Sequential and Coordinated Actions of c-Myc and N-Myc Control Appendicular Skeletal Development

BACKGROUND: During limb development, chondrocytes and osteoblasts emerge from condensations of limb bud mesenchyme. These cells then proliferate and differentiate in separate but adjacent compartments and function cooperatively to promote bone growth through the process of endochondral ossification. While many aspects of limb skeletal formation are understood, little is known about the mechanisms that link the development of undifferentiated limb bud mesenchyme with formation of the precartilaginous condensation and subsequent proliferative expansion of chondrocyte and osteoblast lineages. The aim of this study was to gain insight into these processes by examining the roles of c-Myc and N-Myc in morphogenesis of the limb skeleton. METHODOLOGY/PRINCIPAL FINDINGS: To investigate c-Myc function in skeletal development, we characterized mice in which floxed c-Myc alleles were deleted in undifferentiated limb bud mesenchyme with Prx1-Cre, in chondro-osteoprogenitors with Sox9-Cre and in osteoblasts with Osx1-Cre. We show that c-Myc promotes the proliferative expansion of both chondrocytes and osteoblasts and as a consequence controls the process of endochondral growth and ossification and determines bone size. The control of proliferation by c-Myc was related to its effects on global gene transcription, as phosphorylation of the C-Terminal Domain (pCTD) of RNA Polymerase II, a marker of general transcription initiation, was tightly coupled to cell proliferation of growth plate chondrocytes where c-Myc is expressed and severely downregulated in the absence of c-Myc. Finally, we show that combined deletion of N-Myc and c-Myc in early limb bud mesenchyme gives rise to a severely hypoplastic limb skeleton that exhibits features characteristic of individual c-Myc and N-Myc mutants. CONCLUSIONS/SIGNIFICANCE: Our results show that N-Myc and c-Myc act sequentially during limb development to coordinate the expansion of key progenitor populations responsible for forming the limb skeleton

Magyar Geofizika 1988

Introduction Bipolar disorder (BD) is a chronic psychiatric disease which can take most different and unpredictable courses. It is accompanied by unspecific brainstructural changes and cognitive decline. The neurobiological underpinnings of these processes are still unclear. Emerging evidence suggests that tryptophan catabolites (TRYCATs), which involve all metabolites of tryptophan towards the kynurenine (KYN) branch, are involved in the etiology as well as in the course of BD. They are proposed to be mediators of immune-inflammation and neurodegeneration. In this study we measured the levels of KYN and its main catabolites consisting of the neurotoxic hydroxykynurenine (3-HK), the more neuroprotective kynurenic acid (KYNA) and anthranilic acid (AA) and evaluated the ratios between end-products and substrates as proxies for the specific enzymatic activity (3-HK/KYN, KYNA/KYN, AA/KYN) as well as 3-HK/KYNA as a proxy for neurotoxic vs. neuroprotective end-product relation in individuals with BD compared to healthy controls (HC). Methods We took peripheral TRYCAT blood levels of 143 euthymic to mild depressive BD patients and 101 HC. For statistical analyses MANCOVA's controlled for age, sex, body mass index, cardiovascular disease and smoking were performed. Results The levels of KYNA (F=5,579; p<.05) were reduced in BD compared to HC. The enzymatic activity of the kynurenine-3-monooxygenase (KMO) reflected by the 3-HK/KYN ratio was increased in BD individuals compared to HC (F=5,394; p<.05). Additionally the ratio of 3-HK/KYNA was increased in individuals with BD compared to healthy controls (F=11,357; p<.01). Discussion In conclusion our findings subserve the concept of KYN -pathway alterations in the pathophysiology of BD. We present evidence of increased breakdown towards the neurotoxic branch in KYN metabolism even in a euthymic to mild depressive state in BD. From literature we know that depression and mania are accompanied by inflammatory states which should be capable to produce an even greater imbalance due to activation of key enzymes in the neurotoxic direction of KYN -conversion. These processes could finally be involved in the development of unspecific brain structural changes and cognitive deficits which are prevalent in BD. Further research should focus on state dependent changes in TRYCATs and its relation to cognition, brain structure and staging parameters

Conducting nanofibers and organogels derived from the self-assembly of tetrathiafulvalene-appended dipeptides

We demonstrate the nonaqueous self-assembly of a low-molecular-mass organic gelator based on an electroactive p-type tetrathiafulvalene (TTF)–dipeptide bioconjugate. We show that a TTF moiety appended with diphenylalanine amide derivative (TTF-FF-NH2) self-assembles into one-dimensional nanofibers that further lead to the formation of self-supporting organogels in chloroform and ethyl acetate. Upon doping of the gels with electron acceptors (TCNQ/iodine vapor), stable two-component charge transfer gels are produced in chloroform and ethyl acetate. These gels are characterized by various spectroscopy (UV–vis–NIR, FTIR, and CD), microscopy (AFM and TEM), rheology, and cyclic voltammetry techniques. Furthermore, conductivity measurements performed on TTF-FF-NH2 xerogel nanofiber networks formed between gold electrodes on a glass surface indicate that these nanofibers show a remarkable enhancement in the conductivity after doping with TCNQ

Incidental finding of a giant asymptomatic right atrial tumor

Primary cardiac tumors are very rare, atrial myxoma being the most common benign tumor of the heart. They may present with a great variety of incidental asymptomatic masses to severe life-threatening cardiovascular complications necessitating emergency surgery. Here we report the diagnostic evaluation and successful surgical resection of such a giant cardiac tumor which was found on a routine medical check-up in a 62-year-old patient. Histology confirmed diagnosis of unusually huge myxoma. This article demonstrates it’s necessary to include cardiac tumors in the differential diagnosis of subtle and non-specific cardiothoracic symptoms

Scale-dependent optimized homoepitaxy of InAs(111)A

We combined in-situ scanning tunneling microscopy (STM) with the conventional growth characterization methods of atomic force microscopy (AFM) and reflection high energy electron diffraction (RHEED) to simultaneously assess atomic-scale impurities and the larger-scale surface morphology of molecular beam epitaxy (MBE) grown homoepitaxial InAs(111)A. By keeping a constant substrate temperature and indium flux while increasing the As$_2$ flux, we find two differing MBE growth parameter regions for optimized surface roughness on the macro and atomic scale. In particular, we show that a pure step-flow regime with strong suppression of hillock formation can be achieved, even on substrates without intentional offcut. On the other hand, an indium adatom deficient, low atomic defect surface can be observed for a high hillock density. We identify the main remaining point defect on the latter surface by comparison to STM simulations. Furthermore, we provide a method for extracting root-mean-square surface roughness values and discuss their use for surface quality optimization by comparison to scale-dependent, technologically relevant surface metrics. Finally, mapping the separately optimized regions of the growth parameter space should provide a guide for future device engineering involving epitaxial InAs(111)A growth

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Functional Assessment of Vitamin D Status by a Novel Metabolic Approach: The Low Vitamin D Profile Concept.

peer reviewed[en] BACKGROUND: Determining serum 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D [24,25(OH)2D] and the vitamin D metabolite ratio (VMR) allows the identification of individuals with a low vitamin D metabolite profile. Here, we evaluated if such a functional approach provides superior diagnostic information to serum 25(OH)D alone. METHODS: 25(OH)D, 24,25(OH)2D, and the VMR were determined in participants of the DESIRE (Desirable Vitamin D Concentrations, n = 2010) and the LURIC (Ludwigshafen Risk and Cardiovascular Health, n = 2456) studies. A low vitamin D metabolite profile (vitamin D insufficiency) was defined by a 24,25(OH)2D concentration <1.2 ng/mL (<3 nmol/L) and a VMR <4%. Parathyroid hormone (PTH) and bone turnover markers were measured in both cohorts, whereas 10-year mortality data was recorded in LURIC only. RESULTS: The median age in DESIRE and LURIC was 43.3 and 63.8 years, respectively. Median 25(OH)D concentrations were 27.2 ng/mL (68.0 nmol/L) and 15.5 ng/mL (38.8 nmol/L), respectively. Serum 25(OH)D deficiency, defined as <20.2 ng/mL (<50 nmol/L), was present in 483 (24.0%) and 1701 (69.3%) participants of DESIRE and LURIC, respectively. In contrast, only 77 (3.8%) and 521 (21.2%) participants had a low vitamin D metabolite profile. Regardless of the serum 25(OH)D concentration, a low vitamin D metabolite profile was associated with a significantly higher PTH, accelerated bone metabolism, and higher all-cause mortality than an unremarkable vitamin D metabolite profile. CONCLUSIONS: The personalized assessment of vitamin D status using a functional approach better identifies patients with accelerated bone metabolism and increased mortality than the use of a fixed 25(OH)D cutoff of 20 ng/mL (50 nmol/L)

Mapping nanoscale carrier confinement in polycrystalline graphene by terahertz spectroscopy.

Acknowledgements: We acknowledge funding from the Danish National Research Foundation (DNRF) Center for Nanostructured Graphene (DNRF103), the European Union Quantum Flagship and Graphene Flagship Core 2 (785219) and Core 3 (881603), European Union Horizon 2020 Research and Innovation Programme under Grant Agreement No. 824962 (car2TERA), European Union Seventh Framework Programme (FP7) under grant Agreement No. 604000 (GLADIATOR), Innovation Fund Denmark under grant agreement No. 12-131827 (DA-GATE), ERC grants Hetero2D, GIPT, EPSRC Grants EP/L016087/1, EP/K01711X/1, EP/K017144/1, EP/N010345/1, EP/V000055/1, EP/X015742/1 DSTL, EU Grant Graph-X.Funder: DSTLTerahertz time-domain spectroscopy (THz-TDS) can be used to map spatial variations in electrical properties such as sheet conductivity, carrier density, and carrier mobility in graphene. Here, we consider wafer-scale graphene grown on germanium by chemical vapor deposition with non-uniformities and small domains due to reconstructions of the substrate during growth. The THz conductivity spectrum matches the predictions of the phenomenological Drude-Smith model for conductors with non-isotropic scattering caused by backscattering from boundaries and line defects. We compare the charge carrier mean free path determined by THz-TDS with the average defect distance assessed by Raman spectroscopy, and the grain boundary dimensions as determined by transmission electron microscopy. The results indicate that even small angle orientation variations below 5° within graphene grains influence the scattering behavior, consistent with significant backscattering contributions from grain boundaries

Mapping nanoscale carrier confinement in polycrystalline graphene by terahertz spectroscopy

Abstract Terahertz time-domain spectroscopy (THz-TDS) can be used to map spatial variations in electrical properties such as sheet conductivity, carrier density, and carrier mobility in graphene. Here, we consider wafer-scale graphene grown on germanium by chemical vapor deposition with non-uniformities and small domains due to reconstructions of the substrate during growth. The THz conductivity spectrum matches the predictions of the phenomenological Drude–Smith model for conductors with non-isotropic scattering caused by backscattering from boundaries and line defects. We compare the charge carrier mean free path determined by THz-TDS with the average defect distance assessed by Raman spectroscopy, and the grain boundary dimensions as determined by transmission electron microscopy. The results indicate that even small angle orientation variations below 5° within graphene grains influence the scattering behavior, consistent with significant backscattering contributions from grain boundaries

The Relationship Between Food Craving, Appetite-Related Hormones and Clinical Parameters in Bipolar Disorder

Obesity and weight gain in bipolar disorder (BD) have multifactorial underlying causes such as medication side effects, atypical depressive symptomatology, genetic variants, and disturbances in the neuro-endocrinal system. Therefore, we aim to explore the associations between food craving (FC), clinical parameters, psychotropic medication, and appetite-related hormones. In this cross-sectional investigation, 139 individuals with BD and 93 healthy controls (HC) completed the food craving inventory (FCI). In addition, blood samples (including leptin and acylated ghrelin) were analyzed and sociodemographic and anthropometric data were collected. Individuals with BD reported higher frequencies of total FC as well as craving for fat and fast food than HC. Additionally, we found a significant negative correlation between FC and ghrelin levels in BD. Smokers with BD reported significantly more craving for high fat foods than non-smokers. Age was significantly associated with FC independent of group. Individuals with BD taking olanzapine and quetiapine reported higher frequencies of craving for sweet food, while patients currently taking lithium reported less total FC compared to those without lithium therapy. Likewise, patients currently taking valproate reported less total FC and less craving for sweets than those not taking valproate. FC appears to be of clinical relevance in individuals with BD. Contrary to previous data, this does not seem to be a female phenomenon only and might encompass more than the specific craving for carbohydrates. Although due to the cross sectional design, causality cannot be determined, the association between depressive symptomatology and fast food craving warrants further research