Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival

Phospholipase C-β4 Is Essential for the Progression of the Normal Sleep Sequence and Ultradian Body Temperature Rhythms in Mice

BACKGROUND: THE SLEEP SEQUENCE: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, but the underlying mechanisms are unknown. It has been shown that this sequence is disrupted by sudden REM sleep onset during active wakefulness (i.e., narcolepsy) in orexin-deficient mutant animals. Phospholipase C (PLC) mediates the signaling of numerous metabotropic receptors, including orexin receptors. Among the several PLC subtypes, the beta4 subtype is uniquely localized in the geniculate nucleus of thalamus which is hypothesized to have a critical role in the transition and maintenance of sleep stages. In fact, we have reported irregular theta wave frequency during REM sleep in PLC-beta4-deficient mutant (PLC-beta4-/-) mice. Daily behavioral phenotypes and metabotropic receptors involved have not been analyzed in detail in PLC-beta4-/- mice, however. METHODOLOGY/PRINCIPAL FINDINGS: Therefore, we analyzed 24-h sleep electroencephalogram in PLC-beta4-/- mice. PLC-beta4-/- mice exhibited normal non-REM sleep both during the day and nighttime. PLC-beta4-/- mice, however, exhibited increased REM sleep during the night, their active period. Also, their sleep was fragmented with unusual wake-to-REM sleep transitions, both during the day and nighttime. In addition, PLC-beta4-/- mice reduced ultradian body temperature rhythms and elevated body temperatures during the daytime, but had normal homeothermal response to acute shifts in ambient temperatures (22 degrees C-4 degrees C). Within the most likely brain areas to produce these behavioral phenotypes, we found that, not orexin, but group-1 metabotropic glutamate receptor (mGluR)-mediated Ca(2+) mobilization was significantly reduced in the dorsal lateral geniculate nucleus (LGNd) of PLC-beta4-/- mice. Voltage clamp recordings revealed that group-1 mGluR-mediated currents in LGNd relay neurons (inward in wild-type mice) were outward in PLC-beta4-/- mice. CONCLUSIONS/SIGNIFICANCE: These lines of evidence indicate that impaired LGNd relay, possibly mediated via group-1 mGluR, may underlie irregular sleep sequences and ultradian body temperature rhythms in PLC-beta4-/- mice

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis

AT7519, a Novel Small Molecule Multi-Cyclin Dependent Kinase Inhibitor, Induces Apoptosis in Multiple Myeloma VIA GSK3 beta

Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3beta knockdown restored MM survival, suggesting the involvement of GSK-3beta in AT7519-induced apoptosis. GSK-3beta activation was independent of RNA pol II dephosphorylation confirmed by alpha-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3beta phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3beta in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM

Loss of flight promotes beetle diversification

The evolution of flight is a key innovation that may enable the extreme diversification of insects. Nonetheless, many species-rich, winged insect groups contain flightless lineages. The loss of flight may promote allopatric differentiation due to limited dispersal power and may result in a high speciation rate in the flightless lineage. Here we show that loss of flight accelerates allopatric speciation using carrion beetles (Coleoptera: Silphidae). We demonstrate that flightless species retain higher genetic differentiation among populations and comprise a higher number of genetically distinct lineages than flight-capable species, and that the speciation rate with the flightless state is twice that with the flight-capable state. Moreover, a meta-analysis of 51 beetle species from 15 families reveals higher genetic differentiation among populations in flightless compared with flight-capable species. In beetles, which represent almost one-fourth of all described species, repeated evolution of flightlessness may have contributed to their steady diversification since the Mesozoic era

Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4

The small ubiquitin-like modifier (SUMO) can form polymeric chains that are important signals in cellular processes such as meiosis, genome maintenance and stress response. The SUMO-targeted ubiquitin ligase RNF4 engages with SUMO chains on linked substrates and catalyses their ubiquitination, which targets substrates for proteasomal degradation. Here we use a segmental labelling approach combined with solution nuclear magnetic resonance (NMR) spectroscopy and biochemical characterization to reveal how RNF4 manipulates the conformation of the SUMO chain, thereby facilitating optimal delivery of the distal SUMO domain for ubiquitin transfer

Stochastic population growth in spatially heterogeneous environments

Classical ecological theory predicts that environmental stochasticity increases extinction risk by reducing the average per-capita growth rate of populations. To understand the interactive effects of environmental stochasticity, spatial heterogeneity, and dispersal on population growth, we study the following model for population abundances in $n$ patches: the conditional law of $X_{t+dt}$ given $X_t=x$ is such that when $dt$ is small the conditional mean of $X_{t+dt}^i-X_t^i$ is approximately $[x^i\mu_i+\sum_j(x^j D_{ji}-x^i D_{ij})]dt$, where $X_t^i$ and $\mu_i$ are the abundance and per capita growth rate in the $i$-th patch respectivly, and $D_{ij}$ is the dispersal rate from the $i$-th to the $j$-th patch, and the conditional covariance of $X_{t+dt}^i-X_t^i$ and $X_{t+dt}^j-X_t^j$ is approximately $x^i x^j \sigma_{ij}dt$. We show for such a spatially extended population that if $S_t=(X_t^1+...+X_t^n)$ is the total population abundance, then $Y_t=X_t/S_t$, the vector of patch proportions, converges in law to a random vector $Y_\infty$ as $t\to\infty$, and the stochastic growth rate $\lim_{t\to\infty}t^{-1}\log S_t$ equals the space-time average per-capita growth rate \sum_i\mu_i\E[Y_\infty^i] experienced by the population minus half of the space-time average temporal variation \E[\sum_{i,j}\sigma_{ij}Y_\infty^i Y_\infty^j] experienced by the population. We derive analytic results for the law of $Y_\infty$, find which choice of the dispersal mechanism $D$ produces an optimal stochastic growth rate for a freely dispersing population, and investigate the effect on the stochastic growth rate of constraints on dispersal rates. Our results provide fundamental insights into "ideal free" movement in the face of uncertainty, the persistence of coupled sink populations, the evolution of dispersal rates, and the single large or several small (SLOSS) debate in conservation biology.Comment: 47 pages, 4 figure

Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators

Expression of MK-1 and RegⅣ and its clinicopathological significances in the benign and malignant lesions of gallbladder

<p>Abstract</p> <p>Background</p> <p>To study the expression of MK-1 and RegⅣ and to detect their pathological significances in benign and malignant lesions of gallbladder.</p> <p>Methods</p> <p>The expression of MK-1 and RegⅣ was detected by immunohistochemical method in paraffin-embedded sections of surgical resected specimens from gallbladder adenocarcinoma (n = 108), peritumoral tissues (n = 46), adenomatous polyp (n = 15), and chronic cholecystitis (n = 35).</p> <p>Results</p> <p>The positive rate of MK-1 or RegⅣ expression was significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues (χ²_MK-1= 18.76, <it>P </it>< 0.01; χ²_RegⅣ= 9.92, <it>P </it>< 0.01), denomatous polyp (χ²_MK-1= 9.49, <it>P </it>< 0.01; χ²_RegⅣ= 8.59, <it>P </it>< 0.01) and chronic cholecystitis (χ²_MK-1= 24.11, <it>P </it>< 0.01; χ²_RegⅣ= 19.24, <it>P </it>< 0.01). The positive cases of MK-1 and/or RegⅣ in the benign lesions showed moderately- or severe-atypical hyperplasia of gallbladder epitheli. The positive rates of MK-1 were significantly higher in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (<it>P </it>< 0.05 or <it>P </it>< 0.01). On the contrary, the positive rates of RegⅣ were significantly lower in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (<it>P </it>< 0.05 or <it>P </it>< 0.01). Univariate Kaplan-Meier analysis showed that decreased expression of MK-1 (<it>P </it>= 0.09) or increased expression of RegⅣ (<it>P </it>= 0.003) was associated with decreased overall survival. Multivariate Cox regression analysis showed that decreased expression of MK-1 (<it>P </it>= 0.033) and increased expression of RegⅣ (<it>P </it>= 0.008) was an independent prognostic predictor in gallbladder adenocarcinoma.</p> <p>Conclusions</p> <p>The expression of MK-1 and/or RegⅣ might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.</p