“Animals Like Us”: Identifying with Nonhuman Animals and Support for Nonhuman Animal Rights

While anthropomorphizing nonhuman animals has been shown to increase identification with them and, by extension, concern for their wellbeing, little research has directly tested whether identifying with nonhuman animals is similarly associated with concern for their wellbeing. We tested hypotheses related to this premise across three cross-sectional studies. In study 1 (n = 224), we tested the hypothesis that therians—a group of people who self-identify with nonhuman animals, show greater concern for nonhuman animal rights than non-therian furries—people with a fan-like interest in media featuring anthropomorphized animal characters. In study 2 (n = 206), we further tested this hypothesis using implicit and explicit measures of identification with nonhuman animals to predict behavioral intentions to support nonhuman animal rights. In study 3 (n = 182), we tested the generalizability of our findings in a sample of undergraduate students. Taken together, the studies show that explicit, but not implicit, identification with nonhuman animals predicts greater support for their rights. The implications of these findings for research on anthropomorphism and animal rights activism are discussed, as well as the limitations of these findings and possible avenues for future research.     

Site-specific and hydrophilic ADCs through disulfide-bridged linker and branched PEG

Kadcyla® (T-DM1), an antibody–drug conjugates (ADCs) for HER2+ breast cancer treatment, has been approved by the Food and Drug Administration (FDA) in 2013. An ADC of random lysine conjugation, it has difficulties in DAR control and unsatisfactory PK due to uneven DAR distribution. It also gives rise to aggregation during conjugation because of the hydrophobicity nature of the cytotoxin, DM1. The linker-drug in T-DM1, SMCC-DM1 is hydrophobic and requires certain percentage of organic solvent such as DMA in the conjugation solution, limiting the manufacturing process in an organic-solvent-compatible device and adding extra costs. To address these problems, a site-specific conjugation method was developed involving full reduction of antibody and full conjugation with the bridge-like conjugator-drug, based on the work of Caddick and co-workers, to obtain a site-directed antibody-drug conjugate with DAR 4. The bridge-like conjugator was assembled with SMCC-DM1 and different lengths of hydrophilic polyethylene glycol (PEG) moiety. By applying PEG moiety in the side chain of the linker-drug, the organic solvent used in the conjugation can be reduced. When the PEG length is about 26 units, organic solvent is no longer needed in the conjugation. Reducing the amount of organic solvent in conjugation could also diminish the aggregation occurrence during the conjugation. Moreover, the conjugation configuration with the designed conjugator was also discussed in the article. The binding affinity of the resulting ADCs did not show significant decrease and the cell based assay and animal study have shown the comparable results with T-DM1.     

Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

The design and synthesis of a library of forty novel 2-aminoazole analogues as well as their evaluation as antifungal compounds against Histoplasma capsulatum and Cryptococcus neoformans is described. These structures were derived from N-[5-(1-naphthalenylmethyl)-2-thiazolyl]cyclohexanecarboxamide (41F5), a fungistatic agent previously identified through phenotypic screening (Antimicrob Agents Chemother. 2013;57:4349). Modifications to improve potency and water-solubility of 41F5 focused primarily on the 5-naphthalenyl group, the thiazole core, and the methylene linker between these two structural elements. In general, compounds with lipophilic [5+6] bicyclic ring systems, such as the 7-benzothiophenyl- and 4-indanyl groups, at the 5-position were 2–3 times more active against both fungal species as compared to 41F5. Also, introduction of a carbonyl group at the methylene linker of 41F5 resulted in a 2–3-fold increase in potency. These highly active compounds also showed generally low toxicities against murine P388D1 macrophages resulting in selectivity indices ranging from 63 to >200. Compounds that were highly active against fluconazole-sensitive C. neoformans strains had almost identical activity against fluconazole-resistant variants of this fungus indicating that 14α-demethylase is not their molecular target. Highly active compounds also retained activity against H. capsulatum phagocytosed into P388D1 macrophages.     

Isolation,leishmanicidal evaluation and molecular docking simulations of piperidine alkaloids from Senna spectabilis

Leishmaniasis is one of the most important neglected tropical diseases (NTDs) that are especially common among low-income populations in developing regions of Africa, Asia, and the Americas. Many natural products, particularly alkaloids, have been reported to have inhibitory activity against arginase, the key enzyme in the pathology caused by Leishmania sp. In this way, piperidine alkaloids (–)-cassine (1), (–)-spectaline (2), (–)-3-O-acetylcassine (3), and (–)-3-O-acetylspectaline (4) were isolated from Senna spectabilis flowers. These compounds (1/2 and 3/4) initially present as homologous mixtures were separated by high performance liquid chromatography and evaluated against the promastigote phase of Leishmania amazonensis. In addition, molecular docking simulations were implemented in order to probe the binding modes of the ligands 1–4 to the amino acids in the active site of L. amazonensis arginase. Alkaloid 2 (IC₅₀ 15.81?μg?mL^?1) was the most effective against L. amazonensis. Compounds 2 and 4, with larger side chain, were more effective against the parasite than compounds 1 and 3. The cell viability test on Vero cells revealed that compound 2 (CC₅₀ 66.67?μg?mL^?1) was the most toxic. The acetyl group in the 3-O position of the parent structures reduced the leishmanicidal activity and the toxicity of the alkaloids. Further, molecular docking suggested that Asn143 is essential for arginase to interact with (–)-spectaline-derived compounds, which agreed with the IC₅₀ measurements. Our findings revealed that S. spectabilis is an important source of piperidine alkaloids with leishmanicidal activity. Moreover, the natural compound 3 has been isolated for the first time. Experimental investigation combined with theoretical study advances knowledge about the enzyme binding site mode of interaction and contributes to the design of new bioactive drugs against Leishmania infection.     

Anticancer activity profiling of parthenolide analogs generated via P450-mediated chemoenzymatic synthesis

The plant-derived sesquiterpene lactone parthenolide (PTL) was recently found to possess promising anticancer activity but elaboration of this natural product scaffold for optimization of its pharmacological properties has proven challenging via available chemical methods. In this work, P450-catalyzed C–H hydroxylation of positions C9 and C14 in PTL was coupled to carbamoylation chemistry to yield a panel of novel carbamate-based PTL analogs (‘parthenologs’). These compounds, along with a series of other C9- and C14-functionalized parthenologs obtained via O–H acylation, alkylation, and metal-catalyzed carbene insertion, were profiled for their cytotoxicity against a diverse panel of human cancer cell lines. These studies led to the discovery of several parthenologs with significantly improved anticancer activity (2–14-fold) compared to the parent molecule. Most interestingly, two PTL analogs with high cytotoxicity (LC₅₀ ～ 1–3 μM) against T cell leukemia (Jurkat), mantle cell lymphoma (JeKo-1), and adenocarcinoma (HeLa) cells as well as a carbamate derivative with potent activity (LC₅₀ = 0.6 μM) against neuroblastoma cells (SK-N-MC) were obtained. In addition, these analyses resulted in the identification of parthenologs featuring both a broad spectrum and tumor cell-specific anticancer activity profile, thus providing valuable probes for the future investigation of biomolecular targets that can affect cell viability across multiple as well as specific types of human cancers. Altogether, these results highlight the potential of P450-mediated chemoenzymatic C–H functionalization toward tuning and improving the anticancer activity of the natural product parthenolide.     

Homogenization techniques for population dynamics in strongly heterogeneous landscapes

An important problem in spatial ecology is to understand how population-scale patterns emerge from individual-level birth, death, and movement processes. These processes, which depend on local landscape characteristics, vary spatially and may exhibit sharp transitions through behavioural responses to habitat edges, leading to discontinuous population densities. Such systems can be modelled using reaction–diffusion equations with interface conditions that capture local behaviour at patch boundaries. In this work we develop a novel homogenization technique to approximate the large-scale dynamics of the system. We illustrate our approach, which also generalizes to multiple species, with an example of logistic growth within a periodic environment. We find that population persistence and the large-scale population carrying capacity is influenced by patch residence times that depend on patch preference, as well as movement rates in adjacent patches. The forms of the homogenized coefficients yield key theoretical insights into how large-scale dynamics arise from the small-scale features.     

Stability and Hopf bifurcation for a five-dimensional virus infection model with Beddington–DeAngelis incidence and three delays

In this paper, the dynamical behaviours for a five-dimensional virus infection model with three delays which describes the interactions of antibody, cytotoxic T-lymphocyte (CTL) immune responses and Beddington–DeAngelis incidence are investigated. The reproduction numbers for virus infection, antibody immune response, CTL immune response, CTL immune competition and antibody immune competition, respectively, are calculated. By using the Lyapunov functionals and linearization method, the threshold conditions on the local and global stability of the equilibria for infection-free, immune-free, antibody response, CTL response and interior, respectively, are established. The existence of Hopf bifurcation with immune delay as a bifurcation parameter is investigated by using the bifurcation theory. Numerical simulations are presented to justify the analytical results.