Flavin Mononucleotide as a Biomarker of Organ Quality-A Pilot Study.

BACKGROUND: Flavin mononucleotide (FMN), released from damaged mitochondrial complex I during hypothermic liver perfusion, has been shown to be predictive of 90-day graft loss. Normothermic machine perfusion (NMP) and normothermic regional perfusion (NRP) are used for organ reconditioning and quality assessment before transplantation. This pilot study aimed to investigate the changes of FMN levels during normothermic reperfusion of kidneys, livers, and lungs and examine whether FMN could serve as a biomarker to predict posttransplant allograft quality. METHODS: FMN concentrations, in perfusates collected during NMP of kidneys, abdominal NRP, and ex vivo lung perfusion, were measured using fluorescence spectrometry and correlated to the available perfusion parameters and clinical outcomes. RESULTS: Among 7 transplanted kidneys out of the 11 kidneys that underwent NMP, FMN levels at 60 minutes of NMP were significantly higher in the allografts that developed delayed graft function and primary nonfunction (P = 0.02). Fifteen livers from 23 circulatory death donors that underwent NRP were deemed suitable for transplantation. Their FMN levels at 30 minutes of NRP were significantly lower than those not procured for transplantation (P = 0.004). In contrast, little FMN was released during the 8 lung perfusions. CONCLUSIONS: This proof of concept study suggested that FMN in the perfusates of kidney NMP has the potential to predict posttransplant renal function, whereas FMN at 30 minutes of NRP predicts whether a liver would be accepted for transplantation. More work is required to validate the role of FMN as a putative biomarker to facilitate safe and reliable decision-making before embarking on transplantation.NIHR BTR

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification

Comprehensive comparative outcomes in children with congenital heart disease: The rationale for the Congenital Catheterization Research Collaborative

Clinical research in the treatment of patients with congenital heart disease (CHD) is limited by the wide variety of CHD manifestations and therapeutic options as well as the generally low incidence of CHD. The availability of comprehensive, contemporary outcomes studies is therefore limited. This inadequacy may result in a lack of data‐driven medical decision making. In 2013, clinician scientists at two centers began a research collaboration, the Congenital Catheterization Research Collaborative (CCRC). Over time, the CCRC has grown to include nine cardiac centers from across the United States, with a common data coordinating center. The CCRC seeks to generate high‐quality, contemporary, statistically robust, and generalizable outcomes research which can help address important clinical questions in the treatment of CHD. To date, the CCRC has reported on multicenter outcomes in: neonates with congenital aortic stenosis, infants undergoing right ventricular decompression for pulmonary atresia and intact ventricular septum, and infants with ductal‐dependent pulmonary blood flow. The CCRC has been successful at leveraging large multicenter cohorts of patients in a contemporary period to perform comparative studies. In the future, the CCRC plans to continue to perform hypothesis‐driven retrospective and prospective observational studies of CHD populations where controversy exists or where novel interventions or therapies have emerged. Quality improvement efforts including lesion‐specific registry development may be an additional potential future target.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149494/1/chd12737.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149494/2/chd12737_am.pd

Pink1 and Parkin regulate Drosophila intestinal stem cell proliferation during stress and aging.

Intestinal stem cells (ISCs) maintain the midgut epithelium in Drosophila melanogaster Proper cellular turnover and tissue function rely on tightly regulated rates of ISC division and appropriate differentiation of daughter cells. However, aging and epithelial injury cause elevated ISC proliferation and decreased capacity for terminal differentiation of daughter enteroblasts (EBs). The mechanisms causing functional decline of stem cells with age remain elusive; however, recent findings suggest that stem cell metabolism plays an important role in the regulation of stem cell activity. Here, we investigate how alterations in mitochondrial homeostasis modulate stem cell behavior in vivo via RNA interference-mediated knockdown of factors involved in mitochondrial dynamics. ISC/EB-specific knockdown of the mitophagy-related genes Pink1 or Parkin suppresses the age-related loss of tissue homeostasis, despite dramatic changes in mitochondrial ultrastructure and mitochondrial damage in ISCs/EBs. Maintenance of tissue homeostasis upon reduction of Pink1 or Parkin appears to result from reduction of age- and stress-induced ISC proliferation, in part, through induction of ISC senescence. Our results indicate an uncoupling of cellular, tissue, and organismal aging through inhibition of ISC proliferation and provide insight into strategies used by stem cells to maintain tissue homeostasis despite severe damage to organelles

Flying Squirrel–associated Typhus, United States

In March 2002, typhus fever was diagnosed in two patients residing in West Virginia and Georgia. Both patients were hospitalized with severe febrile illnesses, and both had been recently exposed to or had physical contact with flying squirrels or flying squirrel nests. Laboratory results indicated Rickettsia prowazekii infection

From moral hazard to risk-response feedback

The Intergovernmental Panel on Climate Change assessments (IPCC) Special Report on 1.5 °C of global warming is clear. Nearly all pathways that hold global warming well below 2 °C involve carbon removal (IPCC, 2015). In addition, solar geoengineering is being considered as a potential tool to offset warming, especially to limit temperature until negative emissions technologies are sufficiently matured (MacMartin et al., 2018). Despite this, there has been a reluctance to embrace carbon removal and solar geoengineering, partly due to the perception that these technologies represent what is widely termed a “moral hazard”: that geoengineering will prevent people from developing the will to change their personal consumption and push for changes in infrastructure (Robock et al., 2010), erode political will for emissions cuts (Keith, 2007), or otherwise stimulate increased carbon emissions at the social-system level of analysis (Bunzl, 2008). These debates over carbon removal and geoengineering echo earlier ones over climate adaptation. We argue that debates over “moral hazard” in many areas of climate policy are unhelpful and misleading. We also propose an alternative framework for dealing with the tradeoffs that motivate the appeal to “moral hazard,” which we call “risk-response feedback.

A Low-Diversity Microbiota Inhabits Extreme Terrestrial Basaltic Terrains and Their Fumaroles : Implications for the Exploration of Mars

A major objective in the exploration of Mars is to test the hypothesis that the planet hosted life. Even in the absence of life, the mapping of habitable and uninhabitable environments is an essential task in developing a complete understanding of the geological and aqueous history of Mars and, as a consequence, understanding what factors caused Earth to take a different trajectory of biological potential. We carried out the aseptic collection of samples and comparison of the bacterial and archaeal communities associated with basaltic fumaroles and rocks of varying weathering states in Hawai'i to test four hypotheses concerning the diversity of life in these environments. Using high-throughput sequencing, we found that all these materials are inhabited by a low-diversity biota. Multivariate analyses of bacterial community data showed a clear separation between sites that have active fumaroles and other sites that comprised relict fumaroles, unaltered, and syn-emplacement basalts. Contrary to our hypothesis that high water flow environments, such as fumaroles with active mineral leaching, would be sites of high biological diversity, alpha diversity was lower in active fumaroles compared to relict or nonfumarolic sites, potentially due to high-temperature constraints on microbial diversity in fumarolic sites. A comparison of these data with communities inhabiting unaltered and weathered basaltic rocks in Idaho suggests that bacterial taxon composition of basaltic materials varies between sites, although the archaeal communities were similar in Hawai'i and Idaho. The taxa present in both sites suggest that most of them obtain organic carbon compounds from the atmosphere and from phototrophs and that some of them, including archaeal taxa, cycle fixed nitrogen. The low diversity shows that, on Earth, extreme basaltic terrains are environments on the edge of sustaining life with implications for the biological potential of similar environments on Mars and their exploration by robots and humans.Peer reviewe