm formation. CspL was isolated using classical chromatographic approaches and identified as a galectin-like protein based on sequence similarity, conserved carbohydrate-recognition motifs, and a predominance of β-sheet structures revealed by circular dichroism. Oligomeric analysis indicated a homotetrameric organization, consistent with the quaternary structure described for other sponge proto-type galectins. Carbohydrate-binding assays demonstrated that CspL preferentially recognizes galactoside-containing motifs, showing strong inhibition by mucin-type glycoproteins, while displaying lower affinity toward more complex glycan structures. This binding profile suggests a preference for accessible carbohydrate epitopes, likely associated with its canonical galectin architecture. Regarding antibacterial activity, CspL also exhibited selective, carbohydrate-dependent bacterial agglutination, particularly against Staphylococcus aureus strains. In addition, CspL exhibited antibiofilm activity against S. aureus and Escherichia coli, significantly reducing biofilm biomass and viable cell counts. Additionally, the lectin modulated antibiotic activity, showing synergistic effects with tetracycline and strain-dependent interactions with oxacillin. Together, these findings highlight CspL as a structurally conserved yet functionally relevant member of sponge galectins and reinforce the role of structural diversity in shaping glycan recognition and antimicrobial activity in marine lectins. Full article

The family GH126 represents a potential fourth, but still non-confirmed α-amylase family in CAZy with the founding, partially characterized member, the assumed amylolytic enzyme CPF_2247 from Clostridium perfringens. Proteins of this family adopt an (α/α)₆-barrel domain, structurally distinct from the rather more complex domain arrangement of families GH13, GH57, and GH119. Interestingly, GH126 exhibits structural similarity, including sharing potential functionally important residues with inverting β-glucanases from GH8 and GH48 (clan GH-M); this fact has prompted previous bioinformatics analyses. In the present study, two GH126 members with experimentally determined tertiary structure—the CPF_2247 and the exopolysaccharide-specific hydrolase PssZ from Listeria monocytogenes—were compared with seven GH8 and ten GH48 enzyme-substrate complexes. Family GH126 enzymes display a wide, open binding cleft, with a central tunnel-like cavity along the barrel axis, distinct from the narrow cleft in GH8 and the tunnel-shaped site in GH48. Conserved residues involved in substrate binding and catalysis of GH8 and GH48 were identified in GH126. Molecular docking with α-glucans using the CPF_2247 confirmed predicted binding at the potential active site and revealed also eventual additional binding sites. Targeted docking showed the strongest interactions for acarbose and maltoheptaose, particularly involving a GH126 unique α11-α12 loop in the assumed amylolytic enzyme CPF_2247. Full article

This review describes a novel method for increasing the effectiveness of inactivated enveloped whole-virus vaccines by targeting them for extensive uptake by antigen-presenting cells (APCs). Several inactivated whole-virus vaccines with dense glycan shields display suboptimal effectiveness because the multiple carbohydrate chains (glycans) on the virus mask immunogenic peptides and surround the virus with a negative electrostatic charge that decreases uptake by APCs. It is postulated that engineering such vaccinating viruses to present the carbohydrate antigen “α-gal epitope” on the glycan shields will immunocomplex them with the anti-Gal antibody; thus, it will target them for robust uptake by APCs. Anti-Gal is an abundant natural antibody in humans, constituting ~1% of human circulating immunoglobulins. The ligand of anti-Gal is the α-gal epitope, which is naturally synthesized in non-primate mammals and New World monkeys by the glycosylation enzyme α1,3galactosyltransferase. This enzyme is encoded by the GGTA1-gene. Viral vaccines presenting multiple α-gal epitopes on their glycan shield bind anti-Gal and activate the complement system to produce complement chemotactic cleavage peptides C5a and C3a that induce extensive recruitment of APCs to vaccine injection sites. The virion-bound anti-Gal further targets the viral vaccine for robust uptake by APCs, following binding of its Fc “tail” to Fcγ-receptors on APCs. The efficacy of this method was studied in anti-Gal-producing mice with α-gal presenting inactivated influenza virus vaccine and with gp120 of HIV presenting this epitope. These studies indicated that virus vaccines engineered to present α-gal epitopes increase anti-virus antibody production and virus-specific T-cell activation by 15- to 100-fold in comparison to the same vaccines lacking α-gal epitopes. It is suggested that α-gal presenting inactivated SARS-CoV-2 virus vaccines can induce a similar protective long-term immune memory against S- M-, E-, and N-viral proteins. Furthermore, immune-escaping variants of the mutated S-protein may be destroyed by antibodies to M and E proteins, and cells infected with such variants may be killed by cytotoxic T cells specific to peptides of the N-protein. Such an anti-M-, E-, and N-protein immune protection may prevent expansion of these variants and thus may avoid the need for immunization with COVID-19 vaccines every 6 months or following the appearance of new variants. A similar potent immunization may be achieved with an inactivated Ebolavirus vaccine engineered to present α-gal epitopes on the glycan shield. The resulting immune response to the various Ebolavirus proteins also may contribute to cross-reactive protection against other Ebolavirus species containing proteins with evolutionarily conserved structures. An effective method for the preparation of a whole-virus vaccine presenting α-gal epitopes is by arming it with the GGTA1-gene inserted into the viral genome. Such virions will present multiple α-gal epitopes on their glycan shield, which will amplify their immunogenicity instead of reducing it in the wild-type virus. Full article

Accurate prediction of protein–protein interaction (PPI) interface residues is essential for understanding molecular recognition and supporting structure-guided design. To integrate contextual sequence representations with structure-related physicochemical information, we propose a multimodal framework termed MD-Transformer. The model combines residue-level ProtBERT embeddings with physicochemical descriptors, including B-factor, solvent-accessible surface area (SASA), and hydrophobicity. A hybrid fusion module first aligns heterogeneous features, followed by Transformer encoding and cross-modal attention for multimodal integration. Using the DB5.5 benchmark, physicochemical descriptors were Z-score normalized exclusively with training-set statistics. Under the complex-level split protocol (Official A), MD-Transformer achieved an AUPRC of 0.564, outperforming the ablation model without physicochemical descriptors by 0.159 and reducing false-positive predictions on exposed non-interface residues. Under the homology-aware split protocol (Official B v1), the model maintained an AUPRC of 0.480 and an MCC of 0.242, indicating retained predictive capability under reduced sequence similarity constraints. Under the same aligned evaluation workflow, PeSTo achieved an AUPRC of 0.264. Further SASA-stratified analyses identified SASA as a major contributor to suppressing false-positive predictions across residue exposure environments, while also revealing a precision-recall trade-off in highly exposed residues. These results suggest that contextual sequence representations and residue-level physicochemical descriptors provide complementary predictive signals. Full article

The increasing prevalence of multidrug-resistant Staphylococcus aureus (MRSA) has necessitated the development of alternative therapeutic strategies targeting bacterial virulence factors. This study employed an integrated in silico approach to identifying potential inhibitors of the iron-regulated surface determinant B Near-iron Transporter domain, a key protein involved in heme acquisition and pathogenicity. Virtual screening and molecular docking identified certain similarity-selected small molecules possessing strong binding affinities, with (4-(1-oxoisoindolin-2-yl)benzoic acid (TOP1) and (4-(2-oxochromen-3-yl)benzoic acid (TOP2) exhibiting the most favorable binding energies at −12.0 and −11.8 kcal/mol, respectively. Molecular dynamics simulations over 200 ns confirmed stable protein–ligand interactions that yielded reduced structural fluctuations in ligand-bound complexes when compared with the apo form. Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis revealed that van der Waals interactions were the primary contributors to binding, with TOP1 showing a more favorable overall binding energy. Drug-likeness and pharmacokinetic predictions indicated compliance with Lipinski’s rule of five and moderate bioavailability, although limited intestinal absorption was observed. Toxicity predictions indicated that both compounds are non-mutagenic but may exhibit hepatotoxicity. Notably, TOP1 exhibited potential nephrotoxicity, cardiotoxicity, and carcinogenicity, whereas TOP2 demonstrated a more favorable safety profile. These findings highlight a trade-off between binding affinity and safety, suggesting that TOP2 emerged as a computationally prioritized candidate for future experimental validation. Because the present findings represent computational predictions only, further orthogonal computational analyses and experimental studies are required to confirm the proposed binding modes, biological activity, and therapeutic potential of the identified compounds. Full article

Aspartame is a widely used artificial sweetener, but its possible relationship with rheumatoid arthritis (RA) remains insufficiently understood. This study aimed to explore, rather than prove, potential molecular links between aspartame-related targets and RA-associated gene networks. Three public RA transcriptomic datasets (GSE55235, GSE55457, and GSE77298) from the Gene Expression Omnibus (GEO) database were integrated as discovery/training data. Because these datasets included different tissue origins, batch correction was used to reduce dataset-level technical variation, whereas tissue-origin-related biological variation was not assumed to be fully removable. After differential expression analysis, RA-associated differentially expressed genes (DEGs) were identified. The single-cell dataset GSE200815 was used for cell annotation and cellular expression visualization; because its comparator group consists of psoriatic arthritis (PsA) samples rather than healthy controls, single-cell results were interpreted as RA-vs-PsA observations and were not treated as disease-versus-healthy-control evidence. Potential targets of aspartame were retrieved from ChEMBL, SwissTargetPrediction, and the Similarity Ensemble Approach (SEA), and were intersected with RA-related DEGs to construct an aspartame-gene-RA regulatory network. Diagnostic models were developed using 113 machine-learning algorithm combinations to determine an optimal multigene model and its core genes. HLA-DRB1 was selected for exploratory scTenifoldKnk-based virtual knockout mainly because it was included in the optimal model and has a well-established role in RA immunogenetics; the single-cell analysis was used only to describe cellular distribution in the RA/PsA dataset. Molecular docking was then used to evaluate the possible interaction between aspartame and HLA-DRB1. Forty-four intersected genes linked the predicted aspartame targets with RA DEGs. The random forest plus partial least-squares generalized linear model (RF + plsRglm) identified 16 core genes. Network-level interpretation indicated that these genes were distributed across immune/antigen-processing, inflammatory-signaling, protease/extracellular-matrix-remodeling, adhesion, metabolic, and proliferation-related modules; therefore, HLA-DRB1 was treated as a prioritized immune-module candidate rather than as the sole driver of the network. Following virtual knockout of HLA-DRB1, affected genes were enriched in extracellular matrix organization, extracellular structure organization, extracellular matrix, collagen trimer, extracellular matrix structural constituent, and collagen binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included integrin signaling, focal adhesion, proteoglycans in cancer, cytoskeleton in muscle, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling. Molecular docking showed a minimum binding energy of −6.7 kcal/mol, which was more negative than the preset stability criterion of −5.0 kcal/mol, and the docking pose suggested contacts around ARG-146. This integrative analysis suggests a hypothesis-generating association between aspartame-related predicted targets and RA-relevant molecular networks involving HLA-DRB1 and other core genes. The findings do not establish causality and require experimental, epidemiological, biophysical, and tissue-stratified validation before any causal or clinical inference can be made. Full article

The continuous evolution of the SARS-CoV-2 virus, marked by the emergence of new variants, poses a significant threat to the efficacy of existing vaccines. However, a promising approach to addressing vaccine failure caused by viral mutations (particularly in the spike protein) is the development of a variant-proof (conserved), non-spike, multiepitope universal nanostructure vaccine with multifunctionality, biocompatibility, self-adjuvanticity, and structural similarity to pathogens in terms of size and shape. This study aimed to design a self-assembled nanostructure vaccine (SANV) featuring pentameric and trimeric coiled-coil peptide motifs, as well as other functional motifs, including epitopes, TAT, PADRE, and adjuvant. The cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B lymphocyte (BL) epitopes of SANV were screened from the IEDB with more than 50% individual predicted population coverage (PPC) and fused using linkers to enable self-assembly. The multimerization of the 24 SANV monomers was modeled using the GalaxyHomomer and AlphaFold web servers. Subsequently, the leading SANV constructs with (SANVa9) and without (SANVb6) adjuvant were analyzed for their physicochemical profiles and assessed for antigenicity, allergenicity, solubility, and antioxidant potential. Furthermore, the molecular interactions, specificity, and stability of SANVa9 and SANVb6 with the broadly neutralizing sarbecovirus antibody 5817 and toll-like receptors (TLR2, TLR3, and TLR7) were analyzed using molecular docking and simulation over a 100-nanosecond time scale. Finally, the comparative immune simulation profiles of SANVa9 and SANVb6 with controls indicated stronger, broad-spectrum immune responses that could be translated into in vitro and in vivo studies and warrant further evaluation before clinical use. Full article

KCTD proteins exhibit significant structural complexity, arising from their modular organization, oligomerization, and intricate biological partnerships. Although their biological importance has been assessed for two decades, the biochemical basis of their activities is only partially understood. This is certainly due to the limited structural information that was available until a few years ago. Fortunately, some recent insightful structural studies and the advent of machine-learning-based approaches are rapidly changing the scenario. By surveying the literature and structural databases and integrating this information with ad hoc 3D-structure predictions, we provide a detailed view of the structural biology of these proteins at different levels: individual domains, full-length oligomers, functional hetero-oligomers formed by different family members, and complexes with functional partners. Collectively, these surveys and analyses provide insights into the family’s evolutionary history and its structure–function relationships. The family-wide coverage of structural information also indicates the extent to which structural similarities are reflected in functional analogies. Finally, the potential functional implications of the intricate architecture of these multimeric proteins and the tendency of their members to hetero-oligomerize are discussed from a functional perspective. Full article

Juvenile hormone (JH) analog insecticides are widely used in pest management because of their ability to disrupt insect growth and metamorphosis; however, the molecular mechanisms linking endocrine disruption to metabolic dysregulation remain incompletely understood. In addition to their established roles in diapause and developmental regulation, JH signaling pathways have also been implicated in carbohydrate and lipid metabolism. In the present study, we investigated the effects of two JH analogs, pyriproxyfen and hydroprene, on the migratory locust, Locusta migratoria, with particular emphasis on lipid metabolic regulation and the function of midgut-enriched fatty acid-binding protein gene (Mg-FABP). Bioassays were performed to evaluate insecticidal activity, and transcriptomic analyses were conducted to identify differentially expressed genes associated with endocrine signaling and lipid metabolism. Functional characterization of Mg-FABP was further performed using RNA interference (RNAi) and Oil Red O staining assays. In addition, the tertiary structure of LmMg-FABP was predicted using AlphaFold 3, and molecular docking analyses were carried out to investigate its interactions with fatty acid ligands. Both pyriproxyfen and hydroprene caused approximately 70% mortality in locust nymphs and induced significant transcriptional changes in pathways related to hormone signaling and lipid metabolism. Transcriptomic analysis revealed pronounced downregulation of Mg-FABP following JH analog exposure. RNAi-mediated silencing of Mg-FABP significantly reduced lipid droplet accumulation in the fat body, indicating that Mg-FABP plays an essential role in lipid transport and metabolic homeostasis in L. migratoria. Structural analyses further demonstrated that LmMg-FABP possesses a conserved tertiary structure highly similar to FABP homologs from other insect species. Molecular docking identified key amino acid residues involved in fatty acid binding and suggested that hydrophobic interactions are critical for ligand stabilization within the binding cavity. Collectively, our findings demonstrate that pyriproxyfen and hydroprene disrupt insect development not only through endocrine imbalance but also through perturbation of Mg-FABP-associated lipid metabolic pathways. This study provides new mechanistic insight into the coordinated interaction between hormonal signaling and lipid metabolism during JH analog exposure and identifies FABP-mediated lipid transport as a potential molecular target for the development of more selective insect growth regulators. Full article

Petronia petronia is a highly adaptable passerine bird in the western Palearctic region. Its mitochondrial genome characteristics and intraspecific genetic variation have been poorly studied. This study sequenced and annotated the complete mitochondrial genome of P. petronia. The newly obtained mitochondrial genome was 16,895 bp in length, with an A + T content of 54.50%. By comparing this sequence with another published mitochondrial genome from a different individual of the same species, which differed in elevation by approximately 210 m. The results identified 30 nucleotide variation sites across the 13 protein-coding genes. Among these, ND5 showed the highest number of variations, while COXII and ND6 contained non-synonymous mutations. The similarity between the two control regions was only 70.60%, indicating intraspecific sequence divergence. Divergence time analysis revealed that the genus Petronia diverged from other passerine lineages around 16.5 million years ago, whereas the two haplotypes of P. petronia diverged approximately 0.26 million years ago. This study reports the complete mitochondrial genome of P. petronia and provides a preliminary description of the differences among individuals in mitochondrial sequences and structure, laying a foundation for future population genetics and comparative genomics research on this species. Full article

Background: Tandem leucine-rich repeats (LRRs) are typically classified into eleven types; however, several variant motifs have also been reported. Here, we identified new LRR variants that exhibit dual characteristics of two distinct types. We investigated how the dual characteristics influence the structure and function of LRRs. Methods: We conducted sequence similarity searches using the protein database and analyzed sequence features. We also characterized the structural features of these LRR variant motifs using solved structures and AlphaFold models and investigated their potential biological functions through domain analysis. Results: Of the identified 3222 proteins, approximately 60% originate from the bacterial PVC superphylum. The variants were classified into two groups: one defined by the consensus sequence LxxLxLxx(C/T)xzI TDxxLxx(L/F)xx(L/C)xx, and the other by LxxLxLxxCxxI TDxxLxxLxxLP (where “z” denotes a deletion). The LRRs highly similar to the variants are occasionally observed in solved structures and comprise three types of super-secondary structures (SSSs): β-strand–α-helix adjoining a 3(10)-helix–β-strand, β-strand–3(10)-helix–β-strand, and β-strand–3(10)-helix adjoining an α-helix–β-strand. The AlphaFold models adopt these SSSs and, in addition, include the SSS of the β–α–β motif. Functional annotation identified kinase and F-box domains in a subset of these LRR proteins. Conclusions: The coexistence of these four SSSs and the high frequency of the first SSS appear to reflect the dual characteristics of the LRR variants. The LRR variant-containing proteins suggest potential roles in bacterial immunity and ubiquitination. The present findings expand the structural diversity of LRR proteins and provide new insights into their functional roles. Full article

Huanglongbing, a destructive citrus disease of global importance that is also present in Saudi Arabia, is associated with Candidatus Liberibacter asiaticus (CLas) and remains a major threat to citrus production. Although previous studies have documented sequence variation and prophage polymorphism in CLas, broader comparisons of prophage-associated gene content remain limited. In particular, comparative orthogroup analysis of prophage gene-content conservation across geographically structured CLas populations has rarely been explored. In this study, we analyzed 42 CLas prophage genomes from Saudi Arabia and other geographic regions using a comparative orthogroup framework. OrthoFinder assigned 99.1% of predicted proteins (1825 of 1841) to 64 orthogroups, with only 16 genes remaining unassigned. A small number of rare orthogroups restricted to only a few genomes were identified, and no orthogroup was detected in all genomes. Presence–absence analyses supported a predominantly conserved prophage gene repertoire together with a small accessory component, while also indicating that apparent absences should be interpreted in light of mixed assembly status and prophage-region completeness. Saudi Arabian genomes were distributed within the broader global framework and exhibited generally similar gene-content profiles rather than a deeply separated lineage. Functional interpretation of representative orthogroups identified conserved prophage-associated genes related to replication, helicase activity, and phage packaging, whereas variable orthogroups were primarily associated with hypothetical or accessory prophage-related functions. Overall, these results are consistent with a model in which CLas prophage diversification is associated more with sequence-level variation and localized structural differences than with extensive gain or loss of prophage genes. These findings further refine current understanding of CLas genome evolution and highlight conserved prophage-associated targets that may support molecular diagnostics and epidemiological surveillance. Full article

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) central to metabolic regulation, and its potential modulation by dietary phytochemicals is increasingly recognized as physiologically relevant. Understanding how such compounds interact with GLP-1R is important for clarifying mechanisms that may contribute to gut-to-brain signaling. In this study, we examined three structurally related dietary ginsenosides, Rg1, Rg2, and Rg3, as potential modulators of GLP-1R using luciferase reporter assays and computational analyses. Despite sharing similar molecular weights, a common dammarane scaffold, and comparable sugar moieties, the three ginsenosides displayed distinct effects on GLP-1R activity: Rg2 and Rg3 potently reduced receptor activation in a dose-dependent manner when co-administered with Exendin-4, whereas Rg1 had minimal effect. Computational screening of the GLP-1R structure for binding sites identified a putative extracellular pocket on the protein that can accommodate these compounds, while molecular docking and binding free energy calculations provided predicted affinities qualitatively reflecting the phytochemicals’ experimental activities. These findings point to a plausible extracellular mechanism through which dietary ginsenosides may influence GLP-1R responsiveness at the intestinal interface. Our results point to the possibility that non-absorbed phytochemicals can differentially modulate gut-expressed receptors, suggesting a novel pathway for dietary signaling relevant to ethnopharmacology and metabolic health. Full article

Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease progression in Alzheimer’s disease (AD), Parkinson’s disease (PD), and MS. Emerging evidence suggests a shared mechanism behind MS, AD, and PD, driven by chronic interaction between the peripheral immune system and the central nervous system (CNS). While MS was traditionally viewed as a primary autoimmune condition, recent research indicated that all three disorders involve a breakdown of the blood–brain barrier (BBB). This structural failure enables peripheral immune cells and cytokines to enter the brain, causing sustained neuroinflammation and accelerating disease progression. Here, we propose an end-to-end framework for identification of the diagnostic and therapeutic cell-specific protein markers commonly regulated in mild–moderate AD (MMAD), early-stage PD (ESPD), and MS within peripheral blood mononuclear cells (PBMCs). PBMC markers were first identified based on shared differential protein expression, followed by filtering for BBB permeability. Subsequently, sorted cell markers were mapped to disease-specific neural cell types. Our analysis suggests that PBMC-derived cells, including astrocyte- and monocyte-like populations, share overlapping transcriptional signatures and functional similarity with macrophages and neuroglial cells, indicating potential transcriptional similarity or functional convergence. Furthermore, intra- and inter-cellular pathway analysis suggested both shared and disease-specific signaling mechanisms, with kinase–integrin interactions emerging as key regulatory factors. Selected potential seed markers, primarily kinases and immunoglobulins, were further analyzed through evolutionary sequence–structure space to identify druggable structural features. Next, protein moonlighting possibilities were tested to enhance the temporal functional trajectory of the markers for precise therapeutic impact. Hence, the framework provides a robust strategy to identify immune-based disease-specificcandidate diagnostic andpotential therapeutic targets. Full article