Changing patterns of growth in a changing planet: How a shift in phenology affects critical life‐history traits in annual fishes

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Lamarck redux and other false arguments against SARS‐CoV‐2 vaccination: Pseudoscientific arguments against vaccination do not stand up to scrutiny

The COVID‐19 pandemic has triggered a new bout of anti‐vaccination propaganda. These are often grounded in pseudoscience and misinterpretation of evolutionary biology. Subject Categories: Economics, Law & Politics, Microbiology, Virology & Host Pathogen Interaction, Science Policy & Publishing

Towards the end of summer of 2021, there seemed cause for cautious optimism for putting this pandemic behind us. It was clear that the route of viral transmission was airborne and not via surfaces (Goldman, 2021a), which means that masks are very efficient at reducing the spread of SARS‐CoV‐2. The number of cases in the United States and Europe were declining, and the first vaccines became available with many people lining up to get their jabs. But not all. A significant portion of the population have been refusing to get vaccinated, some of whom were fooled or encouraged by pseudoscientific misinformation propagated on the Internet.     

The plasma membrane Ca2+ pump isoform 4a differs from isoform 4b in the mechanism of calmodulin binding and activation kinetics: implications for Ca2+ signaling

The inhibition by the regulatory domain and the interaction with calmodulin (CaM) vary among plasma membrane calcium pump (PMCA) isoforms. To explore these differences, the kinetics of CaM effects on PMCA4a were investigated and compared with those of PMCA4b. The maximal apparent rate constant for CaM activation of PMCA4a was almost twice that for PMCA4b, whereas the rates of activation for both isoforms showed similar dependence on Ca2+. The inactivation of PMCA4a by CaM removal was also faster than for PMCA4b, and Ca2+ showed a much smaller effect (2- versus 30-fold modification). The rate constants of the individual steps that determine the overall rates were obtained from stopped-flow experiments in which binding of TA-CaM was observed by changes in its fluorescence. TA-CaM binds to two conformations of PMCA4a, an "open" conformation with high activity, and a "closed" one with lower activity. Compared with PMCA4b (Penheiter, A. R., Bajzer, Z., Filoteo, A. G., Thorogate, R., T?r?k, K., and Caride, A. J. (2003) Biochemistry 41, 12115-12124), the model for PMCA4a predicts less inhibition in the closed form and a much faster equilibrium between the open and closed forms. Based on the available kinetic parameters, we determined the constants to fit the shape of a Ca2+ signal in PMCA4b-overexpressing Chinese hamster ovary cells. Using the constants for PMCA4a, and allowing small variations in parameters of other systems contributing to a Ca2+ signal, we then simulated the effect of PMCA4a on the shape of a Ca2+ signal in Chinese hamster ovary cells. The results reproduce the published data (Brini, M., Coletto, L., Pierobon, N., Kraev, N., Guerini, D., and Carafoli, E. (2003) J. Biol. Chem. 278, 24500-24508), and thereby demonstrate the importance of altered regulatory kinetics for the different functional properties of PMCA isoforms.     

Validation of fractal-like kinetic models by time-resolved binding kinetics of dansylamide and carbonic anhydrase in crowded media

Kinetic studies of biochemical reactions are typically carried out in a dilute solution that rarely contains anything more than reactants, products, and buffers. In such studies, mass-action-based kinetic models are used to analyze the progress curves. However, intracellular compartments are crowded by macromolecules. Therefore, we investigated the adequacy of the proposed generalizations of the mass-action model, which are meant to describe reactions in crowded media. To validate these models, we measured time-resolved kinetics for dansylamide binding to carbonic anhydrase in solutions crowded with polyethylene glycol and Ficoll. The measured progress curves clearly show the effects of crowding. The fractal-like model proposed by Savageau was used to fit these curves. In this model, the association rate coefficient k_a allometrically depends on concentrations of reactants. We also considered the fractal kinetic model proposed by Schnell and Turner, in which k_a depends on time according to a Zipf-Mandelbrot distribution, and some generalizations of these models. We found that the generalization of the mass-action model, in which association and dissociation rate coefficients are concentration-dependent, represents the preferred model. Other models based on time-dependent rate coefficients were inadequate or not preferred by model selection criteria.     

Synthesis of 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine, a potent cyclin dependent kinase 1 (CDK1) inhibitor

The novel compound 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described.     

Loss of Kindlin-1 Causes Skin Atrophy and Lethal Neonatal Intestinal Epithelial Dysfunction

Kindler Syndrome (KS), characterized by transient skin blistering followed by abnormal pigmentation, skin atrophy, and skin cancer, is caused by mutations in the FERMT1 gene. Although a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown. The FERMT1 gene product belongs to a family of focal adhesion proteins (Kindlin-1, -2, -3) that bind several β integrin cytoplasmic domains. Here, we show that deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC. This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response.     

Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.