Background & Aims Dkk1 is a secreted antagonist of the Wnt/β-catenin signaling pathway. It is induced by inflammatory cytokines during colitis and exacerbates tissue damage by promoting apoptosis of ...epithelial cells. However, little is known about the physiologic role of Dkk1 in normal intestinal homeostasis and during wound repair following mucosal injury. We investigated whether inhibition of Dkk1 affects the morphology and function of the adult intestine. Methods We used doubleridge mice (Dkk1d/d ), which have reduced expression of Dkk1, and an inhibitory Dkk1 antibody to modulate Wnt/β-catenin signaling in the intestine. Intestinal inflammation was induced with dextran sulfate sodium (DSS), followed by a recovery period in which mice were given regular drinking water. Animals were killed before, during, or after DSS administration; epithelial homeostasis and the activity of major signaling pathways were investigated by morphometric analysis, bromo-2′-deoxyuridine incorporation, and immunostaining. Results Reduced expression of Dkk1 increased proliferation of epithelial cells and lengthened crypts in the large intestine, which was associated with increased transcriptional activity of β-catenin. Crypt extension was particularly striking when Dkk1 was inhibited during acute colitis. Dkk1d/d mice recovered significantly faster from intestinal inflammation but exhibited crypt architectural irregularities and epithelial hyperproliferation compared with wild-type mice. Survival signaling pathways were concurrently up-regulated in Dkk1d/d mice, including the AKT/β-catenin, ERK/Elk-1, and c-Jun pathways. Conclusions Dkk1, an antagonist of Wnt/β-catenin signaling, regulates intestinal epithelial homeostasis under physiologic conditions and during inflammation. Depletion of Dkk1 induces a strong proliferative response that promotes wound repair after colitis.
The CCNY gene, which encodes cyclin Y, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Cyclin Y promotes Wnt/β-catenin signaling and autophagy, which are critical for ...intestinal epithelial cell (IEC) homeostasis, and may thereby contribute to wound repair in colitis. However, whether cyclin Y has an essential function in IECs is unknown. We, therefore, investigated the epithelial injury response and mucosal regeneration in mice with conditional knock-out of Ccny in the intestinal epithelium. We observed that Ccny-deficient mice did not exhibit any differences in cell proliferation and disease activity compared to wild-type littermates in the dextran sulfate sodium (DSS) colitis model. Complementary in vitro experiments showed that loss of CCNY in model IECs did not affect Wnt signaling, cell proliferation, or autophagy. Additionally, we observed that expression of the cyclin-Y-associated cyclin-dependent kinase (CDK) 14 is exceedingly low specifically in IEC. Collectively, these results suggest that cyclin Y does not contribute to intestinal epithelial homeostasis, possibly due to low levels of specific CDKs in these cells. Thus, it is unlikely that CCNY mutations are causatively involved in IBD pathogenesis.
Background
Some persons with obsessive–compulsive disorder (OCD) refuse or drop out of treatment because of the aversive nature of exposure and response prevention therapy when they have to face and ...tolerate unpleasant thoughts, emotions, and bodily sensations. Indeed, one study suggested that a higher willingness to experience unpleasant thoughts, emotions, and bodily sensations (WTE) predicts a better treatment outcome, but this finding has not been replicated yet.
Methods
We examined whether WTE at admission predicted treatment outcome in a sample of 324 inpatients with OCD who received a multimodal treatment that included cognitive-behavioral therapy with exposure and response prevention sessions.
Results
Obsessive–compulsive symptoms (based on OCD-specific self-report questionnaires) decreased with medium-to-large effect sizes (all
ps
< 0.001) and global functioning (based on therapist ratings) increased with a large effect size (
d
= 1.3,
p
< 0.001) from admission to discharge. In contrast to previous findings, however, WTE did not predict treatment outcome (all
ps
> 0.005). The effect of WTE on treatment outcome remained non-significant when controlling for any comorbidity, age, sex, length of stay, and antidepressant medication and was not moderated by these variables.
Conclusions
Results indicate that higher WTE at the beginning of inpatient treatment does not facilitate improvements in obsessive–compulsive symptoms from admission to discharge. However, they also indicate that lower WTE at the beginning of inpatient treatment does not adversely affect treatment outcome, that is, even patients who indicate that they are unwilling to face the negative experiences associated with exposure and response prevention can still achieve considerable symptom reductions.
Objective:
Altered interoception may play a major role in the etiology of medically unexplained symptoms (MUS). It remains unclear, however, if these alterations concern noticing of signals or if ...they are limited to the interpretation of signals. We investigated whether individuals with MUS differ in interoceptive awareness as assessed with the Multidimensional Assessment of Interoceptive Awareness (MAIA) questionnaire.
Methods:
Study 1: A total of 486 individuals completed the Screening for Somatoform Disorders (SOMS-2). Thirty-two individuals each of the upper and lower decile of the SOMS distribution (low symptom reporters/LSR, high symptom reporters/HSR) completed the MAIA. Study 2: MAIA scores of individuals diagnosed with somatoform disorder (SFD;
n
= 26) were compared to individuals with major depressive disorder (MDD;
n
= 25) and healthy controls (HC;
n
= 26).
Results:
HSR had lower scores than LSR on the MAIA scales Not-Distracting and Not-Worrying. The SFD and MDD groups showed lower scores than HC on the MAIA scales Not-Distracting, Self-Regulation, and Trusting. The MDD group scored lower than the other two groups on the scales Body Listening and Attention Regulation. There were no group differences on the scale Noticing.
Conclusion:
HSR, SFD, and MDD patients do not differ from HC in the awareness of noticing of interoceptive signal processing, whereas cognitive facets of interoception, such as distraction or self-regulation are differentially affected. This highlights the necessity of including specifically targeted interventions, which improve interoceptive awareness, in the prevention and treatment of SFDs.
The Wnt/β-catenin pathway is a critical regulator of development and stem cell maintenance. Mounting evidence suggests that the outcome of Wnt signaling is determined by the collaborative action of ...multiple transcription factors, including members of the highly conserved forkhead box (FOX) protein family. However, the contribution of FOX transcription factors to Wnt signaling has not been investigated in a systematic manner. Here, we performed complementary screens of all 44 human FOX proteins to identify new Wnt pathway regulators. By combining β-catenin reporter assays with Wnt pathway–focused qPCR arrays and proximity proteomics of selected candidates, we determine that most FOX proteins are involved in the regulation of Wnt pathway activity. As proof-of-principle, we additionally characterize class D and I FOX transcription factors as physiologically relevant regulators of Wnt/β-catenin signaling. We conclude that FOX proteins are common regulators of Wnt/β-catenin–dependent gene transcription that may control Wnt pathway activity in a tissue-specific manner.
Abstract The electroencephalographically measured Bereitschafts (readiness)-potential in the supplementary motor area (SMA) serves as a signature of the preparation of motor activity. Using a ...multichannel, noninvasive near-infrared spectroscopy (NIRS) imager, we studied the vascular correlate of the readiness potential. Sixteen healthy subjects performed a self-paced or externally triggered motor task in a single or repetitive pattern, while NIRS simultaneously recorded the task-related responses of deoxygenated hemoglobin (HbR) in the primary motor area (M1) and the SMA. Right-hand movements in the repetitive sequence trial elicited a significantly greater HbR response in both the SMA and the left M1 compared to left-hand movements. During the single sequence condition, the HbR response in the SMA, but not in the M1, was significantly greater for self-paced than for externally cued movements. Nonetheless, an unequivocal temporal delay was not found between the SMA and M1. Near-infrared spectroscopy is a promising, noninvasive bedside tool for the neuromonitoring of epileptic seizures or cortical spreading depolarizations (CSDs) in patients with epilepsy, stroke, or brain trauma because these pathological events are associated with typical spatial and temporal changes in HbR. Propagation is a characteristic feature of these events which importantly supports their identification and characterization in invasive recordings. Unfortunately, the present noninvasive study failed to show a temporal delay during self-paced movements between the SMA and M1 as a vascular correlate of the readiness potential. Although this result does not exclude, in principle, the possibility that scalp-NIRS can detect a temporal delay between different regions during epileptic seizures or CSDs, it strongly suggests that further technological development of NIRS should focus on both improved spatial and temporal resolution. This article is part of a Special Issue entitled Status Epilepticus.
Purpose
In the last years the penetration of enterprise resource planning (ERP) systems within small, medium and large organizations increased steadily. Organizations are forced to adapt their ...systems and perform ERP upgrades in order to react to rapidly changing business environments, technological enhancements and rising pressure of competition. The purpose of this paper is to focus on the critical success factors for such projects.
Design/methodology/approach
The paper is based on a literature review and qualitative interviews with CEOs, CIOs, ERP consultants and project managers who recently carried out ERP upgrade projects in their respective organizations.
Findings
This paper identifies 14 critical success factors for ERP upgrade projects. Amongst others, effective project management, external support, the composition of the ERP team and the usage of a multiple system landscape play a key role for the success of the ERP upgrade. Furthermore, a comparison to the critical success factors for ERP implementation projects was conducted, and even though there are many similarities between these types of projects, several differences emerged.
Originality/value
ERP upgrade projects have a huge impact on organizations, but their success and antecedents for it are currently under-researched.
Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer ...differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome—rate of ypT0 status—to justify subsequent prospective validation within the “BladderBRIDGister”. Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal−Wallis, Mann−Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.
In a simultaneous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) study, the predictive value of the individual alpha-frequency at rest (IAF) for the amplitude of neuronal and ...vascular responses to visual stimulation was investigated. Across subjects, we find (i) an inverse relationship between IAF and the amplitude of the alpha-rhythm at rest. The IAF also predicts (ii) the amplitude of the visual evoked potential (VEP), as well as (iii) the amplitude of the alpha-rhythm during stimulation. Most importantly, (iv) IAF correlates with the oxygenation response to visual stimulation: A high IAF predicts a low alpha-amplitude at rest, a small VEP amplitude and a small oxygenation response. Conversely, a low IAF predicts high alpha-amplitude and larger electrophysiological and vascular responses to stimulation. Based on these findings, we assume that the relationship between IAF and neuronal and vascular response stems from the size of the network recruited for visual processing. The relation between IAF, alpha-amplitude, evoked potential and vascular response is discussed in the framework of a simple heuristic model. The results may partly explain the large intersubject variability observed in recently published concurrent EEG-fMRI studies.
•The concentrations and loads of DRP and TP decreased significantly in the 1990s.•Decreases are related to improved waste water treatment techniques.•In the 21st century TP concentrations and loads ...tend to increase.•TP concentrations, in contrast to DRP, closely follow peak flow events.•Intensive flow events may cause internal soil and river bank erosion and an according phosphorus mobilization.
The Warnow River Basin, an agriculturally dominated lowland watershed in North-Eastern Germany with a considerable extent of artificial drainage.
We analyzed a 21-year data set (1990–2010) of dissolved reactive (DRP) and total phosphorus (TP) concentrations in surface waters to evaluate trends and seasonality of phosphorus (P) concentrations and pathways of P losses from soils.
Phosphorus concentrations were moderately spatially variable over the investigation period and mean DRP and TP concentrations ranged from 57 to 132 mg l−1 and 114 to 184 μg l−1 respectively. The mean annual DRP and TP loads ranged from 0.04 ± 0.01 to 0.15 ± 0.05 and 0.12 ± 0.05 to 0.27 ± 0.06 kg ha−1 a−1, respectively. We detected significant negative temporal trends of P concentrations and loads in the decade 1990–2000. In the 21st century, the TP concentrations and loads tend to increase moderately. The results underline the importance of baseflow for DRP export and storm flow events for TP export, and emphasize the importance of artificial drainage systems modifying the hydrological regime of soils and surface waters alike. The P export rates during storm events and the proportion of particulate phosphorus in artificial drainage systems should be monitored at a higher temporal resolution to obtain a comprehensive database necessary for developing management strategies to reduce P loads in agricultural used landscapes.
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