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HMGA2 is an architectonic transcription factor abundantly expressed during embryonic and fetal development and it is associated with the progression of malignant tumors. The protein harbours three basically charged DNA binding domains and an acidic protein binding C-terminal domain. DNA binding induces changes of DNA conformation and hence results in global overall change of gene expression patterns. Recently, using a PCR-based SELEX (Systematic Evolution of Ligands by Exponential Enrichment) procedure two consensus sequences for HMGA2 binding have been identified. In this investigation chromatin immunoprecipitation (ChIP) experiments and bioinformatic methods were used to analyze if these binding sequences can be verified on chromatin of living cells as well. After quantification of HMGA2 protein in different cell lines the colon cancer derived cell line HCT116 was chosen for further ChIP experiments because of its 3.4-fold higher HMGA2 protein level. 49 DNA fragments were obtained by ChIP. These fragments containing HMGA2 binding sites have been analyzed for their AT-content, location in the human genome and similarities to sequences generated by a SELEX study. The sequences show a significantly higher AT-content than the average of the human genome. The artificially generated SELEX sequences and short BLAST alignments (11 and 12 bp) of the ChIP fragments from living cells show similarities in their organization. The flanking regions are AT-rich, whereas a lower conservation is present in the center of the sequences.

Background: The overarching goal of this dissertation was to examine the effects of proprioceptive training and dyad practice on sensorimotor function. It is well established that the human motor and sensory systems are closely linked, such that changes in motor training affect proprioceptive performance and vice versa, and that it affects neural processing in both motor and somatosensory cortical areas. However, there remains uncertainty about what proprioceptive training modalities are most effective to yield meaningful changes in proprioceptive and motor function and which populations may be receptive to such interventions.There is now also convincing empirical evidence that observational practice of motor learning can positively affect proprioceptive performance. Dyad practice is a form of sensorimotor learning in which individuals train in pairs, alternating between physical and observational practice. It is a sensorimotor training regime that has received increasing interest in improving performance in complex motor tasks. Previous research shows that dyad practice can result in improved motor performance and faster learning than physical practice only in tasks including flight simulations, micro-surgery, cup stacking, and balance tasks. Despite these promising effects of dyad practice on motor results, its effects on proprioceptive performance are unknown.Objectives: The objectives of this dissertation are two-fold. Aim 1: To provide a systematic review of literature aimed: A. to document interventions that are used to improve proprioception and motor performance, B. to highlight the measures to quantify the effects on proprioceptive and motor performance due to proprioceptive training, and C. to examine the usefulness of proprioceptive training as a rehabilitation tool to improve motor function and performance in clinical and non-clinical populations. Aim 2: To examine the effects of dyad practice, a form of sensorimotor training, on motor and proprioceptive performance in healthy individuals in a wrist-robotic environment.Methods - Aim 1: Four major databases were searched, based on four inclusion criteria.Results - Aim 1: Of the 3297 articles identified by the database search, 70 studies met the inclusion criteria and were included for further review. Across studies, proprioceptive training led to comparable gains in both proprioceptive (+46%) and motor performance (+45%). The majority of studies (50/70) applied active movement interventions. Interventions applying somatosensory stimulation were most successful in clinical populations. Joint position sense error was the most commonly used proprioceptive measure and presents a reliable and feasible measure for clinical use.Methods - Aim 2: Forty-two healthy participants (18–35 years) were randomized into three groups (n = 14): Dyad practice, physical practice with rest, and physical practice without rest. Participants practiced a 2 degree-of-freedom gamified wrist movement task for 20 trials using a custom-made wrist robotic device. A motor performance score (MPS) that captured temporal and spatial time-series kinematics was computed at baseline, the end of training and 24 h later to assess retention. Wrist position sense acuity was assessed before (baseline) and 24 hours after the end of training (retention), using the Just-noticeable-difference (JND) threshold and Uncertainty.Results - Aim 2: MPS did not differ between groups at baseline. All groups revealed significant motor performance gains by the end of training. However, dyads outperformed the other groups at the end of training (p<0.001) and showed higher retention after 24 hours (p = 0.02). Median MPS improved by 46.5% in dyads, 25.3% in physical practice-rest, and 33.6% in physical practice-no rest at the end of training compared to baseline. Only the PP-no rest group exhibited significantly lower JND thresholds at retention compared to baseline (p = 0.03). There were no differences in position sense Uncertainty within or between groups, and there was no relationship between motor and proprioceptive gains.Conclusion: Proprioceptive training can lead to significant improvements in proprioceptive and motor function across a range of healthy and clinical populations. Those regimens requiring active movement of the trainee tended to be most successful in improving sensorimotor performance. Conclusive evidence on how long training gains are retained is still lacking. There is no solid evidence about the underlying long-term neuroplastic changes associated with proprioceptive training.Compared to physical practice alone, dyad practice leads to superior motor outcomes in a robot-assisted motor learning task. Dyads still outperformed their counterparts 24 hours after practice. However, the superior motor improvements did not translate into comparable gains in proprioceptive acuity. A possible explanation for these findings is that the recruitment of explicit motor learning mechanisms during dyad motor skill practice does not enhance the implicit learning mechanisms underlying proprioceptive learning.Taken together, these results underline the close relationship between somatosensory and sensorimotor function. Future research should assess the neurophysiological effects of proprioceptive training and dyad practice in particular, and aim to implement dyad practice in clinical populations.

Increasing energy consumption, shortages of fossil fuels, and concerns about the environmental impact of energy use, especially emissions of carbon dioxide, give fresh impetus to the development of renewable energy sources. With the advent of renewable energy, it is now indispensable that efficient energy storage systems have to be developed. One of the most promising storage systems to be employed in stationary energy storage applications are lithium-based batteries (LIB), mainly due to their high energy density, high power, and nearly 100 % efficiency. Within the scope of this paper, we carry out a patent search using the patent database PatBase® to assess the development status of LIB technology. The analysis of the generated patent sample reveals disproportionately high growth rates in LIB patent applications over the last years compared to other selected energy-related technologies. Breaking down patent application growth by the different components of LIB shows the principal drivers of growth. The purpose of this paper is to provide current research trends and prospects for the main LIB materials and designs.

Bivalves record seasonal environmental changes in their shells, making them excellent climate archives. However, not every bivalve can be used for this end. The shells have to grow fast enough so that micrometre- to millimetre-sampling can resolve sub-annual changes. Here, we investigate whether the bivalve Angulus benedeni benedeni is suitable as a climate archive. For this, we use ca. 3-million-year-old specimens from the Piacenzian collected from a temporary outcrop in the Port of Antwerp area (Belgium). The subspecies is common in Pliocene North Sea basin deposits, but its lineage dates back to the late Oligocene and has therefore great potential as a high-resolution archive. A detailed assessment of the preservation of the shell material by micro-X-ray fluorescence, X-ray diffraction, and electron backscatter diffraction reveals that it is pristine and not affected by diagenetic processes. Oxygen isotope analysis and microscopy indicate that the species had a longevity of up to a decade or more and, importantly, that it grew fast and large enough so that seasonally resolved records across multiple years were obtainable from it. Clumped isotope analysis revealed a mean annual temperature of 13.5 ± 3.8 ∘C. The subspecies likely experienced slower growth during winter and thus may not have recorded temperatures year-round. This reconstructed mean annual temperature is 3.5 ∘C warmer than the pre-industrial North Sea and in line with proxy and modelling data for this stratigraphic interval, further solidifying A. benedeni benedeni's use as a climate recorder. Our exploratory study thus reveals that Angulus benedeni benedeni fossils are indeed excellent climate archives, holding the potential to provide insight into the seasonality of several major climate events of the past ∼ 25 million years in northwestern Europe.

Oxidant-mediated antibacterial response systems are broadly used to control bacterial proliferation. Hypochlorite (HOCl) is an important component of the innate immune system produced in neutrophils and specific epithelia. Its antimicrobial activity is due to damaging cellular macromolecules. Little is known about how bacteria escape HOCl-inflicted damage. Recently, the transcription factor YjiE was identified that specifically protects Escherichia coli from HOCl killing. According to its function, YjiE is now renamed HypT (hypochlorite-responsive transcription factor). Here we unravel that HypT is activated by methionine oxidation to methionine sulfoxide. Interestingly, so far only inactivation of cellular proteins by methionine oxidation has been reported. Mutational analysis revealed three methionines that are essential to confer HOCl resistance. Their simultaneous substitution by glutamine, mimicking the methionine sulfoxide state, increased the viability of E. coli cells upon HOCl stress. Triple glutamine substitution generates a constitutively active HypT that regulates target genes independently of HOCl stress and permanently down-regulates intracellular iron levels. Inactivation of HypT depends on the methionine sulfoxide reductases A/B. Thus, microbial protection mechanisms have evolved along the evolution of antimicrobial control systems, allowing bacteria to survive within the host environment.

Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely. The local ethics committee approved this study and all subjects gave written informed consent. 66 patients with idiopathic Parkinson's disease and 58 control subjects underwent quantitative MRI at 3T. Susceptibility and R2* maps were reconstructed from a spoiled multi-echo 3D gradient echo sequence. Mean susceptibilities and R2* rates were measured in subcortical deep gray matter nuclei and compared between patients with PD and controls as well as related to clinical variables. Compared to control subjects, patients with PD had increased R2* values in the substantia nigra. QSM also showed higher susceptibilities in patients with PD in substantia nigra, in the nucleus ruber, thalamus, and globus pallidus. Magnetic susceptibility of several of these structures was correlated with the levodopa-equivalent daily dose (LEDD) and clinical markers of motor and non-motor disease severity (total MDS-UPDRS, MDS-UPDRS-I and II). Disease severity as assessed by the Hoehn & Yahr scale was correlated with magnetic susceptibility in the substantia nigra. The established finding of higher R2* rates in the substantia nigra was extended by QSM showing superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways. QSM additionally reflected the levodopa-dosage and disease severity. These results suggest a more widespread pathologic involvement and QSM as a novel means for its investigation, more sensitive than current MRI techniques.

Wet coffee processing generates a large amount of coffee pulp waste that is mostly disposed of in the processing units. To reduce this waste and the associated environmental burden, an alternative strategy would be to exploit the coffee pulp to produce a durable and stable consumable product. Accordingly, a puree produced from Robusta coffee pulp was investigated in relation to its physicochemical and sensory properties. After thermal and chemical stabilization, the obtained puree (pH 3.6) was found to exhibit a multimodal particle size distribution, shear-thinning behavior, and lower discoloration, as well as an antioxidant capacity of 87.9 µmolTE/gDM. The flavor of the puree was examined by sensory evaluation and the corresponding analyses of aroma-active volatile compounds, as determined using aroma extract dilution analyses (AEDA) and gas chromatography-mass spectrometry/olfactometry (GC-MS/O). The puree was characterized by dominant fruity (4.4), floral (3.4), citrusy (3.3) and hay-like (3.3) odor impressions. The aroma-active compounds were predominantly aldehydes, acids, and lactones, whereby (E)-β-damascenone, geraniol, 4-methylphenol, 3-hydroxy-4,5-dimethylfuran-2(5H)-one, and 4-hydroxy-3-methoxybenzaldehyde exhibited the highest flavor dilution (FD) factor (1024), thereby indicating their high impact on the overall aroma of the puree. This study demonstrates an approach to stabilize coffee pulp to produce a sweet, fruity puree with comparable physical properties to other fruit purees and that can be used as a new and versatile flavoring ingredient for various food applications.

Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity.

A causal variant is identified at the LMO1 oncogene locus that drives the genetic association of LMO1 with neuroblastoma susceptibility; the causal SNP disrupts a GATA transcription factor binding site within a tissue-specific super-enhancer element in the first intron of LMO1 , thereby affecting LMO1 expression. LMO1 oncogene involvement in neuroblastoma Polymorphisms at the oncogene LMO1 locus have previously been identified as being highly associated with susceptibility to neuroblastoma, a paediatric cancer. John Maris and colleagues now identify a causal variant at this locus, driving the LMO1 genetic association with neuroblastoma susceptibility. The authors show that the causal single nucleotide polymorphism disrupts a GATA transcription factor binding site in a tissue-specific super-enhancer element within the first intron of LMO1 , thereby affecting expression of the LMO1 oncogene. Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells 1 . Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P  = 7.47 × 10 −29 , odds ratio 0.65, 95% confidence interval 0.60–0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1 . The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression ( P  = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding ( P  < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing ( P  < 0.0001) and reporter assays ( P  = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis , and this leads to an oncogenic dependency in tumour cells.