Co-activation of hedgehog and AKT pathways promote tumorigenesis in zebrafish

The zebrafish has become an important model for cancer research. Several cancer models have been established by transgenic expression of human or mouse oncogenes in zebrafish. Since it is amenable to efficient transgenesis, zebrafish have immense potential to be used for studying interaction of oncogenes and pathways at the organismal level. Using the Gal4VP16-UAS binary transgenic expression approach, we established stable transgenic lines expressing an EGFP fusion protein of an activated zebrafish Smoothened (Smoa1-EGFP). Expression of the zebrafish Smoa1-EGFP itself did not lead to tumor formation either in founder fish or subsequent generations, however, co-expressing a constitutively active human AKT1 resulted in several tumor types, including spindle cell sarcoma, rhabdomyoma, ocular melanoma, astrocytoma, and myoxma. All tumor types showed GFP expression and increased Patched 1 levels, suggesting involvement of zebrafish Smoa1 in tumorigenesis. Immunofluorescence studies showed that tumors also expressed elevated levels of phosphorylated AKT, indicating activation of the PI3K-AKT pathway. These results suggest that co-activation of the hedgehog and AKT pathways promote tumorigenesis, and that the binary transgenic approach is a useful tool for studying interaction of oncogenes and oncogenic pathways in zebrafish

Zebrafish as a Model for Obesity and Diabetes

Obesity and diabetes now considered global epidemics. The prevalence rates of diabetes are increasing in parallel with the rates of obesity and the strong connection between these two diseases has been coined as “diabesity.” The health risks of overweight or obesity include Type 2 diabetes mellitus (T2DM), coronary heart disease and cancer of numerous organs. Both obesity and diabetes are complex diseases that involve the interaction of genetics and environmental factors. The underlying pathogenesis of obesity and diabetes are not well understood and further research is needed for pharmacological and surgical management. Consequently, the use of animal models of obesity and/or diabetes is important for both improving the understanding of these diseases and to identify and develop effective treatments. Zebrafish is an attractive model system for studying metabolic diseases because of the functional conservation in lipid metabolism, adipose biology, pancreas structure, and glucose homeostasis. It is also suited for identification of novel targets associated with the risk and treatment of obesity and diabetes in humans. In this review, we highlight studies using zebrafish to model metabolic diseases, and discuss the advantages and disadvantages of studying pathologies associated with obesity and diabetes in zebrafish

Research on the Leading Value Drive of Rural Homestead Transfer under Rural Revitalization——Based on the Evidences of China

With the development of urban-rural integration in China, the functional value of homestead bases has evolved from a single residential security value to a multiple composite values, and the property income of homestead bases has gradually become the value driver of transfer and the intrinsic demand of farm households. This paper takes Baitafan of Jinzhai County, Chongqing City, and Xiaofang Yu Village of Ji County as examples for in-depth discussion, and finds that the dominant value drivers of home base transfer mainly include three kinds: capitalization income, commercialization income, and non-farm employment income. The study concludes that it is important to give full play to the resource endowment effect and identify the dominant value of home base transfer according to local conditions to promote the standardized home base transfer and implement the rural revitalization strategy

Overlapping Leigh Syndrome/Myoclonic Epilepsy With Ragged Red Fibres in an Adolescent Patient With a Mitochondrial DNA A8344G Mutation

We present the case of a 16-year-old boy with a family history of epilepsy who presented with acute respiratory failure, limb weakness, diabetes mellitus, sinus tachycardia, lactic acidosis, and pneumonia. He went on to develop cranial nerve palsy, myoclonus, generalized seizures, ataxia, recurrent pneumonia, and hypotension. Biochemical investigation revealed elevated lactate, pyruvate, and glucose levels. Cerebral magnetic resonance imaging (MRI) revealed bilateral, symmetric, high-intensity T2-weighted signals in the thalamus, brainstem, and gray matter of the spinal cord. Histochemical analyses revealed ragged red fibers (RRF) and decreased cytochrome oxidase activity. Blood and muscle-derived DNA demonstrated a high level (95% and 96%, respectively) of the m.8344A>G mutation, while almost all of his maternal relatives (n = 17, including his mother) carried the same point mutation. The point mutation level of his mother (who had short stature, high blood lactate levels, and epilepsy) was 77% (blood-derived DNA). Although this mutation has been identified in approximately 30 individuals with these disorders, to our knowledge, this is the first reported case of overlapping Leigh syndrome/myoclonic epilepsy with RRF in an adolescent patient, and the largest reported pedigree of mitochondrial DNA A8344G mutation

Co-activation of hedgehog and AKT pathways promote tumorigenesis in zebrafish

The zebrafish has become an important model for cancer research. Several cancer models have been established by transgenic expression of human or mouse oncogenes in zebrafish. Since it is amenable to efficient transgenesis, zebrafish have immense potential to be used for studying interaction of oncogenes and pathways at the organismal level. Using the Gal4VP16-UAS binary transgenic expression approach, we established stable transgenic lines expressing an EGFP fusion protein of an activated zebrafish Smoothened (Smoa1-EGFP). Expression of the zebrafish Smoa1-EGFP itself did not lead to tumor formation either in founder fish or subsequent generations, however, co-expressing a constitutively active human AKT1 resulted in several tumor types, including spindle cell sarcoma, rhabdomyoma, ocular melanoma, astrocytoma, and myoxma. All tumor types showed GFP expression and increased Patched 1 levels, suggesting involvement of zebrafish Smoa1 in tumorigenesis. Immunofluorescence studies showed that tumors also expressed elevated levels of phosphorylated AKT, indicating activation of the PI3K-AKT pathway. These results suggest that co-activation of the hedgehog and AKT pathways promote tumorigenesis, and that the binary transgenic approach is a useful tool for studying interaction of oncogenes and oncogenic pathways in zebrafish

Taste buds are not derived from neural crest in mouse, chicken, and zebrafish

Our lineage tracing studies using multiple Cre mouse lines showed a concurrent labeling of abundant taste bud cells and the underlying connective tissue with a neural crest (NC) origin, warranting a further examination on the issue of whether there is an NC derivation of taste bud cells. In this study, we mapped NC cell lineages in three different models, Sox10-iCreER(T2)/tdT mouse, GFP(+) neural fold transplantation to GFP(−) chickens, and Sox10-Cre/GFP-RFP zebrafish model. We found that in mice, Sox10-iCreER(T2) specifically labels NC cell lineages with a single dose of tamoxifen at E7.5 and that the labeled cells were widely distributed in the connective tissue of the tongue. No labeled cells were found in taste buds or the surrounding epithelium in the postnatal mice. In the GFP(+)/GFP(−) chicken chimera model, GFP(+) cells migrated extensively to the cranial region of chicken embryos ipsilateral to the surgery side but were absent in taste buds in the base of oral cavity and palate. In zebrafish, Sox10-Cre/GFP-RFP faithfully labeled known NC-derived tissues but did not label taste buds in lower jaw or the barbel. Our data, together with previous findings in axolotl, indicate that taste buds are not derived from NC cells in rodents, birds, amphibians or teleost fish

Spectroscopy of the rotating BTZ black hole via adiabatic invariance

According to Bohr-Sommerfeld quantization rule, an equally spaced horizon area spectrum of a static, spherically symmetric black hole was obtained under an adiabatic invariant action. This method can be extended to the rotating black holes. As an example, we apply this method to the rotating BTZ black hole and obtain the quantized spectrum of the horizon area. It is shown that the area spectrum of the rotating BTZ black hole is equally spaced and irrelevant to the rotating parameter, which is consistent with the Bekenstein conjecture. Specifically, the derivation do not need the quasinormal frequencies and the small angular momentum limit.Comment: 6 pages, 0 figures, to appear in Sci China Ser G-Phys Mech Astron. arXiv admin note: text overlap with arXiv:1106.229

SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation

“Cytokine storm” is common in critically ill COVID-19 patients, however, mechanisms remain largely unknown. Here, we reported that overexpression of SARS-CoV-2 N protein in diabetic db/db mice significantly increased tubular death and the release of HMGB1, one of the damage-associated molecular patterns (DAMPs), to trigger M1 proinflammatory macrophage activation and production of IL-6, TNF-α, and MCP-1 via a Mincle-Syk/NF-κB-dependent mechanism. This was further confirmed in vitro that overexpression of SARS-CoV-2 N protein caused the release of HMGB1 from injured tubular cells under high AGE conditions, which resulted in M1 macrophage activation and production of proinflammatory cytokines via a Mincle-Syk/NF-κB-dependent mechanism. This was further evidenced by specifically silencing macrophage Mincle to block HMGB1-induced M1 macrophage activation and production of IL-6, TNF-α, and MCP-1 in vitro. Importantly, we also uncovered that treatment with quercetin largely improved SARS-CoV-2 N protein-induced AKI in db/db mice. Mechanistically, we found that quercetin treatment significantly inhibited the release of a DAMP molecule HMGB1 and inactivated M1 pro-inflammatory macrophage while promoting reparative M2 macrophage responses by suppressing Mincle-Syk/NF-κB signaling in vivo and in vitro. In conclusion, SARS-CoV-2 N protein-induced AKI in db/db mice is associated with Mincle-dependent M1 macrophage activation. Inhibition of this pathway may be a mechanism through which quercetin inhibits COVID-19-associated AKI