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Mammary and extramammary Paget's Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways - including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

Aqueous Zn-ion batteries (ZIBs) have great potential in the field of large-scale energy storage. However, the dendrite formation on Zn anodes hinders the practical applications of ZIBs. Herein, a zincic perfluorinated sulfonic acid membrane (ZPSAM) is prepared as a quasi-solid single-ion conductor. In this membrane, Zn-ions move along with the negatively charged branched chains which possess a limited degree of freedom, forming fast Zn-ion transport channels. Consequently, ZPSAM exhibits high conductivity (~1.17 ​× ​10−3 ​S ​cm−1), enabling stable Zn plating and stripping processes at a current density of 2 ​mA ​cm−2 over 2000 cycles. In addition, due to the confined anion matrix in the membrane, dendrite formation and side reaction are both effectively suppressed. Finally, by applying the electrolyte in both aqueous super-capacitor and Zn-ion batteries, significantly improved cycling performance can be achieved. This work demonstrates a promising solution for the practical use of Zn metal anode in neutral aqueous media, and thus benefits the development of low-cost, high-performance aqueous energy storage devices.

The differentiation of human pluripotent stem cells (hPSCs) to neural stem cells (NSCs) is the key initial event in neurogenesis and is thought to be dependent on the family of Wnt growth factors, their receptors and signaling proteins. The delineation of the transcriptional pathways that mediate Wnt-induced hPSCs to NSCs differentiation is vital for understanding the global genomic mechanisms of the development of NSCs and, potentially, the creation of new protocols in regenerative medicine. To understand the genomic mechanism of Wnt signaling during NSCs development, we treated hPSCs with Wnt activator (CHIR-99021) and leukemia inhibitory factor (LIF) in a chemically defined medium (N2B27) to induce NSCs, referred to as CLNSCs. The CLNSCs were subcultured for more than 40 passages in vitro, were positive for AP staining, expressed neural progenitor markers such as NESTIN, PAX6, SOX2, and SOX1, and were able to differentiate into three neural lineage cells: neurons, astrocytes, and oligodendrocytes in vitro. Our transcriptome analyses revealed that the Wnt and Hedgehog signaling pathways regulate hPSCs cell fate decisions for neural lineages and maintain the self-renewal of CLNSCs. One interesting network could be the deregulation of the Wnt/β-catenin signaling pathway in CLNSCs via the downregulation of c-MYC, which may promote exit from pluripotency and neural differentiation. The Wnt-induced spinal markers HOXA1-4, HOXA7, HOXB1-4, and HOXC4 were increased, however, the brain markers FOXG1 and OTX2, were absent in the CLNSCs, indicating that CLNSCs have partial spinal cord properties. Finally, a CLNSC simple culture condition, when applied to hPSCs, supports the generation of NSCs, and provides a new and efficient cell model with which to untangle the mechanisms during neurogenesis.

To incorporate spatial memory and nonlocal effect of animal movements, we propose and investigate the spatiotemporal dynamics of the single population model with memory-based diffusion and nonlocal reaction. We first study the stability of a positive equilibrium and the steady state bifurcation induced by diffusion and nonlocality. We then investigate the impact of the averaged memory period on stability and bifurcation, and show that the combination of the averaged memory period and the diffusion can lead to the occurrence of Turing-Hopf and double Hopf bifurcations. The paper originally derives the normal form theory for Turing-Hopf bifurcation in the general reaction-diffusion equation with memory-based diffusion and nonlocal reaction. This novel algorithm can be widely used to classify the spatiotemporal dynamics near the Turing-Hopf bifurcation point. Finally, we apply the obtained results to a model proposed by Britton and numerically illustrate the spatiotemporal patterns induced by Hopf, Turing-Hopf and double Hopf bifurcations. Stable spatially homogeneous/nonhomogeneous periodic solutions, homogeneous/nonhomogeneous steady states and the transition from one of these solutions to another are provided in this paper. We additionally acquire the coexistence of two stable spatially nonhomogeneous steady states or two spatially nonhomogeneous periodic solutions near the Turing-Hopf bifurcation point.

The formation of dendrites on a zinc (Zn) metal anode has limited its practical applications on aqueous batteries. Herein, an artificial composite protective layer consisting of nanosized metal-organic frameworks (MOFs) to improve the poor wetting effect of aqueous electrolytes on the Zn anode is proposed to reconstruct the Zn/electrolyte interface. In this layer, hydrophilic MOF nanoparticles serve as interconnecting electrolyte reservoirs enabling nanolevel wetting effect as well as regulating an electrolyte flux on Zn anode. This zincophilic interface exhibits significantly reduced charge-transfer resistance. As a result, stable and dendrite-free Zn plating/stripping cycling performance is achieved for over 500 cycles. In addition, especially at higher C-rates, the coating layer significantly reduces the overpotentials in a Zn/MnO2 aqueous battery during cycling. The proposed principle and method in this work demonstrate an effective way to reconstruct a stable interface on metal anodes (e.g., Zn) where a conventional solid-electrolyte interface (SEI) cannot be formed.

In this paper, we investigate the influence of the nonlocal intraspecific competition of the prey on the dynamics of the diffusive Rosenzweig–MacArthur model with Holling type II functional response. Using the linear stability analysis, the conditions for the positive constant steady state to remain stable and to undergo Turing–Hopf bifurcation have been studied under the Neumann boundary conditions. We find that the introduction to the nonlocal term can produce Turing patterns, which cannot occur in the original model. Furthermore, we are interested in the interaction of Turing bifurcation and Hopf bifurcation. We also develop the algorithm of the normal form of the Turing–Hopf bifurcation for the model with nonlocality. By applying the developed normal form, the dynamical classification near the Turing–Hopf bifurcation point can be analytically determined. The stable spatially inhomogeneous steady states, stable spatially inhomogeneous periodic solutions and unstable spatially inhomogeneous periodic solutions are found. Especially, we find that two stable spatially inhomogeneous steady states and one stable spatially inhomogeneous periodic solution can coexist for appropriate parameters and that there are transitions from one unstable solution to another stable one.

Background: Despite the continued development of modern medicine, chronic wounds are still a critical issue in clinical treatment, placing a great physiological, psychological, and financial burden on patients. Researchers have investigated many methods to solve this problem, with bioactive peptides gaining increasing attention due to their considerable advantages and diverse functions, as well as low cost, simple storage, and easy transportation. Methods: In this research, a novel peptide (named OA-FF10) was identified from the skin secretions of the odorous frog species Odorrana andersonii. The sequence of mature OA-FF10 was “FFTTSCRSGC”, which was produced by the post-translational processing of a 61-residue prepropeptide. Results: Similar to most frog peptides, OA-FF10 showed an intramolecular disulfide bridge at the C-terminus. OA-FF10 demonstrated no antibacterial, antioxidant, hemolytic, or acute toxic activity, but promoted wound healing and proliferation of human keratinocytes (HaCaT) both time- and dose-dependently. Furthermore, while OA-FF10 had no effect on wound healing of Human Skin Fibroblasts (HSF), it did accelerate healing in a full-thickness skin-wound mouse model. Conclusion: Our research revealed the strong wound-healing activity of OA-FF10 in vivo and in vitro, thus providing a new candidate for the development of novel wound-healing drugs.

In this paper, we study the Hopf bifurcation and spatiotemporal pattern formation of a delayed diffusive logistic model under Neumann boundary condition with spatial heterogeneity. It is shown that for large diffusion coefficient, a supercritical Hopf bifurcation occurs near the non-homogeneous positive steady state at a critical time delay value, and the dependence of corresponding spatiotemporal patterns on the heterogeneous resource function is demonstrated via numerical simulations. Moreover, it is proved that the heterogeneous resource supply contributes to the increase of the temporal average of total biomass of the population even though the total biomass oscillates periodically in time.

Herein, through studying the electronic conductivity of a garnet electrolyte Li7La2.75Ca0.25Zr1.75Nb0.25O12 (LLCZN) at different temperatures, a model to describe the electron transfer process within garnet electrolytes is proposed for the first time. In this model, electronic conductivity is mainly determined by the barrier height and bias between the grain boundaries of LLCZN. As the external voltage polarization increases with ion current densities and finally exceeds a threshold value, electron conductivity concentration at grain boundaries increases sharply to the critical point for the combination between Li-ions and electrons. Lithium metal will consequently deposit on the grain boundaries and short circuit LLCZN. According to the results, lowering the voltage polarization across the solid electrolyte and increasing the electron transfer energy barrier at grain boundaries are two effective approaches to realize practical applications of garnet electrolytes in solid-state lithium metal batteries.

The interactions of diffusion-driven Turing instability and delayinduced Hopf bifurcation always give rise to rich spatiotemporal dynamics. In this paper, we first derive the algorithm for the normal forms associated with the Turing-Hopf bifurcation in the reaction-diffusion system with delay, which can be used to investigate the spatiotemporal dynamical classification near the Turing-Hopf bifurcation point in the parameter plane. Then, we consider a diffusive predator-prey model with weak Allee effect and delay. Through investigating the dynamics of the corresponding normal form of Turing-Hopf bifurcation induced by diffusion and delay, the spatiotemporal dynamics near this bifurcation point can be divided into six categories. Especially, stable spatially homogeneous/inhomogeneous periodic solutions and steady states, coexistence of two stable spatially inhomogeneous periodic solutions, coexistence of two stable spaially inhomogeneous steady states and the transition from one kind of spatiotemporal patterns to another are found.

Herein, a bi-functional homogeneous redox mediator is employed to promote the rate capability of Li–O2 batteries. The addition of this redox mediator not only facilitates the formation of toroid-shaped Li2O2 at high current densities, but also significantly reduces the charging over-potential caused by the bulky Li2O2.

IntroductionMigraine is a common neurological disorder with a higher prevalence occurring in women. Migraine without aura (MwoA) is the most common type of migraine. In recent years, the safety and effectiveness of acupuncture for migraines have been internationally recognised. Contralateral acupuncture (CAT) (Jùcì) is an ancient classic acupuncture technique from Huang Di Nei Jing that refers to the acupoints on the right side (healthy side) selected for diseases on the left (affected side) and vice versa. Some studies have shown that efficacy of CAT on the painful disorder is even better than ipsilateral acupuncture (IAT), but there remains a lack of high-quality evidence to support it.Methods and analysisThis is a single-centre, randomised and sham-controlled clinical trial in China with three parallel groups that aim to evaluate the efficacy of CAT in women with unilateral MwoA. 243 participants will be randomly divided into the experimental group (CAT group), control group 1 (IAT group) and control group 2 (sham acupuncture group) (1:1:1 allocation ratio). Each group will be given 30-minute treatment sessions, once every other day, approximately three times per week, for a total of 24 treatments and follow-up visits two times. The primary outcome is the changes in days of migraine attacks. The secondary outcomes are frequency of migraine attacks, intensity of migraine, migraine duration, the dose of intake of acute medication, the Migraine-Specific Quality of Life Questionnaire, the Migraine Disability Assessment Score, the Headache Impact Test-6 and the Pittsburgh Sleep Quality Index. The data will be collected at the baseline time (week 0), end of treatment (week 4–8) and the follow-up time (week 12–16). Adverse events will be collected and recorded during each treatment.Ethics and disseminationEthics approval was obtained from the Ethics Committee of the Sports Trauma Specialist Hospital of Yunnan Province (2021-01). All participants will provide written informed consent before randomisation. The results of this study will be published in a peer-reviewed journal and presented at conferences.Trial registration numberChinese Clinical Trial Registration Center (ChiCTR2100051479).

A new access control policy model was proposed, in which the concept of policy security domain was put forward which mean that policies was formulated according to domain. Json language were adopted to all the policies. Consistency of policies was detected and processed. A scheduling algorithm based on queue theory was improved in which priority of requests was set based on the complexity of policy conflict, two task processing queue was divided according to priority and all requests was referred to three resource pools. Security analysis manifests the feasibility and effectiveness of the model and algorithm owing to that the model saves storage space and improves transmission efficiency of policies and algorithm reduces the average waiting time for each request.

Metastasis is the main cause of death in breast cancer patients. The initial step of metastasis is invadopodia-mediated extracellular matrix (ECM) degradation, which enables local breast tumor cells to invade surrounding tissues. However, the molecular mechanism underlying invadopodia-mediated metastasis remains largely unknown. Here we found that the RNA-binding protein Musashi1 (Msi1) exhibited elevated expression in invasive breast tumors and promoted lung metastasis of mammary cancer cells. Suppression of Msi1 reduced invadopodia formation in mammary cancer cells. Furthermore, Msi1 deficiency decreased the expression and activity of Mmp9, an important enzyme in ECM degradation. Mechanistically, Msi1 directly suppressed Timp3, an endogenous inhibitor of Mmp9. In clinical breast cancer specimens, TIMP3 and MSI1 levels were significantly inversely correlated both in normal breast tissue and breast cancer tissues and associated with overall survival in breast cancer patients. Taken together, our findings demonstrate that the MSI1-TIMP3-MMP9 cascade is critical for invadopodia-mediated onset of metastasis in breast cancer, providing novel insights into a promising therapeutic strategy for breast cancer metastasis.

The controllable growth of high-quality transition metal dichalcogenides (TMDs) is crucial for their device applications, which rely on the atomic and quantitative understanding of the growth mechanism of TMDs. In this work, we propose a comprehensive picture of the growth of WS

Exhibiting superior safety features and low costs, solid-state sodium (Na)-ion batteries have been proposed as an attractive candidate for energy storage. However, the poor rate capability of solid-state batteries has limited their applications. In this work, an all-solid-state Na-ion battery is fabricated, delivering an unprecedented rate capability (60% capacity retention at a C-rate of 100 C with an areal loading of 1.5 mg cm-2), which far exceeds other reports so far. More importantly, it is further demonstrated that instead of the Na-ion conductivity of the solid electrolyte, the rate-limiting factors are determined to be charge-transfer resistance at electrode/solid electrolyte interfaces and lack of percolation pathways in the electrode, which can be optimized by tuning the electrode design and testing protocols.

MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-κB signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGFβ and Wnt/β-catenin. Particularly, it activates Wnt/β-catenin signaling by directly targeting Wnt antagonists, including Dkk1. Importantly, Dkk1 overexpression partially rescues miR31-induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis.

Animal genetic resources are basic materials for life science studies and are important resources for the survival and economic development of humanity (Min 2010; Liu 2011; Cheng et al. 2018). Wild animal resources are important components of China’s natural resources (Qu 2018). The low-temperature preservation of animal cells is an effective method for the protection of animal genetic resources and is particularly important in the conservation of endangered animal species (Shang 2018). Isolation and cultivation of fibroblasts from different animal tissues for the establishment of fibroblast cell lines are commonly used methods for the preservation of live tissue genetic materials. These cell materials can be stored for “half-permanent” in a – 196°C liquid nitrogen environment (Daorna et al. 2013). Preserved animal genetic resources can be used for animal cloning to revive corresponding species and provide materials for experiments in the fields of stem cells, genetic engineering, cell engineering, and molecular biology (Min 2010). Corsac fox (Vulpes corsac) is mainly lhabitated in Central Asia and is the smallest species among foxes (Zhao et al. 2016b) (Zhao et al. 2016a, b). Previous studies on corsac were mainly focused on their genetics and systematic taxonomy (Graphodatsky et al. 2008; Zhao et al. 2016a; Shang et al. 2017), biochemistry, and physiology (I V et al. 1900; Pozio et al. 1992; Tang et al. 2001; Kuzmin et al. 2004; Botvinkin et al. 2008; Odontsetseg et al. 2009; Ito et al. 2013), as well as ecological distribution (Mal'kova 2000; Tang et al. 2004). Presently, there is no report available on the establishment of fibroblast cell lines in corsac fox and its biological characteristics.

The recent developments in rechargeable aqueous batteries have witnessed a burgeoning interest in the mechanism of proton transport in the cathode materials. Herein, for the first time, we report the Grotthuss proton transport mechanism in α-MnO2 which features wide [2×2] tunnels. Exemplified by the substitution doping of Ni (≈5 at.%) in α-MnO2 that increases the energy density of the electrode by ≈25 %, we reveal a close link between the tetragonal-orthorhombic (TO) distortion of the lattice and the diffusion kinetics of protons in the tunnels. Experimental and theoretical results verify that Ni dopants can exacerbate the TO distortion during discharge, thereby facilitating the hydrogen bond formation in bulk α-MnO2 . The isolated direct hopping mode of proton transport is switched to a facile concerted mode, which involves the formation and concomitant cleavage of O-H bonds in a proton array, namely via Grotthuss proton transport mechanism. Our study provides important insight towards the understanding of proton transport in MnO2 and can serve as a model for the compositional design of cathode materials for rechargeable aqueous batteries.

OBJECTIVE: To compare the effect on hearing of different reconstruction material in type Ⅱ tympanoplasty. METHODS: Retrospectively analysis of 286 patients who accepted type Ⅱ tympanoplasty. The air-bone gap of 0.5, 1, 2, 4 kHz was analyzed before and after operation. We compared the hearing change and the complications between each group. RESULTS: In incus group, the manubrium mallei and the head of stapes were connected with shaped incus, PORP group were implanted with PORP during operation, and cartilage group used auricular cartilage to cover the head of stapes. There was no significant difference in 4 kHz air-bone gap(ABG) between the cartilage group and PORP group either before or after the operation (P>0.05). Air-bone gap of 0.5, 1, 2, 4 kHz of the incus group, and the 0.5, 1, 2 kHz of the cartilage and PORP group were significantly reducedafter the operation(P < 0.05). One patient got severe sensorineural hearing loss in incus group after the operation. The high frequency of bone conduction decreased in 1 patient(2, 4 kHz).In the incus group, 3 patients had temporary facial paralysis after operation. Incus and cartilage group each have 1 patient with dizziness after the operation. Incus, cartilage and PORP group had 5, 3 and 11 patients with perforation again respectively. There was extrusion occurred in 1 patient of PORP group. CONCLUSION: Self incus, cartilage and PORP can be used in typeⅡ tympanoplasty, the effect of hearing reconstruction is similar. The first two are more economical, PORP implantation has the lowest technical difficulty and the most widely application, but there is a certain risk of extrusion.

Aqueous zinc (Zn) batteries (AZBs) are widely considered as a promising candidate for next-generation energy storage owing to their excellent safety features. However, the application of a Zn anode is hindered by severe dendrite formation and side reactions. Herein, an interfacial bridged organic-inorganic hybrid protection layer (Nafion-Zn-X) is developed by complexing inorganic Zn-X zeolite nanoparticles with Nafion, which shifts ion transport from channel transport in Nafion to a hopping mechanism in the organic-inorganic interface. This unique organic-inorganic structure is found to effectively suppress dendrite growth and side reactions of the Zn anode. Consequently, the Zn@Nafion-Zn-X composite anode delivers high coulombic efficiency (ca. 97 %), deep Zn plating/stripping (10 mAh cm-2 ), and long cycle life (over 10 000 cycles). By tackling the intrinsic chemical/electrochemical issues, the proposed strategy provides a versatile remedy for the limited cycle life of the Zn anode.

The Hippo-YAP signaling pathway plays an essential role in epithelial cells during intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here, we report a stroma-epithelium ISLR-YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can inhibit Hippo signaling and activate YAP in epithelial cells. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings provide new insights into the signaling crosstalk between stroma and epithelium during tissue regeneration and tumorigenesis.

Some quantities in the reaction-diffusion models from cellular biology or ecology depend on the spatial average of density functions instead of local density functions. We show that such nonlocal spatial average can induce instability of constant steady state, which is different from classical Turing instability. For a general scalar equation with spatial average, the occurrence of the steady state bifurcation is rigorously proved, and the formula to determine the bifurcation direction and the stability of the bifurcating steady state is given. For the two-species model, spatially non-homogeneous time-periodic orbits could arise due to spatially non-homogeneous Hopf bifurcation from the constant equilibrium. Examples from a nonlocal cooperative Lotka-Volterra model and a nonlocal Rosenzweig-MacArthur predator-prey model are used to demonstrate the bifurcation of spatially non-homogeneous patterns., 43 pages, 10 figures

It is well known that insulin-like growth factor 1 (IGF1) acts as a trophic factor in small intestine under both physiological and pathophysiological conditions. However, it still lacks direct in vivo evidence of the functions of intestinal epithelial cell (IEC)-specific IGF1 under both normal and pathological conditions. Using IEC-specific IGF1-knockout (cKO) mice and Lgr5-eGFP-CreERT mice, we demonstrate that IEC-specific IGF1 can enhance nutrient uptake, reduce protein catabolism and energy consumption, and promote the proliferation and expansion of intestinal epithelial cells, including intestinal epithelial stem cells and intestinal secretory cells. Next, we showed that IEC-specific IGF1 renders IECs resistant to irradiation and promotes epithelial regeneration. Strikingly, transcriptome profiling assay revealed that many differentially expressed genes involved in the differentiation and maturation of lymphoid lineages were significantly suppressed in the cKO mice as compared with the control mice. We demonstrated that deletion of IGF1 in IECs enhances bacterial translocation to the mesenteric lymph nodes and liver. Furthermore, high-throughput sequencing of 16S ribosomal RNA genes of gut microbiota revealed that IEC-specific IGF1 loss profoundly affected the gut microbial composition at various levels of classification. Therefore, our findings shed light on the in vivo roles of IEC-specific IGF1 in intestinal homeostasis, epithelial regeneration, and immunity, broadening our current insights on IGF1 functions.

Wound healing is essential for skin repair after injury, and it consists of hemostasis, inflammation, re-epithelialization, and remodeling phases. Successful re-epithelialization, which relies on proliferation and migration of epidermal keratinocytes, requires a reduction in tissue inflammation. Therefore, understanding the molecular mechanism underlying the transition from inflammation to re-epithelialization will help to better understand the principles of wound healing. Currently, the in vivo functions of specific microRNAs in wound healing are not fully understood. We observed that miR-31 expression is strongly induced in wound edge keratinocytes, and is directly regulated by the activity of NF-κB and signal transducer and activator of transcription 3 signaling pathways during the inflammation phase. We used miR-31 loss-of-function mouse models to demonstrate that miR-31 promotes keratinocyte proliferation and migration. Mechanistically, miR-31 activates the Ras/mitogen-activated protein kinase signaling by directly targeting Rasa1, Spred1, Spred2, and Spry4, which are negative regulators of the Ras/mitogen-activated protein kinase pathway. Knockdown of these miR-31 targets at least partially rescues the delayed scratch wound re-epithelialization phenotype observed in vitro in miR-31 knockdown keratinocytes. Taken together, these findings identify miR-31 as an important cell-autonomous mediator during the transition from inflammation to re-epithelialization phases of wound healing, suggesting a therapeutic potential for miR-31 in skin injury repair.

Concerning the large interfacial resistance of materials within solid-stated batteries (SSBs) caused by the unstable solid contact, an assistant ionic conductor is introduced to improve the interfacial Li+ transport of SSBs. The assistant ionic conductor is achieved by impregnating an ionic liquid (Li-IL) into a porous metal-organic framework (MOF) host. When integrated with LLZO solid-state electrolyte (SSE), the solidified Li-IL guest can make direct contact with the LLZO particles through the open channels in MOF host, which changes the original unstable solid-solid contact into “nanowetted” interfaces to boost Li+ transport. Benefited from the unique nanowetted interfaces, the hybrid SSE demonstrates a high ionic conductivity of 1.0 × 10−4 S cm−1 with a wide electrochemical window of 5.2 V, and also exhibits excellent compatibility with Li metal anode. Furthermore, the LLZO based LiCoO4 and LiFePO4 SSBs with the ionic conductor additive to favor the interfacial Li+ transport achieve high capacity retention of 97% after 150 cycles with reasonable rate capability. The good electrochemical performance is attributed to the effective Li+ transport networks established inside the SSBs by the ionic conductor through the nanowetted interfacial mechanism, which is proved to be a promising approach to the safe and high-power energy storage.

In this paper, we are concerned with a cancer network including a protein module and a corresponding microRNA cluster that inhibits the synthesis of proteins. The existence of multiple steady states and their stability depending on the parameters are firstly determined. Bistability and dependency on the parameters, Hopf bifurcations and the corresponding properties like direction and stability of Hopf bifurcations are determined by computing the normal form on the center manifold. Then, the role of the delay in the process of synthesis of the protein is investigated. We show that the delay can stabilize the unstable equilibrium and destabilize the stable equilibrium. Some simulations are carried out to numerically illustrate the obtained theoretical results. Finally, the biological interpretation of the theoretical results is discussed.

Despite their promised safety and mechanical flexibility, solvent-free polymer electrolytes suffer from low Li-ion conductivities due to poor dissociation of conducting salts and low Li+ -transference numbers due to Li+ -trapping by ether-linkages. In this work, the authors found that oxygen vacancies carried by nanosized Al2 O3 fillers preferentially promotes Li+ -conduction in poly(ethylene oxide) (PEO). These vacancies and free electrons therein, whose concentration can be tuned, effectively break up the ion pairs by weakening the Coulombic attraction within them, while simultaneously interacting with the anions, thus preferentially constraining the movement of anions. This synergistic dissociation-and-trapping effect leads to the significant and selective improvement in Li-ion conductivity. Solid state batteries built on such PEO-based electrolytes exhibits superior performance at high current density. This discovery reveals a molecular-level rationale for the long-observed phenomenon that certain inorganic nano-fillers improve ion conduction in PEO, and provides a universal approach to tailor superior polymer-based electrolytes for the next generation solid-state batteries.

In this paper, we investigate the spatiotemporal dynamics of a single-species model with spatiotemporal delays characterizing spatial memory and maturation. Through stability and bifurcation analysis, we find that the spatial memory-based diffusion coefficient, the spatiotemporal diffusive delay and spatiotemporal reaction delay have important effects on the dynamics of the model and their combined impact can cause the destabilization of the positive constant steady state and give rise to steady state and Hopf bifurcations. Taking the coefficient of spatial memory diffusion as the bifurcation parameter, the critical values of steady state and Hopf bifurcations are rigorously determined. Furthermore, we apply the theoretical results to a modified diffusive logistic model with predation and obtain spatially inhomogeneous steady states and spatially homogeneous and inhomogeneous periodic solutions via numerical simulations.

The stability and Hopf bifurcation of the positive steady state to a general scalar reaction–diffusion equation with distributed delay and Dirichlet boundary condition are investigated in this paper. The time delay follows a Gamma distribution function. Through analyzing the corresponding eigenvalue problems, we rigorously show that Hopf bifurcations will occur when the shape parameter n ≥ 1 , and the steady state is always stable when n = 0 . By computing normal form on the center manifold, the direction of Hopf bifurcation and the stability of the periodic orbits can also be determined under a general setting. Our results show that the number of critical values of delay for Hopf bifurcation is finite and increasing in n, which is significantly different from the discrete delay case, and the first Hopf bifurcation value is decreasing in n. Examples from population biology and numerical simulations are used to illustrate the theoretical results.

MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-κB signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGFβ and Wnt/β-catenin. Particularly, it activates Wnt/β-catenin signaling by directly targeting Wnt antagonists, including Dkk1. Importantly, Dkk1 overexpression partially rescues miR31-induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis.

In this paper, we investigate the dynamics of a time-delay ratio-dependent predator-prey model with stage structure for the predator. This predator-prey system conforms to the realistically biological environment. The existence and stability of the positive equilibrium are thoroughly analyzed, and the sufficient and necessary conditions for the stability and instability of the positive equilibrium are obtained for the case without delay. Then, the influence of delay on the dynamics of the system is investigated using the geometric criterion developed by Beretta and Kuang.[26] We show that the positive steady state can be destabilized through a Hopf bifurcation and there exist stability switches under some conditions. The formulas determining the direction and the stability of Hopf bifurcations are explicitly derived by using the center manifold reduction and normal form theory. Finally, some numerical simulations are performed to illustrate and expand our theoretical results.

Gierer–Meinhardt system is a typical mathematical model to describe chemical and biological phenomena. In this paper, the Gierer–Meinhardt model with a saturating term is considered. By the linear stability analysis, we find the parameter area where possible Turing instability can occur. Then the multiple scales method is applied to obtain the amplitude equations at the critical value of Turing bifurcation, which help us to derive parameter space more specific where certain patterns such as spot-like pattern, stripe-like pattern and the coexistence pattern will emerge. Furthermore, the numerical simulations provide an indication of the wealth of patterns that the system can exhibit and the two-dimensional Fourier transform by the image processing interface of GUI from Matlab enables us to gain intensive understanding of these patterns. Besides, the interesting patterns including labyrinthine-like patterns are also numerically observed. All the results obtained reveal the mechanism of morphogenetic processes in adult mesenchymal cells. The patterns obtained corresponding to the patterns induced by morphogens in the vascular mesenchymal cells may play a role in atherosclerotic vascular calcification.

In this paper, we consider a predator–prey model with herd behavior and prey-taxis subject to the homogeneous Neumann boundary condition. First, by analyzing the characteristic equation, the local stability of the positive equilibrium is discussed. Then, choosing prey-tactic sensitivity coefficient as the bifurcation parameter, we obtain a branch of nonconstant solutions bifurcating from the positive equilibrium by an abstract bifurcation theory, and find the stable bifurcating solutions near the bifurcation point under suitable conditions. We have shown that prey-taxis can destabilize the uniform equilibrium and yields the occurrence of spatial patterns. Furthermore, some numerical simulations to illustrate the theoretical analysis are also carried out, Turing patterns such as spots pattern, spots–strip pattern, strip pattern, stable nonconstant steady-state solutions, and spatially inhomogeneous periodic solutions are obtained, which also expand our theoretical results.

In this paper, we combine first principles calculations and experiments to investigate the influence of Ga-doping and oxygen vacancies on the magnetic properties of rutile TiO 2 films. Ga-doped TiO 2 with few oxygen vacancies exhibits ferromagnetism at room temperature with a T C near 350 K, which can be explained using a modified magnetic polaron model. The number of Ti 3+ ions increases with increasing the oxygen vacancies concentration, which results in a larger magnetic moment along with a higher T C in TiO 2−δ film with the ferromagnetic and antiferromagnetic coupling. The saturation magnetic moment is enhanced in Ga-doped TiO 2−δ due to the absence of antiferromagnetic coupling after Ga-doping. More electrons occupy nearby Ti sites giving rise to the Ti 3+ moments. Our theoretical calculations suggest that the modified magnetic polaron model works well for the ferromagnetism of doped and undoped-TiO 2−δ . Experimental results clearly show that the T C is related to the oxygen vacancies concentration, which is a verification of the polaron percolation theory.

Bulk TMDCs are diamagnetic materials; however, two-dimensional TMDCs exhibit spin polarized edge states, which results in a coupling between the unsaturated transition metal and chalcogenide atoms at the edges. The magnetism in two-dimensional TMDCs broadens their applications in spintronic and multi-functional devices. Herein, by combining macro/micro-magnetic experimental measurements and density functional theory (DFT) calculations, we demonstrate that among five possible edge-terminated WSe2 nanosheets only two types have a magnetic ground state, corresponding to the 100% Se edge terminated and 50% Se edge terminated nanosheets, respectively. The calculation results on WSe2 clusters and WSe2 zig-zag nanoribbons with different terminations and Se coverage rate confirmed that the unpaired electrons of the edge atoms play a crucial role in the appearance of ferromagnetism in WSe2 nanosheets. Furthermore, due to the possible quantum confinement effect and surface effect, there exist thickness-dependent magnetic properties, and the magnitude of magnetism at the edge increases as the number of layers decreases.

Intertidal mussels can self-organize into periodic spot, stripe, labyrinth, and gap patterns ranging from centimeter to meter scales. The leading mathematical explanations for these phenomena are the reaction-diffusion-advection model and the phase separation model. This paper continues the series studies on analytically understanding the existence of pattern solutions in the reaction-diffusion mussel-algae model. The stability of the positive constant steady state and the existence of Hopf and steady-state bifurcations are studied by analyzing the corresponding characteristic equation. Furthermore, we focus on the Turing-Hopf (TH) bifurcation and obtain the explicit dynamical classification in its neighborhood by calculating and investigating the normal form on the center manifold. Using theoretical and numerical simulations, we demonstrates that this TH interaction would significantly enhance the diversity of spatial patterns and trigger the alternative paths for the pattern development.

OBJECTIVE: To analyze the distribution of comorbid psychiatric disorders in patients with chronic otitis media associated tinnitus. METHOD: The data of patients with chronic otitis media associated tinnitus who accepted surgical treatments from July 2017 to September 2018 were retrospectively analyzed. All patients accepted pure tone audiometry and acoustic conductance examination and were requested to fill the tinnitus history questionnaire, THI, TEQ, SAS, SDS and PSQI scales before operation. When the SAS or/and SDS score ≥50 the patient was judged as having comorbid psychiatric disorders. When the PSQI score>6 the patient was judged as having comorbid sleep disorder, and then all the results were analyzed. RESULT: Sixty-two patients were included in the study, 43 cases were diagnosed as chronic suppurative otitis media, and 19 cases were diagnosed as middle ear cholesteatoma. The average course of chronic otitis media or middle ear cholesteatoma was(14.38±14.06) years, while the average course of tinnitus was(8.39±11.69) years. There were 32 cases with mild to moderate tinnitus(gradeⅠ-Ⅱ)(51.61%) and 30 cases with moderate to severe tinnitus(grade Ⅲ-Ⅴ)(48.39%). Before operation, there were 4 cases(6.45%) with normal hearing, 38 cases(61.29%) with conductive hearing loss, and 20 cases(32.36%) with mixed hearing loss. There was no significant difference in tinnitus severity between different hearing loss degrees and types(P>0.05). The average SAS score was 45.10±11.61, and the average SDS score was 43.48±14.67, both higher than the normal modulus(30 points), among which 27 cases(44.00%) comorbid psychiatric disorders. The THI score in patients with comorbid psychiatric disorders(57.85±21.1) was significantly higher than that in patients without comorbid psychiatric disorders(29.2±17.39)(P < 0.05). The PSQI score in patients with comorbid psychiatric disorders(8.86±3.47) was significantly higher than that of those without comorbid psychiatric disorders(6.24±2.54)(P < 0.05). Fifty-three patients were followed up for 0.5 to 1.8 years after operation, and in 43 cases the tinnitus was reduced or disappeared after operation(the effective rate was 81.13%). There were no significant difference between patients in tinnitus relief group and those in tinnitus without relief group in age, sex, course of the disease, type of the disease, with or without comorbid psychiatric disorders and/or sleep disorder, postoperative hearing improvement. CONCLUSION: Comorbid psychiatric disorders are common in patients with chronic otitis media associated tinnitus and the tinnitus in patients with comorbid psychiatric disorders is significantly more serious than that those without. For the treatment of chronic otitis media associated tinnitus, besides surgery, the complications such as psychiatric and sleep disorders and so on should be evaluated and treated accordingly.

Background: Accumulating evidences indicate that nanomedicines greatly decrease the side effects and enhance the efficacy of colorectal cancer (CRC) treatment. In particular, the use of rectal delivery of nanomedicines, with advantages such as fast therapeutic effects and a diminishing hepatic first-pass effect, is currently emerging. Method: We established a CRC targeted delivery system, in which α-lactalbumin peptosomes (PSs) co-loaded with a microRNA (miR)-31 inhibitor (miR-31i) and curcumin (Cur) were encapsuslated in thiolated TEMPO oxidized Konjac glucomannan (sOKGM) microspheres, referred as sOKGM-PS-miR-31i/Cur. The CRC targeting capability, drug release profiles, mucoadhesive-to-penetrating properties and therapeutic efficacy of sOKGM-PS-miR-31i/Cur delivery system were evaluated in colorectal cancer cells and azoxymethane-dextran sodium (AOM-DSS) induced tumor models. Results: sOKGM-PS-miR-31i/Cur delivery system were stable in the harsh gastrointestinal environment after rectal or oral administration; and were also mucoadhesive due to disulfide bond interactions with the colonic mucus layer, resulting in an enhanced drug retention and local bioavailability in the colon. Concomitantly, the released PS-miR-31i/Cur PSs from the microsphere was mucus-penetrating, efficiently passing through the colonic mucus layer, and allowed Cur and miR-31i specifically target to colon tumor cells with the guide of CD133 targeting peptides. Consequently, rectal delivery of sOKGM-PS-miR-31i/Cur microspheres suppressed tumor growth in an azoxymethane-dextran sodium sulfate (AOM-DSS)-induced tumor model. Conclusion: sOKGM-PS-miR-31i/Cur microspheres are effective rectal delivery system with combined advantages of mucoadhesive and mucus-penetrating properties, representing a potent and viable therapeutic approach for CRC.

The YAP signaling activation in epithelial cells is essential for intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here we report a stroma-epithelia YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can directly binds to a transmembrane protocadherin FAT1 on the surface of epithelial cells. This binding suppressed the Hippo signaling by disrupting MST1-FAT1 association, resulting in YAP signaling activation. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration, and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings uncovered a molecular mechanism governing signals for communication between stroma and epithelium during tissue regeneration and tumorigenesis.

Aqueous Zn-MnO

Quiescent satellite cells (SCs) that are activated to produce numerous myoblasts underpin the complete healing of damaged skeletal muscle. How cell-autonomous regulatory mechanisms modulate the balance among cells committed to differentiation and those committed to self-renewal to maintain the stem cell pool remains poorly explored. Here, we show that miR-31 inactivation compromises muscle regeneration in adult mice by impairing the expansion of myoblasts. miR-31 is pivotal for SC proliferation, and its deletion promotes asymmetric cell fate segregation of proliferating cells, resulting in enhanced myogenic commitment and re-entry into quiescence. Further analysis revealed that miR-31 posttranscriptionally suppresses interleukin 34 (IL34) mRNA, the protein product of which activates JAK–STAT3 signaling required for myogenic progression. IL34 inhibition rescues the regenerative deficiency of miR-31 knockout mice. Our results provide evidence that targeting miR-31 or IL34 activities in SCs could be used to counteract the functional exhaustion of SCs in pathological conditions.

Herein, a bi-functional homogeneous redox mediator is employed to promote the rate capability of Li-O2 batteries. The addition of this redox mediator not only facilitates the formation of toroid-shaped Li2O2 at high current densities, but also significantly reduces the charging over-potential caused by the bulky Li2O2.

Objective To observe the effect of calcitonin gene-related peptide (CGRP) on peripheral neuropathy in diabetic mice, and to explore whether overexpressed CGRP improves peripheral neuropathy in diabetic mice. Methods Diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ). The mice were randomly divided into 4 groups according to their body mass and blood glucose: normal control group, model group, Ad-CGRP group and Ad negative control group. The mice in the Ad-CGRP group and the Ad-negative control group were intramuscularly injected with adenovirus in the muscles of left hind limb. The mice in the normal group and the model group were injected with equal volume of normal saline. After 4 weeks of administration, the expression of CGRP mRNA was detected by real-time quantitative PCR. The expression of CGRP protein was detected by Western blot analysis. The latency of pain was measured by hot plate test. The motor nerve conduction velocity (MNCV) was measured by physiological signal acquiring system. The nerve blood flow was monitored with Laser Doppler Flowmetry (LDF). Results Compared with the normal group, the mRNA and protein levels of CGRP in the model group were reduced, the level of glucose was significantly raised, the latency of pain was extended, the MNCV and the nerve blood flow were decreased. Compared with the model group, the mRNA and protein levels of CGRP in the Ad-CGRP group were significantly increased, the latency of pain was shortened, the MNCV and the nerve blood flow was increased. There was no significant change in the Ad-negative control group. Conclusion Overexpression of CGRP may ameliorate diabetic peripheral neuropathy by expanding blood vessel and increasing blood flow.