Diverse peptide presentation of rhesus macaque major histocompatibility complex class I Mamu-A 02 revealed by two peptide complex structures and insights into immune escape of simian immunodeficiency virus

Major histocompatibility complex class I (MHC I)-restricted CD8(+) T-cell responses play a pivotal role in anti-human immunodeficiency virus (HIV) immunity and the control of viremia. The rhesus macaque is an important animal model for HIV-related research. Among the MHC I alleles of the rhesus macaque, Mamu-A 02 is prevalent, presenting in ≥20% of macaques. In this study, we determined the crystal structure of Mamu-A 02, the second structure-determined MHC I from the rhesus macaque after Mamu-A 01. The peptide presentation characteristics of Mamu-A 02 are exhibited in complex structures with two typical Mamu-A 02-restricted CD8(+) T-cell epitopes, YY9 (Nef159 to -167; YTSGPGIRY) and GY9 (Gag71 to -79; GSENLKSLY), derived from simian immunodeficiency virus (SIV). These two peptides utilize similar primary anchor residues (Ser or Thr) at position 2 and Tyr at position 9. However, the central region of YY9 is different from that of GY9, a difference that may correlate with the immunogenic variance of these peptides. Further analysis indicated that the distinct conformations of these two peptides are modulated by four flexible residues in the Mamu-A 02 peptide-binding groove. The rare combination of these four residues in Mamu-A 02 leads to a variant presentation for peptides with different residues in their central regions. Additionally, in the two structures of the Mamu-A 02 complex, we compared the binding of rhesus and human β(2) microglobulin (β(2)m) to Mamu-A 02. We found that the peptide presentation of Mamu-A 02 is not affected by the interspecies interaction with human β(2)m. Our work broadens the understanding of CD8(+) T-cell-specific immunity against SIV in the rhesus macaque.     

MicroRNA-150 Predicts a Favorable Prognosis in Patients with Epithelial Ovarian Cancer,and Inhibits Cell Invasion and Metastasis by Suppressing Transcriptional Repressor ZEB1

MicroRNA (miR)-150 has been reported to be dramatically downregulated in human epithelial ovarian cancer (EOC) tissues and patients’ serum compared to normal controls. This study aimed to investigate clinical significance and molecular mechanisms of miR-150 in EOC. In the current study, quantitative real-time PCR analysis showed that miR-150 was significantly downregulated in human EOC tissues compared to normal tissue samples. Then, we demonstrated the significant associations of miR-150 downregulation with aggressive clinicopathological features of EOC patients, including high clinical stage and pathological grade, and shorter overall and progression-free survivals. More importantly, the multivariate analysis identified miR-150 expression as an independent prognostic biomarker in EOC. After that, luciferase reporter assays demonstrated that Zinc Finger E-Box Binding Homeobox 1 (ZEB1), a crucial regulator of epithelial-to-mesenchymal transition (EMT), was a direct target of miR-150 in EOC cells. Moreover, we found that the ectopic expression of miR-150 could efficiently inhibit cell proliferation, invasion and metastasis by suppressing the expression of ZEB1. Furthermore, we also observed a significantly negative correlation between miR-150 and ZEB1 mRNA expression in EOC tissues (rs = –0.45, P<0.001). In conclusion, these findings offer the convincing evidence that aberrant expression of miR-150 may play a role in tumor progression and prognosis in patients with EOC. Moreover, our data reveal that miR-150 may function as a tumor suppressor and modulate EOC cell proliferation, and invasion by directly and negatively regulating ZEB1, implying the re-expression of miR-150 might be a potential therapeutic strategy for EOC.     

Intentionally introduced species: more easily invited than removed

Alien species are brought into countries world wide on a massive scale for agricultural production, ex situ conservation, landscape aesthetics, gardens, and ecosystem restoration. Unfortunately, some of these species have escaped and adversely impacted on regional as well as global biodiversity conservation and agricultural production. To reduce such risks, it is necessary to implement specific and effective measures. Since various government departments and institutions are involved in the management of alien species, it is difficult to prevent native and agroecosystems from being invaded by invited species. We propose the establishment of a supervision and inspection continuum over intentional species introduction, similar to that which exists in some countries over unintentional species introductions. Namely, a justification of the necessity to import, a risk assessment, assurances as to provision of an adequate containment facility assessment, and a damage-limitation protocol should that need to be invoked. These requirements should be satisfied before an alien species is knowingly imported, and the necessary follow-up supervision is important post- importation.     

Boundary-Free Metal–Organic Framework Glasses Enable Highly Stable All-Solid-State Lithium–Oxygen Battery

Rechargeable lithium–oxygen batteries (LOBs) are considered to be one of the most promising energy storage systems. However, the use of reactive lithium (Li) metal and the formation of Li dendrites during battery operation would lead to serious safety concerns, especially when flammable liquid electrolytes are utilized. Herein, superior metal–organic framework (MOF) glass-based solid-state electrolytes (SSEs) is developed for stable all-solid-state LOBs (SSLOBs). These non-flammable and boundary-free MOF glass SSEs are capable of suppressing the dendrite growth and exhibiting long-term Li stripping/plating stability, contributing to superior Li⁺ conductivity (5 × 10⁻⁴ S cm⁻¹ at 20 °C), high Li⁺ transference number (0.86), and good electrochemical stability. It is discovered that discharge product deposition behavior in the solid-solid interface can be well regulated by the ion/electron mixed conducted cathode fabricated with MOF glass SSEs and electronic conductive polymers. As a result, the SSLOBs can be stably recharged for 400 cycles with a low polarization gap and deliver a high capacity of 13552 mAh g⁻¹. The development of this proposed MOF glass displays great application potential in energy storage systems with good safety and high energy density.     

A recombinant mimetics of the HIV-1 gp41 prehairpin fusion intermediate fused with human IgG Fc fragment elicits neutralizing antibody response in the vaccinated mice

HIV-1 gp41 prehairpin fusion intermediate (PFI) composed of three N-terminal heptad repeats (NHR) plays a crucial role in viral fusion and entry and represents an attractive target for anti-HIV therapeutics (e.g., enfuvirtide) and vaccines. In present study, we constructed and expressed two recombinant gp41 PFI mimetics, designated N46Fd and N46FdFc. N46Fd consists of N46 (residues 536-581) in gp41 NHR and foldon (Fd), a trimerization motif. N46FdFc is composed of N46Fd fused with human IgG Fc fragment as an immunoenhancer. We immunized mice with N46 peptide, N46Fd and N46FdFc, respectively, and found that only N46FdFc elicited neutralizing antibody response in mice against infection by HIV-1 strains IIIB (clade B, X4), 92US657 (clade B, R5), and 94UG103 (clade A, X4R5). Anti-N46FdFc antibodies inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines.     

Solution structure of human SUMO-3 C47S and its binding surface for Ubc9

Small ubiquitin-related modifier SUMO-3 is a member of a growing family of ubiquitin-like proteins (Ubls). So far, four isoforms of SUMO have been identified in humans. It is generally known that SUMO modification regulates protein localization and activity. Previous structure and function studies have been mainly focused on SUMO-1. The sequence of SUMO-3 is 46% identical with that of SUMO-1; nevertheless, functional heterogeneity has been found between the two homologues. Here we report the solution structure of SUMO-3 C47S (residues 14-92) featuring the beta-beta-alpha-beta-beta-alpha-beta ubiquitin fold. Structural comparison shows that SUMO-3 C47S resembles ubiquitin more than SUMO-1. On the helix-sheet interface, a strong hydrophobic interaction contributes to formation of the globular and compact fold. A Gly-Gly motif at the C-terminal tail, extending away from the core structure, is accessible to enzymes and substrates. In vivo, SUMO modification proceeds via a multistep pathway, and Ubc9 plays an indispensable role as the SUMO conjugating enzyme (E2) in this process. To develop a better understanding of SUMO-3 conjugation, the Ubc9 binding surface on SUMO-3 C47S has been detected by chemical shift perturbation using NMR spectroscopy. The binding site mainly resides on the hydrophilic side of the beta-sheet. Negatively charged and hydrophobic residues of this region are highly or moderately conserved among SUMO family members. Notably, the negatively charged surface of SUMO-3 C47S is highly complementary in its electrostatic potentials and hydrophobicity to the positively charged surface of Ubc9. This work indicates dissimilarities between SUMO-3 and SUMO-1 in tertiary structure and provides insight into the specific interactions of SUMO-3 with its modifying enzyme.