Mini review: surveillance of Lyme borreliosis in Southeast Asia and method of diagnosis.

Lyme borreliosis is caused by the Gram-negative spirochetes Borrelia spp., particularly Borrelia burgdorferi sensu lato complex. The disease is transmitted through the bite of the infected black-legged Ixodes tick. Lyme borreliosis extensively occurs in the Northern Hemisphere, mainly in the United States. Lyme borreliosis cases are also detected in Asian countries including Korea, Nepal, China, Taiwan, and Japan. However, there is an inadequate understanding of Lyme borreliosis in the Southeast Asian region. Hence, this review aims to provide a brief update on the prevalence of Lyme borreliosis infection in Southeast Asia based on the latest literature on this issue. Lyme borreliosis has been discovered in human serum in Indonesia, Malaysia, and Singapore. The human serum samples were mainly examined with ELISA test using Borrelia spp. IgG and IgM antigens. Borrelia spp. also has been detected in ticks found on host animals such as Sundamys muelleri and Python in Malaysia, Thailand, and Laos. Polymerase chain reaction (PCR) is used to detect the presence of Borrelia DNAs in the samples. The published studies have demonstrated that Borrelia spp. exists in Southeast Asia and although the incidence is relatively low, it is believed that Lyme disease cases are under-reported.

Plasmodium falciparum protein kinase as a potential therapeutic target for antimalarial drugs development.

Malaria is one of the most dangerous infectious diseases due to its high infection and mortality rates, especially in the tropical belt. Plasmodium falciparum (P. falciparum), the most virulent malaria parasite in humans, was recently reported to develop resistance against the final efficient antimalarial drug, artemisinin. Little is known about the resistance mechanisms, which further complicates the problem as a proper counteraction is unable to be taken. Hence, the understanding of drug mode of action and its molecular target is valuable knowledge that needs to be considered to develop the next generation of antimalarial drugs. P. falciparum protein kinase (Pf PK) is an attractive target for antimalarial chemotherapy due to its vital roles in all P. falciparum life stages. Moreover, overall structural differences and the presence of unique Pf PKs that are absent in human kinome, suggesting specific inhibition of Pf PK without affecting human cells is achievable. To date, at least 86 eukaryotic protein kinases have been identified in P. falciparum kinome, by which less than 40 were validated as potential targets at the erythrocytes stage. In this review, recent progress of the furthest validated Pf PKs; Pf Nek-1, Pf CDPK1, Pf CDPK4, Pf PKG, and Pf CLK-3 will be briefly discussed.

Plasmodium falciparum protein kinase as a potential therapeutic target for antimalarial drugs development

@#Malaria is one of the most dangerous infectious diseases due to its high infection and mortality rates, especially in the tropical belt. Plasmodium falciparum (P. falciparum), the most virulent malaria parasite in humans, was recently reported to develop resistance against the final efficient antimalarial drug, artemisinin. Little is known about the resistance mechanisms, which further complicates the problem as a proper counteraction is unable to be taken. Hence, the understanding of drug mode of action and its molecular target is valuable knowledge that needs to be considered to develop the next generation of antimalarial drugs. P. falciparum protein kinase (Pf PK) is an attractive target for antimalarial chemotherapy due to its vital roles in all P. falciparum life stages. Moreover, overall structural differences and the presence of unique Pf PKs that are absent in human kinome, suggesting specific inhibition of Pf PK without affecting human cells is achievable. To date, at least 86 eukaryotic protein kinases have been identified in P. falciparum kinome, by which less than 40 were validated as potential targets at the erythrocytes stage. In this review, recent progress of the furthest validated Pf PKs; Pf Nek-1, Pf CDPK1, Pf CDPK4, Pf PKG, and Pf CLK-3 will be briefly discussed.

Decreased T cell expression of H/ACA box small nucleolar RNA 12 promotes lupus pathogenesis in patients with systemic lupus erythematosus.

Objective To investigate whether the aberrant expression of non-coding RNAs (ncRNAs) in T cells from patients with systemic lupus erythematosus (SLE) could contribute to the pathogenesis of lupus. Methods Expression profiles of RNA transcripts in T cells from three patients with SLE and three controls were analyzed by microarray analysis. Potentially aberrant-expressed ncRNAs were validated using T cell samples from 23 patients with SLE and 17 controls. Transfection studies and microarray analyses were conducted to search for any gene expression that is regulated by specific ncRNAs. Results Initial analysis revealed differential expression of 18 ncRNAs in SLE T cells. After validation, decreased expression of H/ACA box small nucleolar RNA 12 (SNORA12) was confirmed in SLE T cells (0.69-fold, P = 0.007) compared with normal T cells, and its expression level was inversely associated with higher SLE disease activity scores. Jurkat cells transfected with a plasmid encoding SNORA12 showed increased expression of two genes and decreased expression of 15 genes in Jurkat cells. These changes of gene expression were significantly associated with the SLE pathway in the Kyoto Encyclopedia of Genes and Genomes map using microarray analysis. Overexpression of SNORA12 altered the expression of CD69, decreased the expression of histone cluster 1 H4 family member k (HIST1H4K), inhibited the secretion of interferon gamma and the expression of HIST1H4K was increased in SLE T cells. Conclusion Among the ncRNAs, we found that the expression level of SNORA12, which belongs to the family of small nucleolar RNAs, was lower in SLE T cells and affected T cell function. This novel finding suggests that aberrant-expressed snoRNAs lead to dysfunction of T cells and may be involved in the immunopathogenesis of SLE.

Association of use of rehabilitation services with development of osteoporosis among patients with rheumatoid arthritis: a nationwide population-based cohort study.

This is the first study that has found that rehabilitation services (RS) intervention, following the onset of rheumatoid arthritis (RA), may significantly reduce the risk of osteoporosis in RA patients. Those patients who received more than five sessions of RS had the greatest benefit for the prevention of osteoporosis. INTRODUCTION: People with rheumatoid arthritis have increased risk of developing osteoporosis (OP). It remains unclear whether use of rehabilitation services can reduce the risk of developing OP. We conducted a longitudinal cohort study to compare the effect of RS on the risk of OP in Taiwanese individuals with RA. METHODS: A national health insurance database was used to identify 2693 newly diagnosed RA patients, 20-70 years old, between 1998 and 2007. Among them, 808 received RS after the onset of RA (RS users) and 1885 patients did not receive RS (non-RS users). All enrollees were followed until the end of 2012 to record incident cases of OP. A Cox proportional hazards regression model was used to compute adjusted hazard ratios (aHRs) for the relationship of use of RS with OP. RESULTS: During the 15-year follow-up, 358 RS users and 1238 non-RS users developed OP, corresponding to incidence rates of 87.24 and 129.27 per 1000 person-years, respectively. Use of RS was significantly associated with a lower risk of OP (aHR 0.62; 95% confidence interval [CI] = 0.56-0.71). Those who received more than five sessions of RS had the greatest benefit (aHR 0.47; 95% CI = 0.38-0.56). CONCLUSIONS: The integration of RS into the clinical management of patients with RA may decrease their risk of developing OP.

Higher risk of incident ankylosing spondylitis in patients with uveitis: a secondary cohort analysis of a nationwide, population-based health claims database.

OBJECTIVES: Ankylosing spondylitis (AS) is a progressive, systemic, inflammatory autoimmune disease that typically affects young adults. Uveitis is a common extra-articular manifestation of AS. Nevertheless, the magnitude of the risk of AS among patients with uveitis is not clear. The aim of this secondary retrospective cohort study was to investigate the risk of incident AS in patients with uveitis using data from a nationwide, population-based health claims research database. METHOD: Using Taiwan's National Health Insurance Research Database, we identified 6637 patients with uveitis between 2000 and 2012. A comparison cohort was assembled, which consisted of five patients without uveitis, based on frequency matching for gender, 10 year age interval, and index year, for each patient with uveitis. Both groups were followed until diagnosis of AS or the end of the follow-up period. A Poisson regression model was used to calculate the incidence rate ratio for AS between the uveitis cohort and the comparison cohort. RESULTS: Patients with uveitis exhibited a significantly higher incidence of AS than the comparison cohort (adjusted incidence rate ratio = 2.57, p < 0.001). Subgroup analysis with stratification by the interval between the diagnosis of uveitis and AS indicated that the adjusted incidence rates were significantly higher in the uveitis cohort with an interval of up to 7.9 years. CONCLUSION: A significant increased risk in AS among patients with uveitis was observed, with a time lag of up to 7.9 years between the diagnosis of uveitis and subsequent diagnosis of AS.

TGF-ß upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability.

Crosstalk between transforming growth factor beta (TGF-ß) signaling and p53 has a critical role in cancer progression. TGF-ß signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-ß signaling. However, it remains unknown whether p53 stability is regulated by TGF-ß. In the current study, we identify that USP15 binds to and stabilizes p53 through deubiquitination in U2OS and HEK293 cells. TGF-ß promotes the translation of USP15 through activation of mammalian target of rapamycin by the phosphoinositide 3-kinase/AKT pathway. Upregulation of USP15 translation links the crosstalk between TGF-ß signaling and p53 stability, allowing this cytokine to have a critical role in cancer progression.

Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells.

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are RNA molecules that do not translate into protein. Both miRNAs and lncRNAs are known to regulate gene expression and to play an essential role in T cell differentiation and function. Both systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, and rheumatoid arthritis (RA), a representative disease of inflammatory arthritis, are characterized by a complex dysfunction in the innate and adaptive immunity. T cells play a central role in cell-mediated immune response and multiple defects in T cells from patients with SLE and RA have been observed. Abnormality in T cell signalling, cytokine and chemokine production, T cell activation and apoptosis, T cell differentiation and DNA methylation that are associated closely with the aberrant expression of a number of miRNAs and lncRNAs have been implicated in the immunopathogenesis of SLE and RA. This review aims to provide an overview of the current state of research on the abnormal expression of miRNAs and lncRNAs in T cells and their roles in the immunopathogenesis of SLE and RA. In addition, by comparing the differences in aberrant expression of miRNAs and lncRNAs in T cells between patients with SLE and RA, controversial areas are highlighted that warrant further investigation.

Increased risk of pulmonary and extra-pulmonary tuberculosis in patients with rheumatic diseases.

SETTING: Impaired immunity in patients with rheumatic diseases can increase the risk of pulmonary tuberculosis (PTB). However, it is less clear whether rheumatic diseases affect the risk of extra-pulmonary tuberculosis (EPTB). OBJECTIVE: To investigate the risk of PTB and EPTB in patients with rheumatic diseases using a population-based database. DESIGN: From Taiwan's National Health Insurance Research Database, 8536 patients with tuberculosis (TB) were frequency-matched with 42,680 controls for sex, 10-year age group and index year. Subjects were retrospectively traced back for their first diagnosis of rheumatic diseases. The association between TB and rheumatic diseases was assessed using multivariate logistic regression analyses. RESULTS: The risk of developing PTB was significantly higher in patients with systemic lupus erythematosus (adjusted odds ratio [aOR] 4.90, P < 0.001), rheumatoid arthritis (RA) (aOR 2.00, P < 0.001) and Sjögren's syndrome (aOR 6.11, P < 0.001). In addition, the risks of developing EPTB were significantly higher in RA patients (aOR 4.67, P < 0.001), those with Sjögren's syndrome (aOR 5.94, P < 0.001), and the group comprising progressive systemic sclerosis, polymyositis or dermatomyositis (aOR 8.31, P = 0.021). CONCLUSION: Elevated risks of PTB and EPTB were associated with various rheumatic diseases. Rheumatologists should be vigilant to the possibility of TB, and particularly EPTB, in their patients.

Serum microRNA-210 as a potential noninvasive biomarker for the diagnosis and prognosis of glioma.

BACKGROUND: MicroRNA-210 (miR-210) is an oncogenic miRNA previously associated with prognosis in human gliomas, an incurable tumour type of the central nervous system. Here miR-210 was investigated as a potential serum biomarker in the diagnosis and prognosis of glioma. METHODS: Serum was immediately prepared from blood samples collected from patients with glioma grades I-IV at primary diagnosis (n=136) and healthy controls (n=50) from February 2007 to March 2014 in the Department of Neurosurgery of the First Affiliated Hospital of Wannan Medical College (Wuhu, China). Total RNA was isolated from serum. cDNA was synthesised with primers specific for miR-210 and miR-16-1 (internal control), and quantitative real-time RT-PCR was performed. Results were statistically analysed to determine the role of miR-210 in the diagnosis and prognosis of human glioma patients. RESULTS: An approximately seven-fold increase in miR-210 expression was detected in serum samples from glioblastoma patients relative to healthy controls. A threshold expression value (2.259) was chosen from receiver operator characteristic curves (ROC), and the low and high miR-210 expression groups were analysed by multivariate Cox proportional hazard regression and Kaplan-Meier analyses. Results revealed an association of high serum miR-210 expression with tumour grade and poor patient outcome (P-values <0.001). CONCLUSIONS: Serum miR-210 is a promising diagnostic and prognostic biomarker that can be detected in the peripheral blood of patients with glioma.

Increased prevalence of JC polyomavirus viruria was associated with arthritis/arthralgia in patients with systemic lupus erythematosus.

OBJECTIVE: The objective of this paper is to investigate the prevalence of reactivation of the human polyomavirus John Cunningham virus (JCV) in patients with systemic lupus erythematosus (SLE) and its associated clinical manifestations. METHODS: Sixty-one patients with SLE and 22 controls were enrolled. Urine JCV viral load was quantified by real-time polymerase chain reaction (PCR). Length variants of the VP1 gene were analyzed using capillary electrophoresis. RESULTS: The prevalence of JCV viruria (63.9% vs. 18.2%, p < 0.001) and urine JCV viral load (2.92 ± 2.76 vs. 0.81 ± 1.85 copies/ml by log10 scale, p < 0.001) were significantly higher in patients with SLE compared with controls. JCV viruria (+) SLE patients had a higher occurrence of arthritis/arthralgia compared with JCV viruria (-) SLE patients (64.1% vs. 22.7%, p = 0.003). In SLE patients, the urine JCV viral load was significantly associated with the occurrence of arthritis/arthralgia. SLE patients with urine JCV viral load >10,000 copies/ml exhibited a 12.75-fold (95% confidence interval 2.88-56.40) risk in clinical arthritis/arthralgia, 18.90-fold (95% confidence interval 2.10-170.39) risk in persistent arthritis, and significantly greater number of length variants in the VP1 gene of JCV compared with JCV viruria (-) SLE patients. CONCLUSION: Reactivation of JCV in the urinary tract of SLE patients was very common. Both JCV viruria and urine JCV viral load were associated with the occurrence of arthritis/arthralgia in patients with SLE. High urine JCV viral load also was associated with the genetic variant in the VP1 gene.

Increased miR-223 expression in T cells from patients with rheumatoid arthritis leads to decreased insulin-like growth factor-1-mediated interleukin-10 production.

We hypothesized that the aberrant expression of microRNAs (miRNAs) in rheumatoid arthritis (RA) T cells was involved in the pathogenesis of RA. The expression profile of 270 human miRNAs in T cells from the first five RA patients and five controls were analysed by real-time polymerase chain reaction. Twelve miRNAs exhibited potentially aberrant expression in RA T cells compared to normal T cells. After validation with another 22 RA patients and 19 controls, miR-223 and miR-34b were over-expressed in RA T cells. The expression levels of miR-223 were correlated positively with the titre of rheumatoid factor (RF) in RA patients. Transfection of Jurkat cells with miR-223 mimic suppressed insulin-like growth factor-1 receptor (IGF-1R) and transfection with miR-34b mimic suppressed cAMP response element binding protein (CREB) protein expression by Western blotting. The protein expression of IGF-1R but not CREB was decreased in RA T cells. The addition of recombinant IGF-1-stimulated interleukin (IL)-10 production by activated normal T cells, but not RA T cells. The transfection of miR-223 mimic impaired IGF-1-mediated IL-10 production in activated normal T cells. The expression levels of SCD5, targeted by miR-34b, were decreased in RA T cells after microarray analysis. In conclusion, both miR-223 and miR-34b were over-expressed in RA T cells, but only the miR-223 expression levels were correlated positively with RF titre in RA patients. Functionally, the increased miR-223 expression could impair the IGF-1-mediated IL-10 production in activated RA T cells in vivo, which might contribute to the imbalance between proinflammatory and anti-inflammatory cytokines.

Spin-valley lifetimes in a silicon quantum dot with tunable valley splitting.

Although silicon is a promising material for quantum computation, the degeneracy of the conduction band minima (valleys) must be lifted with a splitting sufficient to ensure the formation of well-defined and long-lived spin qubits. Here we demonstrate that valley separation can be accurately tuned via electrostatic gate control in a metal-oxide-semiconductor quantum dot, providing splittings spanning 0.3-0.8 meV. The splitting varies linearly with applied electric field, with a ratio in agreement with atomistic tight-binding predictions. We demonstrate single-shot spin read-out and measure the spin relaxation for different valley configurations and dot occupancies, finding one-electron lifetimes exceeding 2 s. Spin relaxation occurs via phonon emission due to spin-orbit coupling between the valley states, a process not previously anticipated for silicon quantum dots. An analytical theory describes the magnetic field dependence of the relaxation rate, including the presence of a dramatic rate enhancement (or hot-spot) when Zeeman and valley splittings coincide.

Aberrant expression of microRNAs in T cells from patients with ankylosing spondylitis contributes to the immunopathogenesis.

Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by dysregulated T cells. We hypothesized that the aberrant expression of microRNAs (miRNAs) in AS T cells involved in the pathogenesis of AS. The expression profile of 270 miRNAs in T cells from five AS patients and five healthy controls were analysed by real-time polymerase chain reaction (PCR). Thirteen miRNAs were found potentially differential expression. After validation, we confirmed that miR-16, miR-221 and let-7i were over-expressed in AS T cells and the expression of miR-221 and let-7i were correlated positively with the Bath Ankylosing Spondylitis Radiology Index (BASRI) of lumbar spine in AS patients. The protein molecules regulated by miR-16, miR-221 and let-7i were measured by Western blotting. We found that the protein levels of Toll-like receptor-4 (TLR-4), a target of let-7i, in T cells from AS patients were decreased. In addition, the mRNA expression of interferon (IFN)-γ was elevated in AS T cells. Lipopolysaccharide (LPS), a TLR-4 agonist, inhibited IFN-γ secretion by anti-CD3(+) anti-CD28 antibodies-stimulated normal T cells but not AS T cells. In the transfection studies, we found the increased expression of let-7i enhanced IFN-γ production by anti-CD3(+) anti-CD28(+) lipopolysaccharide (LPS)-stimulated normal T cells. In contrast, the decreased expression of let-7i suppressed IFN-γ production by anti-CD3(+) anti-CD28(+) LPS-stimulated AS T cells. In conclusion, we found that miR-16, miR-221 and let-7i were over-expressed in AS T cells, but only miR-221 and let-7i were associated with BASRI of lumbar spine. In the functional studies, the increased let-7i expression facilitated the T helper type 1 (IFN-γ) immune response in T cells.

Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with abnormal T cell immune responses. We hypothesized that aberrant expression of microRNAs (miRNAs) in T cells may contribute to the pathogenesis of SLE. First, we analysed the expression profiles of 270 human miRNAs in T cells from five SLE patients and five healthy controls and then validated those potentially aberrant-expressed miRNAs using real-time polymerase chain reaction (PCR). Then, the expression of mRNAs regulated by these aberrant-expressed miRNAs was detected using real-time PCR. Finally, miRNA transfection into Jurkat T cells was conducted for confirming further the biological functions of these miRNAs. The initial analysis indicated that seven miRNAs, including miR-145, miR-224, miR-513-5p, miR-150, miR-516a-5p, miR-483-5p and miR-629, were found to be potentially abnormally expressed in SLE T cells. After validation, under-expressed miR-145 and over-expressed miR-224 were noted. We further found that STAT1 mRNA targeted by miR-145 was over-expressed and apoptosis inhibitory protein 5 (API5) mRNA targeted by miR-224 was under-expressed in SLE T cells. Transfection of Jurkat cells with miR-145 suppressed STAT1 and miR-224 transfection suppressed API5 protein expression. Over-expression of miR-224 facilitates activation-induced cell death in Jurkat cells. In the clinical setting, the increased transcript levels of STAT1 were associated significantly with lupus nephritis. In conclusion, we first demonstrated that miR-145 and miR-224 were expressed aberrantly in SLE T cells that modulated the protein expression of their target genes, STAT1 and API5, respectively. These miRNA aberrations accelerated T cell activation-induced cell death by suppressing API5 expression and associated with lupus nephritis by enhancing signal transducer and activator of transcription-1 (STAT)-1 expression in patients with SLE.

HLA-B*15:02 is associated with anemia in patients with chronic hepatitis C treated with pegylated interferon-α and ribavirin.

To investigate the relationship between human leukocyte antigen (HLA) class I and II alleles and treatment-induced anemia in chronic hepatitis C (CHC) patients receiving combination therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV). One hundred six naïve CHC patients (59 females and 47 males; mean age, 53.08 years) who underwent combination treatment were enrolled. The patients were considered positive for hemoglobin (Hb)-related side effects if the Hb concentrations dropped below 10 g/dl during PEG-IFN-α plus RBV treatment. The HLA-A, -B, -C, -DR, and -DQ loci were investigated by sequence-based genotyping. The effects of the clinical characteristics, virologic variables, and the HLA alleles on treatment-induced anemia were evaluated by a logistic regression analysis. Forty patients (37.7%) had Hb levels below 10 g/dl during the treatment course. Low baseline Hb levels and an advanced liver fibrosis stage were associated with decreases in Hb levels to below 10 g/dl. The occurrence of treatment-related anemia (Hb < 10 g/dl) was significantly associated with HLA-B*15:02 as shown by multivariate analysis (adjusted odds ratio, 8.13; 95% confidence interval: 1.19-55.70; P-value after Holm's procedure, 0.03). HLA-B*15:02 is associated with treatment-induced anemia in Taiwanese CHC patients receiving combination therapy with PEG-IFN-α plus RBV.

Combination of nifedipine and subtherapeutic dose of cyclosporin additively suppresses mononuclear cells activation of patients with rheumatoid arthritis and normal individuals via Ca(2+) -calcineurin-nuclear factor of activated T cells pathway.

Abnormal Ca(2+) -mediated signalling contributes to the pathogenesis of rheumatoid arthritis (RA). However, the potential implication of calcium channel blocker in RA remained unknown. We hypothesized that nifedipine, an L-type calcium channel blocker, combined with a calcineurin inhibitor, could suppress T cell activation via targeting different level of the Ca(2+) signalling pathway. The percentage of activated T cells and the apoptotic rate of mononuclear cells (MNCs) was measured by flow cytometry. The MNC viability, cytokine production, cytosolic Ca(2+) level and activity of the nuclear factor of activated T cells (NFAT) were measured by enzyme-linked immunosorbent assay (ELISA). The NFAT-regulated gene expression, including interleukin (IL)-2, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), was measured by real-time polymerase chain reaction (PCR). We found that the percentage of activated T cells in anti-CD3 + anti-CD28-activated MNC was higher in RA patients. High doses of nifedipine (50 µM) increased MNCs apoptosis, inhibited T cell activation and decreased T helper type 2 (Th1) (IFN-γ)/Th2 (IL-10) cytokine production in both groups. The Ca(2+) influx was lower in anti-CD3 + anti-CD28-activated MNC from RA patients than healthy volunteers and suppressed by nifedipine. When combined with a subtherapeutic dose (50 ng/ml) of cyclosporin, 1 µM nifedipine suppressed the percentage of activated T cells in both groups. Moreover, this combination suppressed more IFN-γ secretion and NFAT-regulated gene (GM-CSF and IFN-γ) expression in RA-MNCs than normal MNCs via decreasing the activity of NFATc1. In conclusion, we found that L-type Ca(2+) channel blockers and subtherapeutic doses of cyclosporin act additively to suppress the Ca(2+) -calcineurin-NFAT signalling pathway, leading to inhibition of T cell activity. We propose that this combination may become a potential treatment of RA.

Pauli spin blockade in a highly tunable silicon double quantum dot.

Double quantum dots are convenient solid-state platforms to encode quantum information. Two-electron spin states can be detected and manipulated using quantum selection rules based on the Pauli exclusion principle, leading to Pauli spin blockade of electron transport for triplet states. Coherent spin states would be optimally preserved in an environment free of nuclear spins, which is achievable in silicon by isotopic purification. Here we report on a deliberately engineered, gate-defined silicon metal-oxide-semiconductor double quantum dot system. The electron occupancy of each dot and the inter-dot tunnel coupling are independently tunable by electrostatic gates. At weak inter-dot coupling we clearly observe Pauli spin blockade and measure a large intra-dot singlet-triplet splitting > 1 meV. The leakage current in spin blockade has a peculiar magnetic field dependence, unrelated to electron-nuclear effects and consistent with the effect of spin-flip cotunneling processes. The results obtained here provide excellent prospects for realising singlet-triplet qubits.

Increased multidrug resistance-associated protein activity in mononuclear cells of patients with systemic lupus erythematosus.

UNLABELLED: Multidrug resistance-associated proteins (MRPs, ATP binding cassette sub-family C), P-glycoprotein (P-gp) and ATP binding cassette (ABC) sub-family G member 2 (ABCG2) are important drug efflux pumps emerging after long-term medications. We intended to detect whether these molecules are expressed in immune-related cells of patients with systemic lupus erythematosus (SLE) on long-term immunosuppressants. METHODS: Mono nuclear cells (MNC) and polymorphonuclear neutrophils (PMN) were isolated from healthy volunteers and SLE patients. The MPR-mediated transport activity of these cells was measured by using carboxy-2',7'-dichlorofluorescein diacetate (CFDA) efflux assay. P-gp-mediated transport activity of cells was detected by rhodamine 123 efflux assay. ABCG2-mediated transport assay was evaluated by mitoxantrone efflux assay. The intracellular expression of MRP1, MRP2, and MRP3 molecules in MNC was detected by flow cytometry. The results were compared between MNC and PMN derived from normal and SLE groups. RESULTS: The specific dye-efflux function of MRPs in SLE-MNC is significantly higher than normal MNC. However, the expression of MRP1, MRP2, and MRP3 molecules in SLE-MNC was not different from normal MNC. We also noted that only the duration of corticosteroid treatment in different clinical/laboratory parameters was significantly correlated with the increased activity of MRPs in SLE-MNC. CONCLUSIONS: These results suggest that increased activity of MRPs in SLE-MNC is elicited by long-term corticosteroid therapy.