Associative neuroplasticity, which encompasses the modification of synaptic strength by coactivation of two synaptic inputs, has been linked to learning processes. Because unlimited plasticity ...destabilizes neuronal networks, homeostatic rules were proposed and experimentally proven that control for the amount and direction of plasticity dependent on background network activity. Accordingly, low background activity would enhance facilitatory plasticity, whereas high background activity would inhibit it. However, the impact of background excitability on associative plasticity has not been studied so far in humans. Facilitatory associative plasticity was induced by paired associative stimulation (PAS) in the human motor cortex, whereas background activity was enhanced or diminished by transcranial direct current stimulation (tDCS). When applied before PAS, excitability-enhancing tDCS also boosted the efficacy of PAS, whereas excitability-diminishing tDCS turned it into inhibition. Thus, previous background activity does not influence associative plasticity homeostatically. When tDCS and PAS were applied simultaneously, now in accordance with homeostatic rules of neuroplasticity, reduced background activity resulted in a prolonged excitability enhancement by PAS, whereas enhanced background activity turned it into inhibition. We conclude that background network activity can influence associative plasticity homeostatically. However, only simultaneous modulation of both parameters is in accordance with homeostatic concepts. These findings might be of importance for the development of plasticity-inducing stimulation protocols supporting information processing in humans.
Abstract
Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding ...to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.
In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We ...investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10
and 3.74×10
, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research.
With a lifetime risk for major depressive disorder of up to 50%, depression is a common comorbidity in multiple sclerosis but remains widely underdiagnosed and untreated. We investigated the ...potential of a fully automated, internet-based, cognitive behavioural therapy programme, Deprexis, to reduce depressive symptoms in patients with multiple sclerosis.
For this randomised controlled trial, we recruited patients from an outpatient clinic in Hamburg, Germany. Patients aged 18-65 years were eligible for inclusion if they had multiple sclerosis and self-reported depressive symptoms. By use of a computer-generated randomisation sequence, we allocated 90 patients (1:1; no blocking or stratification) to either the intervention group or a waitlist control group for 9 weeks. The primary endpoint was the Beck Depression Inventory (BDI), as assessed by an intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01663649.
71 patients completed the trial: 35 patients in the intervention group and 36 patients in the control group. During the intervention, BDI scores decreased in the Deprexis group and increased in the control group, yielding a positive effect of Deprexis relative to the waitlist group (mean group difference -4·02 points 95% CI -7·26 to -0·79, p=0·015, effect size d=0·53). Worsening of depressive symptoms from below to above the clinical cutoff (BDI >13) occurred in three (7%) of 45 patients in the control group and no patients in the Deprexis group. We noted no adverse events with respect to new occurrence of suicidal ideation during the trial.
Psychological online-intervention programmes could be suitable for patients with multiple sclerosis who are unable to regularly attend therapeutic sessions because of mobility impairments.
European Union and the Deutsche Forschungsgemeinschaft.
Repetitive transcranial magnetic stimulation is increasingly used as a therapeutic tool in psychiatry and has been demonstrated to attenuate the activity of the stress hormone system. Stress-induced ...structural remodeling in the adult hippocampus may provide a cellular basis for understanding the impairment of neural plasticity in depressive illness. Accordingly, reversal of structural remodeling might be a desirable goal for antidepressant therapy. The present study investigated the effect of chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation treatment on stress hormone regulation and hippocampal neurogenesis.
Adult male rats were submitted to daily psychosocial stress and repetitive transcranial magnetic stimulation (20 Hz) for 18 days. Cell proliferation in the dentate gyrus was quantified by using BrdU immunohistochemistry, and both the proliferation rate of progenitors and the survival rate of BrdU-labeled cells were evaluated. To characterize the activity of the hypothalamic-pituitary-adrenocortical system, plasma corticotropin and corticosterone concentrations were measured.
Chronic psychosocial stress resulted in a significant increase of stress hormone levels and potently suppressed the proliferation rate and survival of the newly generated hippocampal granule cells. Concomitant repetitive transcranial magnetic stimulation treatment normalized the stress-induced elevation of stress hormones; however, despite the normalized activity of the hypothalamic-pituitary-adrenocortical system, the decrement of hippocampal cell proliferation was only mildly attenuated by repetitive transcranial magnetic stimulation, while the survival rate of BrdU-labeled cells was further suppressed by the treatment.
These results support the notion that attenuation of the hypothalamic-pituitary-adrenocortical system is an important mechanism underlying the clinically observed antidepressant effect of repetitive transcranial magnetic stimulation, whereas this experimental design did not reveal beneficial effects of repetitive transcranial magnetic stimulation on adult hippocampal neurogenesis.
•Five Cellulophaga algicola alginate lyases were cloned and expressed.•HPAEC-PAD/MS and HPSEC-RI were used to analyze alginate hydrolysis.•CaAly1 endolytically cleaves both PolyG and PolyM to a ...significant extent.•CaAly2 and CaAly3 are endolytic enzymes and mainly active on G-rich alginates.•CaAly4 and CaAly5 exolytically hydrolyze guluronic acid oligosaccharides.
Alginate lyases can be used for alginate oligosaccharide production and for structural characterization or modification of alginates. For these applications it is important to obtain detailed information on mode of action and substrate specificities of alginate lyases. In this study, five alginate lyase genes were cloned from Cellulophaga algicola DSM 14237 genomic DNA, heterologously expressed, and characterized by using HPSEC-RI and HPAEC-PAD/MS. It was demonstrated that these analytical approaches can provide detailed information on preferred substrates, extent of hydrolysis, and the liberated products. The recombinant enzymes cleaved alginates endolytically (CaAly1, CaAly2, CaAly3) or exolytically (CaAly4, CaAly5). The three endolytic alginate lyases predominantly hydrolyzed guluronic acid-rich alginates, only CaAly1 also showed activity on mannuronic acid-rich alginates. The oligosaccharide profiles further demonstrated that the endolytic enzymes have rather narrow but slightly different substrate specificities and that the two exolytic alginate lyases mainly cleaved unsaturated guluronic acid oligosaccharides to monomers.
Dextran hydrolysis by dextranases is applied in the sugar industry and the medical sector, but it also has a high potential for use in structural analysis of dextrans. However, dextranases are ...produced by several organisms and thus differ in their properties. The aim of this study was to comparatively investigate the product patterns obtained from the incubation of linear as well as
3- and
4-branched dextrans with different dextranases. For this purpose, genes encoding for dextranases from
and
were cloned and heterologously expressed in
. The two recombinant enzymes as well as two commercial dextranases from
sp. and
sp. were subsequently used to hydrolyze structurally different dextrans. The hydrolysis products were investigated in detail by HPAEC-PAD. For dextranases from
sp.,
sp., and
, isomaltose was the end product of the hydrolysis from linear dextrans, whereas
sp. dextranase led to isomaltose and isomaltotetraose. In addition, the latter enzyme also catalyzed a disproportionation reaction when incubated with isomaltotriose. For
3- and
4-branched dextrans, the fungal dextranases yielded significantly different oligosaccharide patterns than the bacterial enzymes. Overall, the product patterns can be adjusted by choosing the correct enzyme as well as a defined enzyme activity.
Total hip arthroplasty (THA) is an effective procedure for patients with end-stage hip osteoarthritis. However, whether or not pre-operatively existing functional deficits are persisting several ...years post-surgery in the affected limb has not been thoroughly researched. Therefore, the primary aim of this preliminary study was to include patients four to five years after undergoing THA and to investigate potential differences between the operated and non-operated leg in hip strength, range of motion (ROM), balance, and gait. The secondary aim was to compare these values from the operated leg of the patients to those of the legs of healthy subjects.
Sixteen patients (age: 65.20 ± 5.32 years) following unilateral THA (post-operation time: 4.7 ± 0.7 years) and ten, healthy, age-matched control subjects (age: 60.85 ± 7.57 years) were examined for maximum isometric hip muscle strength, active ROM of the hip joint, balance and gait on both limbs. Paired t-tests were used to assess the inter-limb differences in the THA group. Analyses of covariance (ANCOVA) were performed to compare groups, using age as a covariate.
The analysis of inter-limb differences in patients following THA revealed significant deficits on the operated side for hip abduction strength (p = 0.02), for hip flexion ROM (p < 0.01) and for balance in terms of the length of center of pressure (COP) (p = 0.04). Compared to values of the control subjects, the patients demonstrated significantly reduced hip strength in flexion, extension and abduction (p < 0.05) on the operated leg as well as reduced ROM measures in hip flexion, extension and abduction (p < 0.05).
The first results of this explorative study indicated that inter-limb differences as well as reduced hip strength and hip ROM compared with control subjects were still present four to five years after THA. These persisting asymmetries and deficits in patients following THA may be one explanation for the decrease in health-related quality of life (HRQoL) seen in patients over the years after surgery. Further studies are required to replicate these findings with a larger sample size.
DRKS, DRKS00016945. Registered 12 March 2019 - Retrospectively registered.
The heparin-binding protein midkine is a potent growth factor with emerging roles in numerous inflammatory diseases. Beyond its characterization in embryogenesis and organ development, ample insights ...into its function have been collected from experimental disease models using knockout animals or knockdown intervention strategies. Here a comprehensive overview on midkine and its functions in atherogenesis and kidney diseases is provided. Molecular clues to key signalling pathways (Akt, ERK, HIF1α) and key events in atherosclerotic vessels link midkine expression with vascular smooth muscle proliferation and (neo)angiogenesis. In acute and chronic kidney diseases, midkine expression is upregulated in tubular as well as endothelial cells. Experimental disease models that mimic diabetic nephropathy and/or immunologic glomerular damage indicate dichotomous midkine activities, with cytoprotective as well as injurious effects. This review also pinpoints the commonalities of the disease models. An understanding of the underlying molecular events will be required in order to design a targeted intervention into cardiovascular or renal diseases as well as inflammatory processes.
Generation of laterality depends on a pathway which involves the asymmetrically expressed genes nodal, Ebaf, Leftb, and Pitx2. In mouse, node monocilia are required upstream of the nodal cascade. In ...chick and frog, gap junctions are essential prior to node/organizer formation. It was hypothesized that differential activity of ion channels gives rise to unidirectional transfer through gap junctions, resulting in asymmetric gene expression. PKD2, which if mutated causes autosomal dominant polycystic kidney disease (ADPKD) in humans, encodes the calcium release channel polycystin-2. We have generated a knockout allele of Pkd2 in mouse. In addition to malformations described previously, homozygous mutant embryos showed right pulmonary isomerism, randomization of embryonic turning, heart looping, and abdominal situs. Leftb and nodal were not expressed in the left lateral plate mesoderm (LPM), and Ebaf was absent from floorplate. Pitx2 was bilaterally expressed in posterior LPM but absent anteriorly. Pkd2 was ubiquitously expressed at headfold and early somite stages, with higher levels in floorplate and notochord. The embryonic midline, however, was present, and normal levels of Foxa2 and shh were expressed, suggesting that polycystin-2 acts downstream or in parallel to shh and upstream of the nodal cascade.
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