Causal relationship between inflammatory bowel disease and erythema nodosum: A two-sample bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have demonstrated the coexistence of erythema nodosum (EN) and inflammatory bowel disease (IBD), while the exact etiology of the co-occurrence of the two disorders remains uncertain. METHODS: A bidirectional two-sample Mendelian randomization (MR) design was employed to determine the causal link between EN and IBD. Genetic variations associated with Crohn's disease (CD) and ulcerative colitis (UC) were derived from accessible genome-wide association studies pertaining to European ancestry. The FinnGen database was used to find the genetic variations containing EN. In the forward model, IBD was identified as the exposure, whereas in the reverse model, EN was identified as the exposure. The causal link between IBD and EN was examined using a range of different analysis techniques, the primary one being the inverse variance weighted (IVW) method, including inverse variance weighted-fixed effects (IVW-FE) and inverse-variance weighted-multiplicative random effects (IVW-MRE). To strengthen the results, assessments of sensitivity, heterogeneity, and pleiotropy were also conducted. RESULTS: MR results showed that IBD increased the risk of EN (IVW-MRE: OR = 1.242, 95% CI = 1.068-1.443, p = 0.005). Furthermore, there was a strong correlation found between CD and a higher risk of EN (IVW-FE: OR = 1.250, 95% CI = 1.119-1.396, p = 8.036 × 10-5 ). However, UC did not appear to be linked to EN (IVW-FE: OR = 1.104, 95% CI = 0.868-1.405, p = 0.421). The reverse MR analysis findings did not imply that EN was linked to IBD. Horizontal pleiotropy did not appear to exist, and the robustness of these findings was confirmed. CONCLUSION: The current investigation found that in European populations, IBD and its subtype CD could raise the incidence of EN.

Organizations of melittin peptides after spontaneous penetration into cell membranes.

The antimicrobial peptide, melittin, is a potential next-generation antibiotic because melittin can spontaneously form pores in bacterial cell membranes and cause cytoplasm leakage. However, the organizations of melittin peptides in cell membranes remain elusive, which impedes the understanding of the poration mechanism. In this work, we use coarse-grained and all-atom molecular dynamics (MD) simulations to investigate the organizations of melittin peptides during and after spontaneous penetration into DPPC/POPG lipid bilayers. We find that the peptides in lipid bilayers adopt either a transmembrane conformation or a U-shaped conformation, which are referred to as T- and U-peptides, respectively. Several U-peptides and/or T-peptides aggregate to form stable pores. We analyze a T-pore consisting of four T-peptides and a U-pore consisting of three U-peptides and one T-peptide. In both pores, peptides are organized in a manner such that polar residues face inward and hydrophobic residues face outward, which stabilizes the pores and produces water channels. Compared with the U-pore, the T-pore has lower energy, larger pore diameter, and higher permeability. However, the T-pore occurs less frequently than the U-pore in our simulations, probably because the formation of the T-pore is kinetically slower than the U-pore. The stability and permeability of both pores are confirmed by 300 ns all-atom MD simulations. The peptide organizations obtained in this work should deepen the understanding of the stability, poration mechanism, and permeability of melittin, and facilitate the optimization of melittin to enhance the antibacterial ability.

Forming a Double-Helix Phase of Single Polymer Chains by the Cooperation between Local Structure and Nonlocal Attraction.

Double-helix structures, such as DNA, are formed in nature to realize many unique functions. Inspired by this, researchers are pursuing strategies to design such structures from polymers. A key question is whether the double helix can be formed from the self-folding of a single polymer chain without specific interactions. Here, using Langevin dynamics simulation and theoretical analysis, we find that a stable double-helix phase can be achieved by the self-folding of single semiflexible polymers as a result of the cooperation between local structure and nonlocal attraction. The critical temperature of double-helix formation approximately follows T^{cri}∼ln(k_{θ}) and T^{cri}∼ln(k_{τ}), where k_{θ} and k_{τ} are the polymer bending and torsion stiffness, respectively. Furthermore, the double helix can exhibit major and minor grooves due to symmetric break for better packing. Our results provide a novel guide to the experimental design of the double helix.

Functionalized Cortical Bone-Inspired Composites Adapt to the Mechanical and Biological Properties of the Edentulous Area to Resist Fretting Wear.

Dental implants with long-term success of osseointegration have always been the goal, however, difficulties exist. The accumulation of fretting damage at the implant-bone interface often gets overlooked. Commonly used titanium is approximately 7-fold harder and stiffer than cortical bone. Stress shielding caused by the mismatching of the elastic modulus aggravates fretting at the interface, which is accompanied by the risk of the formation of proinflammatory metal debris and implant loosening. Thus, the authors explore functionalized cortical bone-inspired composites (FCBIC) with a hierarchical structure at multiple scales, that exhibit good mechanical and biological adaptivity with cortical bone. The design is inspired by nature, combining brittle minerals with organic molecules to maintain machinability, which helps to acquire excellent energy-dissipating capability. It therefore has the comparable hardness and elastic modulus, strength, and elastic-plastic deformation to cortical bone. Meanwhile, this cortical bone analogy exhibits excellent osteoinduction and osseointegration abilities. These two properties also facilitate each other to resist fretting wear, and therefore improve the success rate of implantation. Based on these results, the biological-mechanical co-operation coefficient is proposed to describe the coupling between these two factors for designing the optimized dental implants.

Quantifying the effects of slit confinement on polymer knots using the tube model.

Knots can spontaneously form in DNA, proteins, and other polymers and affect their properties. These knots often experience spatial confinement in biological systems and experiments. While confinement dramatically affects the knot behavior, the physical mechanisms underlying the confinement effects are not fully understood. In this work, we provide a simple physical picture of the polymer knots in slit confinement using the tube model. In the tube model, the polymer segments in the knot core are assumed to be confined in a virtual tube due to the topological restriction. We first perform Monte Carlo simulation of a flexible knotted chain confined in a slit. We find that with the decrease of the slit height from H=+∞ (the 3D case) to H=2a (the 2D case), the most probable knot size L_{knot}^{*} dramatically shrinks from (L_{knot}^{*})_{3D}≈140a to (L_{knot}^{*})_{2D}≈26a, where a is the monomer diameter of the flexible chain. Then we quantitatively explain the confinement-induced knot shrinking and knot deformation using the tube model. Our results for H=2a can be applied to a polymer knot on a surface, which resembles DNA knots measured by atomic force microscopy under the conditions that DNA molecules are weakly absorbed on the surface and reach equilibrium 2D conformations. This work demonstrates the effectiveness of the tube model in understanding polymer knots.

miR-498/DNMT3b Axis Mediates Resistance to Radiotherapy in Esophageal Cancer Cells.

Objective: To explore the role of miR-498 in the radiotherapy resistance of esophageal cancer (EC) and its underlying mechanism. Methods: In vivo models of EC tissues with radioresistance or radiosensitivity were isolated from 72 EC patients who received radiotherapy. In vitro models were established after irradiation of KYSE30 cells. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were employed to measure the expression levels of miR-498 and DNMT3b in EC cells sensitive or resistant to irradiation. Then, protein expression of DNMT3b was verified by immunohistochemistry. The cell viability, colony formation rate, and cell apoptotic rate of EC were correspondingly assessed by CCK-8, colony formation assay, and Annexin V/PI (propidium iodide) double staining. Western blot was utilized to perform the expression levels of PI3K, p-PI3K, AKT, and p-AKT in EC cell lines after irradiation. Results: Highly expressed DNMT3b and lowly expressed miR-498 were found in EC tissues. EC tissues with radiosensitivity had higher miR-498 level and lower DNMT3b expression than EC tissues with radioresistance. Overexpression of miR-498 or knockdown of DNMT3b enhanced the radiosensitivity of EC cells. DNMT3b was a target gene of miR-498. DNMT3b diminished the radiosensitization of miR-498 in EC cells. Conclusions: MiR-498 enhances the sensitivity of EC cells to radiation by DNMT3b inhibition, and exerts biological functions by inactivating the PI3K/AKT signaling pathway.

Computational Design of Extraordinarily Stable Peptide Structures through Side-Chain-Locked Knots.

Extraordinarily stable protein and peptide structures are critically demanded in many applications. Typical approaches to enhance protein and peptide stability are strengthening certain interactions. Here, we develop a very different approach: stabilizing peptide structures through side-chain-locked knots. More specifically, a peptide core consists of a knot, which is prevented from unknotting and unfolding by large side chains of amino acids at knot boundaries. These side chains impose free energy barriers for unknotting. The free energy barriers are quantified using all-atom and coarse-grained simulations. The barriers become infinitely high for large side chains and tight knot cores, resulting in stable peptide structures, which never unfold unless one chemical bond is broken. The extraordinary stability is essentially kinetic stability. Our new approach lifts the thermodynamic restriction in designing peptide structures, provides extra freedom in selecting sequence and structural motifs that are thermodynamically unstable, and should expand the functionality of peptides. This work also provides a bottom-up understanding of how knotting enhances protein stability.

Crowding-induced polymer trapping in a channel.

In this work, we report an intriguing phenomenon: crowding-induced polymer trapping in a channel. Using Langevin dynamics simulations and analytical calculations, we find that for a polymer confined in a channel, crowding particles can push a polymer into the channel corner through inducing an effective polymer-corner attraction due to the depletion effect. This phenomenon is referred to as polymer trapping. The occurrence of polymer trapping requires a minimum volume fraction of crowders, ϕ^{*}, which scales as ϕ^{*}∼(a_{c}/L_{p})^{1/3} for a_{c}≫a_{m} and ϕ^{*}∼(a_{c}/L_{p})^{1/3}(a_{c}/a_{m})^{1/2} for a_{c}≪a_{m}, where a_{c} is the crowder diameter, a_{m} is the monomer diameter, and L_{p} is the polymer persistence length. For DNA, ϕ^{*} is estimated to be around 0.25 for crowders with a_{c}=2nm. We find that ϕ^{*} also strongly depends on the shape of the channel cross section, and ϕ^{*} is much smaller for a triangle channel than a square channel. The polymer trapping leads to a nearly fully stretched polymer conformation along a channel corner, which may have practical applications, such as full stretching of DNA for the nanochannel-based genome mapping technology.

Potential Osteoinductive Effects of Hydroxyapatite Nanoparticles on Mesenchymal Stem Cells by Endothelial Cell Interaction.

Nano-hydroxyapatite (nano-HA) has attracted substantial attention in the field of regenerative medicine. Endothelial cell (EC)-mesenchymal stem cell (MSC) interactions are necessary for bone reconstruction, but the manner in which nano-HA interacts in this process remains unknown. Herein, we investigated the cytotoxicity and osteoinductive effects of HA nanoparticles (HANPs) on MSCs using an indirect co-culture model mediated by ECs and highlighted the underlying mechanisms. It was found that at a subcytotoxic dose, HANPs increased the viability and expression of osteoblast genes, as well as mineralized nodules and alkaline phosphatase production of MSCs. These phenomena relied on HIF-1α secreted by ECs, which triggered the ERK1/2 signaling cascade. In addition, a two-stage cell-lineage mathematical model was established to quantitatively analyze the impact of HIF-1α on the osteogenic differentiation of MSCs. It demonstrated that HIF-1α exerted a dose-dependent stimulatory effect on the osteogenic differentiation rate of MSCs up to 1500 pg/mL, which was in agreement with the above results. Our data implied that cooperative interactions between HANPs, ECs, and MSCs likely serve to stimulate bone regeneration. Furthermore, the two-stage cell-lineage model is helpful in vitro system for assessing the potential influence of effector molecules in bone tissue engineering.

General two-species interacting Lotka-Volterra system: Population dynamics and wave propagation.

The population dynamics of two interacting species modeled by the Lotka-Volterra (LV) model with general parameters that can promote or suppress the other species is studied. It is found that the properties of the two species' isoclines determine the interaction of species, leading to six regimes in the phase diagram of interspecies interaction; i.e., there are six different interspecific relationships described by the LV model. Four regimes allow for nontrivial species coexistence, among which it is found that three of them are stable, namely, weak competition, mutualism, and predator-prey scenarios can lead to win-win coexistence situations. The Lyapunov function for general nontrivial two-species coexistence is also constructed. Furthermore, in the presence of spatial diffusion of the species, the dynamics can lead to steady wavefront propagation and can alter the population map. Propagating wavefront solutions in one dimension are investigated analytically and by numerical solutions. The steady wavefront speeds are obtained analytically via nonlinear dynamics analysis and verified by numerical solutions. In addition to the inter- and intraspecific interaction parameters, the intrinsic speed parameters of each species play a decisive role in species populations and wave properties. In some regimes, both species can copropagate with the same wave speeds in a finite range of parameters. Our results are further discussed in the light of possible biological relevance and ecological implications.