Ca<Superscript>2+</Superscript> signals,cell membrane disintegration,and activation of TMEM16F during necroptosis

Activated receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain like (MLKL) are essential components of the necroptotic pathway. Phosphorylated MLKL (pMLKL) is thought to induce membrane leakage, leading to cell swelling and disintegration of the cell membrane. However, the molecular identity of the necroptotic membrane pore remains unclear, and the role of pMLKL for membrane permeabilization is currently disputed. We observed earlier that the phospholipid scramblase and ion channel TMEM16F/anoctamin 6 cause large membrane currents, cell swelling, and cell death when activated by a strong increase in intracellular Ca²⁺. We, therefore, asked whether TMEM16F is also central to necroptotic cell death and other cellular events during necroptosis. Necroptosis was induced by TNFα, smac mimetic, and Z-VAD (TSZ) in NIH3T3 fibroblasts and the four additional cell lines HT₂₉, 16HBE, H441, and L929. Time-dependent changes in intracellular Ca²⁺, cell morphology, and membrane currents were recorded. TSZ induced a small and only transient oscillatory rise in intracellular Ca²⁺, which was paralleled by the activation of outwardly rectifying Cl^? currents, which were typical for TMEM16F/ANO6. Ca²⁺ oscillations were due to Ca²⁺ release from endoplasmic reticulum, and were independent of extracellular Ca²⁺. The initial TSZ-induced cell swelling was followed by cell shrinkage. Using typical channel blockers and siRNA-knockdown, the Cl^? currents were shown to be due to the activation of ANO6. However, the knockdown of ANO6 or inhibitors of ANO6 did not inhibit necroptotic cell death. The present data demonstrate the activation of ANO6 during necroptosis, which, however, is not essential for cell death.     

Exome sequencing of liver fluke-associated cholangiocarcinoma

Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA.     

关于Wiman－Valiron理论

在本文中利用Ｍａｃｉｎｔｙｒｅ的一个简化方法，证明了Ｗｉｍａｎ－Ｖａｌｉｒｏｎ理论中一个定理的新形式，并给出它对于线性微分方程和代数微分方程的一些应用．     

Einfluß antianaphylaktisch wirkender Stoffe auf die Antikörperproduktion

Summary To produce antisera of high antibody concentration animals after sensitization with protein have been reinjected with lethal doses of the antigen, protected against the shock-effect by substances with antihistamin properties (as example Antistin). The antibody concentration was considerably higher in these animals as in the other non-protected group reinjected with the highest tolerated antigen dosage.     

关于Borel的一个定理

Borel的一个经典性定理是,如果两组整函数G_i(Z)(i=1,2,…,n)和H_i(Z)(i=1,2,…n)满足恒等式sum from j=1 to n G_i(Z)e~Hj~(Z)≡0 并且如果G_i(1≤i≤n)的增长性,在某种意义下,较慢于e~Hj~(-H)k(1≤j,k≤n,j≠k)的增长性,则G_i(Z)≡0 (i=1,2,…,n),在本文中得出了这个定理的几个推广。     

Die «Sprache» der Bienen und ihre Nutzanwendung in der Landwirtschaft

Ohne ZusammenfassungVortrag an der 126. Jahresversammlung der Schweizerischen naturforschenden Gesellschaft in Zürich ant 8. September 1946.     

Mineral lick use by GPS radio-collared mountain goats in southeastern British Columbia

In most populations of mountain goats ( Oreamnos americanus ), mineral lick use is an essential part of the ecology of the species. In many areas, the distribution and use of licks in the landscape is poorly known, rendering planning for resource development difficult. We examined lick use by 28 GPS radio-collared mountain goats in 2 study areas in southeastern British Columbia during 2004&ndash;2005. Viewing collar-location movements on digital orthophotos, we assumed goat use of 6 previously known and 10 suspected mineral licks. Field visits verified that 9 of the 10 suspected sites were mineral licks. Thirteen of the 15 licks used by collared goats were within forests with commercial harvesting potential. All but 3 of the licks were &le;600 m from the closest logging block, and 5 licks were &#60;100 m away. Number of annual visits to licks by individual goats ranged from 0 to 9. Goats often moved considerable distances (up to 17.3 km) to visit licks. Most visits by males occurred between early May and late June (median 9 June), and most visits by females occurred between early June and mid-July (median 21 June). Mean time spent at licks on each visit was 1.5 days for females and 1.6 days for males. Most of the licks were characterized by numerous cavities dug under trees (which we term &ldquo;lick trees&rdquo;). Using GPS collars, we were able to collect data on lower-elevation mineral licks not previously known to researchers.     

Brain homeostasis: VEGF receptor 1 and 2—two unequal brothers in mind

Vascular endothelial growth factors (VEGFs), initially thought to act specifically on the vascular system, exert trophic effects on neural cells during development and adulthood. Therefore, the VEGF system serves as a promising therapeutic target for brain pathologies, but its simultaneous action on vascular cells paves the way for harmful side effects. To circumvent these deleterious effects, many studies have aimed to clarify whether VEGFs directly affect neural cells or if the effects are mediated secondarily via other cell types, like vascular cells. A great number of reports have shown the expression and function of VEGF receptors (VEGFRs), mainly VEGFR-1 and -2, in neural cells, where VEGFR-2 has been described as the major mediator of VEGF-A signals. This review aims to summarize and compare the divergent roles of VEGFR-1 and -2 during CNS development and homeostasis.