K. Bhaskar, G. A. Hobbs, S‐H. Yen and G. Lee (2010) Neuropathology and Applied Neurobiology36, 462–477 Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of ...tauopathy
Aim: Tau protein is a prominent component of paired helical filaments in Alzheimer's disease (AD) and other tauopathies. While the abnormal phosphorylation of tau on serine and threonine has been well established in the disease process, its phosphorylation on tyrosine has only recently been described. We previously showed that the Src family non‐receptor tyrosine kinases (SFKs) Fyn and Src phosphorylate tau on Tyr18 and that phospho‐Tyr18‐tau was present in AD brain. In this study, we have investigated the appearance of phospho‐Tyr18‐tau, activated SFK and proliferating cell nuclear antigen (PCNA) during disease progression in a mouse model of human tauopathy. Methods: We have used JNPL3, which expresses human tau with P301L mutation, and antibodies specific for phospho‐Tyr18‐tau (9G3), ser/thr phosphorylated tau (AT8), activated SFK and PCNA. Antibody staining was viewed by either epifluorescence or confocal microscopy. Results: Phospho‐Tyr18‐tau appeared concurrently with AT8‐reactive tau as early as 4 months in JNPL3. Some 9G3‐positive cells also contained activated SFKs and PCNA. We also investigated the triple transgenic mouse model of AD and found that unlike the JNPL3 model, the appearance of 9G3 reactivity did not coincide with AT8 in the hippocampus, suggesting that the presence of APP/presenilin influences tau phosphorylation. Also, Thioflavin S‐positive plaques were 9G3‐negative, suggesting that phospho‐Tyr18‐tau is absent from the dystrophic neurites of the mouse triple transgenic brain. Conclusions: Our results provide evidence for the association of tyrosine‐phosphorylated tau with mechanisms of neuropathogenesis and indicate that SFK activation and cell cycle activation are also involved in JNPL3.
Decades of speculation about a warmer, wetter Mars climate in the planet's first billion years postulate a denser CO₂ -rich atmosphere than at present. Such an atmosphere should have led to the ...formation of outcrops rich in carbonate minerals, for which evidence has been sparse. Using the Mars Exploration Rover Spirit, we have now identified outcrops rich in magnesium-iron carbonate (16 to 34 weight percent) in the Columbia Hills of Gusev crater. Its composition approximates the average composition of the carbonate globules in martian meteorite ALH 84001. The Gusev carbonate probably precipitated from carbonate-bearing solutions under hydrothermal conditions at near-neutral pH in association with volcanic activity during the Noachian era.
Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response ...genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer.
To describe trends in minimally invasive hysterectomy (MIH) and assess patient, surgical, and provider characteristics associated with differences in vaginal versus laparoscopic rates within an ...integrated healthcare system.
A retrospective cohort study.
Kaiser Permanente Northern California from 2008 to 2018.
Patients who underwent MIH for benign conditions excluding uterine prolapse and incontinence surgeries.
Hysterectomies.
A total of 27518 hysterectomies were performed for benign indications. Of these, the proportion of MIH increased from 29.1% (2008) to 96.7% (2018) (p <.001). The proportion of vaginal hysterectomies (VHs) of all hysterectomies did not change significantly over the study period (p = .07); however, the proportion of VH among MIH cases decreased from a high of 50.6% in 2008 to 13.2% in 2018 (p <.001). VH rates were lower in obese and morbidly obese patients (p <.001 and p = .02, respectively) and in women with uterine weights >250 g (p <.001). The differences persisted after controlling for patient demographic, clinical, and surgery characteristics. Low surgical volume was inversely associated with VH (adjusted relative risk, 7.19; 95% confidence interval, 6.62-7.81; p <.001). VH rates ranged from 11.5% to 27.8% across service areas (hospitals). Service area remained a significant predictor of VH after controlling for patient (including body mass index and uterine weight) and surgery-related characteristics. Postoperative hospital stay decreased from 33.8 ± 16.4 hours (2008) to 6.1 ± 12.2 (2018) for VH. Operative time was shorter for VH than laparoscopic hysterectomies (LHs) (1.7 vs 2.5 hours; p <.001). Overall operative/perioperative complications were low and not significantly different (VH vs LH).
As the proportion of MIH increased, LH became the preferred route despite similar rates of postoperative stay and intraoperative complications and shorter operative time for VH compared with LH. Service area and provider volume were independent predictors of MIH route, suggesting that training and evidence-based guidelines for route selection may help preserve VH rates.
Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by ...the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.
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•Anaerobic uric acid metabolism is widespread among the gut microbiota•Gut bacteria use a conserved gene cluster to convert uric acid to SCFAs•Microbiota depletion in uricase-deficient mice causes severe hyperuricemia•Antibiotics with anaerobic coverage increase risk for gout in humans
Anaerobic bacteria of the gut microbiome are able to metabolize uric acid, compensating for the uricase deficiency of their host. This conversion of uric acid to xanthine or SCFAs is important for maintaining low levels of uric acid in serum, lowering gout risk.
The caspase-recruitment domain-containing adaptor protein CARD9 regulates the innate signaling responses to fungal infection. Here we show that CARD9 is required for innate immune responses against ...intracellular pathogens. We generated Card9(-/-) mice and found that CARD9-deficient macrophages had defects in activation of the kinases p38 and Jnk but not of transcription factor NF-kappaB after bacterial and viral infection. CARD9-deficient mice failed to clear infection and showed altered cytokine production after challenge with Listeria monocytogenes. In wild-type cells, we found CARD9 inducibly associated with both the intracellular 'biosensor' Nod2 and the serine-threonine kinase RICK. Our data demonstrate that CARD9 has a critical function in Nod2-mediated activation of p38 and Jnk in innate immune responses to intracellular pathogens.
With rapid advancements in imaging technology, cardiac computed tomography (CT) and magnetic resonance (MR) imaging are increasingly being used for anatomic evaluation, functional assessment, and ...pathologic diagnosis of the pulmonary valve and right ventricle. MR imaging is especially helpful in evaluating postoperative pulmonary valve function and grading of pulmonary regurgitation. On the other hand, CT has the advantage of high-resolution isovolumetric whole-chest coverage and is able to depict anatomic detail of the pulmonary valve, perivalvular structures, and pulmonary artery branches.
Analyses by the CheMin X-ray diffraction instrument on Mars Science Laboratory show that gypsum, bassanite, and anhydrite are common minerals at Gale crater. Warm conditions (∼6 to 30 °C) within ...CheMin drive gypsum dehydration to bassanite; measured surface temperatures and modeled temperature depth profiles indicate that near-equatorial warm-season surface heating can also cause gypsum dehydration to bassanite. By accounting for instrumental dehydration effects we are able to quantify the in situ abundances of Ca-sulfate phases in sedimentary rocks and in eolian sands at Gale crater. All three Ca-sulfate minerals occur together in some sedimentary rocks and their abundances and associations vary stratigraphically. Several Ca-sulfate diagenetic events are indicated. Salinity-driven anhydrite precipitation at temperatures below ∼50 °C may be supported by co-occurrence of more soluble salts. An alternative pathway to anhydrite via dehydration might be possible, but if so would likely be limited to warmer near-equatorial dark eolian sands that presently contain only anhydrite. The polyphase Ca-sulfate associations at Gale crater reflect limited opportunities for equilibration, and they presage mixed salt associations anticipated in higher strata that are more sulfate-rich and may mark local or global environmental change. Mineral transformations within CheMin also provide a better understanding of changes that might occur in samples returned from Mars.
In 2012, two Kaiser Permanente Northern California (KPNC) hospitals began offering outpatient cervical ripening with oral misoprostol under a study protocol. We evaluated inpatient time from ...admission to delivery and adverse maternal and neonatal outcomes associated with outpatient use of misoprostol for cervical ripening among low-risk women with term pregnancies.
We conducted a retrospective cohort study comparing three groups: women who received misoprostol (1) outpatient, under a study protocol; (2) inpatient, at the study sites; and (3) inpatient, at all KPNC hospitals. Data were obtained from between 2012 and 2017. The primary outcome was time from inpatient admission to delivery. Secondarily, we evaluated maternal and neonatal outcomes, including the duration and maximum rate of oxytocin administered, rate of cesarean delivery, incidence of chorioamnionitis and blood transfusion, Apgar scores, and neonatal intensive care unit admissions. Demographic and clinical characteristics and outcomes of the outpatient group were compared with both inpatient misoprostol groups using the appropriate statistical test. Variables included in the regression analysis were either statistically significant in the bivariate analyses or have been reported in the literature to be potential confounders: maternal age at admission, race/ethnicity, body mass index, cervical dilation at initial misoprostol, and parity.
We analyzed data from 10,253 patients: (1) 345 outpatients, under a study protocol; (2) 1,374 inpatients, at the study sites; and (3) 9,908 inpatients, at all the Kaiser hospitals. Women in the outpatient group were more likely to be white than both inpatient groups (63.3 vs. 56.3% at study sites and 47.1% in all hospitals,
0.002 and <0.001, respectively); other demographics were clinically comparable. Most women undergoing labor induction were nulliparous; however, a greater proportion in the outpatient group were nulliparous compared with inpatient groups (70.8 vs. 61.8% and 64.3%,
= 0.002 and 0.01). On inpatient admission for delivery, women who received outpatient misoprostol were more likely to have a cervical dilation of ≥3 cm (39.8 vs. 12.5% at study sites and 9.7% at all KPNC hospitals,
< 0.001 for both). The outpatient group had a shorter mean time between admission and delivery (23.6 vs. 29.4 at study sites and 29.8 hours at all KPNC,
< 0.001 for both). The adjusted estimated mean difference between the outpatient and inpatient group at all the Kaiser hospitals in time from admission to delivery was -6.48 hours (
< 0.001), and the adjusted estimated mean difference in cervical dilation on admission was +1.02 cm (
< 0.001). There was no difference in cesarean delivery rates between groups. The rate of chorioamnionitis in the outpatient group was higher compared with inpatients at all hospitals (17.7 vs. 10.6%,
0
001), but similar when compared with the inpatients at the study sites (17.7 vs. 15.4%,
= 0.29).
Outpatient use of misoprostol for cervical ripening under the study protocol was associated with reduced inpatient time from admission to delivery compared with inpatient misoprostol. Although there was a higher rate of chorioamnionitis among outpatients under the study protocol compared with inpatients at all hospitals, there was no difference when compared with inpatients at the study sites. There was no difference in rates of cesarean delivery or maternal or neonatal complications with outpatient misoprostol.
· Outpatient misoprostol patients had 6.46 fewer hours from admission to delivery compared with inpatients at all hospitals.. · There was no difference in the rate of cesareans between the outpatient versus inpatient misoprostol groups.. · Other maternal and neonatal complications were low and comparable among outpatients and inpatients who received misoprostol; this study was not large enough to assess rare safety outcomes..
It is important to know the contribution of specific allergens to a complex allergenic extract and to have a dependable method to assess the effector activity of an extract specifically depleted of ...that allergen. We have previously shown that removal of the major peanut allergen, Ara h 2, from a crude peanut extract (CPE) minimally altered the effector activity of the extract. Here we describe in detail the methodology used to generate specific rabbit anti-peptide antibodies to remove a related peanut allergen, Ara h 6, from CPE and describe an improvement in the RBL SX-38 cell assay used to assess the effector activity of treated extracts. Our results show that although Ara h 2 and Ara h 6 can be selectively removed from a CPE, removal of each alone from a CPE had no significant effect on the effector activity. However, removal of Ara h 2 and Ara h 6 together significantly reduced the effector activity of CPE.
► Immunodepletion of Ara h 2 and Ara h 6 from a crude peanut extract (CPE). ► Improvement in the RBL SX-38 cell assay used to assess peanut allergens. ► Removal of Ara h 2 and Ara h 6 together reduced the effector activity of a CPE.
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