Local temperatures inferred from plant communities suggest strong spatial buffering of climate warming across Northern Europe

Recent studies from mountainous areas of small spatial extent (<2500 km²) suggest that fine‐grained thermal variability over tens or hundreds of metres exceeds much of the climate warming expected for the coming decades. Such variability in temperature provides buffering to mitigate climate‐change impacts. Is this local spatial buffering restricted to topographically complex terrains? To answer this, we here study fine‐grained thermal variability across a 2500‐km wide latitudinal gradient in Northern Europe encompassing a large array of topographic complexities. We first combined plant community data, Ellenberg temperature indicator values, locally measured temperatures (LmT) and globally interpolated temperatures (GiT) in a modelling framework to infer biologically relevant temperature conditions from plant assemblages within <1000‐m² units (community‐inferred temperatures: CiT). We then assessed: (1) CiT range (thermal variability) within 1‐km² units; (2) the relationship between CiT range and topographically and geographically derived predictors at 1‐km resolution; and (3) whether spatial turnover in CiT is greater than spatial turnover in GiT within 100‐km² units. Ellenberg temperature indicator values in combination with plant assemblages explained 46–72% of variation in LmT and 92–96% of variation in GiT during the growing season (June, July, August). Growing‐season CiT range within 1‐km² units peaked at 60–65°N and increased with terrain roughness, averaging 1.97 °C (SD = 0.84 °C) and 2.68 °C (SD = 1.26 °C) within the flattest and roughest units respectively. Complex interactions between topography‐related variables and latitude explained 35% of variation in growing‐season CiT range when accounting for sampling effort and residual spatial autocorrelation. Spatial turnover in growing‐season CiT within 100‐km² units was, on average, 1.8 times greater (0.32 °C km^?1) than spatial turnover in growing‐season GiT (0.18 °C km^?1). We conclude that thermal variability within 1‐km² units strongly increases local spatial buffering of future climate warming across Northern Europe, even in the flattest terrains.     

Trafficking of the IKs‐Complex in MDCK Cells: Site of Subunit Assembly and Determinants of Polarized Localization

The voltage‐gated potassium channel K_V7.1 is regulated by non‐pore forming regulatory KCNE β‐subunits. Together with KCNE1, it forms the slowly activating delayed rectifier potassium current I_Ks. However, where the subunits assemble and which of the subunits determines localization of the I_Ks‐complex has not been unequivocally resolved yet. We employed trafficking‐deficient K_V7.1 and KCNE1 mutants to investigate I_Ks trafficking using the polarized Madin‐Darby Canine Kidney cell line. We find that the assembly happens early in the secretory pathway but provide three lines of evidence that it takes place in a post‐endoplasmic reticulum compartment. We demonstrate that K_V7.1 targets the I_Ks‐complex to the basolateral membrane, but that KCNE1 can redirect the complex to the apical membrane upon mutation of critical K_V7.1 basolateral targeting signals. Our data provide a possible explanation to the fact that K_V7.1 can be localized apically or basolaterally in different epithelial tissues and offer a solution to divergent literature results regarding the effect of KCNE subunits on the subcellular localization of K_V7.1/KCNE complexes .     

Individual and combined effects of DNA methylation and copy number alterations on miRNA expression in breast tumors

Background

The global effect of copy number and epigenetic alterations on miRNA expression in cancer is poorly understood. In the present study, we integrate genome-wide DNA methylation, copy number and miRNA expression and identify genetic mechanisms underlying miRNA dysregulation in breast cancer.

Results

We identify 70 miRNAs whose expression was associated with alterations in copy number or methylation, or both. Among these, five miRNA families are represented. Interestingly, the members of these families are encoded on different chromosomes and are complementarily altered by gain or hypomethylation across the patients. In an independent breast cancer cohort of 123 patients, 41 of the 70 miRNAs were confirmed with respect to aberration pattern and association to expression. In vitro functional experiments were performed in breast cancer cell lines with miRNA mimics to evaluate the phenotype of the replicated miRNAs. let-7e-3p, which in tumors is found associated with hypermethylation, is shown to induce apoptosis and reduce cell viability, and low let-7e-3p expression is associated with poorer prognosis. The overexpression of three other miRNAs associated with copy number gain, miR-21-3p, miR-148b-3p and miR-151a-5p, increases proliferation of breast cancer cell lines. In addition, miR-151a-5p enhances the levels of phosphorylated AKT protein.

Conclusions

Our data provide novel evidence of the mechanisms behind miRNA dysregulation in breast cancer. The study contributes to the understanding of how methylation and copy number alterations influence miRNA expression, emphasizing miRNA functionality through redundant encoding, and suggests novel miRNAs important in breast cancer.     

Few Effects of Far Transfer of Working Memory Training in ADHD: A Randomized Controlled Trial

Objective

Studies have shown that children with ADHD profit from working memory training, although few studies have investigated transfer effects comprehensively. The current Randomized Controlled Trial analyzes transfer to other neuropsychological (NP) domains, academic performance and everyday functioning at home and school.

Method

Sixty-seven children with ADHD were randomized into a control group or a training group. The training group underwent Cogmed’s RoboMemo program. All participants were assessed pre-training, immediately after and eight months later with a battery of NP tests, measures of mathematical and reading skills, as well as rating scales filled out by parents and teachers.

Results

There was a significant training effect in psychomotor speed, but not to any other NP measures. Reading and mathematics were improved. There were no training induced changes in symptom rating scales either at home or at school. The increased reading scores remained significant eight months later.

Conclusion

The study is the most comprehensive study of transfer effects to date, and with mixed results compared to previous research. More research is needed regarding how to improve the training program and the conditions and thresholds for successful training.

Trial Registration

Controlled-Trials.com ISRCTN19133620     

RCT of Working Memory Training in ADHD: Long-Term Near-Transfer Effects

Objective

The aim of the study is to evaluate the long-term near-transfer effects of computerized working memory (WM) training on standard WM tasks in children with Attention-Deficit/Hyperactivity Disorder (ADHD).

Method

Sixty-seven children aged 10–12 years in Vestfold/Telemark counties (Norway) diagnosed with F90.0 Hyperkinetic disorder (ICD-10) were randomly assigned to training or control group. The training group participated in a 25-day training program at school, while the control group received treatment-as-usual. Participants were tested one week before intervention, immediately after and eight months later. Based on a component analysis, six measures of WM were grouped into composites representing Visual, Auditory and Manipulation WM.

Results

The training group had significant long-term differential gains compared to the control group on all outcome measures. Performance gains for the training group were significantly higher in the visual domain than in the auditory domain. The differential gain in Manipulation WM persisted after controlling for an increase in simple storage capacity.

Conclusion

Systematic training resulted in a long-term positive gain in performance on similar tasks, indicating the viability of training interventions for children with ADHD. The results provide evidence for both domain-general and domain-specific models. Far-transfer effects were not investigated in this article.Trial Registration: Controlled-Trials.com ISRCTN19133620     

A Non-Coding Genomic Duplication at the HMX1 Locus Is Associated with Crop Ears in Highland Cattle

Highland cattle with congenital crop ears have notches of variable size on the tips of both ears. In some cases, cartilage deformation can be seen and occasionally the external ears are shortened. We collected 40 cases and 80 controls across Switzerland. Pedigree data analysis confirmed a monogenic autosomal dominant mode of inheritance with variable expressivity. All affected animals could be traced back to a single common ancestor. A genome-wide association study was performed and the causative mutation was mapped to a 4 Mb interval on bovine chromosome 6. The H6 family homeobox 1 (HMX1) gene was selected as a positional and functional candidate gene. By whole genome re-sequencing of an affected Highland cattle, we detected 6 non-synonymous coding sequence variants and two variants in an ultra-conserved element at the HMX1 locus with respect to the reference genome. Of these 8 variants, only a non-coding 76 bp genomic duplication (g.106720058_106720133dup) located in the conserved region was perfectly associated with crop ears. The identified copy number variation probably results in HMX1 misregulation and possible gain-of-function. Our findings confirm the role of HMX1 during the development of the external ear. As it is sometimes difficult to phenotypically diagnose Highland cattle with slight ear notches, genetic testing can now be used to improve selection against this undesired trait.     

Enlargement of Cerebral Ventricles as an Early Indicator of Encephalomyelitis

Inflammatory disorders of the central nervous system such as multiple sclerosis and acute disseminated encephalomyelitis involve an invasion of immune cells that ultimately leads to white matter demyelination, neurodegeneration and development of neurological symptoms. A clinical diagnosis is often made when neurodegenerative processes are already ongoing. In an attempt to seek early indicators of disease, we studied the temporal and spatial distribution of brain modifications in experimental autoimmune encephalomyelitis (EAE). In a thorough magnetic resonance imaging study performed with EAE mice, we observed significant enlargement of the ventricles prior to disease clinical manifestation and an increase in free water content within the cerebrospinal fluid as demonstrated by changes in T₂ relaxation times. The increase in ventricle size was seen in the lateral, third and fourth ventricles. In some EAE mice the ventricle size started returning to normal values during disease remission. In parallel to this macroscopic phenomenon, we studied the temporal evolution of microscopic lesions commonly observed in the cerebellum also starting prior to disease onset. Our data suggest that changes in ventricle size during the early stages of brain inflammation could be an early indicator of the events preceding neurological disease and warrant further exploration in preclinical and clinical studies.     

DegS and RseP Homologous Proteases Are Involved in Singlet Oxygen Dependent Activation of RpoE in Rhodobacter sphaeroides

Singlet oxygen (¹O₂) is the main agent of photooxidative stress and is generated by photosensitizers as (bacterio)chlorophylls. It leads to the damage of cellular macromolecules and therefore photosynthetic organisms have to mount an adaptive response to ¹O₂ formation. A major player of the photooxidative stress response in Rhodobacter sphaeroides is the alternative sigma factor RpoE, which is inactivated under non-stress conditions by its cognate anti-sigma factor ChrR. By using random mutagenesis we identified RSP_1090 to be required for full activation of the RpoE response under ¹O₂ stress, but not under organic peroxide stress. In this study we show that both RSP_1090 and RSP_1091 are required for full resistance towards ¹O₂. Moreover, we revealed that the DegS and RseP homologs RSP_3242 and RSP_2710 contribute to ¹O₂ resistance and promote ChrR proteolysis. The RpoE signaling pathway in R. sphaeroides is therefore highly similar to that of Escherichia coli, although very different anti-sigma factors control RpoE activity. Based on the acquired results, the current model for RpoE activation in response to ¹O₂ exposure in R. sphaeroides was extended.