Abstract
Fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥ 200 CGG repeats, and a decrease in
FMR1
mRNA and its protein. However, incomplete silencing from ...FM alleles has been associated with more severe autism features in FXS males. This study compared scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-C
FX
) in 62 males affected with FXS (3 to 32 years) stratified based on presence or absence of mosaicism and/or
FMR1
mRNA silencing. Associations between ABC-C
FX
subscales and
FMR1
mRNA levels, assessed using real-time PCR relative standard curve method, were also examined. The FXS group mosaic for premutation (PM: 55–199 CGGs) and FM alleles had lower irritability (p = 0.014) and inappropriate speech (p < 0.001) scores compared to males with only FM alleles and complete loss of
FMR1
mRNA. The PM/FM mosaic group also showed lower inappropriate speech scores compared to the incomplete silencing (p = 0.002) group. Increased
FMR1
mRNA levels were associated with greater irritability (p < 0.001), and lower health-related quality of life scores (p = 0.004), but only in the incomplete silencing FM-only group. The findings suggest that stratification based on CGG sizing and
FMR1
mRNA levels may be warranted in future research and clinical trials utilising ABC-C
FX
subscales as outcome measures.
Abstract
Objective
High levels of IL-22 are present in serum and synovial fluid of patients with RA. As both pro- and anti-inflammatory roles for IL-22 have been described in studies using animal ...models of RA, its exact function in arthritis remains poorly defined. With this study we aimed to further unravel the mechanism by which IL-22 exerts its effects and to decipher its therapeutic potential by overexpression of IL-22 either locally or systemically during experimental arthritis.
Methods
CIA was induced in DBA-1 mice by immunization and booster injection with type II collagen (col II). Before arthritis onset, IL-22 was overexpressed either locally by intra-articular injection or systemically by i.v. injection using an adenoviral vector and clinical arthritis was scored for a period of 10 days. Subsequently, joints were isolated for histological analysis of arthritis severity and mRNA and protein expression of various inflammatory mediators was determined in the synovium, spleen and serum.
Results
Local IL-22 overexpression did not alter arthritis pathology, whereas systemic overexpression of IL-22 potently reduced disease incidence, severity and pathology during CIA. Mice systemically overexpressing IL-22 showed strongly reduced serum cytokine levels of TNF-α and macrophage inflammatory protein 1α that correlated significantly with the enhanced expression of the negative immune regulator SOCS3 in the spleen.
Conclusion
With this study, we revealed clear anti-inflammatory effects of systemic IL-22 overexpression during CIA. Additionally, we are the first to show that the protective effect of systemic IL-22 during experimental arthritis is likely orchestrated via upregulation of the negative regulator SOCS3.
Collagen/calcium phosphate scaffolds have been used for bone reconstruction due to their inherent similarities to the bone extracellular matrix. Calcium phosphate alone has also been used as a ...non-viral vector for gene delivery. The aim of this study was to determine the capability of a collagen/calcium phosphate scaffold to deliver naked plasmid DNA and mediate transfection in vivo. The second goal of the study was to deliver a plasmid encoding vascular endothelial growth factor(165) (pVEGF(165)) to promote angiogenesis, and hence bone formation, in a mouse intra-femoral model. The delivery of naked plasmid DNA resulted in a 7.6-fold increase in mRNA levels of beta-Galactosidase compared to the delivery of plasmid DNA complexed with a partially degraded PAMAM dendrimer (dPAMAM) in a subcutaneous murine model. When implanted in a muirne intra-femoral model, the delivery of pVEGF(165) resulted in a 2-fold increase in bone volume at the defect site relative to control scaffolds without pVEGF(165). It was concluded that a collagen/calcium phosphate scaffold can mediate transfection without the use of additional transfection vectors and can promote bone formation in a mouse model via the delivery of pVEGF(165).
Molecular characterization of circulating tumor cells is of high clinical relevance. Since circulating tumor cell (CTC) detection and isolation often rely on cell dimensions, we determined the size ...of 71 612 CellSearch‐detected CTCs using accept software. Strikingly, CTC size differs between tumor types and significantly deviates from the size of cultured tumor cells, which is currently used in the development of CTC isolation methods.
Circulating tumor cells (CTCs) in the blood of cancer patients are of high clinical relevance. Since detection and isolation of CTCs often rely on cell dimensions, knowledge of their size is key. We analyzed the median CTC size in a large cohort of breast (BC), prostate (PC), colorectal (CRC), and bladder (BLC) cancer patients. Images of patient‐derived CTCs acquired on cartridges of the FDA‐cleared CellSearch® method were retrospectively collected and automatically re‐analyzed using the accept software package. The median CTC diameter (μm) was computed per tumor type. The size differences between the different tumor types and references (tumor cell lines and leukocytes) were nonparametrically tested. A total of 1962 CellSearch® cartridges containing 71 612 CTCs were included. In BC, the median computed diameter (CD) of patient‐derived CTCs was 12.4 μm vs 18.4 μm for cultured cell line cells. For PC, CDs were 10.3 μm for CTCs vs 20.7 μm for cultured cell line cells. CDs for CTCs of CRC and BLC were 7.5 μm and 8.6 μm, respectively. Finally, leukocytes were 9.4 μm. CTC size differed statistically significantly between the four tumor types and between CTCs and the reference data. CTC size differences between tumor types are striking and CTCs are smaller than cell line tumor cells, whose size is often used as reference when developing CTC analysis methods. Based on our data, we suggest that the size of CTCs matters and should be kept in mind when designing and optimizing size‐based isolation methods.
Worldwide, fisheries face the consequences of climate change and compete with expanding human activities at sea, which may trigger unforeseen reactions of fishers. Hence, knowledge on drivers of ...fishing behavior is crucial for management and needs to be integrated in resource management policies. In this study, we identify factors influencing fishing activity of North Sea demersal fleets. First, we explore drivers of the North Sea demersal fisheries in scientific literature. Subsequently, we study the effects of identified drivers on the spatio-temporal dynamics of German demersal fisheries using boosted regression trees (BRT), a supervised machine learning technique. An exploratory literature review revealed a lack of studies incorporating biophysical, economic and socio-cultural fishing drivers in a single quantitative analysis. Our BRT analysis contributed to filling this research gap and highlighted the importance of biophysical drivers such as temperature, salinity, and bathymetry for fishing behavior. Contrary to findings of previous studies, our empirical analysis identified quotas and market prices to be irrelevant, except for low brown shrimp prices, which counter-intuitively increased fishing effort. Moreover, economic and socio-cultural variables influencing brown shrimp fishing effort differed from the other fleets, especially determined by increased effort on workdays and reduced effort when fuel prices were high. Our findings provide key information for marine spatial planning and supports the integration of fishing fleet behavior into policies.
Display omitted
•Few studies incorporated oceanographic, economic, and cultural drivers of fishing.•Oceanographic parameters were most relevant at driving spatio-temporal fishing effort.•Resource and fuel prices were only relevant for one fleet.•Socio-cultural and economic drivers differ across fleets.
Current studies of the peculiar velocity flow field in the local Universe are limited by either the lack of detection or accurate photometry for galaxies at low Galactic latitudes. The contribution ...to the dynamics of the Local Group of the largely unknown mass distribution in this ‘Zone of Avoidance’ (ZoA) remains controversial. We present here the results of a pilot project to obtain deep near-infrared (NIR) observations of galaxies detected in the systematic Parkes deep H i survey of the ZoA(HIZOA) – 578 galaxies with recession velocities out to 6000 km s−1 were observed with the 1.4 m InfraRed Survey Facility SIRIUS (Simultaneous InfraRed Imager for Unbiased Surveys) camera providing J, H and K
s
imaging 2 mag deeper than 2MASS. After star subtraction, the resulting isophotal magnitudes and inclinations of ZoA galaxies are of sufficient accuracy (magnitude errors under 0.1 mag even at high extinction) to ultimately be used to determine cosmic flow fields ‘in’ the ZoA via the NIR Tully–Fisher relation. We further used the observed NIR colours to assess the ratio of the true extinction to the Diffuse Infrared Background Experiment/IRAS extinction deep into the dust layers of the Milky Way. The derived ratio was found to be 0.87 across the HIZOA survey region with no significant variation with Galactic latitude or longitude. This value is in excellent agreement with the completely independently derived factor of 0.86 by Schlafly & Finkbeiner based on Sloan data far away from the Milky Way.
Fragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the
1 product (FMRP), mosaicism for active and inactive
alleles, ...including alleles termed premutation (PM: 55-199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: ≥ 200 CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete
mRNA silencing from FM alleles and/or levels of
mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS.
The study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1-43 years. A control group of 14 females were used to establish control
mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively.
mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method.
Females with FXS had significantly higher levels of
mRNA (
< 0.001) than males.
mRNA levels were positively associated with age (
< 0.001), but not with intellectual functioning and autistic features in females. FM-only males (aged < 19 years) expressing FM
mRNA had significantly higher ADOS calibrated severity scores compared to FM-only males with completely silenced
(
= 0.011). However, there were no significant differences between these subgroups on intellectual functioning. In contrast, decreased levels of
mRNA were associated with decreased intellectual functioning in FXS males (
= 0.029), but not autism features, when combined with the PM/FM mosaic group.
Incomplete silencing of toxic FM RNA may be associated with autistic features, but not intellectual functioning in FXS males. While decreased levels of mRNA may be more predictive of intellectual functioning than autism features. If confirmed in future studies, these findings may have implications for patient stratification, outcome measure development, and design of clinical and pre-clinical trials in FXS.
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