Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

BACKGROUND: Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. RESULTS: We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10(−3)). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10(−4)), and estimated bone mineral density (eBMD, P< 2× 10(−5)). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10(−24)) or eBMD (SPP1, P=6× 10(−20)) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2(Y228X/Y228X) mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1(P160X/P160X) mutants predominantly showed mineralisation defects. CONCLUSION: We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01209-8

Simulation of Quantum Magnetism in Mixed Spin Systems with Impurity Doped Ion Crystal

We propose the realization of linear crystals of cold ions which contain different atomic species for investigating quantum phase transitions and frustration effects in spin system beyond the commonly discussed case of $s=1/2$. Mutual spin-spin interactions between ions can be tailored via the Zeeman effect by applying oscillating magnetic fields with strong gradients. Further, collective vibrational modes in the mixed ion crystal can be used to enhance and to vary the strength of spin-spin interactions and even to switch those forces from a ferro- to an antiferromagnetic character. We consider the behavior of the effective spin-spin couplings in an ion crystal of spin-1/2 ions doped with high magnetic moment ions with spin S=3. We analyze the ground state phase diagram and find regions with different spin orders including ferrimagnetic states. In the most simple non-trivial example we deal with a linear $\{$Ca$^+$, Mn$^+$, Ca$^+\}$ crystal with spins of \{1/2,3,1/2}. To show the feasibility with current state-of-the-art experiments, we discuss how quantum phases might be detected using a collective Stern-Gerlach effect of the ion crystal and high resolution spectroscopy. Here, the state-dependent laser-induced fluorescence of the indicator spin-1/2 ion, of species $^{40}$Ca$^+$, reveals also the spin state of the simulator spin-3 ions, $^{50}$Mn$^+$ as this does not possess suitable levels for optical excitation and detection.Comment: 15 pages, 5 figure

PPI-Delayed Diagnosis of Gastrinoma: Oncologic Victim of Pharmacologic Success

Functional neuroendocrine tumors are often low-grade malignant neoplasms that can be cured by surgery if detected early, and such detection may in turn be accelerated by the recognition of neuropeptide hypersecretion syndromes. Uniquely, however, relief of peptic symptoms induced by hypergastrinemia is now available from acid-suppressive drugs such as proton-pump inhibitors (PPIs). Here we describe a clinical case in which time to diagnosis from the onset of peptic symptoms was delayed more than 10 years, in part reflecting symptom masking by continuous prescription of the PPI omeprazole. We propose diagnostic criteria for this under-recognized new clinical syndrome, and recommend that physicians routinely measure serum gastrin levels in persistent cases of PPI-dependent dyspepsia unassociated with H. pylori

Stochastic population growth in spatially heterogeneous environments

Classical ecological theory predicts that environmental stochasticity increases extinction risk by reducing the average per-capita growth rate of populations. To understand the interactive effects of environmental stochasticity, spatial heterogeneity, and dispersal on population growth, we study the following model for population abundances in $n$ patches: the conditional law of $X_{t+dt}$ given $X_t=x$ is such that when $dt$ is small the conditional mean of $X_{t+dt}^i-X_t^i$ is approximately $[x^i\mu_i+\sum_j(x^j D_{ji}-x^i D_{ij})]dt$, where $X_t^i$ and $\mu_i$ are the abundance and per capita growth rate in the $i$-th patch respectivly, and $D_{ij}$ is the dispersal rate from the $i$-th to the $j$-th patch, and the conditional covariance of $X_{t+dt}^i-X_t^i$ and $X_{t+dt}^j-X_t^j$ is approximately $x^i x^j \sigma_{ij}dt$. We show for such a spatially extended population that if $S_t=(X_t^1+...+X_t^n)$ is the total population abundance, then $Y_t=X_t/S_t$, the vector of patch proportions, converges in law to a random vector $Y_\infty$ as $t\to\infty$, and the stochastic growth rate $\lim_{t\to\infty}t^{-1}\log S_t$ equals the space-time average per-capita growth rate \sum_i\mu_i\E[Y_\infty^i] experienced by the population minus half of the space-time average temporal variation \E[\sum_{i,j}\sigma_{ij}Y_\infty^i Y_\infty^j] experienced by the population. We derive analytic results for the law of $Y_\infty$, find which choice of the dispersal mechanism $D$ produces an optimal stochastic growth rate for a freely dispersing population, and investigate the effect on the stochastic growth rate of constraints on dispersal rates. Our results provide fundamental insights into "ideal free" movement in the face of uncertainty, the persistence of coupled sink populations, the evolution of dispersal rates, and the single large or several small (SLOSS) debate in conservation biology.Comment: 47 pages, 4 figure

Laplace Operators on Fractals and Related Functional Equations

We give an overview over the application of functional equations, namely the classical Poincar\'e and renewal equations, to the study of the spectrum of Laplace operators on self-similar fractals. We compare the techniques used to those used in the euclidean situation. Furthermore, we use the obtained information on the spectral zeta function to define the Casimir energy of fractals. We give numerical values for this energy for the Sierpi\'nski gasket

Governance Conditions for Improving Quality Drinking Water Resources: the Need for Enhancing Connectivity

Realising the water quality objectives of the European Water Framework Directive have appeared to stagnate over the last decade all across Europe because of their highly complex nature. In the literature, interactive governance approaches tend to be regarded as the best way of dealing with complex water issues, but so far little empirical evidence has been reported on this perspective in regard to water quality issues. In this paper we have analysed how conditions of governance contribute to the realisation of water quality objectives at different types of drinking water resources in the Netherlands. The analysis demonstrates the importance of addressing different hydrological scales, institutional levels and sectors and thus enhance connectivity in order to improve water quality. The two other important conditions of governance approaches for water quality improvement which were identified are the use of joint fact-finding to gain a shared perception of risks, and the use of explicit decision-making and close monitoring of outcomes (re. water quality improvement), both of which contribute to this enhanced connectivity

Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy

BACKGROUND: Hypophosphatasia (HP) is characterized by a genetic defect in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and predominantly an autosomal recessive trait. HP patients suffer from reduced bone mineralization. Biochemically, elevated concentrations of substrates of TNSALP, including pyridoxal-5'-phosphate and inorganic pyrophosphate occur in serum, tissues and urine. The latter has been associated with chronic inflammation and hyperprostaglandinism. CASE PRESENTATION: We report on 2 affected children presenting with multifocal inflammatory bone lesions mimicking malignancy: A 6 years old girl with short stature had been treated with human growth hormone since 6 months. Then she started to complain about a painful swelling of her left cheek. MRI suggested a malignant bone lesion. Bone biopsy, however, revealed chronic inflammation. A bone scan showed a second rib lesion. Since biopsy was sterile, the descriptive diagnosis of chronic non-bacterial osteomyelitis (CNO) was established. The diagnostic tests related to growth failure were repeated and subsequent analyses demonstrated a molecular defect in the TNSALP gene. The second girl (10 years old) complained about back pain after she had fallen from her bike. X rays of her spine revealed compressions of 2 thoracic vertebrae. At first these were considered trauma related, however a bone scan did show an additional lesion in the right 4(th )rib. A biopsy of this rib revealed a sterile lympho- plasmocytoid osteomyelitis suggesting multifocal CNO. Further analyses did show a decreased TNSALP in leukocytes and elevated pyridoxal phosphate in plasma, suggesting a heterozygous carrier status of HP. CONCLUSION: Chronic bone oedema in adult HP and chronic hyper-prostaglandinism in childhood HP do suggest that in some HP patients bone inflammation is present in conjunction with the metabolic defect. Sterile multifocal osteomyelitis could be demonstrated. Non-steroidal anti-inflammatory treatment achieved complete remission. These cases illustrate chronic inflammation of the bone as a new feature of HP

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD