Exploring pharmacodynamics of immunosuppresive agents in transplantation

Supported by advancements in technology, surgical techniques and immunosuppressive drugs, solid organ transplantation has become the preferred solution to end stage organ failure. The first solid organ transplantation was performed in 1954 under supervision of Joseph Murray in the Peter Bent Brigham Hospital in Boston. A kidney from a healthy donor was transplanted into his identical twin, who suffered from chronic glomerulonephritis. The transplanted organ functioned immediately and the recipient survived for 25 years while the donor lived for another 56 years. Since the twins were genetically identical, no suppression of the immune system was needed. Transplantation between individuals other than identical twins was made possible a decade later by the use of the combination of azathioprine and corticosteroids, achieving a 1 year allograft1 survival rate of 40 to 50 percent

A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms

Abstract Matrix metalloproteinase 9 (MMP‐9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype‐based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP‐9 rs20544 C/T single‐nucleotide polymorphism (SNP) located in the 3′untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP‐9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP‐9 3′UTR. We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP‐9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis‐related locomotor hyperactivity in Mmp‐9 heterozygous mice. We propose a novel mechanism that involves MMP‐9‐dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP‐9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients

Breed and adaptive response modulate bovine peripheral blood cells’ transcriptome

Background: Adaptive response includes a variety of physiological modifications to face changes in external or internal conditions and adapt to a new situation. The acute phase proteins (APPs) are reactants synthesized against environmental stimuli like stress, infection, inflammation. Methods: To delineate the differences in molecular constituents of adaptive response to the environment we performed the whole-blood transcriptome analysis in Italian Holstein (IH) and Italian Simmental (IS) breeds. For this, 663 IH and IS cows from six commercial farms were clustered according to the blood level of APPs. Ten extreme individuals (five APP+ and APP- variants) from each farm were selected for the RNA-seq using the Illumina sequencing technology. Differentially expressed (DE) genes were analyzed using dynamic impact approach (DIA) and DAVID annotation clustering. Milk production data were statistically elaborated to assess the association of APP+ and APP- gene expression patterns with variations in milk parameters. Results: The overall de novo assembly of cDNA sequence data generated 13,665 genes expressed in bovine blood cells. Comparative genomic analysis revealed 1,152 DE genes in the comparison of all APP+ vs. all APP- variants; 531 and 217 DE genes specific for IH and IS comparison respectively. In all comparisons overexpressed genes were more represented than underexpressed ones. DAVID analysis revealed 369 DE genes across breeds, 173 and 73 DE genes in IH and IS comparison respectively. Among the most impacted pathways for both breeds were vitamin B6 metabolism, folate biosynthesis, nitrogen metabolism and linoleic acid metabolism. Conclusions: Both DIA and DAVID approaches produced a high number of significantly impacted genes and pathways with a narrow connection to adaptive response in cows with high level of blood APPs. A similar variation in gene expression and impacted pathways between APP+ and APP- variants was found between two studied breeds. Such similarity was also confirmed by annotation clustering of the DE genes. However, IH breed showed higher and more differentiated impacts compared to IS breed and such particular features in the IH adaptive response could be explained by its higher metabolic activity. Variations of milk production data were significantly associated with APP+ and APP- gene expression patterns

Investigation of pile-integrity using novel signal processing methods

As there are a lot of limitations on health monitoring of piles, stress wave propagation tests are of interest among civil engineers and researchers. In these methods, the testing signal recorded by receiver on the pile head should be analyzed to check whether any defect exists. In this paper, the application of low strain pile-integrity tests and interpretation of the results by Continuous wavelet transform (CWT) is studied. Finite element model of some imaginary piles are provided in order to analyze the response of the structures due to a known signal. The results demonstrate that the testing signal can be broken down into time and frequency domain at the same time. As a result, more characteristics of the testing signal can be depicted, and defects can be detected easier than the traditional signal processing methods, such as Fourier transform (FT). Furthermore, the results show that impedance is not a proper criterion to identify damage severity, and damage detection ability of low strain test is a function of defect length as well

DAMAGE ASSESSMENT AND MONITORING OF CULTURAL HERITAGE PLACES IN A DISASTER AND POST-DISASTER EVENT – A CASE STUDY OF SYRIA

In recent decades, and in response to an increased focus on disastrous events ranging from armed conflict to natural events that impact cultural heritage, there is a need for methodologies and approaches to better manage the effects of disaster on cultural heritage. This paper presents the approaches used in the development of a Historic Environment Record (HER) for Syria. It describes the requirements and methodologies used for systematic emergency recording and assessment of cultural heritage. It also presents the type of information needed to record in the aftermath of disaster to assess the scale of damage and destruction. Started as a project at Durham University, the database is now being developed as part of the EAMENA (Endangered Archaeology in the Middle East and North Africa) project. The core dataset incorporates information and data from archaeological surveys undertaken in Syria by research projects in recent decades and began life as a development of the Shirīn initiative1. The focus of this project is to provide a tool not only for the recording and inventory of sites and monuments, but also to record damage and threats, their causes, and assess their magnitude. It will also record and measure the significance in order to be able to prioritize emergency and preservation responses. The database aims to set procedures for carrying out systematic rapid condition assessment (to record damage) and risk assessment (to record threat and level of risk) of heritage places, on the basis of both on the ground and remote assessment. Given the large number of heritage properties damaged by conflict, the implementation of rapid assessment methods to quickly identify and record level of damage and condition is essential, as it will provide the evidence to support effective prioritization of efforts and resources, and decisions on the appropriate levels of intervention and methods of treatment. The predefined data entry categories, use of a data standard, and systematic methods of assessment will ensure that different users choose from the same prefixed data entry and measurement inputs in order to allow for consistent and comparable assessments across different sites and regions. Given the general lack of appropriate emergency response and assessment databases, this system could also be applied in other locations facing similar threats and damage from conflict or natural disasters

A simplified implementation of a gradient-enhanced damage model with transient length scale effects

Gradient-enhanced damage models with constant gradient activity suffer from spurious damage growth at high deformation levels. This issue was resolved by Geers et al. (Comput Methods Appl Mech Eng 160(1-2):133-153, 1998) by expressing the gradient activity parameter as a function of the local equivalent strain at the expense of adding one set of degrees of freedom to those of the standard model. In this contribution, a new formulation of the gradient-enhanced damage model with variable length scale is presented which eliminates the need for the extra set of degrees of freedom. The merits of the proposed formulation are demonstrated, and the choice of the damage evolution law and its impact on the model performance are discussed