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Smoking has gradually become a very common behavior, and the related situation in different groups also presents different forms. Due to the differences of individual smoking cessation time and the interference of environmental factors in the spread of smoking behavior, we establish a stochastic giving up smoking model with quit-smoking duration. We also consider the saturated incidence rate. The total population is composed of potential smokers, smokers, quitters and removed. By using Itô's formula and constructing appropriate Lyapunov functions, we first ensure the existence of a unique global positive solution of the stochastic model. In addition, a threshold condition for extinction and permanence of smoking behavior is deduced. If the intensity of white noise is small, and $ \widetilde{\mathcal{R}}_0 < 1 $, smokers will eventually become extinct. If $ \widetilde{\mathcal{R}}_0 > 1 $, smoking will last. Then, the sufficient condition for the existence of a unique stationary distribution of the smoking phenomenon is studied as $ R_0^s > 1 $. Finally, conclusions are explained by numerical simulations.

Breast cancer (BC) is the most frequently diagnosed cancer and the primary cause of cancer-related mortality in women. Treatment of triple-negative breast cancer (TNBC) remains particularly challenging due to its resistance to chemotherapy and poor prognosis. Extensive research efforts in BC screening and therapy have improved clinical outcomes for BC patients. Therefore, identifying reliable biomarkers for TNBC is of great clinical importance. Here, we found that tyrosine aminotransferase (TAT) expression was significantly reduced in BC and strongly correlated with the poor prognosis of BC patients, which distinguished BC patients from normal individuals, indicating that TAT is a valuable biomarker for early BC diagnosis. Mechanistically, we uncovered that methylation of the TAT promoter was significantly increased by DNA methyltransferase 3 (DNMT3A/3B). In addition, reduced TAT contributes to DNA replication and cell cycle activation by regulating homologous recombination repair and mismatch repair to ensure genomic stability, which may be one of the reasons for TNBC resistance to chemotherapy. Furthermore, we demonstrated that Diazinon increases TAT expression as an inhibitor of DNMT3A/3B and inhibits the growth of BC by blocking downstream pathways. Taken together, we revealed that TAT is silenced by DNMT3A/3B in BC, especially in TNBC, which promotes the proliferation of tumor cells by supporting DNA replication, activating cell cycle, and enhancing DNA damage repair. These results provide fresh insights and a theoretical foundation for the clinical diagnosis and treatment of BC.

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients’ survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Biodegradable metals are promising candidates for bone defect repair. With an evidence-based approach, this study investigated and analyzed the performance and degradation properties of biodegradable metals in animal models for bone defect repair to explore their potential clinical translation. Animal studies on bone defect repair with biodegradable metals in comparison with other traditional biomaterials were reviewed. Data was carefully collected after identification of population, intervention, comparison, outcome, and study design (PICOS), and following the inclusion criteria of biodegradable metals in animal studies. 30 publications on pure Mg, Mg alloys, pure Zn and Zn alloys were finally included after extraction from a collected database of 2543 publications. A qualitative systematic review and a quantitative meta-analysis were performed. Given the heterogeneity in animal model, anatomical site and critical size defect (CSD), biodegradable metals exhibited mixed effects on bone defect repair and degradation in animal studies in comparison with traditional non-degradable metals, biodegradable polymers, bioceramics, and autogenous bone grafts. The results indicated that there were limitations in the experimental design of the included studies, and quality of the evidence presented by the studies was very low. To enhance clinical translation of biodegradable metals, evidence-based research with data validity is needed. Future studies should adopt standardized experimental protocols in investigating the effects of biodegradable metals on bone defect repair with animal models.

Pancreatic cancer ranks fourth among cancer-related deaths, with a 5-years overall survival rate being below 10%. Gemcitabine (dFdC) has been considered the first-line drug for patients with pancreatic cancer. However, the clinical effectiveness is less than 20% due to drug resistance. Most importantly, overwhelming evidence suggested c-Myc and PD-L1 were generally highly expressed in pancreatic cancer patients. However, whether dFdC-resistant pancreatic cancer is associated with c-Myc and PD-L1 has not been elucidated. In our present study, we found that the expression of c-Myc and PD-L1 was markedly increased in pancreatic tumor tissues compared with adjacent tissues. Similarly, c-Myc and PD-L1 expression were also remarkably elevated in dFdC-resistant Panc-1 cells compared with parental cells. In addition, dFdC sensitivity was enhanced by the combination of dFdC and c-Myc inhibitors in Panc-1 cells. Interestingly, its sensitivity was reduced when c-Myc was overexpressed. Moreover, PD-L1 protein expression was dramatically down-regulated when treated with c-Myc inhibitors. Furthermore, artesunate (ARTS) screened from 18 compounds could reverse dFdC resistance in combination with dFdC in dFdC-resistant Panc-1 cells in vitro and suppressed DMBA-induced pancreatic cancer in vivo. In summary, our data revealed that the mechanism of dFdC resistance may be that c-Myc overexpression contributed to increased PD-L1 expression, and ARTS could overcome dFdC-resistant pancreatic cancer by inhibiting c-Myc and PD-L1. Our findings not only suggest c-Myc and PD-L1 as novel prognostic biomarkers in dFdC-resistant pancreatic cancer, but also provide ARTS as a promising candidate for overcoming dFdC resistance.

Congestion is a kind of expression of instability of traffic network. Traffic signal control keeping traffic network stable can reduce the congestion of urban traffic. In order to improve the efficiency of urban traffic network, this study proposes a decentralized traffic signal control strategy based on backpressure algorithm used in Wi-Fi mesh networks for packets routing. Backpressure based traffic signal control algorithm can stabilize urban traffic network and achieve maximum throughput. Based on original backpressure algorithm, the variant parameter and penalty function are considered to balance the queue differential and capacity of downstream links in urban traffic network. For each traffic phase of intersections, phase weight is computed using queue differential and capacity of downstream links, which fixed the deficiency of infinite queue capacity in original backpressure algorithm. It is proved that the extended backpressure traffic signal control algorithm can maintain stability of urban traffic network, and also can prevent queue spillback, so as to improve performance of whole traffic network. Simulations are carried out in Vissim using Vissim COM programming interface and Visual Studio development tools. Evaluation results illuminate that it can get better performance than the backpressure algorithm just based on queue length differential in average queue length and delay of traffic network.

Abstract Although targeting DNA repair signaling pathways has emerged as a promising therapeutic for skin cancer, the relevance of DNA damage responses (DDR) in the development and survival of nonmelanoma skin cancer (NMSC), the most common type of skin cancer, remains obscure. Here, we report that Src‐associated substrate during mitosis of 68 kDa (Sam68), an early signaling molecule in DDR, is elevated in skin tumor tissues derived from NMSC patients and skin lesions from Gli2‐transgenic mice. Downregulation of Sam68 impacts the growth and survival of human tumor keratinocytes and genetic ablation of Sam68 delays the onset of basal cell carcinomas (BCC) in Gli2‐transgenic mice. Moreover, Sam68 plays a critical role in DNA damage‐induced DNA repair and nuclear factor kappa B (NF‐κB) signaling pathways in keratinocytes, hence conferring keratinocyte sensitivity to DNA damaging agents. Together, our data reveal a novel function of Sam68 in regulating DDR in keratinocytes that is crucial for the growth and survival of NMSC.

The intermediate filament protein keratin 14 (K14) provides vital structural support in basal keratinocytes of epidermis. Recent studies evidenced a role for K14-dependent disulfide bonding in the organization and dynamics of keratin IFs in skin keratinocytes. Here we report that knock-in mice harboring a cysteine-to-alanine substitution at Krt14’s codon 373 (C373A) exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in epidermis. A proteomics screen identified 14-3-3 as K14 interacting proteins. Follow-up studies showed that YAP1, a transcriptional effector of Hippo signaling regulated by 14-3-3sigma in skin keratinocytes, shows aberrant subcellular partitioning and function in differentiating Krt14 C373A keratinocytes. Residue C373 in K14, which is conserved in a subset of keratins, is revealed as a novel regulator of keratin organization and YAP function in early differentiating keratinocytes, with an impact on cell mechanics, homeostasis and barrier function in epidermis.

To investigate effects of berberine exerts on A20 expression and regulation of intestinal epithelial tight junctions via the TNF-α-NF-κB-MLCK pathway in Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D).C57BL/6 wild type (WT) and A20 IEC-KO mice (48 each) were randomly divided into normal control (NC), model control (MC), rifaximin and berberine groups (12 mice per group). An experimental model of IBS-D was established using 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. rifaximin and berberine mice were treated with rifaximin and berberine, respectively.Intestinal epithelial space of WT berberine mice improved more than A20 IEC-KO berberine mice compared to MC mice. WT berberine mice exhibited greater expression of A20 compared with MC mice(P

On the foundation of the original backpressure-based traffic light control algorithm, a distributed cooperative backpressure-based traffic light control method is proposed in this paper. The urban traffic network is modeled as a smart agent-controlled queuing network, in which the intersection agents exchange the queue length information and the selected activating light phase information of neighboring intersections through communications and determine the activating light phase at each time slot according to local traffic information. The improved phase pressure computation method considers the phase state of downstream intersections instead of only the queue length of the local intersections. Light phase switching coordination among adjacent intersections is achieved using the consensus-based bundle algorithm, in which the cooperative light phase switching problem is viewed as a task assignment issue among adjacent intersections. Simulation results illustrated that the proposed cooperative backpressure-based traffic light control method obtained better performance than the original backpressure-based and fixed-time traffic control methods.

Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.

Travel time is one of the most critical indexes to describe urban traffic operating states. How to obtain accurate and robust travel time estimates, so as to facilitate to make traffic control decision-making for administrators and trip-planning for travelers, is an urgent issue of wide concern. This paper proposes a reliable estimation method of urban link travel time using multi-sensor data fusion. Utilizing the characteristic analysis of each individual traffic sensor data, we first extract link travel time from license plate recognition data, geomagnetic detector data and floating car data, respectively, and find that their distribution patterns are similar and follow logarithmic normal distribution. Then, a support degree algorithm based on similarity function and a credibility algorithm based on membership function are developed, aiming to overcome the conflicts among multi-sensor traffic data and the uncertainties of single-sensor traffic data. The reliable fusion weights for each type of traffic sensor data are further determined by integrating the corresponding support degree with credibility. A case study was conducted using real-world data from a link of Jingshi Road in Jinan, China and demonstrated that the proposed method can effectively improve the accuracy and reliability of link travel time estimations in urban road systems.

Dried litchi pulp has been used in traditional remedies in China for many years to treat various diseases, and the therapeutic activity has been, at least partly, attributed to the presence of bioactive polysaccharides. Polysaccharide-protein complexes from vacuum freeze-(VF), vacuum microwave-(VM) and heat pump (HP) dried litchi pulp, which were coded as LP-VF, LP-VM and LP-HP, were comparatively studied on the physicochemical and immunomodulatory properties. LP-HP had a predominance of galactose, while glucose was the major sugar component in LP-VF and LP-VM. Compared with LP-VF and LP-VM, LP-HP contained more aspartate and glutamic in binding protein. LP-HP also exhibited a stronger stimulatory effect on splenocyte proliferation at 200 μg/mL and triggered higher NO, TNF-α and IL-6 secretion from RAW264.7 macrophages. Different drying methods caused the difference in physicochemical properties of polysaccharide-protein complexes from dried litchi pulp, which resulted in significantly different immunomodulatory activity. HP drying appears to be the best method for preparing litchi pulp to improve its immunomodulatory properties.

In recent decades, increasing frequency and intensity of saltwater intrusion in the Modaomen Channel has threatened the freshwater supply in the surrounding cities of the Pearl River Estuary, and ulteriorly changed the environmental conditions of the estuarine waters. Phytoplankton biomass, primary production (PP) and species composition, as well as hydrological and chemical parameters were examined along a downstream transect in the Modaomen Channel during neap tide (NT) and spring tide (ST), when a strong saltwater intrusion event occurred in late September, 2011. A total of 46 species phytoplankton were identified, including Bacillariophyta (25 species), Dinoflagellate (14 species), Chlorophyta (4 species), Cyanophyta (2 species) and Euglenozoa (1 species). The dominant species were shifted from freshwater diatoms (e.g., Melosira granulata and Melosira granulata var. angustissima) in the upper reaches to saline water diatoms (e.g., Skeletonema costatum and Coscinodiscus sp.) in the river mouth. Generally, phytoplankton density, biomass (chl-a) and PP decreased from the upper to lower reaches along the channel, and were significantly higher in NT than those of ST. There was a shift from large-sized phytoplankton (>20 μm) in the upper reaches to relative small-sized cells (5-20 μm) in the lower reaches. Compared to NT, low discharge and flow velocity, coupled with strong easterly winds during ST specially aggravated saltwater intrusion further to the upstream (~50 km from the estuary). The intruded saltwater diluted nutrients, N/P ratios, chl-a, and phytoplankton abundances, and thereby led to a decline in PP during ST.

In VANET (vehicular ad hoc network) environment, the successive vehicle position data actually are discrete, so the key to the moving vehicle modeling is to effectively reduce the updating frequency of the position data so as to alleviate the communication and database management load. This paper proposes vehicle position data updating strategy with packet repetition based on Kalman filter predicting. Firstly, we design a position data updating model based on Kalman filter difference predicting equations. Then, we design a packet repetition mode decision algorithm, which is applied to deliver vehicle position updating data. The model with packet repetition can not only generate position updating data according to preset threshold, but also decide packet repetition mode related to the distance of two adjacent vehicles in order to reduce data loss. Both simulated highway and realistic urban road experimental results show that vehicle position data updating frequency could be obviously reduced and the reliability of the communication is greatly improved through packet repetition mechanism by using this position updating strategy.

In a vehicular ad hoc network (VANET), the periodic exchange of single-hop status information broadcasts (beacon frames) produces channel loading, which causes channel congestion and induces information conflict problems. To guarantee fairness in beacon transmissions from each node and maximum network connectivity, adjustment of the beacon transmission power is an effective method for reducing and preventing channel congestion. In this study, the primary factors that influence wireless channel loading are selected to construct the KF-BCLF, which is a channel load forecasting algorithm based on a recursive Kalman filter and employs multiple regression equation. By pre-adjusting the transmission power based on the forecasted channel load, the channel load was kept within a predefined range; therefore, channel congestion was prevented. Based on this method, the CLF-BTPC, which is a transmission power control algorithm, is proposed. To verify KF-BCLF algorithm, a traffic survey method that involved the collection of floating car data along a major traffic road in Changchun City is employed. By comparing this forecast with the measured channel loads, the proposed KF-BCLF algorithm was proven to be effective. In addition, the CLF-BTPC algorithm is verified by simulating a section of eight-lane highway and a signal-controlled urban intersection. The results of the two verification process indicate that this distributed CLF-BTPC algorithm can effectively control channel load, prevent channel congestion, and enhance the stability and robustness of wireless beacon transmission in a vehicular network.

In mammalian cells, the Golgi apparatus undergoes extensive fragmentation during mitosis; this is required not only for the partitioning of the complex but also for the process of mitosis. However, the molecular mechanism underlying the mitotic fragmentation of the Golgi is far from clear. Here, we show that AMP-activated protein kinase (AMPK) is phosphorylated and activated when cells enter mitosis. Activated AMPK phosphorylates GBF1, a guanine nucleotide exchange factor (GEF) for Arf-GTPases, disassociating GBF1 from the Golgi membrane and abolishing the action of GBF1 as an Arf1-GEF. We further demonstrate that the phosphorylation of AMPK and GBF1 is essential for Golgi disassembly and subsequent mitosis entry. These data suggest that AMPK-GBF1-Arf1 signaling is involved in the regulation of Golgi fragmentation during mitosis. [ABSTRACT FROM AUTHOR]

Despite recent advances in understanding the functions of autophagy in developmental and pathological conditions, the underlying mechanism of where and how autophagosomal structures acquire membrane remains enigmatic. Here, we provide evidence that post- Golgi membrane traffic plays a crucial role in autophagosome formation. Increased secretion of constitutive cargo from the trans-Golgi network (TGN) to the plasma membrane induced the formation of microtubule-associated protein light chain 3 (LC3)-positive structures. At the early phase of autophagy, LC3 associated with and then budded off from a distinct TGN domain without constitutive TGN-to-plasma cargo and TGN-to-endosome proteins. The clathrin adaptor protein AP1 and clathrin localized to starvation- and rapamycin-induced autophagosomes. Dysfunction of the AP1-dependent clathrin coating at the TGN but not at the plasma membrane prevented autophagosome formation. Our results thus suggest an essential role of the TGN in autophagosome biogenesis, providing membrane to autophagosomes through an AP1-dependent pathway. [ABSTRACT FROM AUTHOR]

Abstract  The parameter determination of viscoelastic material is a multi-variable, multi-aim nonlinear optimization problem, which made the optimization process very complicated. In this paper a hybrid optimal algorithm was proposed to determine the viscoelastic parameters in the constitutive relation according to the experimentally obtained mechanical properties. This algorithm merges the Broydon–Fletcher–Goldfarb–Shanno search into a genetic algorithm framework as a basic operator in order to enhance the local search capability. The proposed hybrid algorithm not only can reduce the iterative times greatly but can abolish the limitation of initial parameter values. Nonlinear material characteristic curve-fitting was carried out using the proposed algorithm and other existing approaches. And the comparison results show this algorithm is accurate and effective. The numerical simulation and experimental study of viscoelastic cantilever beam also indicates that the finite element formulation and the calculative viscoelastic model parameters are reliable. The proposed optimization method can be extended to further complex parameter estimation researches. [ABSTRACT FROM AUTHOR]

Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16-/- mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16-/- footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment. [ABSTRACT FROM AUTHOR]