Combined analyses of RNA-sequence and Hi-C along with GWAS loci-A novel approach to dissect keloid disorder genetic mechanism.

Keloid disorder is a tumour-like disease with invasive growth and a high recurrence rate. Genetic contribution is well expected due to the presence of autosomal dominant inheritance and various genetic mutations in keloid lesions. However, GWAS failed to reveal functional variants in exon regions but single nucleotide polymorphisms in the non-coding regions, suggesting the necessity of innovative genetic investigation. This study employed combined GWAS, RNA-sequence and Hi-C analyses to dissect keloid disorder genetic mechanisms using paired keloid tissues and normal skins. Differentially expressed genes, miRNAs and lncRNAs mined by RNA-sequence were identified to construct a network. From which, 8 significant pathways involved in keloid disorder pathogenesis were enriched and 6 of them were verified. Furthermore, topologically associated domains at susceptible loci were located via the Hi-C database and ten differentially expressed RNAs were identified. Among them, the functions of six molecules for cell proliferation, cell cycle and apoptosis were particularly examined and confirmed by overexpressing and knocking-down assays. This study firstly revealed unknown key biomarkers and pathways in keloid lesions using RNA-sequence and previously reported mutation loci, indicating a feasible approach to reveal the genetic contribution to keloid disorder and possibly to other diseases that are failed by GWAS analysis alone.

Memristor-Based Bionic Tactile Devices: Opening the Door for Next-Generation Artificial Intelligence.

Bioinspired tactile devices can effectively mimic and reproduce the functions of the human tactile system, presenting significant potential in the field of next-generation wearable electronics. In particular, memristor-based bionic tactile devices have attracted considerable attention due to their exceptional characteristics of high flexibility, low power consumption, and adaptability. These devices provide advanced wearability and high-precision tactile sensing capabilities, thus emerging as an important research area within bioinspired electronics. This paper delves into the integration of memristors with other sensing and controlling systems and offers a comprehensive analysis of the recent research advancements in memristor-based bionic tactile devices. These advancements incorporate artificial nociceptors and flexible electronic skin (e-skin) into the category of bio-inspired sensors equipped with capabilities for sensing, processing, and responding to stimuli, which are expected to catalyze revolutionary changes in human-computer interaction. Finally, this review discusses the challenges faced by memristor-based bionic tactile devices in terms of material selection, structural design, and sensor signal processing for the development of artificial intelligence. Additionally, it also outlines future research directions and application prospects of these devices, while proposing feasible solutions to address the identified challenges.

Nanoparticles that Transcytosed through Cancer Cells Can Elicit Immune Response.

Transcytosis is a crucial process that nanomedicines can experience in various delivery stages. However, little was known about whether it endows biofunctions to the nanomedicines. Here, we reported that transporting photodynamic nanoparticles across cancer cells via the endoplasmic reticulum (ER)-Golgi pathway formulated them with abundant neoantigens and damage-associated molecular patterns. The resultant nanoparticles (Tran-NPs) were potent in dendritic cell maturation and T cell activation. Meanwhile, the photodynamic Tran-NPs maintained their primary function of repolarizing immunosuppressive cells. The immune responses were observed in melanoma B16F10 tumor models. Our work suggested that the transcytosis process reprogrammed the nanoparticles with immunological properties, which might shed light on the design of nanomedicines.

Risk factors for poor progression of addictive internet use across different COVID-19 periods in China.

BACKGROUND AND OBJECTIVES: Addictive behaviors are serious factors for mental health and usually increase during public crises. We identified the vulnerable characteristics for bad prognosis of addictive internet use across different periods of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Self-reported questionnaires were delivered in three waves through jdh.com during the outbreak (n = 17,960), remission (n = 15,666), and dynamic zero (n = 12,158) periods of COVID-19 pandemic in China. Internet addiction degree was assessed using the Internet Addiction Test. The different progression groups were divided using a latent class growth model among 1679 longitudinal participants. Risk factors for bad progression were identified by two-step logistic regression. RESULTS: A total of 40.16% of participants reported an increase in the addictive degree of internet use compared with prepandemic. Across different COVID-19 periods, the overall trend of addictive internet use was downward among general Chinese study participants (Mslope = -1.56). Childhood traumatic experiences, deterioration of physical health, depression, and anxiety during remission and dynamic periods were the main risk factors for the bad progression of pandemic-induced addictive internet use. DISCUSSION AND CONCLUSIONS: Addictive internet use was remitted following relaxed control policies during the COVID-19 pandemic. Negative childhood experiences and bad mental status during the recovery period were harmful to coping with pandemic-related addictive internet use. SCIENTIFIC SIGNIFICANCE: Our findings profiled the general trend of addictive internet use and the vulnerable characteristics of its bad progression across different periods of the first wave of COVID-19 pandemic in China. Our findings provide valuable insights for preventing the long-term adverse effects of negative public events on Internet addiction.

How final year high school students' depression develop during COVID-19 in China? A latent class growth modeling analysis.

Depression increased sharply during the initial months of COVID-19, but how it developed over time is rarely explored, especially for adolescents. The current study measured depression of 605 final year high school students in China over 11 months in 4 waves. The latent growth curve modeling (LGCM) was used to examine overall trends in depression and latent class growth modeling (LCGM) was used to identify potential subgroups of adolescents' depressive trajectories. At the same time, gender, life events, and rumination were included as time-invariant covariates. Overall, the development of depression in the final year of high school students showed a slight downward trend. Meanwhile, the depression trajectories showed heterogeneity, and three categories of depression trajectories were identified, which were low-stable (24.3%), depression-risk (67.9%), and high-stable (7.8%). Neuroticism, rumination, and life events such as punishment and loss were found to significantly predict these trajectories of depression. This study helps to characterize differential depression trajectories among adolescents throughout the COVID-19 pandemic and establish several related predictors of the trajectory of depression.

Circumventing Drug Resistance Pathways with a Nanoparticle-Based Photodynamic Method.

Drug resistance remains the dominant impediment for cancer therapy, not only because compensatory drug resistance pathways are always activated, but also because of the cross-resistance of cancer cells to unrelated therapeutics. Herein, chemodrug-sensitive cancer cells, intrinsic drug-resistant cells, and acquired resistant cells were employed to uncover their biological response to a nanoparticle-based photodynamic method in tumoral, cellular, and molecular levels. We observed that nanoparticle-based photodynamic process with high therapeutic efficiency, intracellular delivery, and tumor penetration effect resulted in the indiscriminate and significant therapeutic outcome, in contrast to the diversiform effect of first-line chemo-drug, Temozolomide (TMZ). By real-time quantitative PCR array technique, we revealed that signals in classical resistance pathways were unaffected or downregulated, and photodynamic effect initiates cell apoptosis via downstream genes. The discovery that nanoparticulate photodynamic therapy bypasses the signals in multiple resistant pathways may imply an alternative route for combating drug resistance of cancer.

Synthesis of Mackinawite (FeSm) and its heterogeneous Fenton-like catalytic degradation performance of rhodamine B.

In this work, Mackinawite (FeSm) was synthesized by homogeneous precipitation method, and flower-like nanoparticles formed by the aggregation of nanosheets with a preferred orientation along the (001) plane. The heterogeneous Fenton-like degradation performance of FeSm on rhodamine B (RhB) was investigated, results illustrated that RhB degradation was the synergistic effect of adsorption, Fenton, and a heterogeneous Fenton-like reaction. In repeated experiments, the reduction of reactivity was attributed to the oxidation of FeSm into lepidocrocite, whereas lepidocrocite has relatively low hydroxyl radicals (•OH) production reactivity. Thus, it showed excellent degradation effects in long-time degradation of RhB. Photoluminescence technology and free radical capture experiments demonstrated that •OH produced on the surface of catalyst was the main active species to remove RhB. In addition, the Fe species on the surface of FeSm was the main active center for surface-mediated reactions. A total organic carbon test revealed that the degradation was not complete and degradation intermediates were formed. Liquid chromatography-mass spectrometry technology was used to identify the degradation intermediates. On this basis, possible degradation pathways were proposed.

Using gelatin/curcumin nano-fiber membranes as scaffolds in a subcutaneous model for tissue engineered cartilages.

Engineered cartilage has several applications in treating cartilage ossification, however, its use is restricted clinically. We explored the feasibility of engineered cartilage in constructing tissues using gelatin/curcumin nano-fiber membranes as scaffolds in subcutaneous models. We constructed cartilage with gelatin nano-fiber membrane (control group) and gelatin/curcumin nano-fiber membrane (experimental group) as scaffolds. After the material was implanted into the back of BALB/c mice, gross view observation was performed. Histological examination was performed 3 and 12 weeks after implantation in vivo, and cartilage formation at different time points was compared. Gross observation showed that compared to the control group, the vascularization of nearby tissues in the experimental group was significantly inhibited. The Scanning electron microscope observation showed that the chondrocytes in both groups adhered well. The growth curve of the chondrocytes showed that curcumin had no significant effect on cell growth. Histological observation showed that the cell-material complexes in both groups had cartilage lacuna formation at 3 and 12 weeks. However, compared with that of the control group, the experimental group showed obvious absorption and thicker cartilage matrix with more homogenization. Gelatin/curcumin scaffolds were successfully used to construct engineered cartilage tissues in subcutaneous animal models. Our findings demonstrate that curcumin-loaded scaffolds have great clinical applications.

Human umbilical cord mesenchymal stem cell-derived and dermal fibroblast-derived extracellular vesicles protect dermal fibroblasts from ultraviolet radiation-induced photoaging in vitro.

Ultraviolet B (UVB) radiation is a major cause of aging in dermal fibroblasts. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show antioxidant activity. In this study, the anti-aging effects of MSC-EVs on dermal fibroblast photoaging induced by UVB radiation were evaluated, and the effects of extracellular vesicles derived from dermal fibroblasts (Fb-EVs) were compared. Human umbilical cord mesenchymal stem cells and human dermal fibroblasts were cultured, and MSC-EVs and Fb-EVs were isolated and characterized. Human dermal fibroblasts were cultured in the absence or presence of different concentrations of EVs 24 hours prior to UVB radiation exposure. Cell proliferation and cell cycle were evaluated, and senescent cells and intracellular ROS were detected. The expressions of matrix metalloproteinase-1 (MMP-1), extracellular matrix protein collagen type 1 (Col-1), and antioxidant proteins such as glutathione peroxidase 1 (GPX-1), superoxide dismutase (SOD), and catalase were also analyzed. Pretreatment with MSC-EVs or Fb-EVs significantly inhibited the production of ROS induced by UVB radiation, increased dermal fibroblast proliferation, protected cells against UVB-induced cell death and cell cycle arrest, and remarkably decreased the percentage of aged cells. Pretreatment with MSC-EVs or Fb-EVs promoted the expressions of GPX-1 and Col-1 and decreased the expression of MMP-1. Both MSC-EVs and Fb-EVs protected dermal fibroblasts from UVB-induced photoaging, likely through their antioxidant activity.

Multilevel resistive switching memory behaviors arising from ion diffusion and photoelectron transfer in α-Fe2O3 nano-island arrays.

Resistive switching (RS) memory behaviors are observed in an Ag|α-Fe2O3|Ti device after operating under an ultralow bias voltage of ±0.1 V. An SET voltage of ∼20 mV is obtained under illumination. Multilevel RS memory is realized under photoelectric signal control. The separation and fast transfer of hole-electron pairs are responsible for the enhanced RS memory under illumination.

Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization.

Keloid is a benign skin tumor characterized by its cell hyperproliferative activity, invasion into normal skin, uncontrolled growth, overproduction and deposition of extracellular matrices and high recurrence rate after various therapies. Nintedanib is a receptor tyrosine kinase inhibitor targeting VEGF, PDGF, FGF, and TGF-ß receptors with proved efficacy in anti-angiogenesis and in treating various types of cancers. In this study, we investigated the effects of nintedanib on keloid fibroblasts in both in vitro and ex vivo models. Keloid fibroblasts were prepared from 54 keloid scar samples in active stages collected from 49 patients. We found that nintedanib (1-4 µM) dose-dependently suppressed cell proliferation, induced G0/G1 cell cycle arrest, and inhibited migration and invasion of keloid fibroblasts. The drug also significantly inhibited the gene and protein expression of collagen I (COL-1) and III (COL-3), fibronectin (FN), and connective growth factor (CTGF), as well as the gene expression of other pathological factors, such as alpha smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), FK506-binding protein 10 (FKBP10), and heat shock protein 47 (HSP47) in keloid fibroblasts. Furthermore, nintedanib treatment significantly suppressed the phosphorylation of p38, JNK, ERK, STAT3, and Smad, enhanced endocytosis of various growth factor receptors. Using an ex vivo tissue explant model, we showed that nintedanib significantly suppressed cell proliferation, migration, and collagen production. The drug also significantly disrupted microvessel structure ex vivo. In summary, our results demonstrate that nintedanib is likely to become a potential targeted drug for keloid systemic therapy.

Transcytosis of Nanomedicine for Tumor Penetration.

The diffusion of nanomedicines used to treat tumors is severely hindered by the microenvironment, which is a challenge that has emerged as a bottleneck for the effective outcome of nanotherapies. Classical strategies for enhancing tumor penetration rely on passive movement in the extracellular matrix (ECM). Here, we demonstrate that nanomedicine also penetrates tumor lesions via an active trans-cell transportation process. This process was discovered by directly observing the movement of nanoparticles between cells, evaluating the intracellular trafficking pathway of nanoparticles via Rab protein labeling, comparing endocytosis-exocytosis between nanoparticles administered with inhibitors, and correlating the transcytosis process with the micro-CT distribution of nanomedicines. We also demonstrated that enhanced tumor penetration promotes the therapeutic efficacy of a photodynamic therapeutic nanomedicine. Our research thus suggests that transcytosis could be an important positive factor for designing cancer nanomedicines.

A Unified Capacitive-Coupled Memristive Model for the Nonpinched Current-Voltage Hysteresis Loop.

The concept of the memristor, a resistor with memory, was proposed by Chua in 1971 as the fourth basic element of electric circuitry. Despite a significant amount of effort devoted to the understanding of memristor theory, our understanding of the nonpinched current-voltage (I-V) hysteresis loop in memristors remains incomplete. Here we propose a physical model of a memristor, with a capacitor connected in parallel, which explains how the nonpinched I-V hysteresis behavior originates from the capacitive-coupled memristive effect. Our model replicates eight types of characteristic nonlinear I-V behavior, which explains all observed nonpinched I-V curves seen in experiments. Furthermore, a reversible transition from a nonpinched I-V hysteresis loop to an ideal pinched I-V hysteresis loop is found, which explains the experimental data obtained in C15H11O6-based devices when subjected to an external stimulus (e.g., voltage, moisture, or temperature). Our results provide the vital physics models and materials insights for elucidating the origins of nonpinched I-V hysteresis loops ascribed to capacitive-coupled memristive behavior.

A Simple, Yet Multifunctional, Nanoformulation for Eradicating Tumors and Preventing Recurrence with Safely Low Administration Dose.

Designing simple-structured nanomedicine without lacking key functionalities, thereby avoiding incomplete damage or relapse of tumor with the administration of a safe dose, is pivotal for successful cancer nanotherapy. We herein presented a nanomedicine of photodynamic therapy (PDT) that simply assembled amphiphilic macromolecules of poly-l-lysine conjugating with photosensitizers onto hydrophobic upconverting nanoparticles. We demonstrated that the nanoformulation, despite its simple structure and synthesis, simultaneously possesses multiple features, including substantial payload of photosensitizers, avid cellular internalization both in vitro and in vivo, efficient diffusion and broad distribution in tumor lesion, and potent fatality for cancer stem cells that are refractory to other therapy modalities. Because of the combination of these functionalities, the tumors in mice were eradicated and no relapse was observed after at least 40 days, just with an extremely low intraperitoneal injection dose of 5.6 mg/kg. Our results suggested a strategy for designing multifunctional nanomedicines with simple construct and efficacious therapeutic response and presented the promising potential of PDT for a radical cure of cancer.

Synergistic Targeting and Efficient Photodynamic Therapy Based on Graphene Oxide Quantum Dot-Upconversion Nanocrystal Hybrid Nanoparticles.

Locating nanotherapeutics at the active sites, especially in the subcellular scale, is of great importance for nanoparticle-based photodynamic therapy (PDT) and other nanotherapies. However, subcellular targeting agents are generally nonspecific, despite the fact that the accumulation of a nanoformulation at active organelles leads to better therapeutic efficacy. A PDT nanoformulation is herein designed by using graphene oxide quantum dots (GOQDs) with rich functional groups as both the supporter for dual targeting modification and the photosensitizer for generating reactive oxygen species, and upconversion nanoparticles (UCNs) as the transducer of excitation light. A tumor-targeting agent, folic acid, and a mitochondrion-targeting moiety, carboxybutyl triphenylphosphonium, are simultaneously attached onto the UCNs-GOQDs hybrid nanoparticles by surface modification, and a synergistic targeting effect is obtained for these nanoparticles according to both in vitro and in vivo experiments. More significant cell death and a higher extent of mitochondrion damage are observed compared to the results of UCNs-GOQDs nanoparticles with no or just one targeting moiety. Furthermore, the PDT efficacy on tumor-bearing mice is also effectively improved. Overall, the current work presents a synergistic strategy to enhance subcellular targeting and the PDT efficacy for cancer therapy, which may also shed light on other kinds of nanotherapies.

Effect of fertilizers on Cd accumulation and subcellular distribution of two cosmos species (Cosmos sulphureus and Cosmos bipinnata).

Addition of fertilizer amendments is regarded as an ideal approach to enhancing phytoextraction. However, there is little information available on the influence of common fertilizers on Cd accumulation of two newly reported Cd accumulators, Cosmos sulphureus and Cosmos bipinnata (C. sulphureus and C. bipinnata). The effects of N (CO(NH2)2), NP (CO(NH2)2 + Ca(H2PO4)2), and NPK (CO(NH2)2 + Ca(H2PO4)2 + KCl) fertilizers on Cd accumulation and subcellular distribution of C. sulphureus and C. bipinnata were studied in a 70-d pot experiment. The results showed that Cd uptake of C. sulphureus and C. bipinnata with NPK fertilizer was significantly higher than control, N, and NP fertilizers, especially 3.8- and 4.7-fold higher than control (p < 0.05). Compared with C. bipinnata, C. sulphureus achieved higher biomass and Cd uptake in aboveground parts under fertilizer treatments, especially NPK fertilizer. The Cd subcellular distribution revealed that segregation of Cd to Cd-rich granules (MRG) might play an important role in Cd detoxification in both species. C. sulphureus is more likely than C. bipinnata to separate the Cd in MRG and reduce the partition in the heat-denatured protein fraction, especially with NPK fertilizer. Therefore, C. sulphureus combined with NPK fertilizers could be an effective method to remediate Cd-polluted farmland soils in China.

Efficacy Dependence of Photodynamic Therapy Mediated by Upconversion Nanoparticles: Subcellular Positioning and Irradiation Productivity.

Singlet oxygen (1 O2 ), as an important kind of reactive oxygen species (ROS) and main therapeutic agent in photodynamic therapy (PDT), only have a half-life of 40 ns and an effective radius of 20 nm, which cause significant obstacles for improving PDT efficacy. In this work, novel upconversion nanoparticle (UCN)-based nanoplatforms are developed with a minimized distance between UCNs and a photosensitizer, protoporphyrin IX (PpIX), and a controllable payload of PpIX, to enhance and control ROS production. The ability of the nanoplatform to target different subcellular organelles such as cell membrane and mitochondria is demonstrated via surface modification of the nanoplatform with different targeting ligands. The results show that the mitochondria-targeting nanoplatforms result in significantly increased capability of both tumor cell killing and inhibition of tumor growth. Subcellular targeting of nanoparticles leads to the death of cancer cells in different manners. However, the efficiency of ROS generation almost have no influence on the tumor cell viability during the period of evaluation. These findings suggest that specific subcellular targeting of the nanoplatforms enhances the PDT efficacy more effectively than the increase of ROS production, and may shed light on future novel designs of effective and controllable PDT nanoplatforms.

Hydrogen-peroxide-modified egg albumen for transparent and flexible resistive switching memory.

Egg albumen is modified by hydrogen peroxide with concentrations of 5%, 10%, 15% and 30% at room temperature. Compared with devices without modification, a memory cell of Ag/10% H2O2-egg albumen/indium tin oxide exhibits obviously enhanced resistive switching memory behavior with a resistance ratio of 104, self-healing switching endurance for 900 cycles and a prolonged retention time for a 104 s @ 200 mV reading voltage after being bent 103 times. The breakage of massive protein chains occurs followed by the recombination of new protein chain networks due to the oxidation of amidogen and the synthesis of disulfide during the hydrogen peroxide modifying egg albumen. Ions such as Fe3+, Na+, K+, which are surrounded by protein chains, are exposed to the outside of protein chains to generate a series of traps during the egg albumen degeneration process. According to the fitting results of the double logarithm I-V curves and the current-sensing atomic force microscopy (CS-AFM) images of the ON and OFF states, the charge transfer from one trap center to its neighboring trap center is responsible for the resistive switching memory phenomena. The results of our work indicate that hydrogen- peroxide-modified egg albumen could open up a new avenue of biomaterial application in nanoelectronic systems.

Induction of predominant tenogenic phenotype in human dermal fibroblasts via synergistic effect of TGF-ß and elongated cell shape.

Micropattern topography is widely investigated for its role in mediating stem cell differentiation, but remains unexplored for phenotype switch between mature cell types. This study investigated the potential of inducing tenogenic phenotype in human dermal fibroblasts (hDFs) by artificial elongation of cultured cells. Our results showed that a parallel microgrooved topography could convert spread hDFs into an elongated shape and induce a predominant tenogenic phenotype as the expression of biomarkers was significantly enhanced, such as scleraxis, tenomodulin, collagens I, III, VI, and decorin. It also enhanced the expression of transforming growth factor (TGF)-ß1, but not α-smooth muscle actin. Elongated hDFs failed to induce other phenotypes, such as adiopogenic, chondrogenic, neurogenic, and myogenic lineages. By contrast, no tenogenic phenotype could be induced in elongated human chondrocytes, although chondrogenic phenotype was inhibited. Exogenous TGF-ß1 could enhance the tenogenic phenotype in elongated hDFs at low dose (2 ng/ml), but promoted myofibroblast transdifferentiation of hDFs at high dose (10 ng/ml), regardless of cell shape. Elongated shape also resulted in decreased RhoA activity and increased Rho-associated protein kinase (ROCK) activity. Antagonizing TGF-ß or inhibiting ROCK activity with Y27632 or depolymerizing actin with cytochalasin D could all significantly inhibit tenogenic phenotype induction, particularly in elongated hDFs. In conclusion, elongation of cultured dermal fibroblasts can induce a predominant tenogenic phenotype likely via synergistic effect of TGF-ß and cytoskeletal signaling.