Obesity, food intake and exercise: Relationship with ghrelin

Obesity, a disorder of body composition, is defined by a relative or absolute excess of body fat. In general adult population, obesity has been associated with a diverse array of adverse health outcomes, including major causes of death such as cancer, diabetes, cardiovascular disease, as well as functional impairment from problems such as osteoarthritis and sleep apnea. Ghrelin is a newly discovered peptide hormone which plays an important role in obesity. It is a powerful, endogenous orexigenic peptide and has a crucial function in appetite regulation, as well as short – and long-term energy homeostasis. In the presence of increased obesity, decreased physical activity, and high food consumption, the relationship between exercise, appetite, food intake and ghrelin levels has important implications. In this review, we discuss the effect of acute and chronic exercise performance on appetite, food intake and ghrelin and their relationships

Gas-rich, field ultra-diffuse galaxies host few globular clusters

We present Hubble Space Telescope imaging of 14 gas-rich, low surface brightness and ultra-diffuse galaxies (UDGs) in the field at distances of 25-36 Mpc. An inspection of point-like sources brighter than the turnover magnitude of the globular cluster luminosity function and within twice the half-light radii of each galaxy reveals that, unlike those in denser environments, gas-rich, field UDGs host very few old globular clusters (GCs). Most of the targets (nine) have zero candidate GCs, with the remainder having one or two candidates each. These findings are broadly consistent with expectations for normal dwarf galaxies of similar stellar mass. This rules out gas-rich, field UDGs as potential progenitors of the GC-rich UDGs that are typically found in galaxy clusters. However, some in galaxy groups may be directly accreted from the field. In line with other recent results, this strongly suggests that there must be at least two distinct formation pathways for UDGs, and that this sub-population is simply an extreme low surface brightness extension of the underlying dwarf galaxy population. The root cause of their diffuse stellar distributions remains unclear, but the formation mechanism appears to only impact the distribution of stars (and potentially dark matter), without strongly impacting the distribution of neutral gas, the overall stellar mass, or the number of GCs.Comment: Submitted to AAS journal

STUB1 polyadenylation signal variant AACAAA does not affect polyadenylation but decreases STUB1 translation causing SCAR16

We present three siblings afflicted with a disease characterized by cerebellar ataxia, cerebellar atrophy, pyramidal tract damage with increased lower limb tendon reflexes, and onset of 31 to 57 years, which is not typical for a known disease. In a region of shared homozygosity in patients, exome sequencing revealed novel homozygous c.*240T>C variant in the 3'UTR of STUB1, the gene responsible for autosomal recessive spinocerebellar ataxia 16 (SCAR16). In other genes, such an alteration of the evolutionarily highly conserved polyadenylation signal from AATAAA to AACAAA is known to highly impair polyadenylation. In contrast, RNA sequencing and quantification revealed that neither polyadenylation nor stability of STUB1 mRNA is affected. In silico analysis predicted that the secondary structure of the mRNA is altered. We propose that this change underlies the extremely low amounts of the encoded protein in patient leukocytes

Co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells attenuates human NK cell-mediated degranulation

Natural killer (NK) cells play an important role in immune rejection in solid organ transplantation. To mitigate human NK cell activation in xenotransplantation, introducing inhibitory ligands on xenografts via genetic engineering of pigs may protect the graft from human NK cell-mediated cytotoxicity and ultimately improve xenograft survival. In this study, non-classical HLA class I molecules HLA-E and HLA-G were introduced in an immortalized porcine liver endothelial cell line with disruption of five genes (GGTA1, CMAH, β4galNT2, SLA-I α chain, and β-2 microglobulin) encoding three major carbohydrate xenoantigens (αGal, Neu5Gc, and Sda) and swine leukocyte antigen class I (SLA-I) molecules. Expression of HLA-E and/or HLA-G on pig cells were confirmed by flow cytometry. Endogenous HLA-G molecules as well as exogenous HLA-G VL9 peptide could dramatically enhance HLA-E expression on transfected pig cells. We found that co-expression of HLA-E and HLA-G on porcine cells led to a significant reduction in human NK cell activation compared to the cells expressing HLA-E or HLA-G alone and the parental cell line. NK cell activation was assessed by analysis of CD107a expression in CD3-CD56+ population gated from human peripheral blood mononuclear cells. CD107a is a sensitive marker of NK cell activation and correlates with NK cell degranulation and cytotoxicity. HLA-E and/or HLA-G on pig cells did not show reactivity to human sera IgG and IgM antibodies. This in vitro study demonstrated that co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells provided a superior inhibition in human xenoreactive NK cells, which may guide further genetic engineering of pigs to prevent human NK cell mediated rejection

Utilization of livers donated after circulatory death for transplantation - An international comparison.

BACKGROUND AND AIM Liver graft utilization rates are a hot topic due to the worldwide organ shortage and an increasing number of transplant candidates on waiting lists. Liver perfusion techniques have been introduced in several countries, and may help to increase the organ supply, as they potentially allow the assessment of livers before use. METHODS Liver offers were counted from donation after circulatory death (DCD) donors (Maastricht-type-III) arising during the past decade in eight countries, including Belgium, France, Italy, the Netherlands, Spain, Switzerland, UK, and US. Initial DCD-type-III liver offers were correlated with accepted, recovered and implanted livers. RESULTS A total number of 34`269 DCD livers were offered, resulting in 9`780 liver transplants (28.5%). The discard rates were highest in UK and US, ranging between 70 and 80%. In contrast, much lower DCD liver discard rates, e.g., between 30-40%, were found in Belgium, France, Italy, Spain and Switzerland. In addition, large differences were recognized in the use of various machine perfusion techniques, and in terms of risk factors in the cohorts of implanted livers. For example, the median donor age and functional donor warm ischemia were highest in Italy, e.g., >40minutes, followed by Switzerland, France, and the Netherlands. Importantly, such varying risk profiles of accepted DCD livers between countries did not translate into large differences in five-year graft survival rates, which ranged between 60-82% in this analysis. CONCLUSIONS We highlight a significant number of discarded and consequently unused DCD liver offers. Countries with more routine use of in- and ex-situ machine perfusion strategies showed better DCD utilization rates without compromised outcome. IMPACT AND IMPLICATIONS A significant number of Maastricht type III DCD livers are discarded across Europe and North America today. The overall utilization rate among eight Western countries is 28.5%, but varies significantly between 18.9% and 74.2%. For example, the median DCD III liver utilization in five countries, e.g., Belgium, France, Italy, Switzerland, and Spain is 65%, in contrast to 24% in the Netherlands, UK and US. Despite this, and despite different rules and strategies for organ acceptance and preservation, the one and five-year graft survival remains currently relatively comparable among all participating countries. Factors which impact on DCD liver acceptance rates include the national pre-selections of donors, before the offer is made, as well as cutoffs for key risk factors, including donor age and donor warm ischemia time. In addition, a highly varying experience with modern machine perfusion technology is noticed. In situ and ex situ liver perfusion concepts, and assessment tools for type III DCD livers before transplantation may be one key part for the observed differences in better DCD III utilization

Genetic engineering of porcine endothelial cell lines for evaluation of human-to-pig xenoreactive immune responses

Xenotransplantation (cross-species transplantation) using genetically-engineered pig organs offers a potential solution to address persistent organ shortage. Current evaluation of porcine genetic modifications is to monitor the nonhuman primate immune response and survival after pig organ xenotransplantation. This measure is an essential step before clinical xenotransplantation trials, but it is time-consuming, costly, and inefficient with many variables. We developed an efficient approach to quickly examine human-to-pig xeno-immune responses in vitro. A porcine endothelial cell was characterized and immortalized for genetic modification. Five genes including GGTA1, CMAH, β4galNT2, SLA-I α chain, and β2-microglobulin that are responsible for the production of major xenoantigens (αGal, Neu5Gc, Sda, and SLA-I) were sequentially disrupted in immortalized porcine endothelial cells using CRISPR/Cas9 technology. The elimination of αGal, Neu5Gc, Sda, and SLA-I dramatically reduced the antigenicity of the porcine cells, though the cells still retained their ability to provoke human natural killer cell activation. In summary, evaluation of human immune responses to genetically modified porcine cells in vitro provides an efficient method to identify ideal combinations of genetic modifications for improving pig-to-human compatibility, which should accelerate the application of xenotransplantation to humans

Liver transplantation as a new standard of care in patients with perihilar cholangiocarcinoma?:Results from an international benchmark study

Objective: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons.Background: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC.Methods: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014–2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥ 50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter &lt;3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers.Results: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤ 5.2%; comprehensive complication index at 1 year of ≤ 33.7; grade ≥ 3 complication rates ≤ 66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n = 106) (62% vs 32%, P &lt; 0.001).Conclusion: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.</p