'Chimeric' Grafts Assembled from Multiple Allodisparate Donors Enjoy Enhanced Transplant Survival

Certain components of a graft that provoke alloimmunity may not be vital for graft function or critical as targets of rejection. Corneal transplantation is an example of this, because graft epithelium plays a role in allosensitization, whereas corneal graft endothelium—which shares the same alloantigens—is the critical target in allorejection. In this study, we found that exploiting this biology by replacing donor epithelium of an allograft with an allodisparate third-party epithelium yields a marked enhancement in transplant survival. Such 'chimeric' allografts consisted of a C3H/He (H-2^k) corneal epithelium over a C57BL/6 (H-2^b) epithelial-denuded cornea (or v.v. ) and orthotopically placed on BALB/c (H-2^d) hosts. Conventional corneal allografts (C3H/He or C57BL/6) or isografts (BALB/c) were also transplanted on BALB/c hosts. Alloreactive T-cell frequencies (CD4⁺ interferon [IFN]-γ⁺) primed to the graft endothelium were strongly diminished in chimeric hosts relative to conventionally allografted hosts. This was corroborated by a decreased T-cell infiltration (p = 0.03) and a marked enhancement of allograft survival (p = 0.001). Our results represent the first successful demonstration of chimeric tissue, epithelial-denuded allograft plus third-party allodisparate epithelium, in the promotion of allograft survival. Moreover, chimeric grafting can be readily performed clinically, whereby corneal allograft rejection remains a significant problem particularly in inflamed graft beds.     

A novel function for programmed death ligand-1 regulation of angiogenesis

Programmed death ligand-1 (PD-L1) plays a critical role in T-cell regulatory function. Here, we report a newly discovered effect of PD-L1 on angiogenesis. We demonstrate that PD-L1 and its receptor CD80, but not PD-1, are expressed by primary murine lung and heart vascular endothelial cells and the miscrovascular endothelial cell line (MS1) at both the mRNA and protein levels in vitro. The inhibition of PD-L1 or CD80 expression in MS1 cells, by small-interfering RNA transfection, led to a significant up-regulation of vascular endothelial growth factor receptor 2 expression and cell proliferation levels in MS1 cells. Furthermore, MS1 cells were found to have a significantly lower proliferation and vascular endothelial growth factor receptor 2 expression levels when they were co-cultured with PD-L1-expressing normal corneal epithelial cells, as compared to MS1 cells co-cultured with PD-L1(-/-) corneal epithelial cells. In a suture-induced corneal angiogenesis model, we observed a significantly higher level of angiogenic response in PD-L1(-/-) knockout mice as compared to wild-type mice, although there was no significant difference in the expression of inflammatory cytokines (interleukin-1α, interleukin-1β, or tumor necrosis factor-α) or the infiltration of innate immune cells (neutrophils and macrophages) between the two groups. We conclude that the expression of PD-L1 in both vascular endothelial cells and corneal epithelial cells regulates corneal angiogenesis.     

From the Cover: Universal robotic gripper based on the jamming of granular material

Gripping and holding of objects are key tasks for robotic manipulators. The development of universal grippers able to pick up unfamiliar objects of widely varying shape and surface properties remains, however, challenging. Most current designs are based on the multifingered hand, but this approach introduces hardware and software complexities. These include large numbers of controllable joints, the need for force sensing if objects are to be handled securely without crushing them, and the computational overhead to decide how much stress each finger should apply and where. Here we demonstrate a completely different approach to a universal gripper. Individual fingers are replaced by a single mass of granular material that, when pressed onto a target object, flows around it and conforms to its shape. Upon application of a vacuum the granular material contracts and hardens quickly to pinch and hold the object without requiring sensory feedback. We find that volume changes of less than 0.5% suffice to grip objects reliably and hold them with forces exceeding many times their weight. We show that the operating principle is the ability of granular materials to transition between an unjammed, deformable state and a jammed state with solid-like rigidity. We delineate three separate mechanisms, friction, suction, and interlocking, that contribute to the gripping force. Using a simple model we relate each of them to the mechanical strength of the jammed state. This advance opens up new possibilities for the design of simple, yet highly adaptive systems that excel at fast gripping of complex objects.     

Distant Relatives of Severe Acute Respiratory Syndrome Coronavirus and Close Relatives of Human Coronavirus 229E in Bats, Ghana

We tested 12 bat species in Ghana for coronavirus (CoV) RNA. The virus prevalence in insectivorous bats (n = 123) was 9.76%. CoV was not detected in 212 fecal samples from Eidolon helvum fruit bats. Leaf-nosed bats pertaining to Hipposideros ruber by morphology had group 1 and group 2 CoVs. Virus concentrations were <45,000 copies/100 mg of bat feces. The diversified group 1 CoV shared a common ancestor with the human common cold virus hCoV-229E but not with hCoV-NL63, disputing hypotheses of common human descent. The most recent common ancestor of hCoV-229E and GhanaBt-CoVGrp1 existed in ≈1686–1800 ad. The GhanaBt-CoVGrp2 shared an old ancestor (≈2,400 years) with the severe acute respiratory syndrome–like group of CoV.     

Insulin pump therapy

Intensive insulin therapy is the mainstay of diabetes care as it prevents or delays the long term complications of Type 1 diabetes mellitus. Insulin pump therapy can deliver improved diabetes control and at the same time reduce the number and serious nature of any hypoglycaemic episodes. The therapy is not associated with an increased risk of diabetic ketoacidosis. Pump therapy should follow National Institute for Health and Care Excellence Guidelines and be instigated and supported by teams experienced in insulin pump therapy, with skills and competences to ensure sustained positive outcomes. Continuous glucose monitoring further improves blood glucose control providing continuous feedback with warnings of rapid changes in glucose and/or attainment of high or low glucose concentrations. Continuous glucose monitoring is cost effective by reducing fear of hypoglycaemia, blood glucose finger prick testing and a marked reduction in hypoglycaemic episodes. The hybrid closed loop systems offering algorithm driven insulin adjustment based on sensor readings are now commercially available bringing into play more effective and safer insulin delivery with a further step change in diabetes control and well being.     

Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study

Renal hypodysplasia (RHD) is characterized by a reduced nephron number, small kidney size, and disorganized renal tissue. A hereditary basis has been established for a subset of affected patients, suggesting a major role of developmental genes that are involved in early kidney organogenesis. Gene mutations that have dominant inheritance and cause RHD, urinary tract anomalies, and defined extrarenal symptoms have been identified in TCF2 (renal cysts and diabetes syndrome), PAX2 (renal-coloboma syndrome), EYA1 and SIX1 (branchio-oto-renal syndrome), and SALL1 (Townes-Brocks syndrome). For estimation of the prevalence of these events, an unselected cohort of 99 unrelated patients with RHD that was associated with chronic renal insufficiency were screened for mutations in TCF2, PAX2, EYA1, SIX1, and SALL1. Mutations or variants in the genes of interest were detected in 17 (17%) unrelated families: One mutation, two variants, and four deletions of TCF2 in eight unrelated patients; four different PAX2 mutations in six families; one EYA1 mutation and one deletion in two patients with branchio-oto-renal syndrome; and one SALL1 mutation in a patient with isolated RHD. Of a total of 27 patients with renal cysts, six (22%) carried a mutation in TCF2. It is interesting that a SIX1 sequence variant was identified in two siblings with renal-coloboma syndrome as a result of a PAX2 mutation, suggesting an oligogenic inheritance. Careful clinical reevaluation that focused on discrete extrarenal symptoms and thorough family analysis revealed syndrome-specific features in nine of the 17 patients. In conclusion, 15% of patients with RHD show mutations in TCF2 or PAX2, whereas abnormalities in EYA1, SALL1, and SIX1 are less frequent.     

How to apply for research grants in allergology

This is a guide for grant application for researchers seeking research grants in the field of allergy and related diseases for the first time. It outlines how to organize proposals and the potential issues to be considered in order to fulfil the criteria of the funding bodies and thus improve chances of obtaining the desired funding when applying for a research grant. We will use this paper as an example of a grant proposal to be presented to the FIS “Fondo de Investigación Sanitaria” (Health Research Fund) of Spain. The general framework can be used for a research proposal to any funding agency. The main research designs are reviewed. Other topics such as hypothesis, objectives, methodology, ethics and legal issues, and budget are presented.