Summary
The desmosome is a type of intercellular junction found in epithelial cells, cardiomyocytes and other specialized cell types. Composed of a network of transmembranous cadherins and ...intracellular armadillo, plakin and other proteins, desmosomes contribute to cell–cell adhesion, signalling, development and differentiation. Mutations in genes encoding desmosomal proteins result in a spectrum of erosive skin and mucosal phenotypes that also may affect hair or heart. This review summarizes the molecular pathology and phenotypes associated with desmosomal dysfunction with a focus on inherited disorders that involve the skin/hair, as well as associated extracutaneous pathologies. We reviewed the relevant literature to collate studies of pathogenic human mutations in desmosomes that have been reported over the last 25 years. Mutations in 12 different desmosome genes have been documented, with mutations in nine genes affecting the skin/mucous membranes (DSG1, DSG3, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP) and eight resulting in hair abnormalities (DSG4, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP). Mutations in three genes can result in cardiocutaneous syndromes (DSC2, JUP, DSP), although mutations have been described in five genes in inherited heart disorders that may lack any dermatological manifestations (DSG2, DSC2, JUP, PKP2, DSP). Understanding the diverse nature of these clinical phenotypes, as well as the desmosome gene mutation(s), has clinical value in managing and counselling patients, as well as demonstrating the biological role and activity of specific components of desmosomes in skin and other tissues.
Air pollution is a key global environmental problem raising human health concern. It is essential to comprehensively assess the long-term characteristics of air pollution and the resultant health ...impacts. We first assessed the global trends of fine particulate matter (PM2.5) during 1980–2020 using a monthly global PM2.5 reanalysis dataset, and evaluated their association with three types of climate variability including El Niño-Southern Oscillation, Indian Ocean Dipole and North Atlantic Oscillation. We then estimated PM2.5-attributable premature deaths using integrated exposure–response functions. Results show a significant increasing trend of ambient PM2.5 during 1980–2020 due to increases in anthropogenic emissions. Ambient PM2.5 caused a total of ∼ 135 million premature deaths globally during the four decades. Occurrence of air pollution episodes was strongly associated with climate variability, which were associated with up to 14 % increase in annual global PM2.5-attributable premature deaths.
Aim
To investigate the effect of simvastatin on lipopolysaccharide (LPS)‐stimulated inflammatory cytokines, cell adhesion molecules and nuclear factor‐κB (NF‐κB) transcription factors in human dental ...pulp cells (HDPCs).
Methodology
The effect of LPS and simvastatin on human dental pulp cell (HDPCs) viability was measured using a 3‐4, 5‐dimethylthiazol‐2‐yl‐2, 5 diphenyltetrazolium bromide (MTT) assay. The expression of inflammatory cytokines and cell adhesion molecules was evaluated by reverse‐transcription polymerase chain reaction (RT‐PCR), enzyme‐linked immunosorbent assay (ELISA) and Western blot analysis. NF‐κB transcription factors were evaluated by Western blot analysis. Statistical analysis was performed with analysis of variance (anova).
Results
The viability of cells exposed to different concentrations of E. coli LPS, P. gingivalis LPS and simvastatin was not significantly different compared with that of control cells (P > 0.05). LPS significantly increased interleukin (IL)‐1β (P < 0.05) and IL‐6 mRNA expression (P < 0.05) and vascular cell adhesion molecule‐1 (VCAM‐1) (P < 0.05) and intercellular adhesion molecule‐1 (ICAM‐1) protein expression (P < 0.05) in HDPCs. Treatment with simvastatin significantly attenuated LPS‐stimulated production of IL‐1β, IL‐6, VCAM‐1 and ICAM‐1 (P < 0.05). Treatment with simvastatin decreased LPS‐induced expression of p65 and phosphorylation of IκB and also significantly decreased the phosphorylation of p65 and IκB in the cytoplasm and the level of p65 in the nucleus (P < 0.05).
Conclusions
Simvastatin has a suppressing effect on LPS‐induced inflammatory cytokine, cell adhesion molecules and NF‐κB transcription factors in HDPCs. Therefore, simvastatin might be a useful candidate as a pulp‐capping agent in vital pulp therapy.
ABSTRACT
Many scientific investigations of photometric galaxy surveys require redshift estimates, whose uncertainty properties are best encapsulated by photometric redshift (photo-z) posterior ...probability density functions (PDFs). A plethora of photo-z PDF estimation methodologies abound, producing discrepant results with no consensus on a preferred approach. We present the results of a comprehensive experiment comparing 12 photo-z algorithms applied to mock data produced for The Rubin Observatory Legacy Survey of Space and Time Dark Energy Science Collaboration. By supplying perfect prior information, in the form of the complete template library and a representative training set as inputs to each code, we demonstrate the impact of the assumptions underlying each technique on the output photo-z PDFs. In the absence of a notion of true, unbiased photo-z PDFs, we evaluate and interpret multiple metrics of the ensemble properties of the derived photo-z PDFs as well as traditional reductions to photo-z point estimates. We report systematic biases and overall over/underbreadth of the photo-z PDFs of many popular codes, which may indicate avenues for improvement in the algorithms or implementations. Furthermore, we raise attention to the limitations of established metrics for assessing photo-z PDF accuracy; though we identify the conditional density estimate loss as a promising metric of photo-z PDF performance in the case where true redshifts are available but true photo-z PDFs are not, we emphasize the need for science-specific performance metrics.
This study evaluates the applicability of electric arc furnace (EAF) oxidising slag as a concrete aggregate for structural members. The test variables are designed to the types of aggregates and ...axial loads. A total of six reinforced concrete columns subjected to reversed cyclic antisymmetric moment are tested in flexure. From experimental results, flexural strength of specimens with EAF oxidising slag aggregates is similar to that of specimens with natural aggregates regardless of axial loads. Furthermore, it can be founded from test results that ductility capacity of slag aggregate specimens is superior to that of natural aggregate specimens.
Although chronic obstructive pulmonary disease (COPD) is a common form of structural lung disease associated with pulmonary non-tuberculous mycobacteria (NTM) infection, no longitudinal studies have ...investigated the role of NTM in COPD disease progression.
From 2000 to 2008, spirometry-confirmed COPD patients with sputum specimens sent for mycobacterial cultures were included. Analysis of clinical, microbiological and pulmonary function data was performed.
The 251 patients were divided into three groups according to the number of NTM isolates: multiple (n = 47), single (n = 63), and no (n = 141) isolates. Mycobacterium avium complex was the most common species in multiple isolates (36.2%) and single isolate (28.6%) groups. Overall, 24.7% of COPD patients had been admitted for exacerbations at least once a year, and patients with multiple and single NTM isolates were more than twice as likely as those with no isolate to experience such exacerbations (38.3% vs. 31.7% vs. 17.0%). After controlling for confounders, patients with multiple NTM isolates had a greater decline in forced expiratory volume in one second than those with single or no isolates (-79.4 ± 32.8 ml vs. -61.6 ± 31.9 ml and -56.2 ± 31.5 ml).
This study suggests that NTM may play a role in disease progression and deterioration of pulmonary function in COPD patients.
Whether the vaccine adjuvant potential of acute exercise is uniform among different populations, e.g., inactive persons, is unknown. This meta-analysis examines influenza vaccine antibody responses ...and the effect of physical activity, acute exercise, and their interaction. Inclusion criteria comprised randomized controlled trials with acute exercise intervention and influenza vaccination antibody measurements at baseline and 4-6 weeks, and participant baseline physical activity measurement; there were no exclusion criteria. Searching via six databases (Medline, Embase, CINAHL, Scopus, Web of Science, and Physiotherapy Evidence) and two clinical registries (WHO and NIH), nine studies were identified and assessed with the Cochrane revised risk-of-bias tool. Data analysis comprised one-stage random-effects generalized linear mixed-effects models with random intercept. Seven of nine identified studies, all of high risk of bias, provided data for 550 included participants. Clinical measures of antibody response tended to be higher in the acute-exercised participants compared to rested controls and physically active compared to inactive. Physical activity significantly increased H1 strain seroconversion (adjusted odds ratio (aOR) 1.69, 95%CI: 1.02-2.82) among all participants and titer response (aOR 1.20, 95%CI: 1.03-1.39) among the acute exercise group. Increasing age frequently reduced immunogenic responses whereas body mass index and sex had little-to-no effect. Adjuvant effects were more pronounced with interventions exercising the same arm in which the vaccination was administered. H1 response was increased by both physical activity and the acute exercise-physical activity interaction. Given the observed modifications by age and the subset analysis suggesting the benefit is more pronounced in older populations, future attention is due for acute exercise-PA interactions to impact vaccination response in the at-risk population of older adults. Further, we identify localized exercise as the likely most-effective protocol and encourage its use to augment the available evidence.
Background
There are few studies on the association between nutrient intake and telomere length, which may reflect cumulative oxidative stress and indicate biological ageing. In the present study, we ...evaluated longitudinal associations between the consumption of micronutrients, including antioxidant nutrients and B vitamins involved in one‐carbon transfer pathways, and leukocyte telomere length (LTL).
Methods
The study included 1958 middle‐aged and older Korean men and women (age range at baseline: 40–69 years) from a population‐based cohort. We collected dietary information at baseline using a semiquantitative food frequency questionnaire (June 2001 to January 2003) and assessed the consumption of micronutrients, including vitamins A, B1, B2, B3, B6, B9 (folate), C and E, as well as calcium, phosphorus, potassium, iron and zinc. We measured LTL using a real‐time polymerase chain reaction at the 10‐year follow‐up examination (February 2011 to November 2012).
Results
In the multiple regression model adjusted for potential confounders, LTL was positively associated with the consumption of vitamin C (P < 0.05), folate (P = 0.05) and potassium (P = 0.05) in all participants. In the age‐stratified analysis, the association between the consumption of vitamin C (P < 0.01), folate (P < 0.05) and potassium (P < 0.05) with LTL was significant only among participants aged <50 years.
Conclusions
Our findings suggest that the earlier consumption of vitamin C, folate and potassium, which are abundant in fruits and vegetables, can delay biological ageing in middle‐aged and older adults.
Epidemiologic data on the etiologic organisms is important for appropriate empirical antibiotic treatment of bacterial meningitis. We identified the etiologies of community-acquired bacterial ...meningitis in Korean adults and the associated epidemiological factors. A retrospective, multicenter nationwide study was carried out. Patients 18 years of age or older with community-acquired bacterial meningitis with a confirmed pathogen were enrolled. Demographic, clinical, and microbiological data were collected. One hundred and ninety-five cases were collected. Streptococcus pneumoniae was the most common pathogen (50.8%), followed by Staphylococcus aureus (10.3%), Klebsiella pneumoniae (7.7%), Listeria monocytogenes (6.7%), and group B Streptococcus (3.1%). The penicillin resistance rate of the S. pneumoniae was 60.3%; 40.0% of the organisms were not susceptible to third-generation cephalosporins. The combination of third-generation cephalosporin with vancomycin was used in 76.3% of cases. Steroids were given before or with the first dose of antibiotics in 37.4% of patients. The 30-day mortality rate was 20.5% and neurological sequelae developed in 15.6% of cases. S. pneumoniae was the most common organism identified in community-acquired bacterial meningitis among Korean adults. S. aureus, K. pneumoniae, L. monocytogenes, and group B Streptococcus were also common. S. pneumoniae had high rates of resistance to penicillin and third-generation cephalosporins.
Lymph node metastasis is one of the most important adverse prognostic factors for pancreatic cancer. The aim of this study was to identify novel lymphatic metastasis-associated markers and ...therapeutic targets for pancreatic cancer.
DNA microarray study was carried out to identify genes differentially expressed between 17 pancreatic cancer tissues with lymph node metastasis and 17 pancreatic cancer tissues without lymph node metastasis. The microarray results were validated by real-time PCR. Immunohistochemistry and western blotting were used to examine the expression of farnesoid X receptor (FXR). The function of FXR was studied by small interfering RNA and treatment with FXR antagonist guggulsterone and FXR agonist GW4064.
Farnesoid X receptor overexpression in pancreatic cancer tissues with lymph node metastasis is associated with poor patient survival. Small interfering RNA-mediated downregulation of FXR and guggulsterone-mediated FXR inhibition resulted in a marked reduction in cell migration and invasion. In addition, downregulation of FXR reduced NF-κB activation and conditioned medium from FXR siRNA-transfected cells showed reduced VEGF levels. Moreover, GW4064-mediated FXR activation increased cell migration and invasion.
These findings indicated that FXR overexpression plays an important role in lymphatic metastasis of pancreatic cancer and that downregulation of FXR is an effective approach for inhibition of pancreatic tumour progression.
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