Search Results (8,414)

The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer’s disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome. Full article

Background: Distinguishing genuine kinase–substrate motifs from background noise is a growing challenge, as mass spectrometry (MS)-based global phosphoproteomics identifies a rapidly expanding set of phosphorylation sites. One of the major limitations is selecting an appropriate background model that systematically controls both technical and biological sources of bias. Although using the entire proteome as a background in a FASTA format considers the overall amino acid composition, it is still prone to biases from protein abundance and the uneven distribution of sequence space (particularly around low-abundance proteins). By contrast, internal background methods can control experiment-specific detection biases, but they may not fully capture residue-specific compositions or general trends in phosphorylation. Methods: I develop a Dual-Background Enrichment (DBE) framework with a position-specific enrichment (PSE) strategy, which involves analyzing motif enrichment against two distinct background models: (1) A residue-heterogeneous internal background composed of phospho-motifs centered on the residue; e.g., phosphoserine (pS) motifs are tested relative to the pool of all detected phosphothreonine (pT) and phosphotyrosine (pY) motifs from the same experiment. (2) A FASTA background that includes all S, T, and Y residues in the UniProtKB proteome sequences. Results: Motifs are classified as high confidence if they meet statistical significance (q ≤ 0.05, fold enrichment > 1.5) against both background models. Conclusion: By applying the DBE strategy to a large-scale phosphoproteomics dataset, we distinguish motifs driven by amino acid composition (enriched in FASTA background only) from those reflecting kinase substrate specificity (enriched in both backgrounds). This dual-reference approach reduces false positives arising from sequence composition bias and enriches high-confidence candidate kinase recognition motifs. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Collapsin Response Mediator Protein 2 (CRMP2) has emerged as a central node in the pathogenesis of chronic pain, functioning as a multimodal ‘molecular switch’ that regulates microtubule dynamics, ion channel trafficking, and synaptic plasticity. The dysregulation of CRMP2, particularly through aberrant post-translational modifications (PTMs) such as phosphorylation and SUMOylation, is a critical driver of both peripheral and central sensitization. This review systematically examines the structure, regulation, and multifaceted roles of CRMP2 in pain signaling pathways. We then critically evaluate a spectrum of CRMP2-targeted therapeutic strategies, including small-molecule inhibitors, peptide-based agents, and gene silencing, highlighting their promising preclinical efficacy and safety profiles. Despite challenges in targeting specificity and central nervous system delivery, we posit that innovations in delivery systems, precision medicine, and AI-assisted drug design will catalyze the clinical translation of CRMP2-based, non-opioid analgesics, offering a paradigm shift in chronic pain management. Full article

Tremella fuciformis extract (TFE) is used in dermocosmetic formulations due to its moisturising, antioxidant, and skin-supportive properties. The present study compared the effects of commercial TFE and hyaluronic acid (HA) on selected functions of human dermal fibroblasts (HDF). The cells were treated with TFE at concentrations of either 200 µg/mL or 500 µg/mL, or with HA at a concentration of 500 µg/mL. The following parameters were the focus of the study: cell viability, DNA and collagen biosynthesis, prolidase activity, scratch-wound closure, and immunofluorescence of selected signalling- and extracellular matrix-related markers. The findings of this study demonstrate that neither TFE nor HA had any effect on HDF viability. TFE led to a significant increase in DNA biosynthesis at both concentrations, while HA had no significant effect. The synthesis of collagen was found to be considerably elevated by both HA and TFE500, with no such effect observed in the presence of TFE200. Prolidase activity was observed to be highest in the HA group and also elevated in the TFE500 group; however, these results should be regarded as descriptive due to the nature of the pooled-sample data. Immunofluorescence analysis revealed increased phosphorylated protein kinase B (p-AKT) fluorescence in images treated with TFE, while phosphorylated mechanistic target of rapamycin (p-mTOR) remained close to the control level. Higher levels of β1-integrin, Insulin-Like Growth Factor-I Receptor (IGF-1R), prolidase, and phosphorylated Extracellular Signal-Regulated Kinases (p-ERK1/2) fluorescence were also observed in selected groups. The mean scratch-wound closure was found to be highest for TFE500. Overall, TFE was found to be associated with DNA biosynthesis, whereas HA and TFE500 were found to enhance collagen biosynthesis. Further studies are required to confirm biological reproducibility and the mechanism. Full article

Collagen peptides have been widely studied for their beneficial effects on skin health; however, their potential role in hair growth remains insufficiently explored. This study aimed to investigate the effects of orally administered low-molecular-weight fish collagen peptide (SH-GT) on hair regrowth and its underlying mechanisms in a hair-removed C57BL/6J mouse model. Mice were administered SH-GT (100, 300, or 600 mg/kg body weight) or a positive control (Pansidil, 400 mg/kg) daily for 28 days. SH-GT significantly enhanced hair regrowth, as evidenced by the increased hair growth area. Histological analysis revealed increased dermal thickness and visible hair follicle structures in SH-GT-treated groups. At the molecular level, SH-GT upregulated proliferation-related proteins, including PCNA and Cyclin D1, and activated Wnt/β-catenin signaling. In addition, SH-GT enhanced PI3K/Akt/mTOR signaling, suggesting improved cellular growth and survival. Conversely, SH-GT suppressed hair growth inhibitory pathways by reducing BMP4 expression and decreasing Smad phosphorylation. Furthermore, SH-GT increased the mRNA expression of growth factors such as IGF-1, HGF, VEGF, EGF, and FGF7. In conclusion, SH-GT promotes hair regrowth by simultaneously activating proliferation-related signaling pathways and suppressing inhibitory mechanisms, thereby improving the dorsal skin microenvironment associated with hair regrowth. These findings suggest that SH-GT may serve as a promising functional ingredient for improving hair growth. Full article

Experimental acute lung injury (ALI) models are widely used to investigate pulmonary inflammation and evaluate therapeutic strategies for acute respiratory distress syndrome (ARDS). Kaempferia marginata is a traditional medicinal plant used to treat fever and has been reported to possess anti-inflammatory properties in lipopolysaccharide (LPS)-activated macrophages. 6β-Acetoxysandaracopimaradien-1α,9α-diol (ASPD), a major isopimarane-type diterpenoid isolated from this plant, has not previously been investigated for its effects on ALI. This study employed an integrated network pharmacology, molecular docking, and experimental validation strategy to investigate the protective effects and potential mechanisms of ASPD against LPS-induced ALI. Network pharmacology analysis identified several inflammation-related hub targets associated with Src, MAPK, and PI3K/Akt signalling. In LPS-stimulated MLE-12 cells, ASPD reduced inflammatory cytokine production and inhibited the phosphorylation of JNK1/2, ERK1/2, p38 MAPK, Akt, and GSK-3β. In mice with LPS-induced ALI, ASPD alleviated histopathological lung injury, pulmonary oedema, and inflammatory cell infiltration while reducing IL-6, TNF-α, and myeloperoxidase activity without apparent toxicity. Immunohistochemical analysis demonstrated reduced Src and ERK1/2 expression in lung tissue. Molecular docking analysis predicted favourable binding affinities between ASPD and selected Src- and MAPK-related signalling proteins. These findings suggest that ASPD attenuates LPS-induced ALI and is associated with alterations in Src-, MAPK-, and Akt/GSK-3β-related signalling. Full article

Efficient milk protein synthesis in dairy cows, particularly casein production, is crucial for milk quality but has low nitrogen conversion efficiency. This study aimed to determine whether an optimal ratio of glycine, asparagine, and phenylalanine could synergistically promote α-casein synthesis in bovine mammary epithelial cells (MAC-T) and to elucidate its mechanism via the PI3K-AKT-mTOR signaling pathway. Single-factor experiments and response surface central composite design were conducted to determine the optimal amino acid combination. α-Casein synthesis was measured by ELISA, gene expression by RT-qPCR, and protein phosphorylation by Western blot. A PI3K-specific inhibitor (LY294002) was used in a blocking experiment to validate the involvement of the PI3K-AKT-mTOR pathway. Results: The optimal ratio was 9.898 mmol/L glycine, 7.014 mmol/L asparagine, and 5.865 mmol/L phenylalanine (molar ratio 1.69:1.20:1.00). This combination significantly increased α-casein synthesis and secretion compared to any single amino acid (p < 0.01), demonstrating a synergistic effect. It also upregulated CSN1S1 and CSN1S2 expression and activated the PI3K-AKT-mTOR pathway at both transcriptional and translational levels. The addition of LY294002 completely abolished these effects, confirming the pathway’s crucial role. The optimal combination of glycine, asparagine, and phenylalanine synergistically enhances α-casein synthesis in MAC-T cells by activating the PI3K-AKT-mTOR pathway. These findings provide a theoretical basis for developing targeted amino acid supplementation strategies to improve milk protein production in dairy cows. Full article

This study investigated the mechanism of TGF-β1-induced Nox4 expression in pulmonary fibrosis (PF) and the anti-fibrotic effects of Tanshinone IIA (Tan-IIA). In a bleomycin-induced pulmonary fibrosis mouse model and in TGF-β1-stimulated fibroblasts, Tan-IIA attenuated fibrosis, oxidative stress, and fibroblast activation. Pharmacological inhibition revealed that the JNK/c-Jun and Smad3 pathways cooperatively mediate TGF-β1-induced expression of Nox4 and fibrotic markers (Collagen I/III, α-SMA). Tan-IIA exerted these effects by dually inhibiting the JNK/c-Jun and Smad2/3 pathways, reducing their phosphorylation and nuclear signaling, which consequently suppressed Nox4 transcription and protein expression. The combination of Tan-IIA with JNK or Smad3 inhibitors synergistically enhanced these effects. We identified a tandem c-Jun/Smad binding element in the Nox4 promoter that is critical for TGF-β1 response. Reporter assays and CUT&RUN experiments confirmed that TGF-β1-induced transcriptional activation depends on an intact c-Jun/Smad binding element and recruitment of c-Jun and Smad2/3. Moreover, Tan-IIA inhibited the enrichment of c-Jun and Smad2/3 at the Nox4 promoter. Collectively, our findings demonstrate that a c-Jun/Smad element integrates profibrotic JNK and Smad signaling to drive Nox4 expression. Tan-IIA presents a novel therapeutic strategy for fibrosis by simultaneously targeting these two key pathways, thereby mitigating Nox4-dependent oxidative stress and fibroblast activation. Full article

Sickle cell disease (SCD) is an autosomal recessive hemoglobin disorder that is mainly characterized by the presence of hemoglobin S (HbS; point mutation [Glu6Val] in the beta-globin gene). Under deoxygenated conditions, HbS polymerizes and serves as the primary trigger of oxidative stress in red blood cells (RBCs), promoting polymerization of Band 3, a major membrane scaffold protein that links the lipid bilayer to the spectrin–ankyrin cytoskeletal network. Phosphorylation at key residues within the cytosolic domain of Band 3 induces conformational changes that weaken ankyrin binding and enhance lateral mobility and clustering of Band 3. These effects are mediated through a coordinated network of erythrocyte tyrosine kinases, primarily spleen tyrosine kinase (SYK) and sarcoma (Src) family kinases, which act sequentially to modify distinct tyrosine residues. Structural features of these kinases, including tandem SH2 domains in SYK and conserved SH2–SH3–kinase domain architecture of Src family members, enable precise recognition of phosphotyrosine motifs and propagation of phosphorylation cascades. Sequence alignment and structural superimposition of SH2 domains across studied kinases demonstrate a highly conserved fold that is critical for phosphotyrosine recognition, suggesting potential overlap in substrate engagement. Therapeutically, targeting these kinases has shown considerable promise, as tyrosine kinase inhibitors (TKIs) reduce Band 3 phosphorylation, restore RBC deformability, and decrease hemolysis and vaso-occlusive interactions in vitro. Thus, in this narrative review, we focus on the regulation of Band 3 by the above-mentioned tyrosine kinases, as well as the therapeutic potential of TKIs in SCD. Full article

Corneal transparency depends on quiescence of stromal cells derived from neural crest cells and a well-controlled extracellular matrix. Disruption of this homeostasis causes fibrotic scarring, a leading cause of blindness. Transforming growth factor-β/Smad3 signaling drives corneal fibrogenesis, but the distinct roles of Smad2 versus Smad3 remain unclear. Smad2 ablation in neural crest cells using Wnt1-Cre mice triggers spontaneous severe corneal opacification along with massive stromal hypercellularity and fibrosis. The fibrotic phenotype occurs in the absence of injury, indicating that Smad2 is essential for balancing Smad3 activity in driving fibrotic signaling. Single-cell RNA sequencing and virtual knockout of Smad2 reveal prominent activation of Smad3-Yes-associated protein (YAP)/TEAD2-transcriptional program in Smad2-null corneas. Biochemical assays confirm that Smad2 loss results in increased Smad3 phosphorylation and formation of nuclear Smad3–YAP–TEAD2 complex. This trimeric complex induces the expression of collagen I, connective tissue growth factor, and cyclin D1. Importantly, pharmacologic inhibition of YAP/TEAD interaction with verteporfin blocks stromal hyperplasia and corneal fibrosis by suppressing the expression of fibrotic and cell cycle genes, which lead to restoration of corneal transparency in Smad2-neural crest-deficient mice. Our findings reveal a unique convergence of YAP/TEAD and TGF-β/Smad3 signaling that can be targeted with verteporfin to prevent corneal scarring and blindness. Full article

Background: Microglial metabolic reprogramming drives neuroinflammation in Diabetes-associated cognitive dysfunction (DACD). This study aims to evaluate Buwang formula (BWF) effects on diabetic neuroinflammation and microglial metabolism. Methods: The chemical constituents present in BWF-containing cerebrospinal fluid (BWF-CCSF) were profiled by UHPLC-MS/MS, and putative targets were predicted via network pharmacology analysis. Diabetic db/db mice were treated with BWF, and behavioral, biochemical, and histopathological assessments were performed. The in vivo findings were further validated in BV2 cells exposed to high glucose (HG) and palmitic acid (PA). Cellular energy metabolism analysis was used to quantify dynamic changes in oxidative phosphorylation (OXPHOS) and glycolysis in BV2 cells, while flow cytometry and immunofluorescence were used to examine BV2 cell polarization. The expression levels of pathway-related proteins were examined by Western blot analysis. Results: A total of 15 chemical components were identified in BWF-CCSF. According to the network pharmacology prediction, the mTOR/HIF-1α pathway might participate in the effects exerted by BWF compounds that enter the brain. In diabetic mice, BWF notably suppressed the expression of pro-inflammatory factors and reduced the accumulation of pathological proteins within the hippocampal tissue, which improved learning and memory impairments, and these improvements were accompanied by suppressed activation of the mTOR/HIF-1α pathway and its downstream glycolysis. In BV2 cells exposed to HG and PA, BWF-CCSF treatment significantly increased OXPHOS and inhibited glycolysis, promoting a polarization toward M2 anti-inflammatory phenotype. Conclusions: BWF regulates microglial metabolic reprogramming and attenuates neuroinflammation, effects that are associated with modulation of the mTOR/HIF-1α pathway, and these findings suggest that BWF warrants further investigation as a potential therapeutic candidate for DACD. Full article

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases. Full article

Background: Obesity is associated with aggressive prostate cancer, but the links between metabolic dysregulation, inflammation, adipocyte-associated signaling, and tumor growth remain incompletely defined. This study examined whether high-fat diet (HFD)-associated systemic changes and adipocyte-derived paracrine interactions are linked to prostate cancer growth in preclinical models. Methods: An HFD xenograft model and adipocyte co-culture systems were used to evaluate systemic and local tumor-supportive features. Pharmacologic/nutritional modulation was tested using green tea or EGCG, arctigenin, and the CCR2 antagonist RS 504393, alone or in combination. Tumor growth, cell proliferation, angiogenesis-related features, circulating metabolic and cytokine levels, and selected tumor-associated signaling proteins were analyzed. Results: HFD feeding was associated with increased circulating free fatty acids, IGF-1, MCP-1, IL-6, and VEGF, together with increased tumor growth, Ki67 staining, and CD31-positive microvessel density. Adipocyte co-culture systems were used to evaluate treatment-associated changes in prostate cancer cell proliferation under adipocyte-associated conditions. Combined modulation with green tea/EGCG, arctigenin, and RS 504393 was associated with greater reductions in adipocyte-associated proliferation, tumor growth, Ki67 staining, and CD31-positive microvessel density than single or dual interventions. Antibody array analysis showed treatment-associated changes in selected stress- and apoptosis-related proteins, including cleaved caspase-7 and phosphorylated Chk1. Conclusions: HFD-associated metabolic and inflammatory alterations, adipocyte-associated interactions, proliferative activity, angiogenesis-related features, and stress/apoptosis-related signaling changes were linked within a tumor-supportive framework in preclinical prostate cancer models. Combined pharmacologic/nutritional modulation was associated with reduced tumor-supportive features under HFD conditions. Further mechanistic and translational validation is needed. Full article

Ebola virus disease (EVD) is characterized by immune dysregulation and damaging hyperinflammation. We aimed to characterize the signaling pathways and regulatory mechanisms dysregulated during EVD. To avoid hyperinflammation, innate immune signaling is regulated by post-translational modifications (PTMs), including protein phosphorylation. Here, we show that the protein tyrosine phosphatase nonreceptor type 13 (PTPN13) negatively regulates Interferon (IFN)-β while also positively regulating the neutrophil chemoattractant CXCL1. Using vectors encoding IRF3 with mutations on phosphorylation sites, we identified Y292 on IRF3 as a PTPN13 target of dephosphorylation. Knockout of PTPN13 increased IRF3 phosphorylation and expression of IFNβ and IFN-stimulated genes (ISGs) following poly(I:C) stimulation. Intriguingly, depletion of PTPN13 during Ebola virus (EBOV) infection resulted in decreased IFNβ and ISG induction at later time points post-infection, which correlated with increased viral titers. We identified PTPN13-mediated dephosphorylation of the viral protein VP35 as one potential mechanism inhibiting virus replication. Additionally, the induction of inflammatory chemokines, including CXCL1, decreased in PTPN13 knockout cells late during EBOV infection. These effects could be explained by increased phosphorylation of the regulatory p85 subunit of PI3K. Dephosphorylation of p85 promotes its degradation, subsequently enhancing PI3K kinase activity and downstream signaling via AKT. Together, our study suggests that PTPN13 is involved in immune regulation and efficient antiviral responses by dephosphorylation of IRF3, EBOV-VP35 and PI3K-p85. Full article