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Pingping Yao,1 Yuying Jia,1 Xuewei Kan,1 Jiaqi Chen,1 Jinliang Xu,1 Huichao Xu,1 Shuyang Shao,1 Bing Ni,2 Jun Tang1 1Department of Dermatology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230000, People’s Republic of China; 2Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, People’s Republic of ChinaCorrespondence: Bing Ni; Jun Tang, Email nibing@tmmu.edu.cn; tangjun0212@ustc.edu.cnBackground: Psoriasis is a common chronic, recurrent, and inflammatory skin disease. Identifying novel and potential biomarkers is valuable in the treatment and diagnosis of psoriasis. The goal of this study was to identify novel key biomarkers of psoriasis and analyze the potential underlying mechanisms.Methods: Psoriasis-related datasets were downloaded from the Gene Expression Omnibus database to screen differential genes in the datasets. Functional and pathway enrichment analyses were performed on the differentially expressed genes (DEGs). Candidate biomarkers for psoriasis were identified from the GSE30999 and GSE6710 datasets using four machine learning algorithms, namely, random forest (RF), least absolute shrinkage and selection operator (LASSO) logistic regression, weighted gene co-expression network analysis (WGCNA), and support vector machine recursive feature elimination (SVM-RFE), and were validated using the GSE41662 dataset. Next, we used CIBERSORT and single-cell RNA analysis to explore the relationship between ADAM23 and immune cells. Finally, we validated the expression of the identified biomarkers expressions in human and mouse experiments.Results: A total of 709 overlapping DEGs were identified, including 426 upregulated and 283 downregulated genes. Enhanced by enrichment analysis, the differentially expressed genes (DEGs) were spatially arranged in relation to immune cell involvement, immune-activating processes, and inflammatory signals. Based on the enrichment analysis, the DEGs were mapped to immune cell involvement, immune-activating processes, and inflammatory signals. Four machine learning strategies and single-cell RNA sequencing analysis showed that ADAM23, a disintegrin and metalloprotease, may be a unique, critical biomarker with high diagnostic accuracy for psoriasis. Based on CIBERSORT analysis, ADAM23 was found to be associated with a variety of immune cells, such as macrophages and mast cells, and it was upregulated in the macrophages of psoriatic lesions in patients and mice.Conclusion: ADAM23 may be a potential biomarker in the diagnosis of psoriasis and may contribute to the pathogenesis by regulating immunological activity in psoriatic lesions.Keywords: psoriasis, machine learning, differential gene analysis, CIBERSORT, ADAM23

Shifei Li,1 Qijun Wu,1 Zhuyan Jiang,1 Yaguang Wu,1 Yuhong Li,2 Bing Ni,3 Jun Xiao,4 Zhifang Zhai1 1Department of Dermatology, Southwest Hospital of Third Military Medical University, Chongqing, People’s Republic of China; 2Department of Cell Biology, Third Military Medical University, Chongqing, People’s Republic of China; 3Department of Pathophysiology, Third Military Medical University, Chongqing, People’s Republic of China; 4Department of Cardiovascular Medicine, Chongqing University Central Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Jun Xiao, Department of Cardiovascular Medicine, Chongqing University Central Hospital, Chongqing, People’s Republic of China, Email xj73wy@163.com Zhifang Zhai, Department of Dermatology, Southwest Hospital of Third Military Medical University, Chongqing, People’s Republic of China, Email zhaizf1004@163.comBackground: Plasmacytoid dendritic cells (pDCs) are the main producers of type I interferon (IFN-I), and the excessive production of IFN-I is a hallmark of systemic lupus erythematosus (SLE). Both SLC15A4 and miR-31-5p are SLE susceptibility-related genes, and SLC15A4 has been implicated an important role in endolysosomal toll-like receptor (TLR) activation in pDCs. However, whether miR-31-5p exerts a regulating effect on SLC15A4 expression in pDCs is unclear.Methods: The expression of SLC15A4 and miR-31-5p in peripheral blood mononuclear cells (PBMCs) of SLE patients was measured by RT-qPCR analyses. The quantitative analysis of IFN-α secretion in the patients’ serum was performed by ELISA assay. Luciferase-reporter assay was applied to confirm the interaction between miR-31-5p and SLC15A4. The expression of miR-31-5p, SLC15A4 and IFN-stimulated genes (ISGs, such as MX1, OAS1 and IFIT3) was detected by Western blot and RT-qPCR assays and further IRF5 phosphorylation was evaluated by immunofluorescence after transfected with miR-31-5p mimics or inhibitor in THP-1 and CAL-1 cells.Results: The expression of miR-31-5p was downregulated and negatively correlated with the overexpression of SLC15A4 in PBMCs of SLE patients. In addition to this, the secretion of IFN-α was overexpressed in sera of SLE and positively correlated with SLC15A4 level. We found that miR-31-5p directly targeted SLC15A4 and negatively regulated the expression of SLC15A4 in THP-1 and CAL-1 cells. In vitro inhibition of miR-31-5p increased the phosphorylation of IRF5 and the induction of ISGs stimulated by R848, overexpression of miR-31-5p get the reverse results.Conclusion: miR-31-5p might involve in SLE pathogenesis through regulating IFN-I expression by negatively regulating SLC15A4 to increase the levels of IFN-α and ISGs in pDCs.Keywords: systemic lupus erythematosus, miR-31-5p, SLC15A4, type I interferon, plasmacytoid dendritic cell, inflammation

Yang Liu,1,2,* Han Wang,1–3,* Beibei Ni,1,2 Jinghua Zhang,1,2 Shi Li,1,2 Yuqian Huang,1,2 Yanling Cai,1,2 Hongbing Mei,1–3 Zesong Li1,2 1Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China; 2Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China; 3Department of Urinary Surgery, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China *These authors contributed equally to this work Background: KCNJ15 belongs to the inwardly rectifying potassium channel (KIR) family. Although members of the KIR family have been proven to play important roles in a variety of developmental processes, the molecular role and clinical effects of KCNJ15 in cancers remain unclear. Purpose: The aim of this study was to identify the expression, biological functions and molecular mechanisms of KCNJ15 in renal cell carcinoma (RCC).Methods: KCNJ15 mRNA expression was evaluated in kidney cancer tissue, paired adjacent normal tissue, and cell lines with qRT-PCR. KCNJ15 protein expression was investigated via western blotting and immunohistochemistry. In addition, the clinical and prognostic significance of KCNJ15 in RCC were assessed using Kaplan-Meier analysis and Cox proportional hazards analysis. In vitro, the effects of KCNJ15 on kidney cancer cells were evaluated by means of a cell counting kit-8, transwell assay along with flow cytometry, respectively. Moreover, the potential mechanism of KCNJ15 was demonstrated by Western blot. Results: Here, we first found that KCNJ15 was significantly downregulated in RCC, and this low expression was an independent prognostic factor for clear cell RCC (ccRCC). Moreover, KCNJ15 was associated with advanced TNM stage (n=150, p=0.014) and histological grade (n=150, p=0.045). Furthermore, KCNJ15 overexpression significantly inhibited RCC cell proliferation, migration, and colony formation, arrested the cell cycle and induced apoptosis of RCC cells in vitro. The inhibitory effect of KCNJ15 overexpression may be regulated by its effects on the epithelial mesenchymal transition (EMT) process and matrix metalloproteinase (MMP)-7 and p21 expression. Conclusion: These findings indicate that KCNJ15 may be a tumour suppressor in RCC and a possible target for RCC therapy. Keywords: KCNJ15, renal cell carcinoma, biomarker, tumor suppressor, prognosis

Jing Zhang,1,* Xizhen Han,1,* Xiang Li,2 Yun Luo,1 Haiping Zhao,1 Ming Yang,1 Bin Ni,1 Zhenggen Liao11Key Laboratory of Modern Preparation of TCM, Ministry of Education, 2National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, People's Republic of China*These authors contributed equally to this workPurpose: Novel panax notoginsenoside-loaded core-shell hybrid liposomal vesicles (PNS-HLV) were developed to resolve the restricted bioavailability of PNS and to enhance its protective effects in vivo on oral administration.Methods: Physicochemical characterizations of PNS-HLV included assessment of morphology, particle size and zeta potential, encapsulation efficiency (EE%), stability and in vitro release study. In addition, to evaluate its oral treatment potential, we compared the effect of PNS-HLV on global cerebral ischemia/reperfusion and acute myocardial ischemia injury with those of PNS solution, conventional PNS-loaded nanoparticles, and liposomes.Results: In comparison with PNS solution, conventional PNS-loaded nanoparticles and liposomes, PNS-HLV was stable for at least 12 months at 4°C. Satisfactory improvements in the EE% of notoginsenoside R1, ginsenoside Rb1, and ginsenoside Rg1 were shown with the differences in EE% shortened and the greater controlled drug release profiles were exhibited from PNS-HLV. The improvements in the physicochemical properties of HLV contributed to the results that PNS-HLV was able to significantly inhibit the edema of brain and reduce the infarct volume, while it could markedly inhibit H2O2, modified Dixon agar, and serum lactate dehydrogenase, and increase superoxide dismutase (P < 0.05).Conclusion: The results of the present study imply that HLV has promising prospects for improving free drug bioactivity on oral administration.Keywords: liposomes, nanoparticles, panax notoginsenoside, physicochemical properties, in vivo animal models

Plasmaspheric hiss plays an important role in controlling the overall structure and dynamics of the Earth's radiation belts. The interaction of plasmaspheric hiss with radiation belt electrons is commonly evaluated using diffusion codes, which rely on statistical models of wave observations that may not accurately reproduce the instantaneous global wave distribution or the limited in situ satellite wave measurements. This paper evaluates the performance and limitations of a novel technique capable of inferring wave amplitudes from low-altitude electron flux observations from the Polar Orbiting Environmental Satellites (POES), which provide extensive coverage in shell and magnetic local time (MLT). We found that, within its limitations, this technique could potentially be used to build a dynamic global model of the plasmaspheric hiss wave intensity. The technique is validated by analyzing the conjunctions between the POES spacecraft and the Van Allen Probes from September 2012 to June 2014. The technique performs well for moderate-to-strong hiss activity (≥30 pT) with sufficiently high electron fluxes. The main source of these limitations is the number of counts of energetic electrons measured by the POES spacecraft capable of resonating with hiss waves. For moderate-to-strong hiss events, the results show that the wave amplitudes from the EMFISIS instruments on board the Van Allen Probes are well reproduced by the POES technique, which provides more consistent estimates than the parameterized statistical hiss wave model based on CRRES data.

Plasmaspheric hiss plays an important role in controlling the overall structure and dynamics of the Earth's radiation belts. The interaction of plasmaspheric hiss with radiation belt electrons is commonly evaluated using diffusion codes, which rely on statistical models of wave observations that may not accurately reproduce the instantaneous global wave distribution or the limited in situ satellite wave measurements. This paper evaluates the performance and limitations of a novel technique capable of inferring wave amplitudes from low-altitude electron flux observations from the Polar Orbiting Environmental Satellites (POES), which provide extensive coverage in shell and magnetic local time (MLT). We found that, within its limitations, this technique could potentially be used to build a dynamic global model of the plasmaspheric hiss wave intensity. The technique is validated by analyzing the conjunctions between the POES spacecraft and the Van Allen Probes from September 2012 to June 2014. The technique performs well for moderate-to-strong hiss activity (≥30 pT) with sufficiently high electron fluxes. The main source of these limitations is the number of counts of energetic electrons measured by the POES spacecraft capable of resonating with hiss waves. For moderate-to-strong hiss events, the results show that the wave amplitudes from the EMFISIS instruments on board the Van Allen Probes are well reproduced by the POES technique, which provides more consistent estimates than the parameterized statistical hiss wave model based on CRRES data.

The excitation of magnetospheric whistler-mode chorus in response to interplanetary (IP) shocks is investigated using wave data from the Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft. As an example, we show a typical chorus wave excitation following an IP shock event that was observed by THEMIS in the postnoon sector near the magnetopause on 3 August 2010. We then analyze characteristic changes during this event and perform a survey of similar events during the period 2008-2014 using the THEMIS and OMNI data set. Our statistical analysis demonstrates that the chorus wave excitation/intensification in response to IP shocks occurs only at high L shells (L > 8) on the dayside. We analyzed the variations of magnetic curvature following the arrival of the IP shock and found that IP shocks lead to more homogeneous background magnetic field configurations in the near-equatorial dayside magnetosphere; and therefore, the threshold of nonlinear chorus wave growth is likely to be reduced, favoring chorus wave generation. Our results provide the observational evidence to support the concept that the geomagnetic field line configuration plays a key role in the excitation of dayside chorus. Key Points Excitation of dayside chorus waves is observed These waves are in response to IP shocks IP shocks change the magnetic field line configuration.

Fifteen months of pitch angle resolved Van Allen Probes Relativistic Electron-Proton Telescope (REPT) measurements of differential electron flux are analyzed to investigate the characteristic variability of the pitch angle distribution of radiation belt ultrarelativistic (>2MeV) electrons during storm conditions and during the long-term poststorm decay. By modeling the ultrarelativistic electron pitch angle distribution as sinnα, where α is the equatorial pitch angle, we examine the spatiotemporal variations of the n value. The results show that, in general, n values increase with the level of geomagnetic activity. In principle, ultrarelativistic electrons respond to geomagnetic storms by becoming more peaked at 90 pitch angle with n values of 2-3 as a supportive signature of chorus acceleration outside the plasmasphere. High n values also exist inside the plasmasphere, being localized adjacent to the plasmapause and exhibiting energy dependence, which suggests a significant contribution from electromagnetic ion cyclotron (EMIC) wave scattering. During quiet periods, n values generally evolve to become small, i.e., 0-1. The slow and long-term decays of the ultrarelativistic electrons after geomagnetic storms, while prominent, produce energy and L-shell-dependent decay time scales in association with the solar and geomagnetic activity and wave-particle interaction processes. At lower L shells inside the plasmasphere, the decay time scales τd for electrons at REPT energies are generally larger, varying from tens of days to hundreds of days, which can be mainly attributed to the combined effect of hiss-induced pitch angle scattering and inward radial diffusion. As L shell increases to L~3.5, a narrow region exists (with a width of ~0.5L), where the observed ultrarelativistic electrons decay fastest, possibly resulting from efficient EMIC wave scattering. As L shell continues to increase, τd generally becomes larger again, indicating an overall slower loss process by waves at high L shells. Our investigation based upon the sinnα function fitting and the estimate of decay time scale offers a convenient and useful means to evaluate the underlying physical processes that play a role in driving the acceleration and loss of ultrarelativistic electrons and to assess their relative contributions. Key Points Ultrarelativistic electron PADs vary dynamically during storms Ultrarelativistic electron fluxes show slow poststorm decays The analyses are useful to evaluate the underlying physics

©2015. American Geophysical Union. All Rights Reserved. A novel technique capable of inferring wave amplitudes from low-altitude electron measurements from the Polar Operational Environmental Satellites (POES) spacecraft has been previously proposed to construct a global dynamic model of chorus and plasmaspheric hiss waves. In this paper we focus on plasmaspheric hiss, which is an incoherent broadband emission that plays a dominant role in the loss of energetic electrons from the inner magnetosphere. We analyze the sensitivity of the POES technique to different inputs used to infer the hiss wave amplitudes during three conjunction events with the Van Allen Probes. These amplitudes are calculated with different input models of the plasma density, wave frequency spectrum, and electron energy spectrum, and the results are compared to the wave observations from the twin Van Allen Probes. Only one parameter is varied at a time in order to isolate its effect on the output, while the two other inputs are set to the values observed by the Van Allen Probes. The results show that the predicted hiss amplitudes are most sensitive to the adopted frequency spectrum, followed by the plasma density, but they are not very sensitive to the electron energy spectrum. Moreover, the standard Gaussian representation of the wave frequency spectrum (centered at 550-Hz) peaks at frequencies that are much higher than those observed in individual cases as well as in statistical wave distributions, which produces large overestimates of the hiss wave amplitude. For this reason, a realistic statistical model of the wave frequency spectrum should be used in the POES technique to infer the plasmaspheric hiss wave intensity rather than a standard Gaussian distribution, since the former better reproduces the observed plasmaspheric hiss wave amplitudes. Key Points Inferred amplitudes are very sensitive to frequency spectrum and plasma density All estimates remain within a factor of 0.48 to 2.09 of the observed hiss waves Statistical frequency spectra should be used instead of standard Gaussian models

Test particle simulation is a useful method for studying both linear and nonlinear wave-particle interactions in the magnetosphere. The gyro-averaged equations of particle motion for first-order and other cyclotron harmonic resonances with oblique whistler-mode waves were first derived by Bell [J. Geophys. Res. 89, 905 (1984)] and the most recent relativistic form was given by Ginet and Albert [Phys. Fluids B 3, 2994 (1991)], and Bortnik [Ph.D. thesis (Stanford University, 2004), p. 40]. However, recently we found there was a (- 1) l - 1 term difference between their formulas of perpendicular motion for the lth-order resonance. This article presents the detailed derivation process of the generalized resonance formulas, and suggests a check of the signs for self-consistency, which is independent of the choice of conventions, that is, the energy variation equation resulting from the momentum equations should not contain any wave magnetic components, simply because the magnetic field does not contribute to changes of particle energy. In addition, we show that the wave centripetal force, which was considered small and was neglect in previous studies of nonlinear interactions, has a profound time derivative and can significantly enhance electron phase trapping especially in high frequency waves. This force can also bounce the low pitch angle particles out of the loss cone. We justify both the sign problem and the missing wave centripetal force by demonstrating wave-particle interaction examples, and comparing the gyro-averaged particle motion to the full particle motion under the Lorentz force.

Recent test particle simulations have shown that energetic electrons traveling through fast magnetosonic (MS) wave packets can experience an effect which is specifically associated with the tight equatorial confinement of these waves, known as transit time scattering. However, such test particle simulations can be computationally cumbersome and offer limited insight into the dominant physical processes controlling the wave-particle interactions, that is, in determining the effects of the various wave parameters and equatorial confinement on the particle scattering. In this paper, we show that such nonresonant effects can be effectively captured with a straightforward analytical treatment that is made possible with a set of reasonable, simplifying assumptions. It is shown that the effect of the wave confinement, which is not captured by the standard quasi-linear theory approach, acts in such a way as to broaden the range of particle energies and pitch angles that can effectively resonate with the wave. The resulting diffusion coefficients can be readily incorporated into global diffusion models in order to test the effects of transit time scattering on the dynamical evolution of radiation belt fluxes.

A new 3-D diffusion code is used to investigate the inward intrusion and slow decay of energetic radiation belt electrons (>0.5MeV) observed by the Van Allen Probes during a 10day quiet period on March 2013. During the inward transport, the peak differential electron fluxes decreased by approximately an order of magnitude at various energies. Our 3-D radiation belt simulation including radial diffusion and pitch angle and energy diffusion by plasmaspheric hiss and electromagnetic ion cyclotron (EMIC) waves reproduces the essential features of the observed electron flux evolution. The decay time scales and the pitch angle distributions in our simulation are consistent with the Van Allen Probe observations over multiple energy channels. Our study suggests that the quiet time energetic electron dynamics are effectively controlled by inward radial diffusion and pitch angle scattering due to a combination of plasmaspheric hiss and EMIC waves in the Earth's radiation belts.

© 2014. American Geophysical Union. All Rights Reserved. Due to its importance for global energy dissipation in the ionosphere, the diffuse aurora has been intensively studied in the past 40years. Its origin (precipitation of 0.5-10keV electrons from the plasma sheet without potential acceleration) has been generally attributed to whistler-mode chorus wave scattering in the inner magnetosphere (R < ~8 R E ), while the scattering mechanism beyond that distance remains unresolved. By modeling the quasi-linear diffusion of electrons with realistic parameters for the magnetic field, loss cone size, and wave intensity (obtained from Time History of Events and Macroscale Interactions during Substorms (THEMIS) observations as a function of magnetospheric location), we estimate the loss cone filling ratio and electron cyclotron harmonic (ECH) wave-induced electron precipitation systematically throughout the entire data set, from 6 R E out to 31 R E (the THEMIS apogee). By comparing the wave-induced precipitation directly with the equatorially mapped energy flux distribution of the diffuse aurora from ionospheric observations (OVATION Prime model) at low altitudes, we quantify the contribution of auroral energy flux precipitated due to ECH wave scattering. Although the wave amplitudes decrease, as expected, with distance from the Earth, due to the smaller loss cone size and stretched magnetic field topology, ECH waves are still capable of causing sufficient scattering of plasma sheet electrons to account for the observed diffuse auroral dissipation. Our results demonstrate that ECH waves are the dominant driver of the diffuse aurora in the outer magnetosphere, beyond ~8 R E .

The critical current densities of polycrystalline bulk SmFeAsO1-xFx prepared by the powder-in-tube (PIT) method and by a conventional solid-state reaction were investigated using the remnant magnetic moment method and Campbell's method. Two types of shielding current, corresponding to global and local critical current densities Jc were observed using both measurement methods. The global and local Jc were on the order of 107 A/m2 and 1010 A/m2 at 5 K, respectively. The local Jc decreased slightly with increasing magnetic field. The global Jc was independent of the preparation method, while the local Jc was larger for samples prepared by PIT than for those prepared by solid-state reaction. © 2009 Elsevier B.V. All rights reserved.

The critical current densities of polycrystalline bulk SmFeAsO1-xFx prepared by the powder-in-tube (PIT) method and by a conventional solid-state reaction were investigated using the remnant magnetic moment method and Campbell's method. Two types of shielding current, corresponding to global and local critical current densities Jc were observed using both measurement methods. The global and local Jc were on the order of 107 A/m2 and 1010 A/m2 at 5 K, respectively. The local Jc decreased slightly with increasing magnetic field. The global Jc was independent of the preparation method, while the local Jc was larger for samples prepared by PIT than for those prepared by solid-state reaction. © 2009 Elsevier B.V. All rights reserved.

The present study investigates the scattering of flexural gravity waves due to uneven bottom topography in the context of wave blocking. Emphasis is given to analyzing the effects of multiple propagating wave modes on the solution procedures. The mathematical model is developed for two scenarios: a bottom step and a submerged rectangular breakwater. For the bottom step case, the complete solution in terms of the velocity potential is obtained using the eigenfunction expansion method. Subsequently, the solution associated with the wave transformation by the bottom step is extended to the case of a submerged rectangular breakwater using symmetry characteristics of the velocity potential. The energy balance relation is derived in both cases using the conservation of energy flux in the presence of multiple propagating wave modes. Wave blocking occurs for four different frequencies in both the cases of the bottom step and the submerged breakwater due to variations in water depth. This makes the problem more complex as, depending on the frequency, multiple propagating wave modes can exist in either the reflected region, the transmitted region, or both. The transmitted wave amplitude associated with the lower wavenumber within the blocking frequencies exceeds unity, and this excess energy is balanced by the corresponding energy transfer rate. Additionally, removable discontinuities are observed at the blocking frequencies in the scattering coefficients, where group velocity ceases. In the context of floating ice sheets, the deflection is analyzed in the time domain for frequencies within and outside the blocking limits. [ABSTRACT FROM AUTHOR]