APC/CCdh1 regulates the balance between maintenance and differentiation of hematopoietic stem and progenitor cells.

Hematopoietic stem and progenitor cells (HSPCs) represent the lifelong source of all blood cells and continuously regenerate the hematopoietic system through differentiation and self-renewal. The process of differentiation is initiated in the G1 phase of the cell cycle, when stem cells leave their quiescent state. During G1, the anaphase-promoting complex or cyclosome associated with the coactivator Cdh1 is highly active and marks proteins for proteasomal degradation to regulate cell proliferation. Following Cdh1 knockdown in HSPCs, we analyzed human and mouse hematopoiesis in vitro and in vivo in competitive transplantation assays. We found that Cdh1 is highly expressed in human CD34+ HSPCs and downregulated in differentiated subsets; whereas, loss of Cdh1 restricts myeloid differentiation, supports B cell development and preserves immature short-term HSPCs without affecting proliferation or viability. Our data highlight a role of Cdh1 as a regulator of balancing the maintenance of HSPCs and differentiation into mature blood cells.

Implicit motives and basic psychological needs.

The present article starts with discussing similarities and differences between conceptualizations of human needs in self-determination theory (SDT; Deci & Ryan [1985], Intrinsic motivation and self-determination in human behavior; Deci & Ryan [2000], Nebraska symposium on motivation: Perspectives on motivation) and motive disposition theory (MDT; McClelland, Human motivation, 1985). The second section focuses on the two-process model of psychological needs (Sheldon [2011], Psychological Review, 118: 552), which aims to integrate the two approaches, whereas the third section highlights some aspects of both theories that are still decoupled or even contradictory, but nevertheless still have a high potential to be linked. These three aspects are (a) the noncorresponding concepts of implicit power motive (MDT) and basic need for autonomy (SDT); (b) the differentiation of needs into hope and fear components, which is theoretically embedded in MDT, but not in SDT; and (c) MDT researchers' differentiation into an implicit and explicit motivational system, which is not included in SDT. Particularly, the last section highlights the potential for areas in which further integration is possible, which provides a foundation for comprehensive and exciting research on human motivation.

Trait Self-Control Outperforms Trait Fatigue in Predicting MS Patients' Cortical and Perceptual Responses to an Exhaustive Task.

Patients with multiple sclerosis (PwMS) frequently suffer from fatigue, but this debilitating symptom is not yet fully understood. We propose that self-control can be conceptually and mechanistically linked to the fatigue concept and might help explain some of the diversity on how PwMS who suffer from fatigue deal with this symptom. To test this claim, we first assessed how cortical oxygenation and measures of motor and cognitive state fatigue change during a strenuous physical task, and then we tested the predictive validity of trait fatigue and trait self-control in explaining the observed changes. A sample of N = 51 PwMS first completed a test battery to collect trait measures of fatigue and self-control. PwMS then performed an isometric hand contraction task at 10% of their maximum voluntary contraction until exhaustion while we repeatedly assessed ratings of perceived cognitive and motor exertion. In addition, we continuously measured oxygenation of the prefrontal cortex (PFC) using functional near-infrared spectroscopy. Linear mixed-effect models revealed significant increases in perceived motor and cognitive exertion, as well as increases in PFC oxygenation. Hierarchical stepwise regression analyses showed that higher trait self-control predicted a less steep increase in PFC oxygenation and perceived cognitive exertion, while trait fatigue did not predict change in any dependent variable. These results provide preliminary evidence for the suggested link between self-control and fatigue. As self-control can be enhanced with training, this finding possibly has important implications for devising nonpharmacological interventions to help patients deal with symptoms of fatigue.

Noninvasive positron emission tomography and fluorescence imaging of CD133+ tumor stem cells.

A technology that visualizes tumor stem cells with clinically relevant tracers could have a broad impact on cancer diagnosis and treatment. The AC133 epitope of CD133 currently is one of the best-characterized tumor stem cell markers for many intra- and extracranial tumor entities. Here we demonstrate the successful noninvasive detection of AC133(+) tumor stem cells by PET and near-infrared fluorescence molecular tomography in subcutaneous and orthotopic glioma xenografts using antibody-based tracers. Particularly, microPET with (64)Cu-NOTA-AC133 mAb yielded high-quality images with outstanding tumor-to-background contrast, clearly delineating subcutaneous tumor stem cell-derived xenografts from surrounding tissues. Intracerebral tumors as small as 2-3 mm also were clearly discernible, and the microPET images reflected the invasive growth pattern of orthotopic cancer stem cell-derived tumors with low density of AC133(+) cells. These data provide a basis for further preclinical and clinical use of the developed tracers for high-sensitivity and high-resolution monitoring of AC133(+) tumor stem cells.

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare malignancy, accounting for <1 % of all pancreatic neoplasms. Very few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic PACC who achieved prolonged survival following doxorubicin treatment. Personalized treatment was based on molecular and in vitro data collected from primary cells developed from their liver metastasis. We now report the characterization of a patient derived tumor xenograft (PDTX) mouse model that originated from this patient's PACC liver metastasis. METHODS: Fragments of biopsy tissue (5 mm(3)) from PACC liver metastasis were implanted into athymic nude mice. Tumors were grown and passaged from the host mice into new mice to be tested for therapeutic response. Immuno-histochemical (IHC) biomarkers were used to confirm that the PDTX model represents human PACC. The antitumor activities of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) were tested. Tumor size was measured over 74 days or until they reached an endpoint volume of ~800 mm(3). Tests to measure serum lipase levels and histological analyses of tumor tissues were also conducted to assess PACC progression and re-differentiation. RESULTS: The model presented here expresses the same IHC markers found in human PACC. In the chemotherapy study, oxaliplatin produced a prolonged durable growth response associated with increased apoptosis, decreased serum lipase levels and increased healthy acinar cells. Bevacizumab also produced a significant growth response, but the effect was not prolonged as demonstrated by oxaliplatin treatment. The other chemotherapies had moderate to little effect, particularly after treatment ceased. Mutations in DNA repair genes are common in PACC and increase tumor susceptibility to oxaliplatin. To explore this we performed IHC and found no nuclear expression of BRCA2 in our model, indicating a mutation affecting nuclear localization. Gene sequencing confirms BRCA2 has a homozygous gene deletion on Exon 10, which frequently causes a protein truncation. CONCLUSIONS: In summary, we report the development and characterization of the first and only preclinical PACC PDTX model. Here we show sustained anti-tumor activity of single agent oxaliplatin, a compound that is more effective in tumors that harbor mutations in DNA repair genes. Our data shows that BRCA2 is mutated in our PACC model, which could contribute to the oxaliplatin sensitivity observed. Further studies on this rare PACC model can serve to elucidate other novel therapies, biomarkers, and molecular mechanisms of signaling and drug resistance.

Do Some People Need Autonomy More Than Others? Implicit Dispositions Toward Autonomy Moderate the Effects of Felt Autonomy on Well-Being.

The present studies examined whether implicit or explicit autonomy dispositions moderate the relationship between felt autonomy and well-being. Study 1 (N = 187 undergraduate students) presents an initial test of the moderator hypothesis by predicting flow experience from the interaction of autonomy need satisfaction and autonomy dispositions. Study 2 (N = 127 physically inactive persons) used vignettes involving an autonomy (un)supportive coach to test a moderated mediation model in which perceived coach autonomy support leads to well-being through basic need satisfaction. Again, the effects of need satisfaction on well-being were hypothesized to be moderated by an implicit autonomy disposition. Study 1 showed that individuals with a strong implicit autonomy (but not power or achievement) motive disposition derived more flow experience from felt autonomy than individuals with a weak implicit autonomy disposition. Study 2 revealed that perceived autonomy support from sports coaches, which we experimentally induced with a vignette method, leads to autonomy satisfaction, leading in turn to positive effects on well-being. This indirect effect held at high and average but not low implicit autonomy disposition. The results indicate that the degree to which people benefit from autonomy need satisfaction depends on their implicit disposition toward autonomy.

Early development of human lymphomas in a prostate cancer xenograft program using triple knock-out immunocompromised mice.

BACKGROUND: There is an urgent need for preclinical models of prostate cancer; however, clinically relevant patient-derived prostate cancer xenografts (PDXs) are demanding to establish. METHODS: Sixty-seven patients who were undergoing palliative transurethral surgery or radical prostatectomy for histologically confirmed, clinically relevant prostate cancer were included in the study. Fresh prostate cancer tissue was identified by frozen analysis in 48 patients. The cancer tissue was transplanted subcutaneously and under the renal capsule of NSG and NOG mice supplemented with human testosterone. All growing PDXs were evaluated by histology and immunohistochemistry. RESULTS: Early assessment of the animals at least three months after transplantation included 27/48 (56.3%) eligible PDX cohorts. PDX growth was detected in 10/27 (37%) mouse cohorts. Eight of the ten PDXs were identified as human donor derived lymphomas, including seven Epstein Barr virus (EBV)-positive diffuse large B-cell lymphomas and one EBV-negative peripheral T-cell lymphoma. One sample consisted of benign prostatic tissue, and one sample comprised a benign epithelial cyst. Prostate cancer was not detected in any of the samples. CONCLUSIONS: Tumors that arise within the first three months after prostate cancer xenografting may represent patient-derived EBV-positive lymphomas in up to 80% of the early growing PDXs when using triple knockout NSG immunocompromised mice. Therefore, lymphoma should be excluded in prostate cancer xenografts that do not resemble typical prostatic adenocarcinoma.

A comprehensive genomic, transcriptomic and proteomic analysis of a hyperosmotic stress sensitive α-proteobacterium.

BACKGROUND: With the aim of remaining viable, bacteria must deal with changes in environmental conditions, including increases in external osmolarity. While studies concerning bacterial response to this stress condition have focused on soil, marine and enteric species, this report is about Caulobacter crescentus, a species inhabiting freshwater oligotrophic habitats. RESULTS: A genomic analysis reported in this study shows that most of the classical genes known to be involved in intracellular solute accumulation under osmotic adaptation are missing in C. crescentus. Consistent with this observation, growth assays revealed a restricted capability of the bacterium to propagate under hyperosmotic stress, and addition of the compatible solute glycine betaine did not improve bacterial resistance. A combination of transcriptomic and proteomic analyses indicated quite similar changes triggered by the presence of either salt or sucrose, including down-regulation of many housekeeping processes and up-regulation of functions related to environmental adaptation. Furthermore, a GC-MS analysis revealed some metabolites at slightly increased levels in stressed cells, but none of them corresponding to well-established compatible solutes. CONCLUSION: Despite a clear response to hyperosmotic stress, it seems that the restricted capability of C. crescentus to tolerate this unfavorable condition is probably a consequence of the inability to accumulate intracellular solutes. This finding is consistent with the ecology of the bacterium, which inhabits aquatic environments with low nutrient concentration.

Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia.

The receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) is implicated in various tumor entities including chronic lymphocytic leukemia (CLL), but its functional significance in this disease remains poorly characterized. Here, we show that the IGF1R protein is overexpressed in various CLL subsets, suggesting a contribution to CLL pathology. Indeed, we show that IGF1R knockdown in primary human CLL cells compromised their viability. Likewise, IGF1R inhibition with 3 structurally distinct compounds induced apoptosis, even in the presence of protective stroma components. Furthermore, IGF1R inhibition effectively limited CLL development in Eµ-TCL1 transgenic mice and of primary human CLL xenografts. In agreement with its prosurvival function, IGF1R inhibition affected the phosphorylation and/or expression of multiple signaling proteins. The multikinase inhibitor sorafenib yielded similar effects on these signaling elements as IGF1R inhibitors. Indeed, IGF1R appears to be a direct sorafenib target because sorafenib decreased IGF1R expression and phosphorylation, counteracted insulin-like growth factor-1 (IGF-1) binding to CLL cells, and lowered the in vitro kinase activity of recombinant, purified IGF1R. Thus, we demonstrate that blockade of IGF1R-mediated signaling represents a novel mechanism of action for sorafenib in CLL. Importantly, IGF1R inhibitors compromise CLL viability in their microenvironment context, implicating this RTK as a promising therapeutic target.

The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells.

BACKGROUND: The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs) such as erlotinib. Chromatin-modifying agents may offer a novel therapeutic approach by sensitizing tumor cells to TKIs. METHODS: The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) and NCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation after panobinostat (LBH-589, PS) and erlotinib treatment were quantified by WST-1 assay and apoptosis by Annexin V/7-AAD flow cytometry. Abundance of target proteins and histone marks (acH3, H3K4me1/2/3) was determined by immunoblotting. RESULTS: As expected, the EGFR wt cell lines A549 and NCI-H460 were quite insensitive to the growth-inhibitory effect of erlotinib (IC50 70-100 µM), compared to HCC827 (IC50<0.02 µM). All three cell lines were sensitive to PS treatment (IC50: HCC827 10 nM, A549 20 nM and NCI-H460 35 nM). The combination of both drugs further reduced proliferation in HCC827 and in A549, but not in NCI-H460. PS alone induced differentiation and expression of p21WAF1/CIP1 and p53 and decreased CHK1 in all three cell lines, with almost no further effect when combined with erlotinib. In contrast, combination treatment additively decreased pEGFR, pERK and pAKT in A549. Both drugs synergistically induced acH3 in the adenocarcinoma lines. Surprisingly, we also observed induction of H3K4 methylation marks after erlotinib treatment in HCC827 and in A549 that was further enhanced by combination with PS. CONCLUSION: PS sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. In these cell lines, the drug combination also had a robust, not previously described effect on histone H3 acetylation and H3K4 methylation.

The isothiocyanate erucin abrogates telomerase in hepatocellular carcinoma cells in vitro and in an orthotopic xenograft tumour model of HCC.

In contrast to cancer cells, most normal human cells have no or low telomerase levels which makes it an attractive target for anti-cancer drugs. The small molecule sulforaphane from broccoli is known for its cancer therapeutic potential in vitro and in vivo. In animals and humans it was found to be quickly metabolized into 4-methylthiobutyl isothiocyanate (MTBITC, erucin) which we recently identified as strong selective apoptosis inducer in hepatocellular carcinoma (HCC) cells. Here, we investigated the relevance of telomerase abrogation for cytotoxic efficacy of MTBITC against HCC. The drug was effective against telomerase, independent from TP53 and MTBITC also blocked telomerase in chemoresistant subpopulations. By using an orthotopic human liver cancer xenograft model, we give first evidence that MTBITC at 50 mg/KG b.w./d significantly decreased telomerase activity in vivo without affecting enzyme activity of adjacent normal tissue. Upon drug exposure, telomerase decrease was consistent with a dose-dependent switch to anti-survival, cell arrest and apoptosis in our in vitro HCC models. Blocking telomerase by the specific inhibitor TMPyP4 further sensitized cancer cells to MTBITC-mediated cytotoxicity. Overexpression of hTERT, but not enzyme activity deficient DNhTERT, protected against apoptosis; neither DNA damage nor cytostasis induction by MTBITC was prevented by hTERT overexpression. These findings imply that telomerase enzyme activity does not protect against MTBITC-induced DNA damage but impacts signalling processes upstream of apoptosis execution level.

The influence of avoidance temperament and avoidance-based achievement goals on flow.

In the present research, we conducted two studies designed to examine the joint influence of avoidance temperament and avoidance-based achievement goals on the experience of flow on a creativity task. In both a laboratory study (N = 101; M(age) = 22.61, SD(age) = 4.03; 74.3% female) and a naturalistic study (N = 102; M(age) = 16.23, SD(age) = 1.13; 48% female), participants high in avoidance temperament were shown to experience greater flow when performance-avoidance goals were induced; no differences were found in any of the other three achievement goal conditions from the 2 × 2 achievement goal framework. These findings reveal a short-term benefit for a disposition-goal match grounded in avoidance motivation, and point to the need for more research on both avoidance-based matches and the short-term versus long-term implications of such matches.

Implicit motives and basic need satisfaction in extreme endurance sports.

Previous research has shown that the effects of basic psychological needs on the flow experience in sports are moderated by implicit motives. However, so far, only leisure and health-oriented sports have been analyzed. In a pilot study and a main study (N = 29, 93), we tested whether the implicit achievement and affiliation motives interact with the need for competence and the need for social relatedness satisfaction, respectively, to predict flow experience and well-being in extreme endurance athletes. Results showed that highly achievement-motivated individuals benefited more from the need for competence satisfaction in terms of flow than individuals with a low achievement motive did. In addition, highly affiliation-motivated individuals whose need for social relatedness is satisfied reported higher positive affect and lower exercise addiction scores than athletes with a low motive. We discuss the differential effects of the interplay between the achievement and affiliation motives and basic needs on different outcome variables.

Easy-to-implement educational interventions to bring climate-smart actions to daily anesthesiologic practice: a cross-sectional before and after study.

BACKGROUND: Anesthesia contributes significantly to a hospital's carbon footprint. Climate-smart actions have the potential to reduce greenhouse gas emissions. Prerequisites for sustainable behavior of providers are knowledge and awareness. We aimed to assess the change in anesthesiologists' climate-friendly behavior before and after educational interventions in three areas that every anesthesiologist can address in their daily clinical routine: 1) energy use; 2) recycling opportunities; 3) consumption of volatile anesthetics. METHODS: We performed a cross-sectional before-and-after single center sub-study within the multicenter "Provider Education and Evaluation Project" at the Department of Anesthesiology, RWTH Aachen University hospital from May3 2021 to May 1 2022. Educational interventions consisted of stickers, posters and a presentation on climate-smart actions in anesthesiologists' work routine between the first and the second assessment. For each cross-sectional assessment, all central 28 ORs were observed for one week. During the before-and-after comparison we analyzed: 1) energy wasted in unoccupied ORs because of running computers and turned-on lights at 9 p.m.; 2) feasibility of recycling preoperative anesthesia plastic packaging by determining the difference between calculated weight of unseparated preoperative plastic waste in the first assessment and the weight of actual separated waste in the second assessment; 3) fresh gas flow in balanced anesthesia cases in steady state at 9 a.m., and purchased hypnotics converted to bottles/1000 general anesthesia cases in 2018-2022. RESULTS: We observed a reduction of wasted energy by 44% in unoccupied ORs. Usage of low fresh gas flow settings increased from 55% to 75%. The average of purchased desflurane in 2018-2020 decreased by 72% in 2022. We calculated 10.33 kg of preoperative plastic waste per week but were unable to implement waste separation for infrastructural and logistical reasons. CONCLUSIONS: We found that environment-friendly working behaviors increased after the implementation of educational interventions. The causality between the interventions and the observed improvements remains to be proven.

The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition.

Targeting aberrantly expressed kinases in malignant pleural mesothelioma (MPM) is a promising therapeutic strategy. We here investigated the effect of the novel and highly selective Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib (IOA-244) on MPM cells and on the immune cells in MPM microenvironment. To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). In a co-culture model of patient-derived MPM cells, autologous peripheral blood mononuclear cells and fibroblasts, the tumor cell viability and changes in immune cell composition were investigated after treatment of roginolisib with nivolumab and cisplatin. PI3K-δ was detected in 66/89 (74%) MPM tumors and was associated with reduced overall survival (12 vs. 25 months, P=0.0452). Roginolisib induced apoptosis in MPM cells and enhanced the anti-tumor efficacy of AKT and mTOR kinase inhibitors by suppressing PI3K-δ/AKT/mTOR and ERK1/2 signaling. Furthermore, the combination of roginolisib with chemotherapy and immunotherapy re-balanced the immune cell composition, increasing effector T-cells and reducing immune suppressive cells. Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin. These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen.

Data visualization in environmental proteomics.

From raw data to gene expression profiles, from single cultures to complex microbial communities, environmental proteomics works with data of different complexity levels that need to be interpreted in detail or in its entirety. Although data visualization is closely connected with data analysis approaches, this work will solely focus on data visualization. Complementing traditional tools such as bar charts or line graphs, scientists and visualization professionals have been provided sophisticated visualization tools. Many rules and concerns regarding the display of single but also complex data will be reviewed and discussed. Visual approaches such as microcharts, heat maps, stream graphs, and tree maps will be brought to the reader's attention and demonstrated by utilizing real data sets.

Potent in vitro and in vivo activity of sorafenib in multiple myeloma: induction of cell death, CD138-downregulation and inhibition of migration through actin depolymerization.

Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363-bearing non-obese diabetic severe combined immunodeficient mice with a deficient interleukin-2 receptor gamma chain (NSG). In vitro, we observed a dose-dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co-expressing histone 2B-mCherry and cytochrome c-GFP, bortezomib- and sorafenib-induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138-downregulation and abolished CXCL12-induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho-ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363-bearing NSG. Correspondingly, sorafenib induced clinical responses in MM-/AL-amyloidosis patients. We conclude that, in addition to the cytotoxic and anti-angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.

Avoidance goal pursuit depletes self-regulatory resources.

OBJECTIVE: Research on the strength model of self-regulation is burgeoning, but little empirical work has focused on the link between distinct types of daily goal pursuit and the depletion of self-regulatory resources. The authors conducted two studies on the link between avoidance goals and resource depletion. METHOD: Study 1 (283 [228 female] Caucasians, ages 18-51) investigated the concurrent and longitudinal relations between avoidance goals and resource depletion over a 1-month period. Study 2 (132 [93 female] Caucasians, ages 18-49) investigated the concurrent and longitudinal relations between avoidance goals and resource depletion over a 1-month period and explored resource depletion as a mediator of the avoidance goal to subjective well-being relation. RESULTS: Studies 1 and 2 documented both a concurrent and a longitudinal negative relationship between avoidance goals and self-regulatory resources, and Study 2 additionally showed that self-regulatory resources mediate the negative link between avoidance goals and subjective well-being. Ancillary analyses demonstrated that the results observed in the two studies were independent of neuroticism. CONCLUSIONS: These findings advance knowledge in both the resource depletion and avoidance goal literatures, and bolster the view that avoidance goal pursuit over time represents a self-regulatory vulnerability.

Inversin relays Frizzled-8 signals to promote proximal pronephros development.

Mutations of inversin cause type II nephronophthisis, an infantile autosomal recessive disease characterized by cystic kidney disease and developmental defects. Inversin regulates Wnt signaling and is required for convergent extension movements during early embryogenesis. We now show that Inversin is essential for Xenopus pronephros formation, involving two distinct and opposing forms of cell movements. Knockdown of Inversin abrogated both proximal pronephros extension and distal tubule differentiation, phenotypes similar to that of Xenopus deficient in Frizzled-8. Exogenous Inversin rescued the pronephric defects caused by lack of Frizzled-8, indicating that Inversin acts downstream of Frizzled-8 in pronephros morphogenesis. Depletion of Inversin prevents the recruitment of Dishevelled in response to Frizzled-8 and impeded the accumulation of Dishevelled at the apical membrane of tubular epithelial cells in vivo. Thus, defective tubule morphogenesis seems to contribute to the renal pathology observed in patients with nephronophthisis type II.

Mind-over-body beliefs in sport and exercise: A driving force for training volume and performance, but with risks for exercise addiction.

We assume that athletic success is associated with certain beliefs that on the one hand promote performance-enhancing behavior (training volume), but on the other hand can also be detrimental to health (sports addiction). These beliefs are succinctly characterized by the title of the 9-item "Mind-over-Body" scale presented here. They are the three beliefs that 1) athletic performance requires a high level of effort, 2) that willpower plays an important role in athletic success, and 3) that athletic success requires pain tolerance. A total of six web-survey-based studies with a total of 1121 participants (approximately gender parity), including individuals with different levels of athletic performance (no competition; amateur sport; regional, national, or international competition), examined the psychometric network and construct and criterion validity of the MoB scale. Exploratory graph analyses, which included the studies with the largest sample sizes, showed that the three belief components (effort, willpower, pain) form separable communities within the MoB network and that the MoB items form communities distinct from self-control and self-efficacy. Meta-analyzed correlations across all six studies showed low positive correlations with self-control and self-efficacy. In terms of criterion validity, MoB beliefs were positively correlated with training volume and exercise addiction. We discuss MoBs as "on the edge of unhealthy" and place MOBs within a framework of related but distinct concepts.