Lifespan of long‐lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning

Growth hormone receptor knockout (GHRKO) mice are remarkably long‐lived and have improved glucose homeostasis along with altered energy metabolism which manifests through decreased respiratory quotient (RQ) and increased oxygen consumption (VO₂). Short‐term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO₂ and RQ. We hypothesized that increased heat loss in the diminutive GHRKO mice housed at 23°C and the consequent metabolic adjustments to meet the increased energy demand for thermogenesis may promote extension of longevity, and preventing these adjustments by chronic exposure to increased eT will reduce or eliminate their longevity advantage. To test these hypotheses, GHRKO mice were housed at increased eT (30°C) since weaning. Here, we report that contrasting with the effects of short‐term exposure of adult GHRKO mice to 30°C, transferring juvenile GHRKO mice to chronic housing at 30°C did not normalize the examined parameters of energy metabolism and glucose homeostasis. Moreover, despite decreased expression levels of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature, the lifespan of male GHRKO mice was not reduced, while the lifespan of female GHRKO mice was increased, along with improved glucose homeostasis. The results indicate that GHRKO mice have intrinsic features that help maintain their delayed, healthy aging, and extended longevity at both 23°C and 30°C.     

“Take My Bone Away?” Hypoxia and bone: A narrative review

To maintain normal cellular and physiological function, sufficient oxygen is required. Recently, evidence has suggested that hypoxia, either pathological or environmental, may influence bone health. It appears that bone cells are distinctly responsive to hypoxic stimuli; for better or worse, this is still yet to be elucidated. Hypoxia has been shown to offer potentially therapeutic effects for bone by inducing an osteogenic–angiogenic response, although, others have noted excessive osteoclastic bone resorption instead. Much evidence suggests that the hypoxic‐inducible pathway is integral in mediating the changes in bone metabolism. Furthermore, many factors associated with hypoxia including changes in energy metabolism, acid–base balance and the increased generation of reactive oxygen species, are known to influence bone metabolism. This review aims to examine some of the putative mechanisms responsible for hypoxic‐induced alterations of bone metabolism, with regard to osteoclasts and osteoblasts, both positive and negative.     

Examining the Gap between Science and Public Opinion about Genetically Modified Food and Global Warming

There is great uncertainty due to challenges of escalating population growth and climate change. Public perception that diverges from the scientific community may decrease the effectiveness of scientific inquiry and innovation as tools to solve these challenges. The objective of this study was to identify the factors associated with the divergence of public opinion from scientific consensus regarding the safety of genetically modified (GM) foods and human involvement in global warming (GW). Results indicate that the effects of knowledge on public opinion are complex and non-uniform across types of knowledge (i.e., perceived and actual) or issues. Political affiliation affects agreement with science; Democrats were more likely to agree that GM food is safe and human actions cause GW. Respondents who had relatively higher cognitive function or held illusionary correlations about GM food or GW were more likely to have an opinion that differed from the scientific community.     

Diabetes screening intervals based on risk stratification

Background

Guidelines for frequency of Type 2 diabetes mellitus (DM) screening remain unclear, with proposed screening intervals typically based on expert opinion. This study aims to demonstrate that HbA1c screening intervals may differ substantially when considering individual risk for diabetes.

Methods

This was a multi-institutional retrospective open cohort study. Data were collected between April 1999 to March 2014 from one urban and one rural cohort in Japan. After categorization by age, we stratified individuals based on cardiovascular disease risk (Framingham 10-year cardiovascular risk score) and body mass index (BMI). We adapted a signal-to-noise method for distinguishing true HbA1c change from measurement error by constructing a linear random effect model to calculate signal and noise of HbA1c. Screening interval for HbA1c was defined as informative when the signal-to-noise ratio exceeded 1.

Results

Among 96,456 healthy adults, 46,284 (48.0%) were male; age (range) and mean HbA1c (SD) were 48 (30–74) years old and 5.4 (0.4)%, respectively. As risk increased among those 30–44 years old, HbA1c screening intervals for detecting Type 2 DM consistently decreased: from 10.5 (BMI <18.5) to 2.4 (BMI?>?30) years, and from 8.0 (Framingham Risk Score <10%) to 2.0 (Framingham Risk Score ≥20%) years. This trend was consistent in other age and risk groups as well; among obese 30–44 year olds, we found substantially shorter intervals compared to other groups.

Conclusion

HbA1c screening intervals for identification of DM vary substantially by risk factors. Risk stratification should be applied when deciding an optimal HbA1c screening interval in the general population to minimize overdiagnosis and overtreatment.

     

A new marine prasinophyte genus alternates between a flagellate and a dominant benthic stage with microrhizoids for adhesion

Prasinophytes (Chlorophyta) are a diverse, paraphyletic group of planktonic microalgae for which benthic species are largely unknown. Here, we report a sand‐dwelling, marine prasinophyte with several novel features observed in clonal cultures established from numerous locations around Australia. The new genus and species, which we name Microrhizoidea pickettheapsiorum (Mamiellophyceae), alternates between a benthic palmelloid colony, where cell division occurs, and a planktonic flagellate. Flagellates are short lived, settle and quickly resorb their flagella, the basal bodies then nucleate novel tubular appendages, termed “microrhizoids”, that lack an axoneme and function to anchor benthic cells to the substratum. To our knowledge, microrhizoids have not been observed in any other green alga or protist, are slightly smaller in diameter than flagella, generally contain nine microtubules, are long (3–5 times the length of flagella) and are not encased in scales. Following settlement, cell divisions result in a loose, palmelloid colony, each cell connected to the substratum by two microrhizoids. Flagellates are round to bean‐shaped with two long, slightly uneven flagella. Both benthic cells and flagellates, along with their flagella, are encased in thin scales. Phylogenies based on the complete chloroplast genome of Microrhizoidea show that it is clearly a member of the Mamiellophyceae, most closely related to Dolichomastix tenuilepsis. More taxon‐rich phylogenetic analyses of the 18S rRNA gene, including metabarcodes from the Tara Oceans and Ocean Sampling Day projects, confidently show the distinctive nature of Microrhizoidea, and that the described biodiversity of the Mamiellophyceae is a fraction of its real biodiversity. The discovery of a largely benthic prasinophyte changes our perspective on this group of algae and, along with the observation of other potential benthic lineages in environmental sequences, illustrates that benthic habitats can be a rich ground for algal biodiscovery.     

Evolutionary pressures on apicoplast transit peptides

Malaria parasites (species of the genus Plasmodium) harbor a relict chloroplast (the apicoplast) that is the target of novel antimalarials. Numerous nuclear-encoded proteins are translocated into the apicoplast courtesy of a bipartite N-terminal extension. The first component of the bipartite leader resembles a standard signal peptide present at the N-terminus of secreted proteins that enter the endomembrane system. Analysis of the second portion of the bipartite leaders of P. falciparum, the so-called transit peptide, indicates similarities to plant transit peptides, although the amino acid composition of P. falciparum transit peptides shows a strong bias, which we rationalize by the extraordinarily high AT content of P. falciparum DNA. 786 plastid transit peptides were also examined from several other apicomplexan parasites, as well as from angiosperm plants. In each case, amino acid biases were correlated with nucleotide AT content. A comparison of a spectrum of organisms containing primary and secondary plastids also revealed features unique to secondary plastid transit peptides. These unusual features are explained in the context of secondary plastid trafficking via the endomembrane system.     

SMP-1, a member of a new family of small myristoylated proteins in kinetoplastid parasites, is targeted to the flagellum membrane in Leishmania

The mechanisms by which proteins are targeted to the membrane of eukaryotic flagella and cilia are largely uncharacterized. We have identified a new family of small myristoylated proteins (SMPs) that are present in Leishmania spp and related trypanosomatid parasites. One of these proteins, termed SMP-1, is targeted to the Leishmania flagellum. SMP-1 is myristoylated and palmitoylated in vivo, and mutation of Gly-2 and Cys-3 residues showed that both fatty acids are required for flagellar localization. SMP-1 is associated with detergent-resistant membranes based on its recovery in the buoyant fraction after Triton X-100 extraction and sucrose density centrifugation and coextraction with the major surface glycolipids in Triton X-114. However, the flagellar localization of SMP-1 was not affected when sterol biosynthesis and the properties of detergent-resistant membranes were perturbed with ketoconazole. Remarkably, treatment of Leishmania with ketoconazole and myriocin (an inhibitor of sphingolipid biosynthesis) also had no affect on SMP-1 localization, despite causing the massive distension of the flagellum membrane and the partial or complete loss of internal axoneme and paraflagellar rod structures, respectively. These data suggest that flagellar membrane targeting of SMP-1 is not dependent on axonemal structures and that alterations in flagellar membrane lipid composition disrupt axoneme extension.     

Serp-1, a viral anti-inflammatory serpin,regulates cellular serine proteinase and serpin responses to vascular injury

Complex DNA viruses have tapped into cellular serpin responses that act as key regulatory steps in coagulation and inflammatory cascades. Serp-1 is one such viral serpin that effectively protects virus-infected tissues from host inflammatory responses. When given as purified protein, Serp-1 markedly inhibits vascular monocyte invasion and plaque growth in animal models. We have investigated mechanisms of viral serpin inhibition of vascular inflammatory responses. In vascular injury models, Serp-1 altered early cellular plasminogen activator (tissue plasminogen activator), inhibitor (PAI-1), and receptor (urokinase-type plasminogen activator) expression (p < 0.01). Serp-1, but not a reactive center loop mutant, up-regulated PAI-1 serpin expression in human endothelial cells. Treatment of endothelial cells with antibody to urokinase-type plasminogen activator and vitronectin blocked Serp-1-induced changes. Significantly, Serp-1 blocked intimal hyperplasia (p < 0.0001) after aortic allograft transplant (p < 0.0001) in PAI-1-deficient mice. Serp-1 also blocked plaque growth after aortic isograft transplant and after wire-induced injury (p < 0.05) in PAI-1-deficient mice indicating that increase in PAI-1 expression is not required for Serp-1 to block vasculopathy development. Serp-1 did not inhibit plaque growth in uPAR-deficient mice after aortic allograft transplant. We conclude that the poxviral serpin, Serp-1, attenuates vascular inflammatory responses to injury through a pathway mediated by native uPA receptors and vitronectin.     

Regulated degradation of an endoplasmic reticulum membrane protein in a tubular lysosome in Leishmania mexicana

The cell surface of the human parasite Leishmania mexicana is coated with glycosylphosphatidylinositol (GPI)-anchored macromolecules and free GPI glycolipids. We have investigated the intracellular trafficking of green fluorescent protein- and hemagglutinin-tagged forms of dolichol-phosphate-mannose synthase (DPMS), a key enzyme in GPI biosynthesis in L. mexicana promastigotes. These functionally active chimeras are found in the same subcompartment of the endoplasmic reticulum (ER) as endogenous DPMS but are degraded as logarithmically growing promastigotes reach stationary phase, coincident with the down-regulation of endogenous DPMS activity and GPI biosynthesis in these cells. We provide evidence that these chimeras are constitutively transported to and degraded in a novel multivesicular tubule (MVT) lysosome. This organelle is a terminal lysosome, which is labeled with the endocytic marker FM 4-64, contains lysosomal cysteine and serine proteases and is disrupted by lysomorphotropic agents. Electron microscopy and subcellular fractionation studies suggest that the DPMS chimeras are transported from the ER to the lumen of the MVT via the Golgi apparatus and a population of 200-nm multivesicular bodies. In contrast, soluble ER proteins are not detectably transported to the MVT lysosome in either log or stationary phase promastigotes. Finally, the increased degradation of the DPMS chimeras in stationary phase promastigotes coincides with an increase in the lytic capacity of the MVT lysosome and changes in the morphology of this organelle. We conclude that lysosomal degradation of DPMS may be important in regulating the cellular levels of this enzyme and the stage-dependent biosynthesis of the major surface glycolipids of these parasites.