Make-or-Buy in the Age of Open Source: A Transaction Cost Analysis

Since their appearance, open source communities have become increasingly successful and seemingly pose a real threat to traditional proprietary software vendors. Because open source software has now achieved both recognition and legitimacy, obtaining products and services from communities offers firms an additional alternative in traditional make-or-buy decisions. Transaction cost economics has been widely used as a theory to explain and predict the appropriate governance structure for make-or-buy decisions. By comparing transaction and production costs along a continuum of variable asset specificity, transaction cost economics helps to explain and predict the circumstances in which the open source community is the appropriate governance structure for specific make-or-buy decisions. Our work contributes to existing open source software research by shedding light on the factors that influence the appropriateness of this form of software production for firms. We are also contributing to the body of research surrounding transaction cost economics by incorporating into the original analysis the addition of “communities” as a unique governance alternative

Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates

The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions

Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- Prkdc(scid)IL2rg(tm1Wjl)/Sz (null; NSG) mice were transplanted with human (h)CD34(+) hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non-small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8(+) T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research

Thymic Involution in Viable Motheaten (meυ) Mice is Associated with a Loss of Intrathymic Precursor Activity

Mice homozygous for the viable motheaten (meυ) allele manifest abnormalities in thymocytopoiesis, are severely immunodeficient, and develop autoimmune disorders early in life. Premature thymic involution occurs in meυ/meυ mice, and their bone marrow prothymocytes are unable to repopulate the thymus of adoptive recipients following intravenous (i.v.) transfer. However, analysis of thymocytopoiesis following intrathymic (i.t.) adoptive transfer of bone marrow from meυ/meυ mice demonstrates the presence of normal numbers of prothymocytes. To investigate intrathymic development in meυ/meυ mice, we determined intrathymic precursor cell number and activity. Dual labeling analyses showed that an involuted meυ/meυ thymus is relatively enriched (fivefold) in CD4– CD8– thymocytes (intrathymic precursor phenotype) compared with wild-type (+/+) thymus. However, thymocytes from meυ/meυ mice were deficient in precursor activity when adoptively transferred i.t. into irradiated recipients. Thymocytes recovered from the involuted thymus of aged or steroid-treated normal mice also displayed reduced precursor activity. However, the phenotypic profile of thymocyte subsets from steroid-treated mice was enriched in single positive cells (mature phenotype) and was distinctly different from the subset distribution of thymocytes in meυ/meυ and aged mice. These results suggest that intrathymic precursor activity in meυ/meυ mice is decreased, and may be reflective of decreased prothymocyte seeding to the thymus in vivo, In addition, the results suggest that the thymic involution in meυ/meυ mice is not due solely to effects of corticosteroids

Thymic involution in viable motheaten (me(v)) mice is associated with a loss of intrathymic precursor activity

Mice homozygous for the viable motheaten (me(v)) allele manifest abnormalities in thymocytopoiesis, are severely immunodeficient, and develop autoimmune disorders early in life. Premature thymic involution occurs in me(v)/me(v) mice, and their bone marrow prothymocytes are unable to repopulate the thymus of adoptive recipients following intravenous (i.v.) transfer. However, analysis of thymocytopoiesis following intrathymic (i.t.) adoptive transfer of bone marrow from me(v)/me(v) mice demonstrates the presence of normal numbers of prothymocytes. To investigate intrathymic development in me(v)/me(v) mice, we determined intrathymic precursor cell number and activity. Dual labeling analyses showed that an involuted me(v)/me(v) thymus is relatively enriched (fivefold) in CD4-CD8- thymocytes (intrathymic precursor phenotype) compared with wild-type (+/+) thymus. However, thymocytes from me(v)/me(v) mice were deficient in precursor activity when adoptively transferred i.t. into irradiated recipients. Thymocytes recovered from the involuted thymus of aged or steroid-treated normal mice also displayed reduced precursor activity. However, the phenotypic profile of thymocyte subsets from steroid-treated mice was enriched in single positive cells (mature phenotype) and was distinctly different from the subset distribution of thymocytes in me(v)/me(v) and aged mice. These results suggest that intrathymic precursor activity in me(v)/me(v) mice is decreased, and may be reflective of decreased prothymocyte seeding to the thymus in vivo. In addition, the results suggest that the thymic involution in me(v)/me(v) mice is not due solely to effects of corticosteroids

In vivo correction of anaemia in beta-thalassemic mice by gammaPNA-mediated gene editing with nanoparticle delivery

The blood disorder, beta-thalassaemia, is considered an attractive target for gene correction. Site-specific triplex formation has been shown to induce DNA repair and thereby catalyse genome editing. Here we report that triplex-forming peptide nucleic acids (PNAs) substituted at the gamma position plus stimulation of the stem cell factor (SCF)/c-Kit pathway yielded high levels of gene editing in haematopoietic stem cells (HSCs) in a mouse model of human beta-thalassaemia. Injection of thalassemic mice with SCF plus nanoparticles containing gammaPNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood haemoglobin levels into the normal range, reduced reticulocytosis, reversal of splenomegaly and up to 7% beta-globin gene correction in HSCs, with extremely low off-target effects. The combination of nanoparticle delivery, next generation gammaPNAs and SCF treatment may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration

Viral Infection: A Potent Barrier to Transplantation Tolerance

Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance

alpha Cell Function and Gene Expression Are Compromised in Type 1 Diabetes

Many patients with type 1 diabetes (T1D) have residual beta cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual beta cells and alpha cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant beta cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D alpha cells was markedly reduced, and these cells had alterations in transcription factors constituting alpha and beta cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of alpha-to-beta cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia