Beneficial impacts of biochar as a potential feed additive in animal husbandry

In the last decade, biochar production and use have grown in popularity. Biochar is comparable to charcoal and activated charcoal because it is a pyrogenic carbonaceous matter made by pyrolyzing organic carbon-rich materials. There is a lack of research into the effects of adding biochar to animal feed. Based on the reviewed literature, including its impact on the adsorption of toxins, blood biochemistry, feed conversion rate, digestion, meat quality, and greenhouse gas emissions, adding biochar to the diet of farm animals is a good idea. This study compiles the most important research on biochar's potential as a supplement to the diets of ruminants (including cows and goats), swine, poultry, and aquatic organisms like fish. Biochar supplementation improves animal growth, haematological profiles, meat, milk and egg yield, resistance to illnesses (especially gut pathogenic bacteria), and reduced ruminant methane emission. Biochar's strong sorption capacity also helps efficiently remove contaminants and poisons from the animals' bodies and the farm surroundings where they are raised. Animal farmers are predicted to make greater use of biochar in the future. Biochar could potentially be of value in the healthcare and human health fields; hence research into this area is encouraged. The present review highlights the potential benefits of biochar as an additive to animal feed and demonstrates how, when combined with other environmentally friendly practices, biochar feeding can extend the longevity of animal husbandry

Farnesoid X Receptor and its ligands inhibit the function of platelets

Objective - While initially seemingly paradoxical due to the lack of nucleus, platelets possess a number of transcription factors that regulate their function through DNA-independent mechanisms. These include the Farnesoid X Receptor (FXR), a member of the superfamily of ligand-activated transcription factors that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6-ECDCA, modulate platelet activation nongenomically. Approach and Results - FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization and secretion, fibrinogen binding and aggregation. Exposure to FXR ligands also reduced integrin alphaIIbbeta3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cGMP levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the non-genomic actions of these ligands to the FXR receptor. Conclusion – This study provides support for the ability of FXR ligands to modulate platelet activation. The athero-protective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for prevention of athero-thrombotic disease

Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design

β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer’s disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors

Zafirlukast is a broad-spectrum thiol isomerase inhibitor that inhibits thrombosis without altering bleeding times

Background and purpose Multiple members of the thiol isomerase (TI) family of enzymes are present in, and released by platelets. Inhibition of these enzymes results in diminished platelet responses including aggregation, adhesion and thrombus formation. In recent years, the therapeutic potential of TI inhibition has been recognised and drug-development technologies used to identify selective small molecule inhibitors. To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin is known to be nephrotoxic which prohibits its systemic therapeutic usage. Experimental approach We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. 3641 compounds were screened for inhibitory effects on the redox activity of ERp5, PDI, ERp57, ERp72 and thioredoxin (TRX) in an insulin turbidity assay. Of the lead compounds identified, zafirlukast (ZFL) was selected for further investigation. Key results When applied to platelets, ZFL diminished platelet responses in vitro. ZFL was antithrombotic in murine models of thrombosis but did not impair responses in a model of haemostasis. Since thiol isomerases are known to modulate adhesion receptor function, we explored the effects of ZFL on cell migration. This was inhibited independently of cysteinyl leukotriene receptor expression and was associated with modulation of cell-surface free thiol levels consistent with alterations in redox activity on the cell surface. Conclusion and implications We identify zafirlukast to be a novel, potent, broad-spectrum TI inhibitor, with wide ranging effects on platelet function, thrombosis and integrin-mediated cell migration. ZFL is antithrombotic but does not cause bleeding

Temperatures of the Lacus Mortis Region of the Moon

Over 11&nbsp;years of data acquired by the Diviner Lunar Radiometer Experiment instrument aboard Lunar Reconnaissance Orbiter have been compiled into a comprehensive data set of surface temperatures in the Lacus Mortis region which includes the landing ellipse of the Astrobotic Mission One lander mission. These data provide diurnal brightness temperatures at 128 pixels per degree (ppd) spatial resolution and 0.1&nbsp;hr of local time resolution. From this data set, we highlight several features that display variations in radiative and thermophysical properties in the Lacus Mortis region and characterize the temperatures of the Astrobotic Mission One landing ellipse. We identify distinctly contrasting properties of materials in the walls of B&uuml;rg crater, hummocks of materials on the southeast margin of the mare basalts, and materials exposed or excavated by impacts. Additionally, we describe an exceptionally rocky fault scarp that predates the formation of B&uuml;rg crater suggesting the observed boulders are replenished on a timescale &lt;1&nbsp;Ga. Within the Astrobotic landing ellipse, temperatures are observed to range from &sim;88 to &sim;359&nbsp;K with sunrise and sunset local times constrained to 5.8&ndash;6.3&nbsp;hr and 17.8 and 18.1&nbsp;hr respectively. &nbsp;</p

NAHA, a Novel Hydroxamic Acid-Derivative, Inhibits Growth and Angiogenesis of Breast Cancer In Vitro and In Vivo

BACKGROUND: We have recently synthesized novel N-alkylated amino acid-derived hydroxamate, 2-[Benzyl-(2-nitro-benzenesulfonyl)-amino]-N-hydroxy-3-methyl-N-propyl-butyramide (NAHA). Here, we evaluate the anticancer activity of NAHA against highly invasive human breast cancer cells MDA-MB-231 in vitro and in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Cell growth was evaluated by MTT and soft agar assays. Protein expression was determined by DNA microarray and Western blot analysis. Metastatic potential was evaluated by cell adhesion, migration, invasion, capillary morphogenesis, and ELISA assays. The anticancer activity in vivo was evaluated in mouse xenograft model. NAHA inhibited proliferation and colony formation of MDA-MB-231 cells together with the down-regulation of expression of Cdk2 and CDC20 proteins. NAHA inhibited cell adhesion, migration, and invasion through the suppression of secretion of uPA. NAHA suppressed secretion of VEGF from MDA-MB-231 cells and inhibited capillary morphogenesis of human aortic endothelial cells (HAECs). Finally, NAHA at 50 mg/kg was not toxic and decreased tumor volume and tumor weight in vivo. This suppression of tumor growth was associated with the inhibition of mitotic figures and induction of apoptosis, and the reduction of CD31 and VEGF positive cells in tumors. CONCLUSION: NAHA could be a novel promising compound for the development of new drugs for the therapy of invasive breast cancers

Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease

Science Opportunities offered by Mercury's Ice-Bearing Polar Deposits

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Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21

BACKGROUND: Down syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood. METHODS: We used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry. RESULTS: We found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78(MX1 )protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR. CONCLUSION: Different subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects

RETRACTED ARTICLE: Age-dependent Increase in Desmosterol Restores DRM Formation and Membrane-related Functions in Cholesterol-free DHCR24−/− Mice

Cholesterol is a prominent modulator of the integrity and functional activity of physiological membranes and the most abundant sterol in the mammalian brain. DHCR24-knock-out mice lack cholesterol and accumulate desmosterol with age. Here we demonstrate that brain cholesterol deficiency in 3-week-old DHCR24−/− mice was associated with altered membrane composition including disrupted detergent-resistant membrane domain (DRM) structure. Furthermore, membrane-related functions differed extensively in the brains of these mice, resulting in lower plasmin activity, decreased β-secretase activity and diminished Aβ generation. Age-dependent accumulation and integration of desmosterol in brain membranes of 16-week-old DHCR24−/− mice led to the formation of desmosterol-containing DRMs and rescued the observed membrane-related functional deficits. Our data provide evidence that an alternate sterol, desmosterol, can facilitate processes that are normally cholesterol-dependent including formation of DRMs from mouse brain extracts, membrane receptor ligand binding and activation, and regulation of membrane protein proteolytic activity. These data indicate that desmosterol can replace cholesterol in membrane-related functions in the DHCR24−/− mouse