METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

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Quality assessment of cryopreserved biospecimens reveals presence of intact biomolecules

Recapitulation of tumor features in isolated biomolecules is preeminently dependent on obtaining reliable quality biospecimen. Moreover, quality assessment of biobanked specimens at regular intervals is an essential intervention for carrying out effective translational and clinical research. In the current study, genomic DNA was extracted from 140 fresh frozen tissues of oral, breast and colorectal specimens cryopreserved over a period of 3 to 8 months (short term) and 3 to 4 years (long term). Quantification of genomic DNA by absorption and fluorescence spectroscopy confirmed high concentration while qualitative analysis by gel electrophoresis showed intact bands for 94% and 87% of short‐ and long‐term cohorts, respectively. PC‐LDA based classification of Raman spectra showed overlapping groups of both cohorts suggesting the quality of DNA being preserved irrespective of storage period. To the best of our knowledge this is the first Indian biobank study reporting quality analysis of biospecimens cryopreserved at different time periods.     

Effects of Alpha Interferon Treatment on Intrinsic Anti-HIV-1 Immunity In Vivo

Alpha interferon (IFN-α) suppresses human immunodeficiency virus type 1 (HIV-1) replication in vitro by inducing cell-intrinsic retroviral restriction mechanisms. We investigated the effects of IFN-α/ribavirin (IFN-α/riba) treatment on 34 anti-HIV-1 restriction factors in vivo. Expression of several anti-HIV-1 restriction factors was significantly induced by IFN-α/riba in HIV/hepatitis C virus (HCV)-coinfected individuals. Fold induction of cumulative restriction factor expression in CD4⁺ T cells was significantly correlated with viral load reduction during IFN-α/riba treatment (r² = 0.649; P < 0.016). Exogenous IFN-α induces supraphysiologic restriction factor expression associated with a pronounced decrease in HIV-1 viremia.     

N-terminal Isoforms of the Large-conductance Ca2+-activated K+ Channel Are Differentially Modulated by the Auxiliary β1-Subunit

The large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel is essential for maintaining the membrane in a hyperpolarized state, thereby regulating neuronal excitability, smooth muscle contraction, and secretion. The BK_Ca α-subunit has three predicted initiation codons that generate proteins with N-terminal ends starting with the amino acid sequences MANG, MSSN, or MDAL. Because the N-terminal region and first transmembrane domain of the α-subunit are required for modulation by auxiliary β1-subunits, we examined whether β1 differentially modulates the N-terminal BK_Ca α-subunit isoforms. In the absence of β1, all isoforms had similar single-channel conductances and voltage-dependent activation. However, whereas β1 did not modulate the voltage-activation curve of MSSN, β1 induced a significant leftward shift of the voltage activation curves of both the MDAL and MANG isoforms. These shifts, of which the MDAL was larger, occurred at both 10 μm and 100 μm Ca²⁺. The β1-subunit increased the open dwell times of all three isoforms and decreased the closed dwell times of MANG and MDAL but increased the closed dwell times of MSSN. The distinct modulation of voltage activation by the β1-subunit may be due to the differential effect of β1 on burst duration and interburst intervals observed among these isoforms. Additionally, we observed that the related β2-subunit induced comparable leftward shifts in the voltage-activation curves of all three isoforms, indicating that the differential modulation of these isoforms was specific to β1. These findings suggest that the relative expression of the N-terminal isoforms can fine-tune BK_Ca channel activity in cells, highlighting a novel mechanism of BK_Ca channel regulation.     

Synthesis of L‐Lys‐Aminoxy‐Goralatide

Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported to be rather unstable in solution (half‐life 4.5 min). In this work, we report the synthesis of an aminoxy analog of Goralatide. Aminoxy moiety is expected to provide increased stability and bioavailability of the Goralatide analog. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

Antihyperlipidemic Effect of Fisetin,a Bioflavonoid of Strawberries,Studied in Streptozotocin‐Induced Diabetic Rats

Chronic hyperglycemia in diabetes is associated with profound changes in lipid and lipoprotein metabolism, with resultant alterations in particle distribution within lipoprotein classes. In the present study, an attempt has been made to explore the antihyperlipidemic effect of fisetin in streptozotocin‐induced experimental diabetes in rats. Upon fisetin treatment to diabetic rats, the levels of blood glucose were significantly reduced with an improvement in plasma insulin. The increased levels of lipid contents in serum, hepatic, and renal tissues observed in diabetic rats were normalized upon fisetin administration. Also, the decreased levels of high‐density lipoprotein cholesterol, and increased levels of low‐density lipoprotein (LDL) and very LDL (VLDL) cholesterol in serum of diabetic rats were normalized. Oil Red O staining established a large number of intracellular lipid droplets accumulation in the diabetic rats. Fisetin treatment exacerbated the degree of lipid accumulation. The results of the present study exemplify the antihyperlipidemic property of the fisetin.     

The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs

Piwi-interacting RNAs (piRNAs) guide Piwi Argonautes to suppress transposon activity in animal gonads. Known piRNA populations are extremely complex, with millions of individual sequences present in a single organism. Despite this complexity, specific Piwi proteins incorporate piRNAs with distinct nucleotide- and transposon strand-biases (antisense or sense) of unknown origin. Here, we examined the contribution of structural domains in Piwi proteins toward defining these biases. We report the first crystal structure of the MID domain from a Piwi Argonaute and use docking experiments to show its ability to specify recognition of 5′ uridine (1U-bias) of piRNAs. Mutational analyses reveal the importance of 5′ end-recognition within the MID domain for piRNA biogenesis in vivo. Finally, domain-swapping experiments uncover an unexpected role for the MID-PIWI module of a Piwi protein in dictating the transposon strand-orientation of its bound piRNAs. Our work identifies structural features that allow distinguishing individual Piwi members during piRNA biogenesis.     

The cryptic role of biodiversity in the emergence of host–microbial mutualisms

The persistence of mutualisms in host‐microbial – or holobiont – systems is difficult to explain because microbial mutualists, who bear the costs of providing benefits to their host, are always prone to being competitively displaced by non‐mutualist ‘cheater’ species. This disruptive effect of competition is expected to be particularly strong when the benefits provided by the mutualists entail costs such as reduced competitive ability. Using a metacommunity model, we show that competition between multiple cheaters within the host's microbiome, when combined with the spatial structure of host–microbial interactions, can have a constructive rather than a disruptive effect by allowing the emergence and maintenance of mutualistic microorganisms within the host. These results indicate that many of the microorganisms inhabiting a host's microbiome, including those that would otherwise be considered opportunistic or even potential pathogens, play a cryptic yet critical role in promoting the health and persistence of the holobiont across spatial scales.     

Mmp25β facilitates elongation of sensory neurons during zebrafish development

Matrix metalloproteinases (MMPs) are a large and complex family of zinc‐dependent endoproteinases widely recognized for their roles in remodeling the extracellular matrix (ECM) during embryonic development, wound healing, and tissue homeostasis. Their misregulation is central to many pathologies, and they have therefore been the focus of biomedical research for decades. These proteases have also recently emerged as mediators of neural development and synaptic plasticity in vertebrates, however, understanding of the mechanistic basis of these roles and the molecular identities of the MMPs involved remains far from complete. We have identified a zebrafish orthologue of mmp25 (a.k.a. leukolysin; MT6‐MMP), a membrane‐type, furin‐activated MMP associated with leukocytes and invasive carcinomas, but which we find is expressed by a subset of the sensory neurons during normal embryonic development. We detect high levels of Mmp25β expression in the trigeminal, craniofacial, and posterior lateral line ganglia in the hindbrain, and in Rohon‐Beard cells in the dorsal neural tube during the first 48 h of embryonic development. Knockdown of Mmp25β expression with morpholino oligonucleotides results in larvae that are uncoordinated and insensitive to touch, and which exhibit defects in the development of sensory neural structures. Using in vivo zymography, we observe that Mmp25β morphant embryos show reduced Type IV collagen degradation in regions of the head traversed by elongating axons emanating from the trigeminal ganglion, suggesting that Mmp25β may play a pivotal role in mediating ECM remodeling in the vicinity of these elongating axons. genesis 52:833–848, 2014. © 2014 Wiley Periodicals, Inc.