Loss of Setd2 associates with aberrant microRNA expression and contributes to inflammatory bowel disease progression in mice.

Both SETD2-mediated H3K36me3 and miRNAs play critical epigenetic roles in inflammatory bowel disease (IBD) and involve in the dysfunctional intestinal barrier. However, little is known about cross-talk between these two types of regulators in IBD progression. We performed small RNA sequencing of Setd2 epithelium-specific knockout mice (Setd2Vil-KO) and wild-type controls, both with DSS-induced colitis, and designed a framework for integrative analysis. Firstly, we integrated the downloaded ChIP-seq data with miRNA expression profiles and identified a significant intersection of pre-miRNA expression and H3K36me3 modification. A significant inverse correlation was detected between changes of H3K36me3 modification and expression of the 171 peak-covered miRNAs. We further integrated RNA-seq data with predicted miRNA targets to screen negatively regulated miRNA-mRNA pairs and found the H3K36me3-associated differentially expressed microRNAs significantly enriched in cell-cell junction and signaling pathways. Using network analysis, we identified ten hub miRNAs, among which six are H3K36me3-associated, suggesting therapeutic targets for IBD patients with SETD2-deficiency.

The MDM2 rs937283 A > G variant significantly increases the risk of lung and gastric cancer in Chinese population.

BACKGROUND: Currently, the MDM2 promoter rs937283 A > G variant that is able to alter MDM2 gene expression has been widely studied to explore the association of MDM2 with cancer risk. In this report, we investigate the association of MDM2 rs937283 A > G variant with risk of lung cancer (LC) and gastric cancer (GC) in a Chinese population of Hubei province, which was followed by a meta-analysis. METHODS: The genotyping of rs937283 was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by sequencing. RESULTS: The results of the present study showed that rs937283 was significantly associated with the risk of LC, and the factors of age, gender, smoking status and drinking status would affect such association. However, rs937283 was only associated with the risk of GC in male, smoking and drinking subgroups. The following meta-analysis demonstrated that rs937283 was associated with the overall cancer risk particularly in Chinese population, which reinforced our present finding. Moreover, the meta-analysis according to cancer types revealed that rs937283 was associated with retinoblastoma risk, but not squamous cell carcinoma risk. CONCLUSION: Collectively, the MDM2 rs937283 A > G variant may be a valuable risk factor or diagnostic biomarker for Chinese cancer patients.

Altered white matter functional network in nicotine addiction.

Nicotine addiction is a neuropsychiatric disorder with dysfunction in cortices as well as white matter (WM). The nature of the functional alterations in WM remains unclear. The small-world model can well characterize the structure and function of the human brain. In this study, we utilized the small-world model to compare the WM functional connectivity between 62 nicotine addiction participants (called the discovery sample) and 66 matched healthy controls (called the control sample). We also recruited an independent sample comprising 32 nicotine addicts (called the validation sample) for clinical application. The WM functional network data at the network level showed that the nicotine addiction group revealed decreased small-worldness index (σ) and normalized clustering coefficient (γ) compared with healthy controls. For clinical application, the small-world topology of WM functional connectivity could distinguish nicotine addicts from healthy controls (classification accuracy=0.59323, p = 0.0464). We trained abnormal small-world properties on the discovery sample to identify the severity of nicotine addiction, and the identification was successfully applied to the validation sample (classification accuracy=0.65625, p = 0.0106). Our neuroimaging findings provide direct evidence for WM functional changes in nicotine addiction and suggest that the small-world properties of WM function could be qualified as potential biomarkers in nicotine addiction.

How far is brain-inspired artificial intelligence away from brain?

Fueled by the development of neuroscience and artificial intelligence (AI), recent advances in the brain-inspired AI have manifested a tipping-point in the collaboration of the two fields. AI began with the inspiration of neuroscience, but has evolved to achieve a remarkable performance with little dependence upon neuroscience. However, in a recent collaboration, research into neurobiological explainability of AI models found that these highly accurate models may resemble the neurobiological representation of the same computational processes in the brain, although these models have been developed in the absence of such neuroscientific references. In this perspective, we review the cooperation and separation between neuroscience and AI, and emphasize on the current advance, that is, a new cooperation, the neurobiological explainability of AI. Under the intertwined development of the two fields, we propose a practical framework to evaluate the brain-likeness of AI models, paving the way for their further improvements.

De novo mutations identified by whole-genome sequencing implicate chromatin modifications in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder with a substantial genetic basis and a broadly undiscovered etiology. Recent studies of de novo mutation (DNM) exome-sequencing studies for OCD have reinforced the hypothesis that rare variation contributes to the risk. We performed, to our knowledge, the first whole-genome sequencing on 53 parent-offspring families with offspring affected with OCD to investigate all rare de novo variants and insertions/deletions. We observed higher mutation rates in promoter-anchored chromatin loops (empirical P = 0.0015) and regions with high frequencies of histone marks (empirical P = 0.0001). Mutations affecting coding regions were significantly enriched within coexpression modules of genes involved in chromatin modification during human brain development. Four genes­SETD5, KDM3B, ASXL3, and FBL­had strong aggregated evidence and functionally converged on transcription's epigenetic regulation, suggesting an important OCD risk mechanism. Our data characterized different genome-wide DNMs and highlighted the contribution of chromatin modification in the etiology of OCD.

Alternatively Splicing Interactomes Identify Novel Isoform-Specific Partners for NSD2.

Nuclear receptor SET domain protein (NSD2) plays a fundamental role in the pathogenesis of Wolf-Hirschhorn Syndrome (WHS) and is overexpressed in multiple human myelomas, but its protein-protein interaction (PPI) patterns, particularly at the isoform/exon levels, are poorly understood. We explored the subcellular localizations of four representative NSD2 transcripts with immunofluorescence microscopy. Next, we used label-free quantification to perform immunoprecipitation mass spectrometry (IP-MS) analyses of the transcripts. Using the interaction partners for each transcript detected in the IP-MS results, we identified 890 isoform-specific PPI partners (83% are novel). These PPI networks were further divided into four categories of the exon-specific interactome. In these exon-specific PPI partners, two genes, RPL10 and HSPA8, were successfully confirmed by co-immunoprecipitation and Western blotting. RPL10 primarily interacted with Isoforms 1, 3, and 5, and HSPA8 interacted with all four isoforms, respectively. Using our extended NSD2 protein interactions, we constructed an isoform-level PPI landscape for NSD2 to serve as reference interactome data for NSD2 spliceosome-level studies. Furthermore, the RNA splicing processes supported by these isoform partners shed light on the diverse roles NSD2 plays in WHS and myeloma development. We also validated the interactions using Western blotting, RPL10, and the three NSD2 (Isoform 1, 3, and 5). Our results expand gene-level NSD2 PPI networks and provide a basis for the treatment of NSD2-related developmental diseases.

Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity.

G(IIKK)3I-NH2 has been recently shown to be highly effective at killing bacteria and inhibiting cancer cell growth while remaining benign to normal host mammalian cells. The aim of this work is to evaluate how residue substitutions of Ala (A), Val (V), Glu (E), and Lys (K) for the N-terminal Gly (G) or C-terminal Ile (I) of G(IIKK)3I-NH2 affect the physiochemical properties and bioactivity of the variants. All substitutions caused the reduction of peptide hydrophobicity, while N-terminal substitutions had a less noticeable effect on the surface activity and helix-forming ability than C-terminal substitutions. N-terminal variants held potent anticancer activity but exhibited reduced hemolytic activity; these actions were related to the maintenance of their moderate surface pressures (12-16 mN m-1), while their hydrophobicity was reduced. Thus, N-terminal substitutions enhanced the cell selectivity of the mutants relative to the control peptide G(IIKK)3I-NH2. In contrast, C-terminal variants exhibited lower anticancer activity and much lower hemolytic activity except for G(IIKK)3V-NH2. These features were correlated well with their lower surface pressures (≤10 mN m-1) and decreased hydrophobicity. In spite of its very low helical content, the C-terminal variant G(IIKK)3V-NH2 still displayed potent anticancer activity while retaining high hemolytic activity as well, again correlating well with its relatively high surface pressure and hydrophobicity. These results together indicated that surface activity governs the anticancer activity of the peptides, but hydrophobicity influences their hemolytic activity. In contrast, helicity appears to be poorly correlated to their bioactivity. This work has demonstrated that N-terminal modifications provide a useful strategy to optimize the anticancer activity of helical anticancer peptides (ACPs) against its potential toxicity to mammalian host cells.

Direct exfoliation of graphite into graphene in aqueous solutions of amphiphilic peptides.

Different amphiphilic peptides were used to mediate the direct exfoliation of graphite into few-layered graphene flakes in aqueous solutions. Charge was found to be an important parameter in determining their graphite exfoliating efficiency. The anionic molecules were more favorable than the cationic ones leading to a higher efficiency. The gemini-type peptide IleIleIleCys-CysIleIleIle (I3C-CI3) exhibited the highest efficiency, which might be attributed to its specific physicochemical properties and interactions with graphene sheets. I3C-CI3 adsorbed onto the graphene surface as either monomers or self-assembled nanoaggregates. These adsorbed species increased both electrostatic and steric repulsions between the graphene/I3C-CI3 composites. More interestingly, the graphene/I3C-CI3 composites showed a reversible pH-dependent dispersion/aggregation. This behavior resulted from the pH-sensitive protonation of the peptide molecules and was rarely found in the graphene dispersions exfoliated by traditional surfactants. Moreover, the graphene/I3C-CI3 dispersion was used to fabricate free-standing macroscopic composite films that contained different nanostructures. The study expands the library of available agents for direct graphite exfoliation to produce graphene sheets. Employing peptide molecules as graphene exfoliating and stabilizing agents avoids the use of toxic reagents, which may allow fabrication of functional composite materials for biocompatible applications.

High Selective Performance of Designed Antibacterial and Anticancer Peptide Amphiphiles.

Short designed peptide amphiphiles are attractive at killing bacteria and inhibiting cancer cell growth, and the flexibility in their structural design offers a great potential for improving their potency and biocompatibility to mammalian host cells. Amino acid sequences such as G(IIKK)nI-NH2 (n≥3) have been shown to be membrane lytic, but terminal amino acid modifications could impose a huge influence on their performance. We report in this work how terminal amino acid modifications to G(IIKK)3I-NH2 influence its α-helical structure, membrane penetrating ability, and selective actions against different cell types. Deletion of an N-terminal Gly or a C-terminal Ile did not affect their antibacterial activity much, an observation consistent with their binding behavior to negatively charged membrane lipid monolayers. However, the cytotoxicity against mammalian cells was much worsened by the N-terminal Gly deletion, consistent with an increase in its helical content. Despite little impact on the antibacterial activity of G(IIKK)3I-NH2, deletion of both terminal amino acids greatly reduced its antitumor activity. Cholesterol present in tumor cell membrane-mimic was thought to constrain (IIKK)3-NH2 from penetrating into the cancerous membranes, evident from its lowest surface physical activity at penetrating model lipid membranes. On the other hand, its low toxicity to normal mammalian cells and high antibacterial activity in vitro and in vivo made it an attractive antibacterial agent. Thus, terminal modifications can help rebalance the different interactions involved and are highly effective at manipulating their selective membrane responses.

High cell selectivity and low-level antibacterial resistance of designed amphiphilic peptide G(IIKK)(3)I-NH(2).

On the basis of cell cultures involving bacterial strains (Escherichia coli 5α and Bacillus subtilis 168) and a mammalian cell line (NIH 3T3), the potent antibacterial activity and distinct selectivity from designed amphiphilic peptides G(IIKK)nI-NH2 (n = 2-4) have been demonstrated. This work extends these studies to multidrug resistant pathogens (ESBL-producing E. coli) and primary human cells (HDFa), followed by the in vivo mouse model investigation of ESBL-producing bacterial infection. G(IIKK)3I-NH2 exhibits high antibacterial activity against the pathogenic strain both in vitro and in vivo while displaying low toxicity toward the primary cells and the mice. Peptide molecules can kill bacteria by selectively interacting with bacterial membranes, causing structural disruptions. Furthermore, multidrug resistant ESBL-producing bacteria do not develop resistance after multiple treatments with G(IIKK)3I-NH2. The high cellular selectivity, low toxicity toward mammalian hosts and noninducing bacterial resistance indicate great potential for developing the peptides as anti-infection agents.

Tuning gelation kinetics and mechanical rigidity of ß-hairpin peptide hydrogels via hydrophobic amino acid substitutions.

Self-assembling peptide hydrogels with faster gelation kinetics and higher mechanical rigidity are favorable for their practical applications. A design strategy to control the folding, self-assembly, and hydrogelation of ß-hairpin peptides via hydrophobic amino acid substitutions has been explored in this study. Isoleucine has higher hydrophobicity and stronger propensity for ß-sheet hydrogen bonding than valine. After the valine residues of MAX1 (VKVKVKVKV(D)PPTKVKVKVKV-NH2) were replaced with isoleucines, oscillatory rheometry and circular dichroism (CD) spectroscopy characterizations indicated that the variants had clearly faster self-assembly and hydrogelation rates and that the resulting gels displayed higher mechanical stiffness. Transmission electron microscopy (TEM) indicated the parent MAX1 and its variants all formed networks of long and entangled fibrils with the similar diameters of ∼3 nm, suggesting little effect of hydrophobic substitutions on the self-assembled morphology. The MAX1I8 (IKIKIKIKV(D)PPTKIKIKIKI-NH2) hydrogel showed the fastest gelation rate (within 5 min) and the highest gel rigidity with the series, supporting the homogeneous cell distribution within its 3D scaffold. In addition, the MAX1I8 hydrogel showed quick shear-thinning and rapid recovery upon cessation of shear strain, and the MTT and immunological assays indicated its low cytotoxicity and good biocompatibility. These features are highly attractive for its widespread use in 3D cell culturing and regenerative medical treatments.