MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice

Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155−/− mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155−/− livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155−/− mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes

Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3',5'-adenosine monophosphate (Epac) in murine skeletal muscle.

We investigated effects of pharmacological triggering of exchange protein directly activated by cyclic-3',5'-adenosine monophosphate (Epac) on Nav1.4 currents from intact murine (C67BL6) skeletal muscle fibres for the first time. This employed a loose patch clamp technique which examined ionic currents in response to superimposed 10-ms V1 steps to varying degrees of depolarisation, followed by V2 steps to a fixed, +100 mV depolarisation relative to resting membrane potential following 40 mV hyperpolarising prepulses of 50 ms duration. The activation and inactivation properties of the resulting Na+ membrane current densities revealed reduced maximum currents and steepnesses in their voltage dependences after addition of the Epac activator 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphate (1 µM) to the bathing Krebs-Henseleit solutions. Contrastingly, voltages at half-maximal current and timecourses of currents obtained in response to the V1 depolarising steps were unchanged. These effects were abolished by further addition of the RyR-inhibitor dantrolene (10 µM). In contrast, challenge by dantrolene alone left both currents and their parameters intact. These effects of Epac activation in inhibiting skeletal muscle, Nav1.4, currents, complement similar effects previously reported in the homologous Nav1.5 in murine cardiomyocytes. They are discussed in terms of a hypothesis implicating Epac actions in increasing RyR-mediated SR Ca2+ release resulting in a Ca2+-mediated inhibition of Nav1.4. The latter effect may form the basis for Ca2+-dependent Na+ channel dysregulation in SCN4A channelopathies associated with cold- and K+-aggravated myotonias.Wellcome Trus

From covalent bonding to coalescence of metallic nanorods

Growth of metallic nanorods by physical vapor deposition is a common practice, and the origin of their dimensions is a characteristic length scale that depends on the three-dimensional Ehrlich-Schwoebel (3D ES) barrier. For most metals, the 3D ES barrier is large so the characteristic length scale is on the order of 200 nm. Using density functional theory-based ab initio calculations, this paper reports that the 3D ES barrier of Al is small, making it infeasible to grow Al nanorods. By analyzing electron density distributions, this paper shows that the small barrier is the result of covalent bonding in Al. Beyond the infeasibility of growing Al nanorods by physical vapor deposition, the results of this paper suggest a new mechanism of controlling the 3D ES barrier and thereby nanorod growth. The modification of local degree of covalent bonding, for example, via the introduction of surfactants, can increase the 3D ES barrier and promote nanorod growth, or decrease the 3D ES barrier and promote thin film growth

Hominin occupation of the Chinese Loess Plateau since about 2.1 million years ago

Considerable attention has been paid to dating the earliest appearance of hominins outside Africa. The earliest skeletal and artefactual evidence for the genus Homo in Asia currently comes from Dmanisi, Georgia, and is dated to approximately 1.77-1.85 million years ago (Ma)(1). Two incisors that may belong to Homo erectus come from Yuanmou, south China, and are dated to 1.7 Ma(2); the next-oldest evidence is an H. erectus cranium from Lantian (Gongwangling)-which has recently been dated to 1.63 Ma(3) and the earliest hominin fossils from the Sangiran dome in Java, which are dated to about 1.5-1.6 Ma(4). Artefacts from Majuangou III5 and Shangshazui(6) in the Nihewan basin, north China, have also been dated to 1.6-1.7 Ma. Here we report an Early Pleistocene and largely continuous artefact sequence from Shangchen, which is a newly discovered Palaeolithic locality of the southern Chinese Loess Plateau, near Gongwangling in Lantian county. The site contains 17 artefact layers that extend from palaeosol S15-dated to approximately 1.26 Ma-to loess L28, which we date to about 2.12 Ma. This discovery implies that hominins left Africa earlier than indicated by the evidence from Dmanisi

Freshwater transport in the coupled ocean-atmosphere system: a passive ocean

Conservation of water demands that meridional ocean and atmosphere freshwater transports (FWT) are of equal magnitude but opposite in direction. This suggests that the atmospheric FWT and its associated latent heat (LH) transport could be thought of as a \textquotedblleft coupled ocean/atmosphere mode\textquotedblright. But what is the true nature of this coupling? Is the ocean passive or active? Here we analyze a series of simulations with a coupled ocean-atmosphere-sea ice model employing highly idealized geometries but with markedly different coupled climates and patterns of ocean circulation. Exploiting streamfunctions in specific humidity coordinates for the atmosphere and salt coordinates for the ocean to represent FWT in their respective medium, we find that atmospheric FWT/LH transport is essentially independent of the ocean state. Ocean circulation and salinity distribution adjust to achieve a return freshwater pathway demanded of them by the atmosphere. So, although ocean and atmosphere FWTs are indeed coupled by mass conservation, the ocean is a passive component acting as a reservoir of freshwater

Hydrothermal Synthesis, Microstructure and Photoluminescence of Eu3+-Doped Mixed Rare Earth Nano-Orthophosphates

Eu3+-doped mixed rare earth orthophosphates (rare earth = La, Y, Gd) have been prepared by hydrothermal technology, whose crystal phase and microstructure both vary with the molar ratio of the mixed rare earth ions. For LaxY1–xPO4: Eu3+, the ion radius distinction between the La3+ and Y3+ is so large that only La0.9Y0.1PO4: Eu3+ shows the pure monoclinic phase. For LaxGd1–xPO4: Eu3+ system, with the increase in the La content, the crystal phase structure of the product changes from the hexagonal phase to the monoclinic phase and the microstructure of them changes from the nanorods to nanowires. Similarly, YxGd1–xPO4: Eu3+, Y0.1Gd0.9PO4: Eu3+ and Y0.5Gd0.5PO4: Eu3+ samples present the pure hexagonal phase and nanorods microstructure, while Y0.9Gd0.1PO4: Eu3+ exhibits the tetragonal phase and nanocubic micromorphology. The photoluminescence behaviors of Eu3+ in these hosts are strongly related to the nature of the host (composition, crystal phase and microstructure)

Crosstalk between Spinal Astrocytes and Neurons in Nerve Injury-Induced Neuropathic Pain

Emerging research implicates the participation of spinal dorsal horn (SDH) neurons and astrocytes in nerve injury-induced neuropathic pain. However, the crosstalk between spinal astrocytes and neurons in neuropathic pain is not clear. Using a lumbar 5 (L5) spinal nerve ligation (SNL) pain model, we testified our hypothesis that SDH neurons and astrocytes reciprocally regulate each other to maintain the persistent neuropathic pain states. Glial fibrillary acidic protein (GFAP) was used as the astrocytic specific marker and Fos, protein of the protooncogene c-fos, was used as a marker for activated neurons. SNL induced a significant mechanical allodynia as well as activated SDH neurons indicated by the Fos expression at the early phase and activated astrocytes with the increased expression of GFAP during the late phase of pain, respectively. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or astroglial toxin L-α-aminoadipate (L-AA) reversed the mechanical allodynia, respectively. Immunofluorescent histochemistry revealed that intrathecal administration of c-fos ASO significantly suppressed activation of not only neurons but also astrocytes induced by SNL. Meanwhile, L-AA shortened the duration of neuronal activation by SNL. Our data offers evidence that neuronal and astrocytic activations are closely related with the maintenance of neuropathic pain through a reciprocal “crosstalk”. The current study suggests that neuronal and non-neuronal elements should be taken integrally into consideration for nociceptive transmission, and that the intervention of such interaction may offer some novel pain therapeutic strategies

Biogenic and Synthetic Polyamines Bind Cationic Dendrimers

Biogenic polyamines are essential for cell growth and differentiation, while polyamine analogues exert antitumor activity in multiple experimental model systems, including breast and lung cancer. Dendrimers are widely used for drug delivery in vitro and in vivo. We report the bindings of biogenic polyamines, spermine (spm), and spermidine (spmd), and their synthetic analogues, 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) to dendrimers of different compositions, mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4). FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyze polyamine binding mode, the binding constant and the effects of polyamine complexation on dendrimer stability and conformation. Structural analysis showed that polyamines bound dendrimers through both hydrophobic and hydrophilic contacts with overall binding constants of Kspm-mPEG-G3 = 7.6×104 M−1, Kspm-mPEG-PAMAM-G4 = 4.6×104 M−1, Kspm-PAMAM-G4 = 6.6×104 M−1, Kspmd-mPEG-G3 = 1.0×105 M−1, Kspmd-mPEG-PAMAM-G4 = 5.5×104 M−1, Kspmd-PAMAM-G4 = 9.2×104 M−1, KBE-333-mPEG-G3 = 4.2×104 M−1, KBe-333-mPEG-PAMAM-G4 = 3.2×104 M−1, KBE-333-PAMAM-G4 = 3.6×104 M−1, KBE-3333-mPEG-G3 = 2.2×104 M−1, KBe-3333-mPEG-PAMAM-G4 = 2.4×104 M−1, KBE-3333-PAMAM-G4 = 2.3×104 M−1. Biogenic polyamines showed stronger affinity toward dendrimers than those of synthetic polyamines, while weaker interaction was observed as polyamine cationic charges increased. The free binding energies calculated from docking studies were: −3.2 (spermine), −3.5 (spermidine) and −3.03 (BE-3333) kcal/mol, with the following order of binding affinity: spermidine-PAMAM-G-4>spermine-PAMMAM-G4>BE-3333-PAMAM-G4 consistent with spectroscopic data. Our results suggest that dendrimers can act as carrier vehicles for delivering antitumor polyamine analogues to target tissues

Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small-molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (A beta) peptides by decreasing the cleavage of amyloid precursor protein (APP) by beta-secretase, without notably affecting alpha- and gamma-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates