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Based on the polarization property of fluorescent dipoles, fluorescence super-resolution microscopy recently has been proposed by modulating the polarization of the excitation light. In this technique, the super-resolution image is reconstructed by processing the polarization-modulated fluorescence image stack with an iteration algorithm. However, the mechanism of resolution improvement by polarization modulation has been questioned. In this paper, the mechanism of resolution enhancement by polarization modulation is analyzed in reciprocal space. The mathematical model and the reconstruction algorithm of fluorescence super-resolution microscopy via polarization modulation are proposed in reciprocal space. The corresponding simulation results and analysis show that polarization modulation can enlarge the highest detected spatial frequency of fluorescence microscopy to achieve super resolution, which verifies the role of polarization modulation in resolution improvement and provides a useful reference to study fluorescence super-resolution microscopy via polarization modulation in reciprocal space.

Aging is a natural biological process associated with cognitive decline and neuroendocrine-immune system changes; the neuroendocrine-immune system plays crucial role in brain aging and neurodegeneration, and it is essential to discern beneficial attempts to delay the aging progress based on immunological aging. In this study, we have investigated the effects of Traditional Chinese Medicine (TCM)-Liuwei Dihuang decoction (LW)-and donepezil, memantine, and melatonin on cognitive decline in aging mice. The aged SAMR1 mice received oral administration of donepezil (1mg/kg), memantine (10 mg/kg), melatonin (10 mg/kg), and LW (10 g/kg) for 3 months. A shuttle box, Morris water maze, and elevated-zero maze were performed to assess cognitive function, and flowcytometry, Luminex, and radioimmunoassay were performed to measure the lymphocyte subsets, inflammatory factors, and hormones. We observed that survival days of mice was increased with melatonin and LW, the anxiety behavior was significantly improved by memantine, melatonin, and LW treatment, active avoidance responses significantly improved by LW, donepezil, and memantine, the spatial learning ability was significantly improved by donepezil, and LW and melatonin were beneficial to the spatial memory of old mice. For immune function, LW increased CD4+ and CD4+CD28+ cells and reduced TNF-α, IL-1β, and G-CSF in plasma, and it also promoted the secretion of anti-inflammatory factors IL-4, IL-5, and IL-10 by regulating the active of Th2 cells in spleen. Donepezil and memantine exerted protective effects against CD4+CD28+ cell decrease caused by aging and reduced the pro-inflammatory factors TNF-α, IL-1β, and G-CSF in plasma. Melatonin could reverse CD8+CD28+ cell imbalances and increased B cells. For endocrine factors, LW increased TSH levels in the pituitary, and melatonin increased the GH level in blood. Our findings indicated that LW improved the cognitive decline in aging mice, and this might be associated with modulation of the active T cells and HPG axis hormones as well as increasing anti-inflammatory factors. Meanwhile, donepezil and memantine have advantages in regulating adaptive immunity, melatonin has advantages in the regulation of B cells and pituitary hormones, and LW exhibits a better effect on neuroendocrine immune function compared with the others from a holistic point of view. LW might be a potential therapeutic strategy for anti-aging-related syndromes, and it can also provide a value on medication guidance about drug combinations or treatment in clinic.

Two-photon fluorescence polarization microscopy is widely used to monitor the orientation and structural information of biomolecules labeled by fluorescence dipoles, while suffering from the spatial resolution limitation. In this paper, we propose an effective reconstruction algorithm for two-photon fluorescence polarization microscopy to reconstruct the super-resolution image and obtain the finer orientation information of dipoles at corresponding super-resolution scale. First, a conventional statistic model is employed to characterize the orientation distribution of dipole-clusters. By combining the model with the two-photon microscope imaging theory, then an optimization model is proposed and the reconstruction algorithm is developed based on conjugate gradient least square method and applied to various samples. The reconstruction results demonstrate that the imaging resolution of 90 nm can be reached and the finer orientation distribution information of dipole-clusters at the corresponding resolution can be obtained. Finally, Monte Carlo analysis has been performed, which verifies that the algorithm has high accuracy in reconstructing the parameters of the finer orientation distribution of dipole-clusters. The analysis of sample noise proves that the reconstruction algorithm can be utilized to actual samples within the appropriate noise range.

Despite the widely recognized change of career management in the new career era, little is known about whether the organizational career management practices are different from previous ones and th...

// Jian-hui Wang 1,2,* , Xiao-rui Cheng 1,2,* , Xiao-rui Zhang 1,2 , Tong-xing Wang 1,2 , Wen-jian Xu 3 , Fei Li 3 , Feng Liu 1,2 , Jun-ping Cheng 1,2 , Xiao-chen Bo 3 , Sheng-qi Wang 3 , Wen-xia Zhou 1,2 and Yong-xiang Zhang 1,2 1 Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China 2 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China 3 Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China * These authors contributed equally to this work and as co-first authors Correspondence to: Xiao-rui Cheng, email: // Wen-xia Zhou, email: // Yong-xiang Zhang, email: // Keywords : Alzheimer's disease, neuroendocrine immunomodulation, Senescence-accelerated mouse prone 8 strain (SAMP8), PrPhAβPPswe/PS1ΔE9 (APP/PS1) mice, learning and memory, Gerotarget Received : February 14, 2016 Accepted : March 18, 2016 Published : March 28, 2016 Abstract Senescence-accelerated mouse prone 8 strain (SAMP8) and PrP-hAβPPswe/PS1 ΔE9 (APP/PS1) mice are classic animal models of sporadic Alzheimer’s disease and familial AD respectively. Our study showed that object recognition memory, spatial learning and memory, active and passive avoidance were deteriorated and neuroendocrine immunomodulation (NIM) network was imbalance in SAMP8 and APP/PS1 mice. SAMP8 and APP/PS1 mice had their own specific phenotype of cognition, neuroendocrine, immune and NIM molecular network. The endocrine hormone corticosterone, luteinizing hormone and follicle-stimulating hormone, chemotactic factor monocyte chemotactic protein-1, macrophage inflammatory protein-1β, regulated upon activation normal T cell expressed and secreted factor and eotaxin, pro-inflammatory factor interleukin-23, and the Th1 cell acting as cell immunity accounted for cognitive deficiencies in SAMP8 mice, while adrenocorticotropic hormone and gonadotropin-releasing hormone, colony stimulating factor granulocyte colony stimulating factor, and Th2 cell acting as humoral immunity in APP/PS1 mice. On the pathway level, chemokine signaling and T cell receptor signaling pathway played the key role in cognition impairments of two models, while cytokine-cytokine receptor interaction and natural killer cell mediated cytotoxicity were more important in cognitive deterioration of SAMP8 mice than APP/PS1 mice. This mechanisms of NIM network underlying cognitive impairment is significant for further understanding the pathogenesis of AD and can provide useful information for development of AD therapeutic drug.

Due to the inherent polarization property of fluorescence, the imaging sparsity of neighboring fluorophores can be enhanced by excitation scheme with polarization modulation. Based on this fact, the super-resolution images have been successfully reconstructed from the polarization modulated wide-field fluorescence images by sparse deconvolution method realized with fast iterative shrinkage-thresholding algorithm (FISTA). Here, a new algorithm is proposed to reconstruct the super-resolution images based on the conjugate gradient method. The algorithm is analyzed theoretically and verified by simulations and the experimental data. The reconstruction results proves the feasibility of the algorithm and presents the influences of the steps of iteration and polarization modulation.

Conventional fluorescence polarization microscopy has been largely used to monitor the orientation and the structural information of biomolecules labeled with fluorescence dipoles but suffers from the optical diffraction limit. Here, we put forward a novel algorithm to simultaneously acquire the super-resolution image and the effective orientation distribution information of dipole clusters at corresponding super-resolution. In this paper, the orientation distribution of dipole clusters is statistically modeled by its mean orientation and orientation deviation, which are, respectively, represented by the middle direction and the opening angle of a sector shape. According to this model and microscopy imaging theory, the joint reconstruction algorithm is deduced mathematically in detail based on the conjugate gradient least-squares method. By applying this algorithm to different samples, the reconstructed results prove more than twice the resolution of wide-field images and the orientation distribution information at corresponding spatial resolution. Furthermore, the high accuracy of this algorithm in reconstructing super-resolution orientation distribution information is verified by Monte Carlo simulations.

AEOL-10150 is a broad-spectrum metalloporphyrin superoxidase dismutase (SOD) mimic specifically designed to neutralize reactive oxygen and nitrogen species. Research has shown that AEOL-10150 is a potent medical countermeasure against national security threats including sulfur mustard (SM), nerve agent exposure and radiation pneumonitis following a radiological/nuclear incident sufficient to cause acute radiation syndrome (ARS). AEOL-10150 performed well in animal safety studies, and two completed phase 1 safety studies in patients demonstrated that the drug was safe and well tolerated, indicating that AEOL-10150 has potential as a new catalytic antioxidant drug. In this article, we review improvements in AEOL-10150 in preclinical pharmacodynamic studies, especially regarding anti-SM, chlorine gas and radiation exposure studies.

IntroductionThe aim of this study was to investigate the potential role of a microRNA panel as early diagnostic markers for Alzheimer’s disease (AD).MethodsThe differentially expressed serum microRNAs were screened with microarray among cognitively normal controls (CNC), mild cognitive impairment (MCI), and AD. QRT-PCR assay was applied to evaluate differentially expressed microRNAs with two independent cohorts including 202 participants. Logistic regression model based on microRNA panel was constructed using a training cohort and then validated using an independent cohort.ResultsFirst, four differentially expressed serum microRNAs (let-7g, miR-197, miR-126 and miR-29a) were found, which expressions were positively correlated with mini mental state examination (MMSE) score. Second, a microRNA panel with the four microRNAs demonstrated good diagnostic performance for MCI and AD with 84% and 92% accuracy. Third, when combined with MMSE score, the diagnostic performance of the microRNA panel was further improved.DiscussionBlood microRNAs are potential AD biomarkers that may lead to new diagnostic strategies.

To investigate specific changes in metabolites and proteins of Kidney-Yin Deficiency Syndrome (KYDS) patients with diabetes mellitus (DM) in China. KYDS (n=29) and non-KYDS (n=23) patients with DM were recruited for this study. The KYDS was diagnosed by two senior TCM clinicians separately. The metabonomic and proteomic profiles of the patients were assessed using a metabonomic strategy based on NMR with multivariate analysis and a proteomic strategy based on MALDI-TOF-MS, respectively. Eighteen upregulated peptides and thirty downregulated peptides were observed in the plasma of the KYDS patients. Comparing the proteomic profiles of the KYDS and non-KYDS groups, however, no significantly differentially expressed peptides were found. At the same time, major metabolic alterations were found to distinguish the two groups, including eight significantly changed metabolites (creatinine, citrate, TMAO, phenylalanine, tyrosine, alanine, glycine and taurine). The levels of creatinine, citrate, TMAO, phenylalanine and tyrosine were decreased, whereas the levels of alanine, glycine and taurine were increased in the KYDS patients. These biochemical changes were found to be associated with alterations in amino acid metabolism, energy metabolism and gut microflora. The identification of distinct expression profiles of metabolites and signaling pathways in KYDS patients with DM suggests that there are indeed molecular signatures underlying the principles of 'Syndrome Differentiation' in traditional Chinese medicine.

Background In clinical studies, the findings on sulfur mustard (SM) toxicity for CD3+CD4+ and CD3+CD8+ T lymphocyte subsets are contradictory. In animal experiments, the effect of SM on the T cell number and proliferation is incompatible and is even the opposite of the results in human studies. In this study, we observed the dynamic changes of T lymphocytes in the first week in a high-dose SM-induced model. Methods Mice were exposed to SM by subcutaneous injection (20 mg/kg) and were sacrificed 4 h, 24 h, 72 h and 168 h later. Spleen T lymphocyte proliferation was evaluated by 3H-TdR. Flow cytometric analysis was used to observe the percentage of CD3+CD4+ and CD3+CD8+ T lymphocyte subsets. The IL-1β, IL-6, IL-10 and TNF-α levels in plasma were assayed using the Luminex method. DNA damage in bone marrow cells was observed with the single cell gel electrophoresis technique (SCGE). Results SM continuously inhibited the proliferation of lymphocytes for 7 days, and there was a significant rebound of Con A-induced T lymphocyte proliferation only at 24 h. The percentage of CD3+CD4+ and CD3+CD8+ lymphocytes was upregulated, which was accompanied by increased IL-1β and TNF-α and decreased IL-10. The IL-6 level was gradually decreased in the PG group at 4 h. The peak of lymphocytic apoptosis and DNA damage occurred at 24 h and 72 h, respectively. Conclusion Our results show that SM significantly inhibited T lymphocyte proliferation as well as induced CD3+CD4+ and CD3+CD8+ upregulation. SM intoxication also significantly increased the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and inhibited the level of anti-inflammatory cytokine IL-10. Our results may partly be due to the significant SM induced significant apoptosis and necrosis of lymphocytes as well as DNA damage of bone marrow cells. The results provided a favorable evaluation of SM immune toxicity in an animal model.

This study compared the effects of estrogen (E) on the hyperactivity induced by (+)-3,4-methylenedioxymethamphetamine (MDMA) with E effects on cocaine-evoked hyperactivity in female rats. Sprague-Dawley rats were ovariectomized (OVX); half of them received a 17beta-estradiol (E2) implant (OVX + E). Three weeks later, rats received saline, (+)-MDMA (1, 2, or 4 mg/kg) or cocaine (5, 10, or 20 mg/kg), and locomotor activity was monitored. OVX + E rats exhibited greater locomotor hyperactivity in response to both psychostimulants than did OVX rats. The enhanced response to cocaine appeared within 5 min following drug injection whereas the enhanced response to (+)-MDMA was delayed for approximately 30 min. The differential effects of E on hyperactivity may be due to the unique profiles of DA and 5-HT in response to (+)-MDMA and cocaine.

Alzheimer’s disease (AD) is the leading cause of dementia that affects millions of elderly people worldwide. The currently available therapies have limited efficacy. Liuwei Dihuang decoction (LW), a classical traditional Chinese medicine (TCM) formula, has long been used to treat various diseases, including dementia. A large number of pharmacological studies have shown that LW has beneficial effects on AD. LW-AFC is a new formula consisting of the main active components prepared from LW. In this study, we found that administration of LW-AFC significantly improved behavioural performances in spontaneous locomotor activity, object recognition memory, spatial learning and memory, passive and active avoidance impairment in some AD mouse models, such as SAMP8 and APP/PS1 transgenic mice. Meanwhile, the impairments of long-term potentiation (LTP) were significantly ameliorated by LW-AFC administration in SAMP8 mice, as well as in the corticosterone-induced LTP inhibition mouse model. These effects were companied by an alleviation in neuron loss in the hippocampus, suppression of A-beta deposition in the brain, and a reduction in the concentration of Abeta42 in the hippocampus and plasma of APP/PS1 mice. The restoring and correcting of imbalance in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, the disorder of lymphocyte subsets, and the abnormalities in cytokine production were also observed in LW-AFC treated SAMP8 and APP/PS1 mice. These findings indicated that LW-AFC ameliorated the behavioural and pathological deterioration of AD mice via the restoration of the NIM network in a holistic way, suggesting that LW-AFC might be a promising therapy for AD.

Mitral valvular disease is strongly related to atrial fibrillation (AF), but the different types of mitral valvular disease have a different prevalence of AF. In this study we explored the expressions of the circulating and local renin-angiotensin-aldosterone system (RAAS) in order to determine the relationship between circulating and local RAAS expressions and its effects on AF in different types of mitral valvular disease patients. Our study group consisted of 24 mitral valvular disease patients scheduled for mitral valve replacement surgery. Peripheral blood samples and left atrial appendage tissue samples were obtained from all patients. Radioimmunoassay was performed to assess the expression levels of circulating and local renin, angiotensin II and aldosterone. In mitral valvular diseases, linear correlation analyses were done for local and circulating renin, angiotensin II and aldosterone; the p values were 0.979, 0.518 and 0.125, respectively. Expression levels of local angiotensin II, circulating angiotensin II and local aldosterone were significantly increased in the AF group compared with sinus rhythm; the p values were 0.023, 0.042 and 0.035, respectively. In mitral stenosis patients, AF was primarily associated with local angiotensin II ( p =0.010), as well as being associated with circulating angiotensin II ( p =0.038). In mitral regurgitation patients, AF was only significantly associated with local angiotensin II ( p =0.038). Circulating and local RAAS expressions are associated with AF in mitral valvular disease patients. The levels of circulating and local RAAS expressions were different in AF patients with different types of mitral valvular diseases. The differentiation of circulating and local RAAS expression levels in AF patients between different types of mitral valvular disease can potentially improve the specific pharmacological interventions outcomes for these patients.

Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury. The results showed that in both the mouse ear vesicant model (MEVM) and HaCaT cell model, PARP inhibitor ABT-888 can reduce cell damage induced by severe SM injury. ABT-888 significantly reduced SM induced edema and epidermal necrosis in MEVM. In the HaCaT cell model, ABT-888 can reduce SM-induced NAD+/ATP depletion and apoptosis/necrosis. Then, we studied the mechanism of PARP-1 in SM injury by knockdown of PARP-1 in HaCaT cells. Knockdown of PARP-1 protected cell viability and downregulated the apoptosis checkpoints, including p-JNK, p-p53, Caspase 9, Caspase 8, c-PARP and Caspase 3 following SM-induced injury. Furthermore, the activation of AKT can inhibit autophagy via the regulation of mTOR. Our results showed that SM exposure could significantly inhibit the activation of Akt/mTOR pathway. Knockdown of PARP-1 reversed the SM-induced suppression of the Akt/mTOR pathway. In summary, the results of our study indicated that the protective effects of downregulation of PARP-1 in SM injury may be due to the regulation of apoptosis, necrosis, energy crisis and autophagy. However, it should be noticed that PARP inhibitor ABT-888 further enhanced the phosphorylation of H2AX (S139) after SM exposure, which indicated that we should be very careful in the application of PARP inhibitors in SM injury treatment because of the enhancement of DNA damage.

Neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are one of leading causes of death all over the world. Traditional medicine (TM), especially traditional Chinese medicine (TCM), usually having good clinical tolerability, is applied to treat NDD in China based on TCM or modern pharmacological theories. This issue on TM for treatment of NDD compiles 12 exciting manuscripts, most of which reported the efficacy and possible mechanisms of action of TM or active constituents on AD, PD, and ALS both in clinical and experimental levels.

This paper explored LMX' impact on employees' organizational affective commitment and chose the perceived organizational support as a mediated variable, using structural equation model technology to verify the relationship of them. The results showed that: affection, loyalty and professional respect had a significant impact on affective commitment but the result of contribution is not significant. So work exchange (contribution) was different from social exchange (affect, loyalty and professional respect) in the influence on employee's organizational affective commitment. Perceived organizational support had a mediated effect between the affect exchange and affective commitment in the organization. Leader-member relationship had an important implication on the employee-organization relationships. The exchanges of different dimensions between leaders and members were different no matter for the affected contents of the attitude to the organization of the employee or for the affecting mechanism.

Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral administration of roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by roquinimex treatment. These data suggested that the beneficial effect of roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.

Background Accumulating evidence implicates the neuroendocrine immunomodulation (NIM) network in the physiopathological mechanism of Alzheimer’s disease (AD). Notably, we previously revealed that the NIM network is dysregulated in the PrP-hAβPPswe/PS1ΔE9 (APP/PS1) transgenic mouse model of AD. Methods After treatment with a novel Liuwei Dihuang formula (LW-AFC), mice were cognitively evaluated in behavioral experiments. Neuron loss, amyloid-β (Aβ) deposition, and Aβ level were analyzed using Nissl staining, immunofluorescence, and an AlphaLISA assay, respectively. Multiplex bead analysis, a radioimmunoassay, immunochemiluminometry, and an enzyme-linked immunosorbent assay (ELISA) were used to measure cytokine and hormone levels. Lymphocyte subsets were detected using flow cytometry. Data between two groups were compared using a Student’s t test. Comparison of the data from multiple groups against one group was performed using a one-way analysis of variance (ANOVA) followed by a Dunnett’s post hoc test or a two-way repeated-measures analysis of variance with a Tukey multiple comparisons test. Results LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice, including the impairment of object recognition memory, spatial learning and memory, and active and passive avoidance. In addition, LW-AFC alleviated the neuron loss in the hippocampus, suppressed Aβ deposition in the brain, and reduced the concentration of Aβ1–42 in the hippocampus and plasma of APP/PS1 mice. LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone in the pituitary. Moreover, LW-AFC increased CD8+CD28+ T cells, and reduced CD4+CD25+Foxp3+ T cells in the spleen lymphocytes, downregulated interleukin (IL)-1β, IL-2, IL-6, IL-23, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor-α and -β, and upregulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice. Conclusions LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic mice via the restoration of the NIM network to a greater extent than either memantine or donepezil, which supports the use of LW-AFC as a potential agent for AD therapy.