The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem ...cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.
Issue
Geodiversity (i.e., the variation in Earth's abiotic processes and features) has strong effects on biodiversity patterns. However, major gaps remain in our understanding of how relationships ...between biodiversity and geodiversity vary over space and time. Biodiversity data are globally sparse and concentrated in particular regions. In contrast, many forms of geodiversity can be measured continuously across the globe with satellite remote sensing. Satellite remote sensing directly measures environmental variables with grain sizes as small as tens of metres and can therefore elucidate biodiversity–geodiversity relationships across scales.
Evidence
We show how one important geodiversity variable, elevation, relates to alpha, beta and gamma taxonomic diversity of trees across spatial scales. We use elevation from NASA's Shuttle Radar Topography Mission (SRTM) and c. 16,000 Forest Inventory and Analysis plots to quantify spatial scaling relationships between biodiversity and geodiversity with generalized linear models (for alpha and gamma diversity) and beta regression (for beta diversity) across five spatial grains ranging from 5 to 100 km. We illustrate different relationships depending on the form of diversity; beta and gamma diversity show the strongest relationship with variation in elevation.
Conclusion
With the onset of climate change, it is more important than ever to examine geodiversity for its potential to foster biodiversity. Widely available satellite remotely sensed geodiversity data offer an important and expanding suite of measurements for understanding and predicting changes in different forms of biodiversity across scales. Interdisciplinary research teams spanning biodiversity, geoscience and remote sensing are well poised to advance understanding of biodiversity–geodiversity relationships across scales and guide the conservation of nature.
Aim
We may be able to buffer biodiversity against the effects of ongoing climate change by prioritizing the protection of habitat with diverse physical features (high geodiversity) associated with ...ecological and evolutionary mechanisms that maintain high biodiversity. Nonetheless, the relationships between biodiversity and habitat vary with spatial and biological context. In this study, we compare how well habitat geodiversity (spatial variation in abiotic processes and features) and climate explain biodiversity patterns of birds and trees. We also evaluate the consistency of biodiversity–geodiversity relationships across ecoregions.
Location
Contiguous USA.
Time period
2007–2016.
Taxa studied
Birds and trees.
Methods
We quantified geodiversity with remotely sensed data and generated biodiversity maps from the Forest Inventory and Analysis and Breeding Bird Survey datasets. We fitted multivariate regressions to alpha, beta and gamma diversity, accounting for spatial autocorrelation among Nature Conservancy ecoregions and relationships among taxonomic, phylogenetic and functional biodiversity. We fitted models including climate alone (temperature and precipitation), geodiversity alone (topography, soil and geology) and climate plus geodiversity.
Results
A combination of geodiversity and climate predictor variables fitted most forms of bird and tree biodiversity with < 10% relative error. Models using geodiversity and climate performed better for local (alpha) and regional (gamma) diversity than for turnover‐based (beta) diversity. Among geodiversity predictors, variability of elevation fitted biodiversity best; interestingly, topographically diverse places tended to have higher tree diversity but lower bird diversity.
Main conclusions
Although climatic predictors tended to have larger individual effects than geodiversity, adding geodiversity improved climate‐only models of biodiversity. Geodiversity was correlated with biodiversity more consistently than with climate across ecoregions, but models tended to have a poor fit in ecoregions held out of the training dataset. Patterns of geodiversity could help to prioritize conservation efforts within ecoregions. However, we need to understand the underlying mechanisms more fully before we can build models transferable across ecoregions.
Summary
The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively ...from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.
A combined liver and kidney transplantation (CLKT) is advocated for selected individuals with chronic kidney disease undergoing liver transplantation (LT). The aim was to develop a risk score to ...identify the patients whose estimated glomerular filtration rate (eGFR) would decline during the year post-LT to aid future patient selection for CLKT.
A training dataset of LT recipients was identified retrospectively from a prospectively compiled database (2000-2007). The eGFR was calculated at 1 year and those with an eGFR less than 30 mL/min were identified. Variables determined at the LT assessment were analyzed by logistic regression, discriminant function, and area under the receiver operating characteristic curve (AUC) analysis to develop the score. The score was validated in a prospective patient cohort.
Three hundred sixty-eight LT recipients were followed up for 1 year (training dataset). The mean eGFR declined by 11.2+/-23.5 mL/min during that time (P<0.001). A pre-LT risk score to predict an eGFR less than 30 mL/min at 1-year post-LT was generated: -1.8+(1.5 if a history of hypertension)+(0.65 x proteinuria in g/24 hr)+(0.013 x serum creatinine in micromol/L)+(0.001 x duration of acute kidney injury or eGFR <60 mL/min in days). Reversible renal impairment should first be excluded. Progression was likely with a score more than 2.16. Sensitivity, specificity, and AUC were 99.2%, 100%, and 0.99, respectively. All, but one patient, in the validation cohort (n=149) were correctly classified.
This information will complement previously published criteria for CLKT patient selection.
The European Liver Transplant Registry (ELTR) currently allows for the analysis of 44,286 liver transplantations (LTs) performed on 39,196 patients in a 13-year period. After an exponential increase, ...the number of LTs is plateauing due to a lack of organs. To cope with this, alternatives to cadaveric LT, such as split LT, domino LT, or living-related LT (LRLT) are being used increasingly. They now account for 11% of all procedures. One of the most important findings in the evolution of LT is the considerable improvement of results along time with, for the mean time, a one-year survival of 83%, all indications confounded. The improvement is particularly significant for cancers. This improvement is mainly represented by hepatocellular carcinoma, with a gain of 17% for 5-year survival rate from 1990 to 2000. Increasingly, older donors are used to augment the donor pool and older recipients are transplanted due to improved results and a better selection of patients. More than two thirds of deaths and three quarters of retransplantations occurred within the first year of transplantation. Retransplantation is associated with much less optimal results than first LT. One of the prominent features of recent years is the development of LRLT. LRLT is now performed by almost half of the European centers. As with split LT or domino LT, LRLT aims to provide more patients to be transplanted. Special attention is paid to reducing the risk for the donor, which is now estimated to be 0.5% mortality and 21% postoperative morbidity.
Aims
Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the ...specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ‐aminobutyric acid (GABA)‐ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease.
Methods
Histochemical, immunohistochemical and immunofluorescent assays were performed on post‐mortem brain tissue from 10 patients and 10 age‐matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring.
Results
We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss.
Conclusions
We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease.
Reduced expression of mitochondrial respiratory chain components may give rise to the selective vulnerability of GABAergic interneurons in mitochondrial disease and contribute to neurological impairment.
To increase the number of livers available for transplantation a non-heartbeating donor (NHBD) liver transplant program was started after obtaining hospital ethical committee approval.
Controlled ...donors with a warm ischemia of <30 minutes were considered. A 5-minute stand-off period was observed from asystole to skin incision. A super-rapid technique was used for the retrieval. Methods used to assess the suitability for transplantation included liver function tests, morphologic and histologic assessment, and hepatocyte viability testing.
Sixty livers were retrieved from NHBDs. Of these, 33 were judged suitable for transplantation. Of these one was exported and transplanted, and one could not be matched to a suitable recipient. A further 27 were not used because of liver appearance in 21, prolonged hypoxia and hypotension in 4, poor perfusion in 1, and donor malignancy in 1. Mean donor age was 39.4 years (range, 0.75-67 years). Causes of death were head trauma in 10 donors, intracranial bleed in 24, and anoxic/ischemic brain injury in 26. Mean warm ischemia time was 14.7 minutes (range, 7-40 minutes). Thirty-two patients were transplanted (one split liver), and the mean age of the recipients was 38.4 years (range, 0.7-72 years). All grafts had good early function except one right lobe split. There were 4 deaths resulting from ischemic brain injury, chronic rejection, biliary sepsis, and multiorgan failure following retransplantation for primary nonfunction. Overall patient and graft survival is 87% and 84%, respectively, at a median follow-up of 15 months.
Early results suggest that controlled NHBDs are a significant new source of grafts, but careful donor selection and short cold ischemia are mandatory.
The stem cell niche is a specialized environment that dictates the proper functioning of stem cells during normal development and homeostasis. Despite recent progress, the identity of the mammary ...gland stem cell (MaSC) niche remains largely unknown. Here, we show that Dll1, a Notch pathway ligand, is enriched in MaSCs and mediates critical interactions between these cells and their surrounding niche. Conditional deletion of Dll1 resulted in reduced number of MaSCs and defective ductal morphogenesis in both virgin and pregnant mammary glands. Dll1-mediated Notch signaling maintains the MaSC function via its activation of Notch signaling in stromal macrophages, leading to increased expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, which feed back to Dll1
+
mammary stem cells to promote their activity. These findings revealed a functionally important cross talk between MaSCs and their macrophageal niche through Dll1/Notch-mediated signaling.
Dll1-mediated crosstalk between mammary stem cells and macrophages is critical for mammary gland development and function
Long‐term follow‐up of 27 patients with hepatitis B virus—related chronic liver disease treated by transplantation showed that 23 had hepatitis B virus recurrence. In 13 patients late changes in the ...grafts were similar to those described in other series: minor abnormalities in five cases, chronic active hepatitis in five cases and non‐hepatitis B virus—related graft dysfunction in three cases. Three patients had incomplete histological follow‐up. Analysis of the histological changes and viral antigen expression in six cases revealed a distinct and novel pattern termed fibrosing cholestatic hepatitis. Development of fibrosing cholestatic hepatitis was associated with rapidly progressive graft dysfunction. It is postulated that this pattern of fibrosing cholestatic hepatitis develops because of a high cytoplasmic expression of viral antigens, including HBsAg. The remaining case had some features of fibrosing cholestatic hepatitis. The main histological features of this unique syndrome include thin, perisinusoidal bands of fibrosis extending from portal tracts to surround plates of ductular‐type epithelium; prominent cholestasis; ground‐glass transformation; and ballooning of hepatocytes with cell loss and mild mixed inflammatory reaction. (HEPATOLOGY 1991;13:150–157).
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