Does Human Nature Conflict with Itself?: Human Form and the Harmony of the Virtues

Does possessing some human virtues make it impossible for a person to possess other human virtues? Isaiah Berlin and Bernard Williams both answered “yes” to this question, and they argued that to hold otherwise—to accept the harmony of the virtues—required a blinkered and unrealistic view of “what it is to be human.” In this essay, I have two goals: (1) to show how the harmony of the virtues is best interpreted, and what is at stake in affirming or denying it; and (2) to provide a partial defense of the harmony of the virtues. More specifically, I show how the harmony of the virtues can be interpreted and defended within the kind of Aristotelian naturalism developed by philosophers such as Philippa Foot, Rosalind Hursthouse, and Michael Thompson. I argue that far from being an embarrassing liability for Aristotelianism—based in an “archaic metaphysical biology”—the harmony thesis is an interesting and plausible claim about human excellences, supported by a sophisticated account of the representation of life, and fully compatible with a realistic view of our human situation

β-AR stimulation increases post-translational modifications of NF2 in nuclear and cytosolic fractions.

<p>ARVMs were treated with ISO for 15 mins. The cytosolic (CF) and nuclear fractions (NF) were analyzed by western blot using phospho-specific anti-NF2 antibodies. The lower panels exhibit the mean data normalized to GAPDH (CF) or PARP (NF), *p<0.05 vs CTL; n = 5–7.</p

β-AR stimulation induces post-translational modifications of NF2 in ARVMs.

<p>ARVMs were treated with ISO (10 μM) for 15 mins. Total cell lysates were analyzed by western blot using phospho-specific anti-NF2 antibodies. This antibody recognized ~70 kDa (phosphorylated NF2; A) and ~100 kDa (phosphorylated and sumoylated NF2; B) proteins. The lower panels exhibit the mean data normalized to total NF-2 (T-NF2) or GAPDH, *p<0.05 vs CTL; n = 3–7. (C) To confirm NF2 sumoylation, cell lysates were immunoprecipitated with anti-NF2 antibodies. Immunoprecipitates were analyzed by western blot using anti-SUMO-1 antibodies. Panel C exhibits quantitative increase in NF2 sumoylation in response to ISO. *p<0.05 vs CTL; n = 3.</p

β-AR stimulation and adenoviral-mediated expression of NF2 increase phosphorylation of MST1/2 in ARVMs.

<p>ARVMs were treated with ISO for 15 min (A) or infected with adenoviruses expressing WT-NF2 or GFP for 48 h (B). Total cell lysates were analyzed by western blot using phosho-specific anti-MST1/2 antibodies. The lower panels exhibit the mean data normalized to GAPDH, *p<0.05 vs CTL or GFP; n = 5.</p

Proposed schematic representation of signaling pathway involved in β-AR-stimulated increase in post-translational modifications of NF2.

<p>β-AR-stimulation using isoproterenol increases phosphorylation and sumoylation of NF2. This pathway may involve β₁-AR and cAMP/PKA pathway since β₁-AR antagonism and H89 inhibit β-AR-stimulated increase in NF2 phosphorylation and sumoylation. Direct activation of adenylyl cyclase mimics the effects of β-AR-stimulation on NF2 phosphorylation and sumoylation. β-AR-stimulation increases levels of phosphorylated and sumoylated NF2 in the nucleus. β-AR-stimulation increases phosphorylation of MST1/2 and YAP, downstream targets of NF2. Expression of WT-NF2 using adenoviruses stimulates mitochondrial death pathway by activating JNKs, increasing Bax expression and enhancing cytosolic levels of cytochrome c.</p

Knockdown of NF2 using siRNA decreases β-AR-stimulated increase in NF2 and YAP phosphorylation.

<p>H9C2 cells were transfected with NF2 siRNA for 48 h followed by treatment with ISO for 15 min. Cell lysates were analyzed by western blot using anti-NF2 (A), phospho-specific anti-NF2 (B) and phospho-specific anti-YAP (C) antibodies. The lower panels exhibit the mean data normalized to GAPDH, *P<0.05 vs.CTL; ^$p<0.05 vs. ISO; n = 3.</p

Stimulation of β-AR and adenoviral-mediated expression of NF2 increase YAP phosphorylation.

<p>ARVMs were treated with ISO for 15 min (A) or infected with adenoviruses expressing WT-NF2 or GFP for 48 h (B). Total cell lysates were analyzed by western blot using phospho-specific anti-YAP antibodies. There was no significant change in total YAP expression following ISO treatment. Therefore, data was normalized to GAPDH. The lower panels exhibit the mean data normalized to GAPDH, *p<0.05 vs CTL or GFP; n = 3–7.</p

Adenoviral-mediated expression of NF2 activates mitochondrial death pathway in ARVMs.

<p>ARVMs were infected with adenoviruses expressing WT-NF2 or GFP for 48 h. Cell lysates were analyzed by western blots using phospho-specific anti-JNKs (A), anti-Bax (B), and anti-Bcl₂ antibodies (data not shown), while cytosolic fractions were analyzed by western blot using anti-cytochrome c (D) antibodies. The lower panels exhibit the mean data normalized to total JNKs (T-JNKs) or GAPDH. Fig 9 (C) represents Bcl₂/Bax ratio. *p<0.05 vs GFP; n = 4–6.</p

Effect of Lipid Corona on Phenylalanine-Functionalized Gold Nanoparticles to Develop Stable and Corona-Free Systems

Conventional gold nanoparticles (Au NPs) have many limitations, such as aggregation and subsequent precipitation in the medium of high ionic strength and protein molecules. Furthermore, when exposed to biological fluids, nanoparticles form a protein corona, which controls different biological processes such as the circulation lifetime, drug release profile, biodistribution, and in vivo cellular distribution. These limitations reduce the functionality of Au NPs in targeted delivery, bioimaging, gene delivery, drug delivery, and other biomedical applications. To circumvent these problems, there are numerous attempts to design corona-free and stable nanoparticles. Here, we report for the first time that lipid corona (coating of lipid) formation on phenylalanine-functionalized Au NPs (AuPhe NPs) imparts excellent stability against the high ionic strength of bivalent metal ions, amino acids, and proteins of different charges as compared to bare nanoparticles. Moreover, this work is focused on the ability of lipid corona formation on AuPhe NPs to prevent protein adsorption in the presence of cell culture medium (CCM), oppositely charged protein (e.g., histone 3), and human serum albumin (HSA). The results demonstrate that the lipid corona successfully protects the AuPhe NPs from protein adsorption, leading to the development of corona-free character. This unique achievement has profound implications for enhancing the biomedical utility and safety of these nanoparticles

Expression of TIMPs.

<p>Total LV lysates (50 µg), prepared from sham and non-infarct (NINF) and infarct (INF) LV regions, were analyzed by western blot using anti-TIMP-2 (A) and anti-TIMP-4 (B) antibodies. The upper panels show autoradiograms indicating immunostaining for TIMP-2, TIMP-4, and GAPDH. The lower panels exhibit quantitative analyses of TIMP-2, TIMP-4 normalized to GAPDH. *p<0.05 vs sham; ^#p<0.05 vs NINF; ^$p<0.05 vs WT-INF; n=7.</p