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Abstract Horizontal transfer of transposable elements (TEs) is an important mechanism contributing to genetic diversity and innovation. Bats (order Chiroptera) have repeatedly been shown to experience horizontal transfer of TEs at what appears to be a high rate compared with other mammals. We investigated the occurrence of horizontally transferred (HT) DNA transposons involving bats. We found over 200 putative HT elements within bats; 16 transposons were shared across distantly related mammalian clades, and 2 other elements were shared with a fish and two lizard species. Our results indicate that bats are a hotspot for horizontal transfer of DNA transposons. These events broadly coincide with the diversification of several bat clades, supporting the hypothesis that DNA transposon invasions have contributed to genetic diversification of bats.

Syncytins are genes of retroviral origin captured by eutherian mammals, with a role in placentation. Here we show that some marsupials—which are the closest living relatives to eutherian mammals, although they diverged from the latter ∼190 Mya—also possess a syncytin gene. The gene identified in the South American marsupial opossum and dubbed syncytin-Opo1 has all of the characteristic features of a bona fide syncytin gene: It is fusogenic in an ex vivo cell–cell fusion assay; it is specifically expressed in the short-lived placenta at the level of the syncytial feto–maternal interface; and it is conserved in a functional state in a series of Monodelphis species. We further identify a nonfusogenic retroviral envelope gene that has been conserved for >80 My of evolution among all marsupials (including the opossum and the Australian tammar wallaby), with evidence for purifying selection and conservation of a canonical immunosuppressive domain, but with only limited expression in the placenta. This unusual captured gene, together with a third class of envelope genes from recently endogenized retroviruses—displaying strong expression in the uterine glands where retroviral particles can be detected—plausibly correspond to the different evolutionary statuses of a captured retroviral envelope gene, with only syncytin-Opo1 being the present-day bona fide syncytin active in the opossum and related species. This study would accordingly recapitulate the natural history of syncytin exaptation and evolution in a single species, and definitely extends the presence of such genes to all major placental mammalian clades. Significance Syncytins are “captured” genes of retroviral origin, corresponding to the fusogenic envelope gene of endogenized retroviruses. They are present in a series of eutherian mammals, including humans and mice where they play an essential role in placentation. Here we show that marsupials—which diverged from eutherian mammals ∼190 Mya but still possess a primitive, short-lived placenta (rapidly left by the embryo for development in an external pouch)—have also captured such genes. The present characterization of the syncytin-Opo1 gene in the opossum placenta, together with the identification of two additional endogenous retroviral envelope gene captures, allow a recapitulation of the natural history of these unusual genes and definitely extends their “symbiotic niche” to all clades of placental mammals.

The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the need for clinical application of siRNA. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect. In this study, the vascular endothelial growth factor (VEGF)-specific siRNAs were first electrostatically condensed into a ternary nanocomplex composed of polycation and hyaluronate, which was subsequently enveloped by LipoMET through membrane fusion. In comparison with common cationic control group, the resulting envelope-type nanoparticles (PH@LipoMET nanoparticles [NPs]) showed the ability of rapid cellular internalization and effective endosomal escape of siRNA during intracellular trafficking studies. Systemic administration of the targeted LipoMETs was capable of inducing apoptosis and tumor growth inhibition in the NCI-H460 xenograft model. When carrying VEGF-specific siRNAs, PH@LipoMET NPs remarkably downregulated the expression of VEGF and led to even more tumor suppression in vivo. Thus, LipoMET originated envelope-type nanoparticles may serve as a potential dual-functional siRNA delivery system to improve therapeutic effect of oncogene silencing. The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the clinical need of siRNA delivery. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect.

To better understand peptide-induced membrane fusion at a molecular level, we set out to determine the structure of the fusogenic peptide FP23 from the HIV-1 protein gp41 when bound to a lipid bilayer. An established solid-state 19 F nuclear magnetic resonance (NMR) approach was used to collect local orientational constraints from a series of CF 3 -phenylglycine-labeled peptide analogues in macroscopically aligned membranes. Fusion assays showed that these 19 F-labels did not significantly affect peptide function. The NMR spectra were characteristic of well-behaved samples, without any signs of heterogeneity or peptide aggregation at 1:300 in 1,2-dimyristoyl- sn -glycero-3-phosphatidylcholine (DMPC). We can conclude from these NMR data that FP23 has a well-defined (time-averaged) conformation and undergoes lateral diffusion in the bilayer plane, presumably as a monomer or small oligomer. Attempts to evaluate its conformation in terms of various secondary structures, however, showed that FP23 does not form any type of regular helix or β-strand. Therefore, all-atom molecular dynamics (MD) simulations were carried out using the orientational NMR constraints as pseudo-forces to drive the peptide into a stable alignment and structure. The resulting picture suggests that FP23 can adopt multiple β-turns and insert obliquely into the membrane. Such irregular conformation explains why the structure of the fusion peptide could not be reliably determined by any biophysical method so far.

We have characterized the fusogenic activity of a plasmid expression system encoding vesicular stomatitis virus G protein (VSVG) in vitro and in vivo. Over 70% of murine colon and renal carcinoma cells (MC38 and Renca, respectively) transfected with VSVG plasmid in vitro fused and formed polykaryons upon incubation with pH 5.5 media. Using a plasmid expression system encoding VSVG and bacterial green fluorescent protein (GFP) formulated in a polyvinyl pyrrolidone (PVP) delivery system, diffusion of GFP throughout the VSVG-induced syncytia was shown in vivo in MC38 and Renca tumors. Moreover, tumor-bearing mice showed tumor growth inhibition following in vivo transfection with VSVG plasmid at an optimal dose of 48 microg. We have previously shown that direct injection of interleukin -12 (IL -12) plasmid complexed with PVP into tumors induces a strong immune response. In the current study, we assessed the ability of VSVG to elicit an antitumor response by enhancing cytokine gene delivery within the tumor mass. Tumor-bearing mice treated intratumorally with both VSVG/PVP and IL-12/PVP (48 and 24 microg, respectively) showed increase in tumor rejection when compared to IL- 12 plasmid alone (75% vs. 50%, respectively). These data suggest that VSVG gene therapy can be used in combination with other therapeutic genes to induce an antitumor response in vivo by enhancing the expression of the gene of interest.

Modified bovine leukemia virus (BLV) glycoproteins were expressed by using vaccinia virus recombinants, and their fusogenic capacities were examined by a syncytia-formation assay. This analysis indicates that (i) both BLV envelope glycoproteins gp51 and gp30 are necessary for cell fusion; (ii) insertion of the N-terminal segment of gp30 (fusion peptide) into the lipid bilayer in an oblique orientation, as predicted by computer conformational analysis, results in fusogenic capacities higher than insertion in a perpendicular or parallel orientation; and (iii) replacement of the BLV fusion peptide with its simian immunodeficiency virus counterpart does not modify the fusogenic capacity of the BLV glycoprotein.