Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. ...It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann–Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) 2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls), and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31–0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.
•Activity was measured for 5 lysosomal enzymes in blood spots of PD and controls.•Alpha galactosidase A (deficient in Fabry disease) activity is reduced in PD cases.•Alpha galactosidase A and acid sphingomylinase are elevated in LRRK2 carriers.
Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still ...die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
Highlights • BDNF exon VI was up-regulated in the hippocampus of TLE patients. • Expression of BDNFVI was related to the use of Topiramate or Sertraline. • Methylation levels at BDNF promoter VI were ...not associated to these effects.
We compared cold static with acellular normothermic ex vivo liver perfusion (NEVLP) as a novel preservation technique in a pig model of DCD liver injury. DCD livers (60 min warm ischemia) were cold ...stored for 4 h, or treated with 4 h cold storage plus 8 h NEVLP. First, the livers were reperfused with diluted blood as a model of transplantation. Liver injury was determined by ALT, oxygen extraction, histology, bile content analysis and hepatic artery (HA) angiography. Second, AST levels and bile production were assessed after DCD liver transplantation. Cold stored versus NEVLP grafts had higher ALT levels (350 ± 125 vs. 55 ± 35 U/L; p < 0.0001), decreased oxygen extraction (250 ± 65 mmHg vs. 410 ± 58 mmHg, p < 0.01) and increased hepatocyte necrosis (45% vs. 10%, p = 0.01). Levels of bilirubin, phospholipids and bile salts were fivefold decreased, while LDH was sixfold higher in cold stored versus NEVLP grafts. HA perfusion was decreased (twofold), and bile duct necrosis was increased (100% vs. 5%, p < 0.0001) in cold stored versus NEVLP livers. Following transplantation, mean serum AST level was higher in the cold stored versus NEVLP group (1809 ± 205 U/L vs. 524 ± 187 U/L, p < 0.05), with similar bile production (2.5 ± 1.2 cc/h vs. 2.8 ± 1.4 cc/h; p = 0.2). NEVLP improved HA perfusion and decreased markers of liver duct injury in DCD grafts.
Normothermic ex vivo liver perfusion decreases hepatocyte death and bile duct injury of grafts obtained after cardiac death.
Biliary strictures remain the most challenging aspect of adult right lobe living donor liver transplantation (RLDLT). Between 04/2000 and 10/2005, 130 consecutive RLDLTs were performed in our center ...and followed prospectively. Median follow‐up was 23 months (range 3–67) and 1‐year graft and patient survival was 85% and 87%, respectively. Overall incidence of biliary leaks (n = 19) or strictures (n = 22) was 32% (41/128) in 33 patients (26%). A duct‐to‐duct (D‐D) or Roux‐en‐Y (R‐Y) anastomosis were performed equally (n = 64 each) with no difference in stricture rate (p = 0.31). The use of ductoplasty increased the number of grafts with a single duct for anastomosis and reduced the biliary complication rate compared to grafts ≥2 ducts (17% vs. 46%; p = 0.02). Independent risk factors for strictures included older donor age and previous history of a bile leak. All strictures were managed nonsurgically initially but four patients ultimately required conversion from D‐D to R‐Y. Ninety‐six percent (123/128) of patients are currently free of any biliary complications. D‐D anastomosis is safe after RLDLT and provides access for future endoscopic therapy in cases of leak or stricture. When presented with multiple bile ducts, ductoplasty should be considered to reduce the potential chance of stricture.
The pattern and management of biliary strictures after right‐lobe living donor liver transplantation (RLDLT) from this experience from a single Western center shows that, although biliary strictures are common in RLDLT, they can usually be managed non‐operatively and do not affect short‐term graft survival.
By a combined angle-resolved photoemission spectroscopy and density functional theory study, we discover that the surface metallicity is polarity driven in SmB6. Two surface states, not accounted for ...by the bulk band structure, are reproduced by slab calculations for coexisting B6 and Sm surface terminations. Our analysis reveals that a metallic surface state stems from an unusual property, generic to the (001) termination of all hexaborides: the presence of boron 2p dangling bonds, on a polar surface. The discovery of polarity-driven surface metallicity sheds new light on the 40-year old conundrum of the low-temperature residual conductivity of SmB6, and raises a fundamental question in the field of topological Kondo insulators regarding the interplay between polarity and nontrivial topological properties.
More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we ...determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 ± 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel–Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.
We present photometric redshift estimates for galaxies used in the weak lensing analysis of the Dark Energy Survey Science Verification (DES SV) data. Four model- or machine learning-based ...photometric redshift methods-annz2, bpz calibrated against BCC-Ufig simulations, skynet, and tpz-are analyzed. For training, calibration, and testing of these methods, we construct a catalogue of spectroscopically confirmed galaxies matched against DES SV data. The performance of the methods is evaluated against the matched spectroscopic catalogue, focusing on metrics relevant for weak lensing analyses, with additional validation against COSMOS photo-z's. From the galaxies in the DES SV shear catalogue, which have mean redshift 0.72 + or - 0.01 over the range 0.3 < z< 1.3, we construct three tomographic bins with means of z= {0.45,0.67,1.00}. These bins each have systematic uncertainties delta sub(z)<, ~ 0.05 in the mean of the fiducial skynet photo-z n(z). We propagate the errors in the redshift distributions through to their impact on cosmological parameters estimated with cosmic shear, and find that they cause shifts in the value of sigma sub(8) of approximately 3%. This shift is within the one sigma statistical errors on sigma sub(8) for the DES SV shear catalogue. We further study the potential impact of systematic differences on the critical surface density, capital sigma sub(crit), finding levels of bias safely less than the statistical power of DES SV data. We recommend a final Gaussian prior for the photo-z bias in the mean of n(z) of width 0.05 for each of the three tomographic bins, and show that this is a sufficient bias model for the corresponding cosmology analysis.
Post-traumatic stress disorder (PTSD) is a common and disabling condition with high incidence after an earthquake. The objective of the present study was to identify risk factors associated with the ...occurrence and persistence of PTSD. Individuals (18–65 years old) who experienced the earthquake of September 19th, 2017, attended the National Institute of Psychiatry (INPRFM) between October and November 2017 (baseline n = 68). Participants were followed 4–6 (first follow-up, n = 40) and 7–9 (second follow-up n = 41) months after the earthquake. Delay returning to normal activities, a negative emotional valence to a previous earthquake, comorbidity with depression, history of childhood maltreatment, and low expression of Glucocorticoid Receptor (GR) were associated with PTSD in the basal assessment. The earthquake-related variable associated with the persistence of PTSD at the second follow-up was that the earthquake had directly affected the participants, either because they were evicted, had damage to their homes, or suffered some injury. Comorbidity with dysthymia, history of childhood maltreatment, and higher severity of PTSD in the basal assessment were associated with persistent PTSD in the second follow-up. The lower expression of the FK506 binding protein 5 (FKBP5) in participants with persistent PTSD in the second follow-up was better explained by childhood physical abuse than with PTSD severity. These findings suggest that acute exposure to earthquake-related stressful situations is relevant for the initial risk of PTSD, while potential long-term stressful conditions are associated with its persistence. Likewise, molecular markers associated with hypothalamus-pituitary-adrenal-axis dysregulation were differentially associated with PTSD diagnosis at the different assessment times.
Secondary organic aerosols (SOA) exert a significant influence on ambient air quality and regional climate. Recent field, laboratorial and modeling studies have confirmed that in-cloud processes ...contribute to a large fraction of SOA production with large space-time heterogeneity. This study evaluates the key factors that govern the production of cloud-process SOA (SOAcld) on a global scale based on the GFDL coupled chemistry-climate model AM3 in which full cloud chemistry is employed. The association between SOAcld production rate and six factors (i.e., liquid water content (LWC), total carbon chemical loss rate (TCloss), temperature, VOC/NOx, OH, and O3) is examined. We find that LWC alone determines the spatial pattern of SOAcld production, particularly over the tropical, subtropical and temperate forest regions, and is strongly correlated with SOAcld production. TCloss ranks the second and mainly represents the seasonal variability of vegetation growth. Other individual factors are essentially uncorrelated spatiotemporally to SOAcld production. We find that the rate of SOAcld production is simultaneously determined by both LWC and TCloss, but responds linearly to LWC and nonlinearly (or concavely) to TCloss. A parameterization based on LWC and TCloss can capture well the spatial and temporal variability of the process-based SOAcld formation (R2 = 0.5) and can be easily applied to global three dimensional models to represent the SOA production from cloud processes.
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