A Novel Multi-Component Formulation Reduces Inflammation In Vitro and Clinically Lessens the Symptoms of Chronic Eczematous Skin.

Long-term treatments for inflammatory skin diseases like atopic dermatitis or eczema can cause adverse effects. Super Protein Multifunction (SPM) was investigated as a potential treatment for managing skin inflammation by monitoring the expression of pro-inflammatory cytokines induced using LPS and poly(I:C)/TNFα in HaCaT keratinocytes and Hs27 fibroblasts as measured via RT-PCR. SPM solution was also assessed for its effect on cytokine release, measured using ELISA, in a UVB-irradiated 3D human skin model. To evaluate the efficiency of SPM, 20 patients with mild eczematous skin were randomized to receive SPM or vehicle twice a day for three weeks in a double-blind controlled trial. In vitro studies showed SPM inhibited inflammation-induced IL-1ß, IL-6, IL-33, IL-1α, TSLP, and TNFα expression or release. In the clinical study, the SPM group showed significant improvements in the IGA, PA, and DLQI scores compared to the vehicle group. Neither group showed significant differences in VAS (pruritus). Histological analysis showed reduced stratum corneum thickness and inflammatory cell infiltration. The results suggest that SPM may reduce inflammation in individuals with chronic eczematous skin.

Predicting the severity of postoperative scars using artificial intelligence based on images and clinical data.

Evaluation of scar severity is crucial for determining proper treatment modalities; however, there is no gold standard for assessing scars. This study aimed to develop and evaluate an artificial intelligence model using images and clinical data to predict the severity of postoperative scars. Deep neural network models were trained and validated using images and clinical data from 1283 patients (main dataset: 1043; external dataset: 240) with post-thyroidectomy scars. Additionally, the performance of the model was tested against 16 dermatologists. In the internal test set, the area under the receiver operating characteristic curve (ROC-AUC) of the image-based model was 0.931 (95% confidence interval 0.910‒0.949), which increased to 0.938 (0.916‒0.955) when combined with clinical data. In the external test set, the ROC-AUC of the image-based and combined prediction models were 0.896 (0.874‒0.916) and 0.912 (0.892‒0.932), respectively. In addition, the performance of the tested algorithm with images from the internal test set was comparable with that of 16 dermatologists. This study revealed that a deep neural network model derived from image and clinical data could predict the severity of postoperative scars. The proposed model may be utilized in clinical practice for scar management, especially for determining severity and treatment initiation.

Brownian ratchet for directional nanoparticle transport by repetitive stretch-relaxation of DNA.

Brownian motion subject to a periodic and asymmetric potential can be biased by external, nonequilibrium fluctuations, leading to directional movement of Brownian particles. Sequence-dependent flexibility variation along double-stranded DNA has been proposed as a tool to develop periodic and asymmetric potentials for DNA binding of cationic nanoparticles with sizes below tens of nanometers. Here, we propose that repetitive stretching and relaxation of a long, double-stranded DNA molecule with periodic flexibility gradient can induce nonequilibrium fluctuations that tune the amplitude of asymmetric potentials for DNA-nanoparticle binding to result in directional transport of nanometer-sized particles along DNA. Realization of the proposed Brownian ratchet was proven by Brownian dynamics simulations of coarse-grained models of a single, long DNA molecule with flexibility variation and a cationic nanoparticle.

Sequence-dependent twist-bend coupling in DNA minicircles.

Looping of double-stranded DNA molecules with 100-200 base pairs into minicircles, catenanes, and rotaxanes has been suggested as a potential tool for DNA nanotechnologies. However, sharp DNA bending into a minicircle with a diameter of several to ten nanometers occurs with alterations in the DNA helical structure and may lead to defective kink formation that hampers the use of DNA minicircles, catenanes, and rotaxanes in nanoscale DNA applications. Here, we investigated local variations of a helical twist in sharply bent DNA using microsecond-long all-atom molecular dynamics simulations of six different DNA minicircles, focusing on the sequence dependence of the coupling between DNA bending and its helical twist. Twist angles between consecutive base pairs were analyzed at different locations relative to the direction of DNA bending and, among 10 unique dinucleotide steps, we identified four dinucleotide steps with strong twist-bend coupling, the pyrimidine-purine dinucleotide steps of TA/TA, CG/CG, and CA/TG and the purine-purine dinucleotide step of GA/TC. This work suggests the sequence-dependent structural responses of DNA to strong mechanical deformation, providing new molecular-level insights into the structure and stability of sharply bent DNA minicircles for nanoscale applications.

Effect of DNA Flexibility on Complex Formation of a Cationic Nanoparticle with Double-Stranded DNA.

We present extensive molecular dynamics simulations of a cationic nanoparticle and a double-stranded DNA molecule to discuss the effect of DNA flexibility on the complex formation of a cationic nanoparticle with double-stranded DNA. Martini coarse-grained models were employed to describe double-stranded DNA molecules with two different flexibilities and cationic nanoparticles with three different electric charges. As the electric charge of a cationic nanoparticle increases, the degree of DNA bending increases, eventually leading to the wrapping of DNA around the nanoparticle at high electric charges. However, a small increase in the persistence length of DNA by 10 nm requires a cationic nanoparticle with a markedly increased electric charge to bend and wrap DNA around. Thus, a more flexible DNA molecule bends and wraps around a cationic nanoparticle with an intermediate electric charge, whereas a less flexible DNA molecule binds to a nanoparticle with the same electric charge without notable bending. This work provides solid evidence that a small difference in DNA flexibility (as small as 10 nm in persistence length) has a substantial influence on the complex formation of DNA with proteins from a biological perspective and suggests that the variation of sequence-dependent DNA flexibility can be utilized in DNA nanotechnology as a new tool to manipulate the structure of DNA molecules mediated by nanoparticle binding.

Mesenchymal stem cells co-cultured with colorectal cancer cells showed increased invasive and proliferative abilities due to its altered p53/TGF-ß1 levels.

Signaling between cancer cells, their neighboring cells, and mesenchymal stem cells (MSCs) forms the tumor microenvironment. The complex heterogeneity of this microenvironment varies depending on the tumor type and its origins. However, most of the existing cancer-based studies have focused on cancer cells. In this study, we used a direct co-culture system (cross-talk signaling) to induce cross-interaction between cancer cells and mesenchymal stem cells. This induced deformation of MSCs. MSCs showed a diminished ability to maintain homeostasis. In particular, increase in the invasion ability of MSCs by TGF-ß1 and decrease in p53, which plays a key role in cancer development, is an important discovery. It can thus be deduced that blocking these changes can effectively inhibit metastatic colorectal cancer. In conclusion, understanding the interactions and changes in MSCs associated with cancer will help develop novel therapeutic strategies for cancer.

Entropic effect of macromolecular crowding enhances binding between nucleosome clutches in heterochromatin, but not in euchromatin.

Sharp increase in macromolecular crowding induces abnormal chromatin compaction in the cell nucleus, suggesting its non-negligible impact on chromatin structure and function. However, the details of the crowding-induced chromatin compaction remain poorly understood. In this work, we present a computer simulation study on the entropic effect of macromolecular crowding on the interaction between chromatin structural units called nucleosome clutches. Nucleosome clutches were modeled by a chain of nucleosomes collapsed by harmonic restraints implicitly mimicking the nucleosome association mediated by histone tails and linker histones. The nucleosome density of the clutches was set close to either that of high-density heterochromatin or that of low-density euchromatin. The effective interactions between these nucleosome clutches were calculated in various crowding conditions, and it was found that the increase in the degree of macromolecular crowding induced attractive interaction between two clutches with high nucleosome density. Interestingly, the increased degree of macromolecular crowding did not induce any attraction between two clutches with low nucleosome density. Our results suggest that the entropic effect of macromolecular crowding can enhance binding between nucleosome clutches in heterochromatin, but not in euchromatin, as a result of the difference in nucleosome packing degrees.

Phase separation of a Lennard-Jones fluid interacting with a long, condensed polymer chain: implications for the nuclear body formation near chromosomes.

Phase separation in a biological cell nucleus occurs in a heterogeneous environment filled with a high density of chromatins and thus it is inevitably influenced by interactions with chromatins. As a model system of nuclear body formation in a cell nucleus filled with chromatins, we simulate the phase separation of a low-density Lennard-Jones (LJ) fluid interacting with a long, condensed polymer chain. The influence of the density variation of LJ particles above and below the phase boundary and the role of attractive interactions between LJ particles and polymer segments are investigated at a fixed value of strong self-interaction between LJ particles. For a density of LJ particles above the phase boundary, phase separation occurs and a dense domain of LJ particles forms irrespective of interactions with the condensed polymer chain whereas its localization relative to the polymer chain is determined by the LJ-polymer attraction strength. Especially, in the case of moderately weak attractions, the domain forms separately from the polymer chain and subsequently associates with the polymer chain. When the density is below the phase boundary, however, the formation of a dense domain is possible only when the LJ-polymer attraction is strong enough, for which the domain grows in direct contact with the interacting polymer chain. In this work, different growth behaviors of LJ particles result from the differences in the density of LJ particles and in the LJ-polymer interaction, and this work suggests that the distinct formation of activity-dependent and activity-independent nuclear bodies (NBs) in a cell nucleus may originate from the differences in the concentrations of body-specific NB components and in their interaction with chromatins.

Unusual size-dependence of effective interactions between collapsed polymers in crowded environments.

We investigate the influence of macromolecular crowding on interactions between collapsed polymers using computer simulations, to gain insights into biomacromolecular interactions in crowded biological environments. The effective attraction is induced between two collapsed polymers due to the macromolecular crowding, and it is found that the strength of the effective attraction decreases as the crowder size is reduced for a fixed crowder volume fraction, which is sharply contrasted with the conventional viewpoint based on the depletion attraction observed for hard-core spherical colloids. This unusual trend of size-dependence is interpreted by dividing the effective interaction into the polymer-mediated repulsion and crowder-mediated attraction. It is found that the ranges of repulsive and attractive contributions overlap significantly due to the flexible nature of polymer boundaries, resulting in partial cancellation over this range which leads to the observed size-dependence. Thus, this work suggests that the effective interactions between biomacromolecules in crowded environments may be qualitatively different from the depletion interactions predicted for hard-core spherical colloids.