The objective of this study is to determine the risk of tuberculosis (TB) disease in biologics users among rheumatoid arthritis (RA) patients in Taiwan from 2000 to 2015. This retrospective cohort ...study enrolled adult RA patients initiated on first biologics at Taichung Veterans General Hospital. TB risks were determined as hazard ratio (HR) with 95% confidence interval (CI) using cox regression. A total of 951 patients were recruited; etanercept (n = 443), adalimumab (n = 332), abatacept (n = 74), golimumab (n = 60), tocilizumab (n = 31) and tofacitinib (n = 11). Twenty-four TB cases were identified; 13 in etanercept and 11 in adalimumab group with the TB incidence rate of 889.3/ 100,000 and 1055.6/ 100,000 patient-years respectively. There was no significant difference in TB risk between adalimumab and etanercept users with an incidence rate ratio of 1.27 (p = 0.556 by Poisson model). Significant 2-year TB risk factors included elderly patient >65 year-old (HR: 2.72, 95% CI: 1.06-6.99, p = 0.037), history of TB (HR: 6.24, 95% CI: 1.77-22.00, p = 0.004) and daily glucocorticoid use ≥5mg (HR:5.01, 95% CI: 1.46-17.21, p = 0.010). Sulfasalazine treatment appeared to be protective (HR: 0.32, 95% CI: 0.11-0.97, p = 0.043). Risk management plan (RMP) for TB before initiation of biologics commenced in 2012. The 2-year TB risks after RMP was compared with that before 2012 (HR:0.67, 95% CI: 0.30-1.49, p = 0.323). Elderly RA patients with a history of previous TB infection and concomitant moderate dose glucocorticoid were at higher risk of TB disease. Concurrent sulfasalazine treatment appeared to be a protective factor against TB disease.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diet has a profound effect on tissue regeneration in diverse organisms, and low caloric states such as intermittent fasting have beneficial effects on organismal health and age-associated loss of ...tissue function. The role of adult stem and progenitor cells in responding to short-term fasting and whether such responses improve regeneration are not well studied. Here we show that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting. Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting, but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance. These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology, and they may represent a viable strategy for enhancing intestinal regeneration.
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•Fasting induces fatty acid oxidation (FAO) in intestinal stem and progenitor cells•Aging reduces ISC numbers and function, correlating with decreased FAO•PPAR/CPT1a-mediated FAO augments ISC function in aging and during regeneration•PPARδ agonists boost and restore ISC and progenitor function in young and old age
Mihaylova et al. show that short-term fasting promotes intestinal stem and progenitor cell function in young and aged mice by inducing a robust fatty acid oxidation (FAO) program. PPARδ agonists emulate these effects, showing that fatty acid metabolism has positive effects on young and old ISCs.
Over a period that includes the 1998 Russian crisis and 2007–2009 financial crisis,banks with overconfident chief executive officers (CEOs) were more likely to weaken lending standards and increase ...leverage than other banksin advance of a crisis,making them more vulnerable to the shock of the crisis.During crisis years, they generally experienced more increases in loan defaults, greater drops in operating and stock return performance, greater increases in expected default probability, and higher likelihood of CEO turnover or failure than other banks.CEO overconfidence thus canexplain the cross-sectional heterogeneity in risk-taking behavior among banks.
Alzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau ...neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear.
We screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology.
In summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Biomolecules that respond to different external stimuli enable the remote control of genetically modified cells. We report herein a sonogenetic approach that can manipulate target cell activities by ...focused ultrasound stimulation. This system requires an ultrasound-responsive protein derived from an engineered auditory-sensing protein prestin. Heterologous expression of mouse prestin containing two parallel amino acid substitutions, N7T and N308S, that frequently exist in prestins from echolocating species endowed transfected mammalian cells with the ability to sense ultrasound. An ultrasound pulse of low frequency and low pressure efficiently evoked cellular calcium responses after transfecting with prestin(N7T, N308S). Moreover, pulsed ultrasound can also noninvasively stimulate target neurons expressing prestin(N7T, N308S) in deep regions of mouse brains. Our study delineates how an engineered auditory-sensing protein can cause mammalian cells to sense ultrasound stimulation. Moreover, our sonogenetic tools will serve as new strategies for noninvasive therapy in deep tissues.
The major challenge in COVID‐19 vaccine effectiveness is immune escape by SARS‐CoV‐2 variants. To overcome this, an Omicron‐specific messenger RNA (mRNA) vaccine was designed. The extracellular ...domain of the spike of the Omicron variant was fused with a modified GCN4 trimerization domain with low immunogenicity (TSomi). After immunization with TSomi mRNA in hamsters, animals were challenged with SARS‐CoV‐2 virus. The raised nonneutralizing antibodies or cytokine secretion responses can recognize both Wuhan S and Omicron S. However, the raised antibodies neutralized SARS‐CoV‐2 Omicron virus infection but failed to generate Wuhan virus neutralizing antibodies. Surprisingly, TSomi mRNA immunization protected animals from Wuhan virus challenge. These data indicated that non‐neutralizing antibodies or cellular immunity may play a more important role in vaccine‐induced protection than previously believed. Next‐generation COVID‐19 vaccines using the Omicron S antigen may provide sufficient protection against ancestral or current SARS‐CoV‐2 variants.
Tea is the second most popular beverage in the world after water. Vast accumulative evidence attest that tea consumption may promote human health, such as antioxidant, anti-obesity, and anticancer ...activities. Therefore, tea phytochemicals have drawn exceeding attention from researchers in structure confirmation, formation mechanism, component clarification, and bioactivity screening of interested constituents. Particularly, most investigations of chemical or biochemical reactions of catechins have concentrated on the B ring of the C6–C3–C6 skeleton. Hence, in this perspective, we reviewed the profound findings of the carbon–carbon (C–C) connection from the unambiguous characterization of novel A-ring addition derivatives of tea catechins, including catechin–carbonyl and catechin–theanine conjugates and the C–C formation mechanisms, and offered our view of the potential effects of catechin–carbonyl interactions on flavor generation and bioactive action in tea.
Thoracic MRA displayed an absence of right renal artery flow without aorta narrowing (Figure 1C). ...there was no coronary artery involvement which was precluded as heart failure etiology. Heart ...failure in TA may result from various conditions, including pressure and volume overload, coronary arteritis, and myocarditis. 2 LV thrombus formation is rare, as reported in limited studies. 3,4 In this case, the fulminant course of acute heart failure was suspected due to sepsis-related cardiomyopathy superimposed on increased afterload. CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.
A self-assembled nanocomposite is prepared from an aqueous mixture of aptamer-modified gold nanoparticles (Apt–Au NPs), bismuth ions and chloride ions. The Apt–Au NPs are immobilized on bismuth ...oxychloride (BiOCl) nanosheets in situ to form Apt–Au NPs/BiOCl nanocomposites. The as-prepared nanocomposites exhibit high peroxidase-like activity for the catalytic conversion of Amplex Red (AR) to fluorescent resorufin in the presence of H2O2. The catalytic activity of Apt–Au NPs/BiOCl nanocomposites is at least 90-fold higher than that of Apt–Au NPs or BiOCl nanosheets, revealing synergistic effects on their activity. The catalytic activity of Apt–Au NPs/BiOCl nanocomposites is suppressed by vascular endothelial growth factor-A165 (VEGF-A165) molecules that specifically interact with the aptamer units (Del-5-1 and v7t-1) on the nanocomposite surface. The AR/H2O2–Apt–Au NPs/BiOCl nanocomposites probe shows high selectivity (>1000-fold over other proteins) and sensitivity (detection limit ~0.5nM) for the detection of VEGF-A165. Furthermore, the probe is employed for the detection of VEGF isoforms and for the study of interactions between VEGF and VEGF receptors. The practicality of this simple, rapid, cost-effective probe is validated by the analysis of VEGF-A165 in cell culture media, showing its great potential for the analysis of VEGF in biological samples.
Aptamer-modified gold nanoparticles (Apt–Au NPs) are immobilized onto bismuth oxychloride (BiOCl) nanosheets in situ to form Apt–Au NPs/BiOCl nanocomposites. The peroxidase-like activity of Apt–Au NPs/BiOCl nanocomposites is suppressed by vascular endothelial growth factor-A165 (VEGF-A165) molecules that specifically interact with the aptamer units on the nanocomposite surface.
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•Aptamer-modified gold nanoparticles are immobilized on BiOCl nanosheets.•The nanocomposites exhibit high peroxidase-like activity.•Catalytic activity of the nanocomposites is suppressed by VEGF.•Analysis of VEGF isoforms and their interaction to receptors.
Rheumatoid arthritis (RA) is associated with a high risk of osteoporosis and fracture. Interleukin (IL)-6 inhibitors may suppress osteoclast activation. Anticitrullinated protein antibody (ACPA) ...titers are inversely associated with bone mineral density (BMD). However, the differential effect of ACPA on bone turnover marker (BTM) and BMD changes after IL-6 inhibition remains unclear. This prospective study recruited patients with active RA with inadequate response to methotrexate or biologics. BMD was measured before and after 2-year tocilizumab (TCZ) treatment. Serum osteocalcin, N-terminal propeptide of type I collagen (P1NP), and C-terminal cross-linking telopeptide of type I collagen (CTX) levels were assessed at the baseline and after treatment. We enrolled 76 patients with RA (89.5% women, age: 57.2 ± 13.3 years) receiving TCZ. The 28-joint disease activity score was negatively correlated with BMD and T-scores of the lumbar spine and bilateral femoral neck. ACPA-positive patients had lower lumbar spine and femoral neck T-scores. After 2-year TCZ treatment, CTX levels significantly decreased (0.32 ± 0.21 vs. 0.26 ± 0.17, p = 0.038). Femoral neck BMD increased significantly (0.71 ± 0.22 vs. 0.69 ± 0.55, p = 0.008). Decreased CTX levels and improved BMD were observed only in ACPA-positive patients. After treatment, femoral neck BMD significantly increased only in patients receiving a glucocorticoid dose of ≥5 mg/day. Two-year TCZ treatment reduced bone resorption and increased femoral BMD in ACPA-positive patients. The net effects of glucocorticoids and IL-6 inhibition on BMD imply that strict inflammation control might affect bone metabolism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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