Beyond Experience: Getting Retributive Justice Right

How central should hedonic adaptation be to the establishment of sentencing policy? In earlier work, Professors Bronsteen, Buccafusco, and Masur (BBM) drew some normative significance from the psychological studies of adaptability for punishment policy. In particular, they argued that retributivists and utilitarians alike are obliged on pain of inconsistency to take account of the fact that most prisoners, most of the time, adapt to imprisonment in fairly short order, and therefore suffer much less than most of us would expect. They also argued that ex-prisoners don\u27t adapt well upon re-entry to society and that social planners should consider their post-release experiences as part of the suffering the state imposes as punishment. In subsequent articles, we challenged BBM’s arguments (principally from the perspective of retributive justice) -- see below for SSRN links. The fundamental issue between BBM and us is whether punishment should be defined, measured, and justified according to the subjective negative experiences of those who are punished, an approach we refer to as subjectivism, or whether the more compelling approach is to define and justify punishment, more or less, in objective terms such that the amount need not vary based on experiences of offenders alone. In their responsive essay, Retribution and the Experience of Punishment, BBM responded to our challenges. This essay of ours now assesses the impact of their responses, again from the perspective of retributive justice. We remain unpersuaded by their conceptual and normative responses. We also use this essay to explain further the wrong turns associated with BBM\u27s decision to endorse subjectivist concerns as the principal measure and justification for the infliction of retributive punishment. Markel and Flanders, Bentham on Stilts: The Bare Relevance of Subjectivity to Retributive Punishment, https://bit.ly/3fvFT8X Gray, Punishment as Suffering, http://ssrn.com/abstract=1573600 BBM, Retribution and the Experience of Punishment, http://ssrn.com/abstract=169292

Shear Force at Failure and Stiffness of All-Inside Meniscal Repair Devices

The purpose of this study was to determine the failure load and stiffness of various meniscal repair devices. A total of 61 fresh-frozen porcine menisci (medial and lateral) were used for the study. A 30-mm vertical, full-thickness tear was created and repaired using one of three all-inside fixation devices and one inside–out repair in the vertical mattress pattern. We used the MaxBraid (Biomet, Warsaw, IN) inside–out suture as a control. The other devices tested were the Meniscal Cinch (Arthrex, Naples, FL), Ultra FasT-Fix (Smith & Nephew, Andover, MA), and the MaxFire MarXmen (Biomet, Warsaw, IN). In addition, two devices, MaxFire MarXmen and Ultra FasT-Fix, were tested using a horizontal mattress configuration. Using the vertical mattress pattern, the Meniscal Cinch had the highest average load to failure. The Meniscal Cinch was significantly less stiff than the other three devices (p \u3c 0.04). For the MarXmen and Ultra FasT-Fix, no differences were noted for load to failure between horizontal and vertical mattress patterns. The mode of failure was significantly different when comparing the two different surgical techniques for the MaxFire MarXmen (p = 0.005). The MaxFire MarXmen device produced a significantly stiffer (p  \u3c 0.001) construct when following the manufacturer\u27s instructions (5.8 N/mm) than with the technique used for the other all-inside devices (2.5 N/mm) The Meniscal Cinch had the highest load-to-failure value but the lowest stiffness of the group in the vertical mattress configuration. There was little difference in biomechanical properties between vertical and horizontal repair. Importantly, there was a significant difference in stiffness and failure mode for the MaxFire MarXmen when the manufacturer guidelines were not specifically followed

Characterization of the inflammatory response to four commercial bone graft substitutes using a murine biocompatibility model

Bone grafting is utilized in nearly all orthopedic subspecialties and in most anatomic regions. Bone graft substitutes have the potential to offer similar efficacy as autogenous grafts without the morbidity of harvest. Several studies have noted the efficacy of new-generation bone substitute products, but few studies have evaluated their safety. This study characterizes and quantifies the inflammatory reaction to four different commercially available bone graft substitutes, which were examined using the in vivo murine air pouch biocompatibility model. One coralline hydroxyapatite product was chosen as an example of a purely osteoconductive material. Three demineralized bone matrix products were chosen to represent products that are both osteoconductive and osteoinductive. Samples were implanted in a murine air pouch and harvested after 14 days in situ. Pouch fluid was extracted, mRNA isolated, and reverse transcription polymerase chain reactions carried out to detect interleukin-1 gene expression as a marker for inflammation. In addition, multiple histological characteristics were examined to quantify cellular responses to the implanted materials. All bone graft substitutes induced a significant inflammatory response compared with negative controls. Histology and polymerase chain reaction data indicated that the level of inflammatory reaction was elevated in materials with a higher demineralized bone matrix to carrier proportion. The hydroxyapatite product generated a low inflammatory reaction. In conclusion, this study used an in vivo model of biocompatibility to demonstrate that a significant inflammatory reaction occurs when using implanted bone graft substitutes. When choosing a bone grafting method, surgeons should consider both the efficacy and safety of methods and materials used. Further studies are necessary to determine the ideal bone graft material to maximize efficacy while minimizing morbidity

Cyclodextrin-erythromycin complexes as a drug delivery device for orthopedic application

Wei Song1, Xiaowei Yu2, Sunxi Wang5, Ralph Blasier4, David C Markel3, Guangzhao Mao5, Tong Shi1, Weiping Ren1,31Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA; 2Department of Orthopedic Surgery, Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China; 3Detroit Medical Center and Providence Hospital Orthopedic Residency, Detroit, 4Orthopedic Section, St Francis Hospital, Escanaba, 5Department of Chemical Engineering, Wayne State University, Detroit, MI, USABackground: Erythromycin, a hydrophobic antibiotic used to treat infectious diseases, is now gaining attention because of its anti-inflammatory effects and ability to inhibit osteoclasts formation. The aim of this study was to explore a cyclodextrin-erythromycin (CD-EM) complex for sustained treatment of orthopedic inflammation.Methods and results: Erythromycin was reacted with ß-cyclodextrin to form a nonhost-guest CD-EM complex using both kneading and stirring approaches. Physiochemical measurement data indicated that erythromycin and cyclodextrin formed a packing complex driven by intermolecular forces instead of a host-guest structure due to the limited space in the inner cavity of ß-cyclodextrin. The CD-EM complex improved the stability of erythromycin in aqueous solution and had a longer duration of bactericidal activity than free erythromycin. Cytotoxicity and cell differentiation were evaluated in both murine MC3T3 preosteoblast cells and RAW 264.7 murine macrophage cells. The CD-EM complex was noncytotoxic and showed significant inhibition of osteoclast formation but had little effect on osteoblast viability and differentiation.Conclusion: These attributes are especially important for the delivery of an adequate amount of erythromycin to the site of periprosthetic inflammation and reducing local inflammation in a sustained manner.Keywords: erythromycin, cyclodextrin, drug stability, bactericidal activity, osteoclastogenesi

Engineering Chemoselectivity in Hemoprotein-Catalyzed Indole Amidation

Here we report a cytochrome P450 variant that catalyzes C_2-amidation of 1-methylindoles with tosyl azide via nitrene transfer. Before evolutionary optimization, the enzyme exhibited two undesired side reactivities resulting in reduction of the putative iron-nitrenoid intermediate or cycloaddition between the two substrates to form triazole products. We speculated that triazole formation was a promiscuous cycloaddition activity of the P450 heme domain, while sulfonamide formation likely arose from surplus electron transfer from the reductase domain. Directed evolution involving mutagenesis of both the heme and reductase domains delivered an enzyme providing the desired indole amidation products with up to 8400 turnovers, 90% yield, and a shift in chemoselectivity from 2:19:1 to 110:12:1 in favor of nitrene transfer over reduction or triazole formation. This work expands the substrate scope of hemoprotein nitrene transferases to heterocycles and highlights the adaptability of the P450 scaffold to solve challenging chemoselectivity problems in non-natural enzymatic catalysis

Engineering Chemoselectivity in Hemoprotein-Catalyzed Indole Amidation

Here we report a cytochrome P450 variant that catalyzes C_2-amidation of 1-methylindoles with tosyl azide via nitrene transfer. Before evolutionary optimization, the enzyme exhibited two undesired side reactivities resulting in reduction of the putative iron-nitrenoid intermediate or cycloaddition between the two substrates to form triazole products. We speculated that triazole formation was a promiscuous cycloaddition activity of the P450 heme domain, while sulfonamide formation likely arose from surplus electron transfer from the reductase domain. Directed evolution involving mutagenesis of both the heme and reductase domains delivered an enzyme providing the desired indole amidation products with up to 8400 turnovers, 90% yield, and a shift in chemoselectivity from 2:19:1 to 110:12:1 in favor of nitrene transfer over reduction or triazole formation. This work expands the substrate scope of hemoprotein nitrene transferases to heterocycles and highlights the adaptability of the P450 scaffold to solve challenging chemoselectivity problems in non-natural enzymatic catalysis

'Just’ punishment? Offenders’ views on the meaning and severity of punishment

In England and Wales, ‘punishment’ is a central element of criminal justice. What punishment entails exactly, however, and how it relates to the other aims of sentencing (crime reduction, rehabilitation, public protection and reparation), remains contested. This article outlines different conceptualizations of punishment and explores to what extent offenders subscribe to these perspectives. The analysis is supported by findings from two empirical studies on the subjective experiences of imprisonment and probation, respectively. Semi-structured interviews were conducted with 15 male and 15 female prisoners and seven male and two female probationers. Two primary conceptualizations of punishment were identified: ‘punishment as deprivation of liberty’ and ‘punishment as hard treatment’. The comparative subjective severity of different sentences and the collateral (unintended) consequences of punishment are also discussed. It is shown that there are large individual differences in the interpretation and subjective experience of punishment, which has implications for the concept of retributive proportionality, as well as the function of punishment more generally

Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.

BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)β(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. CONCLUSIONS: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation

Plant biosystems design research roadmap 1.0

Human life intimately depends on plants for food, biomaterials, health, energy, and a sustainable environment. Various plants have been genetically improved mostly through breeding, along with limited modification via genetic engineering, yet they are still not able to meet the ever-increasing needs, in terms of both quantity and quality, resulting from the rapid increase in world population and expected standards of living. A step change that may address these challenges would be to expand the potential of plants using biosystems design approaches. This represents a shift in plant science research from relatively simple trial-and-error approaches to innovative strategies based on predictive models of biological systems. Plant biosystems design seeks to accelerate plant genetic improvement using genome editing and genetic circuit engineering or create novel plant systems through de novo synthesis of plant genomes. From this perspective, we present a comprehensive roadmap of plant biosystems design covering theories, principles, and technical methods, along with potential applications in basic and applied plant biology research. We highlight current challenges, future opportunities, and research priorities, along with a framework for international collaboration, towards rapid advancement of this emerging interdisciplinary area of research. Finally, we discuss the importance of social responsibility in utilizing plant biosystems design and suggest strategies for improving public perception, trust, and acceptance