Cyclic Derivatives of the Chemerin C-Terminus as Metabolically Stable Agonists at the Chemokine-Like Receptor 1 for Cancer Treatment

Chemerin is a small chemotactic protein and a modulator of the innate immune system. Its activity is mainly mediated by the chemokine-like receptor 1 (CMKLR1), a receptor expressed by natural killer cells, dendritic cells, and macrophages. Downregulation of chemerin is part of the immune evasion strategy exploited by several cancer types, including melanoma, breast cancer, and hepatocellular carcinoma. Administration of chemerin can potentially counteract these effects, but synthetically accessible, metabolically stable analogs are required. Other tumors display overexpression of CMKLR1, offering a potential entry point for targeted delivery of chemotherapeutics. Here, we present cyclic derivatives of the chemerin C-terminus (chemerin-9), the minimal activation sequence of chemerin. Chemerin-9 derivatives that were cyclized through positions four and nine retained activity while displaying full stability in blood plasma for more than 24 h. Therefore, these peptides could be used as a drug shuttle system to target cancer cells as demonstrated here by methotrexate conjugates.

Linear evasion differential game of one evader and several pursuers with integral constraints

An evasion differential game of one evader and many pursuers is studied. The dynamics of state variables $$x_1,\ldots , x_m$$ x 1 , … , x m are described by linear differential equations. The control functions of players are subjected to integral constraints. If $$x_i(t) \ne 0$$ x i ( t ) ≠ 0 for all $$i \in \{1,\ldots ,m\}$$ i ∈ { 1 , … , m } and $$t \ge 0$$ t ≥ 0 , then we say that evasion is possible. It is assumed that the total energy of pursuers doesn’t exceed the energy of evader. We construct an evasion strategy and prove that for any positive integer m evasion is possible.

The system of means of expressing the strategy of evasion in dialogical unity

The research of the system of linguistic means, which express the strategy of evasion in dialogues within the framework of pragmalinguistics, contributes to a comprehensive study of this phenomenon, meeting the requirements of the nowadays scientific demands. The appeal to this topic is due to insufficient knowledge of the system of linguistic and pragmatic means that realize the strategy of evasion in dialogical speech. The aim of this paper describe the specifics of such language system analyzing some works of G. Ibsen, A. Miller, T. Williams and other well-known modern writers. The paper reveals the specifics of a dialogue as well as the phenomenon of speech influence, whose aim is to convince interlocutors consciously and / or unconsciously to accept someone else's point of view. The authors reveal the realization of the strategy of evasion in the dialogical unity studying some corresponding communicative tactics such as repetitions (including resentment, replay, reproach and overexpression), delay of response and mitigation of categoricity of response. All of them are represented by a great variety of multi-level linguistic means. The identified set of communicative tactics of the evasion strategy makes it possible to understand what communicative actions an addresser can perform to influence the addressee.

Discovery of multiple anti-CRISPRs highlights anti-defense gene clustering in mobile genetic elements

Many prokaryotes employ CRISPR–Cas systems to combat invading mobile genetic elements (MGEs). In response, some MGEs have developed strategies to bypass immunity, including anti-CRISPR (Acr) proteins; yet the diversity, distribution and spectrum of activity of this immune evasion strategy remain largely unknown. Here, we report the discovery of new Acrs by assaying candidate genes adjacent to a conserved Acr-associated (Aca) gene, aca5, against a panel of six type I systems: I–F (Pseudomonas, Pectobacterium, and Serratia), I–E (Pseudomonas and Serratia), and I–C (Pseudomonas). We uncover 11 type I–F and/or I–E anti-CRISPR genes encoded on chromosomal and extrachromosomal MGEs within Enterobacteriaceae and Pseudomonas, and an additional Aca (aca9). The acr genes not only associate with other acr genes, but also with genes encoding inhibitors of distinct bacterial defense systems. Thus, our findings highlight the potential exploitation of acr loci neighborhoods for the identification of previously undescribed anti-defense systems.

Rosettes integrity protects Plasmodium vivax of being phagocytized

Plasmodium vivax is the most prevalent cause of malaria outside of Africa. P. vivax biology and pathogenesis are still poorly understood. The role of one highly occurring phenotype in particular where infected reticulocytes cytoadhere to noninfected normocytes, forming rosettes, remains unknown. Here, using a range of ex vivo approaches, we showed that P. vivax rosetting rates were enhanced by plasma of infected patients and that total immunoglobulin M levels correlated with rosetting frequency. Moreover, rosetting rates were also correlated with parasitemia, IL-6 and IL-10 levels in infected patients. Transcriptomic analysis of peripheral leukocytes from P. vivax-infected patients with low or moderated rosetting rates identified differentially expressed genes related to human host phagocytosis pathway. In addition, phagocytosis assay showed that rosetting parasites were less phagocyted. Collectively, these results showed that rosette formation plays a role in host immune response by hampering leukocyte phagocytosis. Thus, these findings suggest that rosetting could be an effective P. vivax immune evasion strategy.

Collaborative Pursuit-Evasion Strategy of UAV/UGV Heterogeneous System in Complex Three-Dimensional Polygonal Environment

The UAV/UGV heterogeneous system combines the air superiority of UAV (unmanned aerial vehicle) and the ground superiority of UGV (unmanned ground vehicle). The system can complete a series of complex tasks and one of them is pursuit-evasion decision, so a collaborative strategy of UAV/UGV heterogeneous system is proposed to derive a pursuit-evasion game in complex three-dimensional (3D) polygonal environment, which is large enough but with boundary. Firstly, the system and task hypothesis are introduced. Then, an improved boundary value problem (BVP) is used to unify the terrain data of decision and path planning. Under the condition that the evader knows the position of collaborative pursuers at any time but pursuers just have a line-of-sight view, a worst case is analyzed and the strategy between the evader and pursuers is studied. According to the state of evader, the strategy of collaborative pursuers is discussed in three situations: evader is in the visual field of pursuers, evader just disappears from the visual field of pursuers, and the position of evader is completely unknown to pursuers. The simulation results show that the strategy does not guarantee that the pursuers will win the game in complex 3D polygonal environment, but it is optimal in the worst case.

Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins

Novel therapies to counteract multidrug-resistant gonorrhea are urgently needed. A unique gonococcal immune evasion strategy involves capping of lipooligosaccharide (LOS) with sialic acid by gonococcal sialyltransferase (Lst), utilizing host-derived CMP-sialic acid (CMP-Neu5Ac in humans). LOS sialylation renders gonococci resistant to complement and cationic peptides, and down-regulates the inflammatory response by engaging siglecs. CMP-sialic acid analogs (CMP-nonulosonates [CMP-NulOs]) such as CMP-Leg5,7Ac2 and CMP-Kdn are also utilized by Lst. Incorporation of these NulO analogs into LOS maintains gonococci susceptible to complement. Intravaginal administration of CMP-Kdn or CMP-Leg5,7Ac2 attenuates gonococcal colonization of mouse vaginas. Here, we identify a key mechanism of action for the efficacy of CMP-NulOs. Surprisingly, CMP-NulOs remained effective in complement C1q-/- and C3-/- mice. LOS Neu5Ac, but not Leg5,7Ac2 or Kdn, conferred resistance to the cathelicidins LL-37 (human) and mouse cathelicidin-related antimicrobial peptide in vitro. CMP-NulOs were ineffective in Camp-/- mice, revealing that cathelicidins largely mediate the efficacy of therapeutic CMP-NulOs.

A Systematic Review on Parasite Induced Carcinogenesis

Parasitic pathogens through cross infection exert carcinogenesis in human body. The immune evasion strategy that has been adapted by several parasites is recognized to be associated with human carcinogenicity. In this review, studies have been analyzed which depicts how carcinogenicity occurs through several parasitic infection. Among the parasites that are involved toward developing carcinogenicity, Helminth is found to be dominant as per the recent studies. One reason for this that they mostly have prolonged life cycle than the other parasites, therefore more complex network through molecular endeavour has been adapted by them that would leads the host cell malignancy. This review particularly summarizes the parasites that are involved in carcinogenicity and the mechanism that they adapt to develop so. Targeting the molecules that are being modulated by parasites to trigger carcinogenesis, drug development can be done. Drug designing can also be made by targeting the parasite induced secretory molecules which mainly cross talk to develop carcinogenicity. Specially conjugated therapy of parasitic drugs with anticancer drugs that are target specific should be used at minimum doses so that to block the parasite induced carcinogenicity in host body.