•lincRNAs are transcripts from non-coding DNA.•We found that IL-6 and TNF-α regulate different types of lincRNAs in vivo.•Our data suggest a role for lincRNA in the pathophysiology of RA.•Our data ...indicate lincRNAs to be specifically regulated by pharmaceutical agents.
lincRNAs recently have been discovered as evolutionary conserved transcripts of non-coding DNA sequences and have been implicated in the regulation of cellular differentiation. In humans, molecular studies have suggested a functional role for lincRNAs in cancer development. The aim of the present study was to examine whether these novel molecules are specifically regulated by different cytokines in cells of the innate immune system in humans in vivo and whether lincRNAs thereby might be involved in the pathophysiology of rheumatoid arthritis (RA). Therefore, CD14+ monocytes were isolated from RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-α (adalimumab) therapy and lincRNA transcription was analysed by a microarray based experiment. As expected, we found lincRNAs to be present in CD14+ monocytes of RA patients. However, of the total number of 7.419 lincRNAs examined in this study only a very small number was significantly regulated by either IL-6 or TNF-α (85 lincRNAs, corresponding to 1.1%). The numbers of lincRNAs regulated was higher due to TNF-α compared to IL-6. Interestingly, none of the identified lincRNAs was influenced by both, IL-6 and TNF-α, suggesting the regulation of lincRNA transcription to be highly specific for distinct cytokines. Taken together, our results suggest (1) that lincRNAs are novel intracellular molecular effectors of specific cytokines in cells of the innate immune system in humans in vivo and (2) that lincRNAs might be involved in the molecular pathophysiology of RA.
Aim
Recombinant secreted frizzled‐related protein 5 (sFRP5) improved periodontal status in mice. Thus, this study aimed to investigate this finding in human periodontitis using an epidemiological ...approach.
Materials and Methods
sFRP5 and wnt5a concentrations were determined in human serum from the Food Chain Plus cohort using ELISAs. A total of 128 patients with periodontitis and tooth loss and 245 patients with periodontitis without tooth loss were compared to 373 sex‐, smoker‐, age‐ and BMI‐matched individuals in a nested case–control design.
Results
Systemic sFRP5 serum levels were significantly lower in patients with periodontitis and tooth loss (2.5 0.0–10.4 ng/ml, median IQR) compared to patients with periodontitis without tooth loss (6.0 2.5–15.8 ng/ml, median IQR, p = 0.04 and matched controls (7.0 2.5–18.3 ng/ml, median IQR, p = 0.02). No significant differences in sFRP5 serum levels were found among patients with periodontitis without tooth loss (6.0 2.5–15.8 ng/ml, median IQR) and controls (3.1 0.0–10.6 ng/ml, median IQR, p = 0.06).
Conclusions
sFRP5 might serve as a novel biomarker for periodontitis severity. Modulating the inflammatory background of severe forms of periodontitis, in the time of precision medicine, needs to be revealed in further studies.
There are several meta-analyses of treatment effects for children and adolescents with attention deficit hyperactivity disorder (ADHD). The conclusions of these meta-analyses vary considerably. Our ...aim was to synthesize the latest evidence of the effectiveness of psychological, pharmacological treatment options and their combination in a systematic overview and meta-meta-analyses. A systematic literature search until July 2022 to identify meta-analyses investigating effects of treatments for children and adolescents with ADHD and ADHD symptom severity as primary outcome (parent and teacher rated) yielded 16 meta-analyses for quantitative analyses. Meta-meta-analyses of pre-post data showed significant effects for pharmacological treatment options for parent (SMD = 0.67, 95% CI 0.60 to 0.74) and teacher ADHD symptom ratings (SMD = 0.68, 95% CI 0.54 to 0.82) as well as for psychological interventions for parent (SMD = 0.42, 95% CI 0.33 to 0.51) and teacher rated symptoms (SMD = 0.25, 95% CI 0.12 to 0.38). We were unable to calculate effect sizes for combined treatments due to the lack of meta-analyses. Our analyses revealed that there is a lack of research on combined treatments and for therapy options for adolescents. Finally, future research efforts should adhere to scientific standards as this allows comparison of effects across meta-analyses.
•Psychological and pharmacological treatment options seem to effectively reduce ADHD symptoms in childhood.•There is a dearth of studies on combined treatment options for ADHD.•ADHD research should focus on developing and evaluating interventions for youth.•Meta-analyses need international standardization regarding conducting and reporting.
The benthic boundary layer plays a crucial role in the exchange of trace metals between surface sediments and the water column. So far it has been difficult to study dissolved–particulate ...interactions of trace metals in this highly reactive interface layer due to the lack of suitable sampling methods. We developed a new device, called Benthic Trace Profiler (BTP), which enables simultaneous sampling of near‐bottom water and suspended particles in high depth resolution within the first 3 m above the seafloor. The device was tested successfully in the Baltic Sea. The concentrations of several trace metals (Co, Ni, Cu, Zn, and Cd) in the collected bottom waters overlapped with concentrations in water column samples above collected with conventional methods. This observation indicates that the sampling device and method is trace metal clean. The trace metals Fe and Mn showed concentration gradients within the benthic boundary layer indicating an upward diffusive flux. This observation is consistent with a diffusive benthic flux of these trace metals across the sediment–water interface, which was independently verified using pore‐water profiles. Suspended particles can be used to study precipitation processes and to determine the carrier phases of trace metals. The BTP fulfilled all the intended requirements as it allowed a simultaneous, uncontaminating and oxygen‐free sampling of seawater and suspended particles to gather high‐resolution profiles of dissolved and particulate trace metal concentrations above the seafloor. The device closes the gap between water column and sediment sampling and helps researchers to better understand trace metal exchange processes across the ocean's lower boundary.
Osteoclasts form special integrin-mediated adhesion structures called sealing zones that enable them to adhere to and resorb bone. Sealing zones consist of densely packed podosomes tightly ...interconnected by actin fibers. Their formation requires the presence of the hematopoietic integrin regulator kindlin-3 (also known as Fermt3). In this study, we investigated osteoclasts and their adhesion structures in kindlin-3 hypomorphic mice expressing only 5-10% of the kindlin-3 level of wild-type mice. Low kindlin-3 expression reduces integrin activity, results in impaired osteoclast adhesion and signaling, and delays cell spreading. Despite these defects, in vitro-generated kindlin-3-hypomorphic osteoclast-like cells arrange their podosomes into adhesion patches and belts, but their podosome and actin organization is abnormal. Remarkably, kindlin-3-hypomorphic osteoclasts form sealing zones when cultured on calcified matrix in vitro and on bone surface in vivo. However, functional assays, immunohistochemical staining and electron micrographs of bone sections showed that they fail to seal the resorption lacunae properly, which is required for secreted proteinases to digest bone matrix. This results in mild osteopetrosis. Our study reveals a new, hitherto understudied function of kindlin-3 as an essential organizer of integrin-mediated adhesion structures, such as sealing zones.
Powered exoskeletons are a promising approach to restore the ability to walk after spinal cord injury (SCI). However, current exoskeletons remain limited in their walking speed and ability to support ...tasks of daily living, such as stair climbing or overcoming ramps. Moreover, training progress for such advanced mobility tasks is rarely reported in literature. The work presented here aims to demonstrate the basic functionality of the VariLeg exoskeleton and its ability to enable people with motor complete SCI to perform mobility tasks of daily life.
VariLeg is a novel powered lower limb exoskeleton that enables adjustments to the compliance in the leg, with the objective of improving the robustness of walking on uneven terrain. This is achieved by an actuation system with variable mechanical stiffness in the knee joint, which was validated through test bench experiments. The feasibility and usability of the exoskeleton was tested with two paraplegic users with motor complete thoracic lesions at Th4 and Th12. The users trained three times a week, in 60 min sessions over four months with the aim of participating in the CYBATHLON 2016 competition, which served as a field test for the usability of the exoskeleton. The progress on basic walking skills and on advanced mobility tasks such as incline walking and stair climbing is reported. Within this first study, the exoskeleton was used with a constant knee stiffness.
Test bench evaluation of the variable stiffness actuation system demonstrate that the stiffness could be rendered with an error lower than 30 Nm/rad. During training with the exoskeleton, both users acquired proficient skills in basic balancing, walking and slalom walking. In advanced mobility tasks, such as climbing ramps and stairs, only basic (needing support) to intermediate (able to perform task independently in 25% of the attempts) skill levels were achieved. After 4 months of training, one user competed at the CYBATHLON 2016 and was able to perform 3 (stand-sit-stand, slalom and tilted path) out of 6 obstacles of the track. No adverse events occurred during the training or the competition.
Demonstration of the applicability to restore ambulation for people with motor complete SCI was achieved. The CYBATHLON highlighted the importance of training and gaining experience in piloting an exoskeleton, which were just as important as the technical realization of the robot.
MK5 (MAPK-activated protein kinase 5) or PRAK (p38-regulated and -activated kinase) are alternative names for a serine/threonine protein kinase downstream to ERK3/4 and p38 MAPK. A previous gene ...targeting approach for MK5/PRAK (termed here MK5/PRAK-Δex8) revealed a seemingly tumor-suppressive role of MK5/PRAK in DMBA-induced one step skin carcinogenesis and Ras-induced transformation. Here we demonstrate that an alternative targeting strategy of MK5/PRAK (termed MK5/PRAK-Δex6) increased neither tumor incidence in the one step skin carcinogenesis model, nor Ras-induced transformation in primary cells. Interestingly, due to the targeting strategies and exon skipping both knockouts do not completely abolish the generation of MK5/PRAK protein, but express MK5/PRAK deletion mutants with different biochemical properties depending on the exon targeted: Targeting of exon 6 leads to expression of an unstable cytoplasmic catalytically inactive MK5/PRAK-Δex6 mutant while targeting of exon 8 results in a more stable nuclear MK5/PRAK-Δex8 mutant with residual catalytic activity. The different properties of the MK5/PRAK deletion mutants could be responsible for the observed discrepancy between the knockout strains and challenge the role of MK5/PRAK in p53-dependent tumor suppression. Further MK5/PRAK knockout and knock-in mouse strains will be necessary to assign a physiological function to MK5/PRAK in this model organism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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