Akt is a protein serine/threonine kinase that is involved in the regulation of diverse cellular processes. Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full ...activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells. Akt was shown to associate with ectopically expressed B55α subunit in NIH3T3 cells. The direct interaction between B55α subunit and Akt was confirmed using in vitro pulldown analyses. Intriguingly, we found that overexpression of B55α subunit significantly impaired phosphorylation at Thr-308, but to a lesser extent at Ser-473 of Akt in both FL5.12 and NIH3T3 cells. Concomitantly, phosphorylation of a subset of Akt substrates, including FoxO3a, was substantially decreased by B55α overexpression in these cells. Silencing of B55α expression markedly increased phosphorylation at Thr-308 but not at Ser-473 in both FL5.12 cells and NIH3T3 cells. Consistently, PP2A AB55αC holoenzymes preferentially dephosphorylated phospho-Thr-308 rather than phospho-Ser-473 in in vitro dephosphorylation assays. Furthermore, B55α overexpression retarded proliferation of NIH3T3 cells, and knockdown of B55α expression increased survival of FL5.12 cells upon interleukin-3 deprivation. Together, our data demonstrate that B55α-dependent targeting of the PP2A holoenzyme to Akt selectively regulates Akt phosphorylation at Thr-308 to regulate cell proliferation and survival.
Abstract
One recent study showed that atomoxetine-oxybutynin combination (AOC) use is effective in reducing obstructive sleep apnea (OSA) severity. We used a nationwide database to examine the ...association between AOC use and the risk of OSA incidence. This retrospective cohort study used Taiwan’s National Health Insurance Research Database between the years 2000 and 2015. The patients who used atomoxetine or oxybutynin were included as an exposed cohort. The exposed and unexposed groups were selected in a ratio of 1:3 with sex, age, and index year matching. We used the multivariate Cox proportional regression model to evaluate the association between AOC use and the risk of an incident diagnosis of OSA. The incidence rates of OSA in the exposed cohort (N = 8940) and the unexposed cohort (N = 26,820), were 21.92 and 22.93 per 100,000 person-years, respectively. The adjusted hazard ratio of oxybutynin use only and AOC with a treatment duration of ≥ 366 days were 0.307 (95% CI 0.204–0.995,
P
= 0.045) and 0.299 (95% CI 0.102–0.933,
P
= 0.002), respectively. Long-term atomoxetine-oxybutynin combination therapy may be beneficial to reduce the risk of obstructive sleep apnea. Further studies to examine these mechanisms are warranted.
A novel non-porous separator that possesses an outstanding lithium transference number (0.92) and effectively suppresses lithium dendrite formation upon lithium deposition is developed. The separator ...is made of triblock copolymer poly(styrene-block-isoprene-block-sulfonated isoprene) bearing pendant lithium sulfonates and, while taking up only 30 wt% liquid electrolyte (1 M Lithium hexafluorophosphate in ethylene carbonate/diethyl carbonate/ethyl methyl carbonate (v/v/v = 4/3/3)), it allows a high ion conductivity of 10−4 S cm−1. With good mechanical strength and processing feasibility, the new non-porous separator is shown to enable dendrite-free lithium electro-deposition and stripping with flat overpotential profiles upon prolonged galvanostatic cycling of the lithium symmetrical cells in the carbonate-based electrolyte.
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•Single ion conducting triblock copolymer is synthesized via anionic polymerization.•SII membrane exhibits an interpenetrated bicontinuous network microstructure.•SII-LE membrane shows high conductivity and high TLi+ at room temperature.•More than 500 h lithium cycle life time is achieved upon galvanostatic cycling.•SII-LE membrane stabilized lithium electrodeposition.
Background and Aims. Dementia with Lewy bodies (DLB) is the third most common form of dementia. Epidemiological studies of DLB in Taiwan are scarce. In this study, we estimated the incidence of DLB ...and comorbidity in the population of Taiwan. Methods. Data were obtained from the Taiwan National Health Insurance Research Database (NHIRD). DLB patients between 2000 and 2013 were enrolled in assessments of incidence and comorbidity. Results. The incidence of DLB was shown to be 7.10 per 100,000 person-years (95% CI = 6.63–7.59), which increased with age. The average age at diagnosis was 76.3, and this was higher for males than for females. The comorbidity rates of hypertension and hyperlipidemia in DLB patients were higher in females than in males. Conclusions. Epidemiologic data from large-scale retrospective studies is crucial to the prevention of DLB.
This retrospective cohort study aimed to evaluate the association between acetylcholinesterase inhibitors (AChEI) usage and the risk of lung cancer. Data from 116,106 new users of AChEI and 348,318, ...at a ratio of 1:3, matched by age, sex, and index-year, between 2000 and 2015 controls were obtained from the Taiwan Longitudinal Health Insurance Database in this cohort study. The Cox regression model was used to compare the risk of lung cancer. The adjusted hazard ratio (aHR) of lung cancer for AChEI users was 1.198 (95% confidence interval CI = 0.765-1.774, p = 0.167). However, the adjusted HR for patients aged ≥ 65 was adjusted to HR: 1.498 (95% CI = 1.124-1.798, p < 0.001), in contrast to the comparison groups. In addition, patients with comorbidities such as pneumonia, bronchiectasis, pneumoconiosis, pulmonary alveolar pneumonopathy, hypertension, stroke, coronary artery disease, diabetes mellitus, chronic kidney disease, depression, anxiety, smoking-related diseases, dementia, and seeking medical help from medical centers and regional hospitals, were associated with a higher risk in lung cancer. Furthermore, longer-term usage of rivastigmine (366-730 days, ≥ 731 days) and galantamine (≥ 731 days) was associated with the risk of lung cancer. AChEI increased the risk of lung cancer in the older aged patients, several comorbidities, and a longer-term usage of rivastigmine and galantamine. Therefore, physicians should estimate the risks and benefits of AChEI usage and avoid prescribing antidepressants concurrently.
Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis and annually infects approximately 276 million people worldwide. We observed an ambiguously higher probability of ...trichomoniasis in patients from the psychiatric department of Tri-Service General Hospital. Herein, we aimed to investigate the association between trichomoniasis and the risk of developing psychiatric disorders.
The nationwide population-based study utilized the database of the National Health Insurance (NHI) programme in Taiwan. A total of 46,865 subjects were enrolled in this study from 2000-2013, comprising 9373 study subjects with trichomoniasis and 37,492 subjects without trichomoniasis as the control group. Cox proportional hazards regression analysis was performed to calculate the hazard ratio (HR) of psychiatric disorders during the 14 years of follow-up.
Of the study subjects with trichomoniasis, 875 (9.34%) developed psychiatric disorders compared with 1988 (5.30%) in the control group (P < 0.001). The adjusted hazard ratio (aHR) of overall psychiatric disorders in the study subjects was 1.644 (95% confidence interval, CI: 1.514-1.766; P < 0.001). More specifically, the study subjects had a higher risk for developing an individual psychiatric disorder, including depression, anxiety, bipolar disorder, schizophrenia and substance abuse. Although metronidazole treatment reduced the risk for developing several subgroups of psychiatric disorders, significant reduction was detected for depression only. Furthermore, refractory trichomoniasis (trichomoniasis visits ≥ 2) enhanced the risk of psychiatric disorders.
We show herein that T. vaginalis infection increases the overall risk for psychiatric disorders. The novel role of T. vaginalis in developing psychiatric disorders deserves more attention, and the control of such a neglected pathogen is of urgent public health importance.
Nasal spray vaccination is viewed as a promising strategy for inducing both mucosal and systemic protection against respiratory SARS-CoV-2 coronavirus. Toward this goal, a safe and efficacious ...mucosal adjuvant is necessary for the transportation of the antigen across the mucosal membrane and antigen recognition by the mucosal immune system to generate broad-spectrum immune responses. This study describes the immunological aspects of SARS-CoV-2 spike (S)-protein after being formulated with CpG oligodeoxynucleotides (ODNs) and squalene nanoparticles (termed PELC). Following intranasal delivery in mice, higher expression levels of major histocompatibility complex (MHC) class II and costimulatory molecules CD40 and CD86 on CD11c
cells were observed at the draining superficial cervical lymph nodes in the CpG-formulated S protein group compared with those vaccinated with S protein alone. Subsequently, the activated antigen-presenting cells downstream modulated the cytokine secretion profiles and expanded the cytotoxic T lymphocyte activity of S protein-restimulated splenocytes. Interestingly, the presence of PELC synergistically enhanced cell-mediated immunity and diminished individual differences in S protein-specific immunogenicity. Regarding humoral responses, the mice vaccinated with the PELC:CpG-formulated S protein promoted the production of S protein-specific IgG in serum samples and IgA in nasal and bronchoalveolar lavage fluids. These results indicate that PELC:CpG is a potential mucosal adjuvant that promotes mucosal/systemic immune responses and cell-mediated immunity, a feature that has implications for the development of a nasal spray vaccine against COVID-19.
DNA vaccines for infectious diseases and cancer have been explored for years. To date, only one DNA vaccine (ZyCoV-D) has been authorized for emergency use in India. DNA vaccines are inexpensive and ...long-term thermostable, however, limited by the low efficiency of intracellular delivery. The recent success of mRNA/lipid nanoparticle (LNP) technology in the coronavirus disease 2019 (COVID-19) pandemic has opened a new application for nucleic acid-based vaccines. Here, we report that plasmid encoding a trimeric spike protein with LNP delivery (pTS/LNP), similar to those in Moderna’s COVID-19 vaccine, induced more effective humoral responses than naked pTS or pTS delivered via electroporation. Compared with TSmRNA/LNP, pTS/LNP immunization induced a comparable level of neutralizing antibody titers and significant T helper 1-biased immunity in mice; it also prolonged the maintenance of higher antigen-specific IgG and neutralizing antibody titers in hamsters. Importantly, pTS/LNP immunization exhibits enhanced cross-neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and protects hamsters from the challenge of SARS-CoV-2 (Wuhan strain and the Omicron BA.1 variant). This study indicates that pDNA/LNPs as a promising platform could be a next-generation vaccine technology.
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Liu and colleagues introduce a DNA vaccine delivery system with easy administration using LNPs. This study highlights prolonged protein expression, robust humoral responses, and increased protection against viral challenges, including the Omicron variant. This DNA/LNP vaccine technology promises a potent alternative to current mRNA-based vaccines.
Renal function is a key factor of cardiovascular disease. Carotid intima-media thickness (IMT) has been widely used as a marker of early subclinical atherosclerosis. The determinants of cystatin C, a ...novel marker of renal function, have not been extensively studied in the Asian population. This study aimed to assess the determinants of cystatin C and explore whether carotid thickening was associated with urinary albumin-creatinine ratio and cystatin C in community-living Taiwanese adults.
A cross-sectional study was conducted on participants from Taichung City, Taiwan. All the participants underwent carotid ultrasonography. Carotid IMT-mean and IMT-maximum were derived. Kidney biomarkers were measured on the basis of urinary albumin-to-creatinine ratio (ACR) and cystatin C. Multiple linear regression analysis was used.
A total of 1032 individuals were recruited, and 469 (45.44%) of them were men. An increased cystatin C level was significantly associated with older age, male gender, lack of physical activity, low HDL cholesterol, abdominal obesity, high hs-CRP, and high ACR. The multivariate-adjusted mean carotid IMT-mean and IMT-maximum values significantly increased by 80.49 and 195.23 μm for every one unit of increase in cystatin C level and by 0.07 and 0.14 μm for every one unit of increase in ACR, respectively (all p < 0.001 except ACR on IMT-maximum with p < 0.01). Lack of physical activity, low HDL, abdominal obesity, high hs-CRP, and high ACR were the determinants of cystatin C.
Cystatin C and ACR were strongly and linearly associated with carotid thickening, a marker of subclinical atherosclerosis.
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