Did geckos ride the Palawan raft to the Philippines?

Aim We examine the genetic diversity within the lizard genus Gekko in the Philippine islands to understand the role of geography and geological history in shaping species diversity in this group. We test multiple biogeographical hypotheses of species relationships, including the recently proposed Palawan Ark Hypothesis. Location Southeast Asia and the Philippines. Methods Samples of all island endemic and widespread Philippine Gekko species were collected and sequenced for one mitochondrial gene (NADH dehydrogenase subunit 2) and one nuclear gene (phosducin). We used maximum likelihood and Bayesian phylogenetic methods to derive the phylogeny. Divergence time analyses were used to estimate the time tree of Philippine Gekko in order to test biogeographical predictions of species relationships. The phylogenetic trees from the posterior distribution of the Bayesian analyses were used for testing biogeographical hypotheses. Haplotype networks were created for the widespread species Gekko mindorensis to explore genetic variation within recently divergent clades. Results Both maximum likelihood and Bayesian phylogenetic analyses indicated that Philippine Gekko species are a diverse clade with a long history in the archipelago. Ancestral range reconstruction and divergence time analyses suggest a Palawan microcontinental origin for this clade, coinciding with Palawan’s separation from Asia beginning 30 Ma, with subsequent diversification in the oceanic Philippine islands. The widespread species G. mindorensis and G. monarchus diversified in the late Miocene/early Pliocene and are potentially complexes of numerous undescribed species. Main conclusions The view of the Philippine islands as a ‘fringing archipelago’ does not explain the pattern of species diversity in the genus Gekko. Philippine Gekko species have diversified within the archipelago over millions of years of isolation, forming a large diverse group of endemic species. Furthermore, the Philippine radiation of gekkonid lizards demonstrates biogeographical patterns most consistent with stochastic colonization followed by in situ diversification. Our results reveal the need to consider deeper time geological processes and their potential role in the evolution of some Philippine terrestrial organisms.     

Coupling of N7-methyltransferase and 3′-5′ exoribonuclease with SARS-CoV-2 polymerase reveals mechanisms for capping and proofreading

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Comparison of the biochemical and kinetic properties of the type 1 receptor tyrosine kinase intracellular domains. Demonstration of differential sensitivity to kinase inhibitors.

Epidermal growth factor receptor (EGFR), ErbB-2, and ErbB-4 are members of the type 1 receptor tyrosine kinase family. Overexpression of these receptors, especially ErbB-2 and EGFR, has been implicated in multiple forms of cancer. Inhibitors of EGFR tyrosine kinase activity are being evaluated clinically for cancer therapy. The potency and selectivity of these inhibitors may affect the efficacy and toxicity of therapy. Here we describe the expression, purification, and biochemical comparison of EGFR, ErbB-2, and ErbB-4 intracellular domains. Despite their high degree of sequence homology, the three enzymes have significantly different catalytic properties and substrate kinetics. For example, the catalytic activity of ErbB-2 is less stable than that of EGFR. ErbB-2 uses ATP-Mg as a substrate inefficiently compared with EGFR and ErbB-4. The three enzymes have very similar substrate preferences for three optimized peptide substrates, but differences in substrate synergies were observed. We have used the biochemical and kinetic parameters determined from these studies to develop an assay system that accurately measures inhibitor potency and selectivity between the type 1 receptor family. We report that the selectivity profile of molecules in the 4-anilinoquinazoline series can be modified through specific aniline substitutions. Moreover, these compounds have activity in whole cells that reflect the potency and selectivity of target inhibition determined with this assay system.     

Acetazolamide reduces exercise capacity and increases leg fatigue under hypoxic conditions.

Acetazolamide (Acz) is used at altitude to prevent acute mountain sickness, but its effect on exercise capacity under hypoxic conditions is uncertain. Nine healthy men completed this double-blind, randomized, crossover study. All subjects underwent incremental exercise to exhaustion with an inspired O(2) fraction of 0.13, hypoxic ventilatory responses, and hypercapnic ventilatory responses after Acz (500 mg twice daily for 5 doses) and placebo. Maximum power of 203 +/- 38 (SD) W on Acz was less than the placebo value of 225 +/- 40 W (P < 0.01). At peak exercise, arterialized capillary pH was lower and Po(2) higher on Acz (P < 0.01). Ventilation was 118.6 +/- 20.0 l/min at the maximal power on Acz and 102.4 +/- 20.7 l/min at the same power on placebo (P < 0.02), and Borg score for leg fatigue was increased on Acz (P < 0.02), with no difference in Borg score for dyspnea. Hypercapnic ventilatory response on Acz was greater (P < 0.02), whereas hypoxic ventilatory response was unchanged. During hypoxic exercise, Acz reduced exercise capacity associated with increased perception of leg fatigue. Despite increased ventilation, dyspnea was not increased.     

A device for the application of known simulated orthodontic forces to human cells in vitro

Connective tissues are responsive to mechanical forces. In orthodontic tooth movement it appears that the periodontal ligament (PDL) is the source of a pleuropotential cell population and extracellular matrix structure which translates mechanical perturbation information into a host of cellular events. These include proliferation, repair, differentiation, and shape change. We have designed, built, and tested a simple, adaptable machine which enables us to examine molecular changes or events in the cell nucleus, cell membrane, and the cytoskeleton of any eukasytic cell that will adhere to a membrane. These responses to clinically simulated forces applied to an in vitro system can be measured.