Despite the remarkable electrochemical properties of graphene, strong van der Waals attraction between graphene and biomolecules often causes cytotoxicity, which hinders its applications in the ...biomedical field. Unfortunately, surface passivation of graphene might stimulate undesired immune response as the nanomaterial triggers cytokine production through membrane receptor activation. Herein, we use all-atom Molecular Dynamics (MD) simulations to unravel the underlying mechanism of graphene-induced inside-out activation of integrin αvβ8, a prominent membrane receptor expressed in immune cells. We model the transmembrane (TM) domains of integrin αvβ8 in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer and observe the structural changes in the integrin–membrane complex when interacting with a graphene nanosheet across the membrane. We find that the β8 TM domain interacts with the graphene nanosheet directly or indirectly through extracted lipids, facilitating the pulling of a β8 subunit away from an αv subunit and thus leading to the disruption of the TM domain association by breaking the hydrophobic cluster in the cytoplasmic domains of the αv and β8 subunits. Alanine substitution of two conserved phenylalanine residues on the αv subunit at this hydrophobic cluster further reveals the importance of a stable T-shaped structure in retaining integrin in its inactive state. Our results agree with previous studies on the interactions between other integrin subtypes and their endogenous activators, suggesting an intriguing role that the graphene nanosheet may play in the integrin-related signal transduction during its interaction with the membrane.
Can treating oneself with compassion after making a mistake increase self-improvement motivation? In four experiments, the authors examined the hypothesis that self-compassion motivates people to ...improve personal weaknesses, moral transgressions, and test performance. Participants in a self-compassion condition, compared to a self-esteem control condition and either no intervention or a positive distraction control condition, expressed greater incremental beliefs about a personal weakness (Experiment 1); reported greater motivation to make amends and avoid repeating a recent moral transgression (Experiment 2); spent more time studying for a difficult test following an initial failure (Experiment 3); exhibited a preference for upward social comparison after reflecting on a personal weakness (Experiment 4); and reported greater motivation to change the weakness (Experiment 4). These findings suggest that, somewhat paradoxically, taking an accepting approach to personal failure may make people more motivated to improve themselves.
Glycosylation of secondary metabolites involves plant UDP-dependent glycosyltransferases (UGTs). UGTs have shown promise as catalysts in the synthesis of glycosides for medical treatment. However, ...limited understanding at the molecular level due to insufficient biochemical and structural information has hindered potential applications of most of these UGTs. In the absence of experimental crystal structures, we employed advanced molecular modeling and simulations in conjunction with biochemical characterization to design a workflow to study five Group H Arabidopsis thaliana (76E1, 76E2, 76E4, 76E5, 76D1) UGTs. Based on our rational structural manipulation and analysis, we identified key amino acids (P129 in 76D1; D374 in 76E2; K275 in 76E4), which when mutated improved donor substrate recognition than wildtype UGTs. Molecular dynamics simulations and deep learning analysis identified structural differences, which drive substrate preferences. The design of these UGTs with broader substrate specificity may play important role in biotechnological and industrial applications. These findings can also serve as basis to study other plant UGTs and thereby advancing UGT enzyme engineering.
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Two-dimensional (2D) nanomaterials such as graphene are increasingly used in research and industry for various biomedical applications. Extensive experimental and theoretical studies ...have revealed that 2D nanomaterials are promising drug delivery vehicles, yet certain materials exhibit toxicity under biological conditions. So far, it is known that 2D nanomaterials possess strong adsorption propensities for biomolecules. To mitigate potential toxicity and retain favorable physical and chemical properties of 2D nanomaterials, it is necessary to explore the underlying mechanisms of interactions between biomolecules and nanomaterials for the subsequent design of biocompatible 2D nanomaterials for nanomedicine. The purpose of this review is to integrate experimental findings with theoretical observations and facilitate the study of 2D nanomaterial interaction with biomolecules at the molecular level. We discuss the current understanding and progress of 2D nanomaterial interaction with proteins, lipid membranes, and DNA based on molecular dynamics (MD) simulation. In this review, we focus on the 2D graphene nanosheet and briefly discuss other 2D nanomaterials. With the ever-growing computing power, we can image nanoscale processes using MD simulation that are otherwise not observable in experiment. We expect that molecular characterization of the complex behavior between 2D nanomaterials and biomolecules will help fulfill the goal of designing effective 2D nanomaterials as drug delivery platforms.
Why do some people report more personal improvement from their regret experiences than others? Three studies examined whether self-compassion promotes personal improvement derived from recalled ...regret experiences. In Study 1, we coded anonymous regret descriptions posted on a blog website. People who spontaneously described their regret with greater self-compassion were also judged as having expressed more personal improvement. In Study 2, higher trait self-compassion predicted greater self-reported and observer-rated personal improvement derived from recalled regret experiences. In Study 3, people induced to take a self-compassionate perspective toward a recalled regret experience reported greater acceptance, forgiveness, and personal improvement. A multiple mediation analysis comparing acceptance and forgiveness showed self-compassion led to greater personal improvement, in part, through heightened acceptance. Furthermore, self-compassion’s effects on personal improvement were distinct from self-esteem and were not explained by adaptive emotional responses. Overall, the results suggest that self-compassion spurs positive adjustment in the face of regrets.
Utilities incorporating the potable reuse of municipal wastewater are interested in converting from the UV/H2O2 to the UV/free chlorine advanced oxidation process (AOP). The AOP treatment of reverse ...osmosis (RO) permeate often includes the de facto UV/chloramine AOP because chloramines applied upstream permeate RO membranes. Models are needed that accurately predict oxidant photolysis and subsequent radical reactions. By combining radical scavengers and kinetic modeling, we have derived quantum yields for radical generation by the UV photolysis of HOCl, OCl–, and NH2Cl of 0.62, 0.55, and 0.20, respectively, far below previous estimates that incorporated subsequent free chlorine or chloramine scavenging by the •Cl and •OH daughter radicals. The observed quantum yield for free chlorine loss actually decreased with increasing free chlorine concentration, suggesting scavenging of radicals participating in free chlorine chain decomposition and even free chlorine reformation. Consideration of reactions of •ClO and its daughter products (e.g., ClO2 –), not included in previous models, were critical for modeling free chlorine loss. Radical reactions (indirect photolysis) accounted for ∼50% of chloramine decay and ∼80% of free chlorine loss or reformation. The performance of the UV/chloramine AOP was comparable to the UV/H2O2 AOP for degradation of 1,4-dioxane, benzoate and carbamazepine across pH 5.5–8.3. The UV/free chlorine AOP was more efficient at pH 5.5, but only by 30% for 1,4-dioxane. At pH 7.0–8.3, the UV/free chlorine AOP was less efficient. •Cl converts to •OH. The modeled •Cl:•OH ratio was ∼20% for the UV/free chlorine AOP and ∼35% for the UV/chloramine AOP such that •OH was generally more important for contaminant degradation.
When nanoparticles interact with cellular or organelle membranes, the coating ligands are known to affect the integrity of the membranes, which regulate cell death and inflammation. However, the ...molecular mechanisms of this modulation remain unresolved. Here, we use synchrotron X-ray liquid surface scattering and molecular dynamics simulations to study interface structures between phospholipids and gold nanorods (AuNRs) coated by surfactant and polyelectrolyte. These ligands are two types of widely used surface modification with different self-assembled structures and stabilities on the surface of nanoparticles. We reveal distinct mechanisms of the ligand stability in disrupting membrane integrity. We find that the cationic surfactant ligand cetyltrimethylammonium bromide detaches from the AuNRs and inserts into phospholipids, resulting in reduced membrane thickness by compressing the phospholipids to align with the shorter ligand. Conversely, the cationic polyelectrolyte ligand poly(diallyldimethylammonium chloride) is more stable on AuNRs; although it adsorbs onto the membrane, it does not cause much impairment. The distinct coating ligand interactions with phospholipids are further verified by cellular responses including impaired lysosomal membranes and triggered inflammatory effects in macrophages. Together, the quantitative analysis of interface structures elucidates key bio–nano interactions and highlights the importance of surface ligand stability for safety and rational design of nanoparticles.
Abstract
Characterizing structural ensembles of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins is essential for studying structure–function ...relationships. Due to the different neutron scattering lengths of hydrogen and deuterium, selective labeling and contrast matching in small‐angle neutron scattering (SANS) becomes an effective tool to study dynamic structures of disordered systems. However, experimental timescales typically capture measurements averaged over multiple conformations, leaving complex SANS data for disentanglement. We hereby demonstrate an integrated method to elucidate the structural ensemble of a complex formed by two IDRs. We use data from both full contrast and contrast matching with residue‐specific deuterium labeling SANS experiments, microsecond all‐atom molecular dynamics (MD) simulations with four molecular mechanics force fields, and an autoencoder‐based deep learning (DL) algorithm. From our combined approach, we show that selective deuteration provides additional information that helps characterize structural ensembles. We find that among the four force fields, a99SB
‐disp
and CHARMM36m show the strongest agreement with SANS and NMR experiments. In addition, our DL algorithm not only complements conventional structural analysis methods but also successfully differentiates NMR and MD structures which are indistinguishable on the free energy surface. Lastly, we present an ensemble that describes experimental SANS and NMR data better than MD ensembles generated by one single force field and reveal three clusters of distinct conformations. Our results demonstrate a new integrated approach for characterizing structural ensembles of IDPs.
Specific components of independent and interdependent self-construal have been associated with psychopathology. However, most studies on this topic have been cross-sectional, precluding causal ...inferences. We used contemporaneous and temporal cross-lagged network analysis to establish weak causal effects in understanding the association between self-construal and psychopathology components.
Middle-aged and older community-dwelling adults (n = 3294) participated in the Midlife Development in the United States study across two time-points, spaced nine years apart. Six self-construal (interdependence: connection to others, commitment to others, receptiveness to influence; independence: behavioral consistency, sense of difference from others, self-reliance) and three psychopathology nodes (major depressive disorder (MDD), generalized anxiety disorder (GAD), and panic disorder (PD) symptom severity) were examined. All network analyses controlled for age, sex, race, and number of chronic illnesses as covariates.
Contemporaneous and temporal networks yielded relations between elevated MDD and PD and increased receptiveness to influence. Heightened GAD symptom severity was associated with future increased difference from others and decreased connection to others, commitment to others, and receptiveness to influence. Higher MDD, GAD, and PD severity were associated with future lower self-reliance. Network comparison tests revealed no consistent network differences across sex and race.
DSM-III-R measures of MDD, GAD, and PD were used. Results may not generalize to culturally diverse racial groups.
Changes in self-construal may result from increased MDD, GAD, and PD severity. Findings suggest the importance of targeting common mental health symptoms to positively influence how individuals view the self and others in various social contexts.
•Psychopathology predicts changes in cultural values.•Depression and panic predict higher receptiveness to influence.•Generalized anxiety predicts lower interdependence overall.•Psychopathology predicts lower self-reliance.•Targeting psychopathology may impact view of the self and others in social contexts.
Structural defects in nanomaterials can alter their physical and chemical properties including magnetization, electronic and thermal conductivities, light absorption, and emission capabilities. Here, ...we investigated the potential impact of these defects on their biological effects through molecular dynamics simulations. By modeling the interaction between a graphene nanosheet and a widely used model protein, the chicken villin headpiece subdomain (HP35), we observed severe protein denaturation upon contact with defective graphene, while the protein remained intact on ideal graphene. The enhanced toxicity of defective graphene was due to the stronger attraction of the surface residues of HP35 from the defect edges (represented by carboxyl groups in our simulations) than from the ideal graphene. Upon binding to defective graphene, the contacting residues were restrained near the defective sites, which acted as "anchors" for the adsorbed protein. The "anchors" subsequently caused the protein to expose its aromatic and hydrophobic core residues to the graphene surface,
via
strong π-π stacking and hydrophobic interactions, thus leading to the unfolding of the protein. These findings not only highlight the importance of defects in nanomaterials' impact on biological systems, but also provide insights into fine-tuning the potential biological properties of nanomaterials through defect engineering.
Structural defects in nanomaterials can alter their physical and chemical properties beyond normal magnetization, electronic and thermal conductivities, to include even their biological effects, such as enhancing protein denaturation.
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