After permanent atmospheric oxygenation, anomalous sulfur isotope compositions were lost from sedimentary rocks, demonstrating that atmospheric chemistry ceded its control of Earth's surficial sulfur ...cycle to weathering. However, mixed signals of anoxia and oxygenation in the sulfur isotope record between 2.5 to 2.3 billion years (Ga) ago require independent clarification, for example via oxygen isotopes in sulfate. Here we show <2.31 Ga sedimentary barium sulfates (barites) from the Turee Creek Basin, W. Australia with positive sulfur isotope anomalies of ∆
S up to + 1.55‰ and low δ
O down to -19.5‰. The unequivocal origin of this combination of signals is sulfide oxidation in meteoric water. Geochemical and sedimentary evidence suggests that these S-isotope anomalies were transferred from the paleo-continent under an oxygenated atmosphere. Our findings indicate that incipient oxidative continental weathering, ca. 2.8-2.5 Ga or earlier, may be diagnosed with such a combination of low δ
O and high ∆
S in sulfates.
Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover ...processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.
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•We report an X-ray structure of the ectodomain of the α-secretase ADAM10•Access to the active site is partially occluded by a C-terminal regulatory domain•A modulatory antibody that binds the regulatory region liberates the active site•Catalytically inactive forms of ADAM10 exhibit dominant-negative activity
The X-ray structure of the ADAM10 ectodomain, together with biochemical and cell-based studies, reveals mechanistic insights into its enzymatic function in Notch signaling and in processing of the Alzheimer's precursor protein APP.
In the Wnt-β-catenin pathway, Wnt binding to Frizzled (Fzd) and LRP5 or LRP6 (LRP5/6) co-receptors inhibits the degradation of the transcriptional coactivator β-catenin by recruiting the cytosolic ...effector Dishevelled (Dvl). Polymerization of Dvl at the plasma membrane recruits the β-catenin destruction complex, enabling the phosphorylation of LRP5/6, a key step in inhibiting β-catenin degradation. Using purified Fzd proteins reconstituted in lipid nanodiscs, we investigated the factors that promote the recruitment of Dvl to the plasma membrane. We found that the affinity of Fzd for Dvl was not affected by Wnt ligands, in contrast to other members of the GPCR superfamily for which the binding of extracellular ligands affects the affinity for downstream transducers. Instead, Fzd-Dvl binding was enhanced by increased concentration of the lipid PI(4,5)P
, which is generated by Dvl-associated lipid kinases in response to Wnt and which is required for LRP5/6 phosphorylation. Moreover, binding to Fzd did not promote Dvl DEP domain dimerization, which has been proposed to be required for signaling downstream of Fzd. Our findings suggest a positive feedback loop in which Wnt-stimulated local PI(4,5)P
production enhances Dvl recruitment and further PI(4,5)P
production to support Dvl polymerization, LRP5/6 phosphorylation, and β-catenin stabilization.
All-terrain vehicle (ATV) injuries among children represent a significant and growing problem. Although state-level analyses have characterized some aspects of pediatric ATV-related injuries, little ...information on the national impact on hospitalization is available. This study was designed to characterize more fully the patterns of injury, hospital length of stay, and hospital charges associated with ATV-related injuries, with a nationally representative sample.
Analyses were based on the 1997 and 2000 Healthcare Cost and Utilization Project Kids' Inpatient Database (KID). The KID is the only national, all-payer database of hospital discharges for children. KID data were weighted to represent all discharges from general hospitals in the United States. Discharges with external cause-of-injury codes consistent with off-road ATV-related injuries were selected, and the affected population was described. Nationally representative rates of ATV-related injuries were calculated, and changes between 1997 and 2000 were documented.
An estimated 5292 children were hospitalized because of ATV-related injuries during the 2-year period, and hospitalizations increased 79.1% between 1997 and 2000. Rates of ATV-related hospitalization were highest among adolescent white male subjects, consistent with previous studies. Most patients had hospital lengths of stay of <4 days (68%), but 10% had stays of >8 days. Injury severity varied considerably, with more than one third of patients sustaining moderate to severe injuries. Approximately 1% of hospitalizations resulted in in-hospital deaths. Total hospital charges for this injury mechanism were 74367677 dollars for the 2-year study period. Most of these charges were paid by private insurers.
This study provides evidence supporting recent substantial increases in childhood ATV-related injuries. The hospitalization impact of ATV-related injuries among children is considerable. Our data support the need for ongoing creative attempts to identify effective strategies to decrease ATV injuries among children.
Objective: A variety of educational efforts, policies, and regulations have been adopted to reduce all-terrain vehicle (ATV) injury in children. Despite this, ATV use by children continues and ...serious injuries are common. The purpose of this study was to investigate the knowledge, practices, and beliefs of ATV users to help develop effective educational strategies to promote safer ATV use. Design: Focus groups were conducted to characterize participant ATV use and safety awareness as well as to explore avenues for prevention. Feedback on draft ATV safety public service announcements was elicited. Themes of transcribed focus group data were summarized. Setting: Rural state with high ATV use and injury rates. Subjects: Adult and adolescent ATV users. Interventions: None. Main outcome measures: Summaries of focus group discussions. Results: ATV riders frankly discussed current use and safety behaviors and were aware of some ATV risks. Youths felt that age specific regulation was unlikely to be a helpful strategy. Participants endorsed messages demonstrating graphic consequences as likely to get the attention of young riders regarding risks. Educational settings were suggested, including hunter and driver safety classes. Conclusions: Efforts to improve ATV safety awareness should clearly show pediatric ATV injury risk and safety practices. Campaigns must also show realistic understanding of current use practices to be credible for users. Messages emphasizing the consequences of ATV use were endorsed as most likely to have impact. Approaches based on age based restrictions were considered unrealistic and alternative strategies were suggested.
Triple oxygen isotope (∆17O with δ18O) signals of H2O and O2 found in sulfate of oxidative weathering origin offer promising constraints on modern and ancient weathering, hydrology, atmospheric gas ...concentrations, and bioproductivity. However, interpretations of the sulfate-water-O2 system rely on assuming fixed oxygen-isotope fractionations between sulfate and water, which, contrastingly, are shown to vary widely in sign and amplitude. Instead, here we anchor sulfate-water-O2 triple oxygen isotope systematics on the homogeneous composition of atmospheric O2 with empirical constraints and modeling. Our resulting framework does not require a priori assumptions of the O2- versus H2O‑oxygen ratio in sulfate and accounts for the signals of mass-dependent and mass-independent fractionation in the ∆17O and δ18O of sulfate's O2‑oxygen source. Within this framework, new ∆17O measurements of sulfate constrain ~2.3 Ga Paleoproterozoic gross primary productivity to between 6 and 160 times present-day levels, with important implications for the biological carbon cycle response to high CO2 concentrations prevalent on the early Earth.
The Early Triassic is generally portrayed as a time of various, high ecological stresses leading to a delayed biotic recovery after the devastating end-Permian mass extinction. This interval is ...notably characterized by repeated biotic crises (e.g., during the late Smithian), large-scale fluctuations of the global carbon, nitrogen and sulfur cycles as well as harsh marine conditions including a combination of ocean acidification, anoxia, extreme seawater temperatures and shifting productivity. Observations from different paleolatitudes suggest that sulfidic (H2S-rich) conditions may have developed widely during the Early Triassic, possibly reaching up to ultra-shallow environments in some places. However, the existence and the spatio-temporal extent of such redox swings remain poorly constrained. In order to explore Early Triassic paleoceanographic redox changes and their potential influences on the biotic recovery, we analyzed multiple sulfur isotopes (32S, 33S, 34S, and 36S) of sedimentary pyrite and carbonate associated sulfate (δ34SCAS) from the Mineral Mountains section, Utah. Sediments from this section were mainly deposited in shallow waters and span the Smithian and lower Spathian. We report a 68‰ range of variations in δ34Spy associated with Δ33Spy varying from −0.01‰ to +0.12‰, whereas the δ34SCAS varies between +19.5‰ and + 34.8‰. We interpret the observed signal of multiple sulfur isotopes as reflecting the operation of pore-water synsedimentary microbial sulfate reduction in open system with respect to sulfates before the late Smithian, evolving to a closed system, sulfate limited, Rayleigh-type distillation across the Smithian/Spathian boundary (SSB) and immediately after the SSB. We argue that this marked change is driven by the effectiveness of the connection between the sedimentary pore waters and the overlying water column, which is, in this case, controlled by the local sedimentological conditions such as the bioturbation intensity and the sedimentation rate. Therefore, our results suggest that changes in the sulfur cycle before and across the SSB at Mineral Mountains is probably a local consequence of the loss of the mixed sedimentary layer during the late Smithian extinction event, as opposed to reflecting the development of a lethal anoxic ocean at the global scale.
Introduction
The purpose of this study was to assess the impact of body mass index (BMI) on tension-free vaginal tape (TVT) success rates, patient satisfaction, and complications 1 year following ...surgery.
Methods
Baseline and 1-year postsurgery outcomes were abstracted, including Urogenital Distress Inventory (UDI-6) scores, Incontinence Impact Questionnaire (IIQ-7) scores, and patient satisfaction ratings. Multivariable logistic and linear regression analyses were performed to examine relationships between outcomes and BMI.
Results
Subjects (
N
= 195) with a mean age of 59.3 ± 12.6 were included. There was significant improvement within each group (all
p
values <0.01) in total UDI-6 and IIQ-7 scores from baseline to 1 year postsurgery; all groups had high patient satisfaction. No differences in improvement or complications rates were observed among the BMI cohorts (all
p
values >0.05).
Conclusion
Differential counseling of overweight or obese women regarding outcomes of the TVT procedure is not supported by these results; longer follow-up is warranted.
This study examines the incidence, utilization of procedures, and outcomes for critically ill children hospitalized with traumatic brain injury over the period 1988-1999 to describe the benefits of ...improved treatment.
Retrospective analysis of hospital discharges was conducted using data from the Health Care Cost and Utilization Project Nationwide Inpatient Sample that approximates a 20% sample of U.S. acute care hospitals.
Hospital inpatient stays from all types of U.S. community hospitals.
The study sample included all children aged 0-21 with a primary or secondary ICD-9-CM diagnosis code for traumatic brain injury and a procedure code for either endotracheal intubation or mechanical ventilation.
None.
Deaths occurring during hospitalization were used to calculate mortality rates. Use of intracranial pressure monitoring and surgical openings of the skull were investigated as markers for the aggressiveness of treatment. Patients were further classified by insurance status, household income, and hospital characteristics. Over the 12-yr study period, mortality rates decreased 8 percentage points whereas utilization of intracranial pressure monitoring increased by 11 percentage points. The trend toward more aggressive management of traumatic brain injury corresponded with improved hospital outcomes over time. Lack of insurance was associated with vastly worse outcomes. An estimated 6,437 children survived their traumatic brain injury hospitalization because of improved treatment, and 1,418 children died because of increased mortality risk associated with being uninsured. Improved treatment was valued at approximately dollar 17 billion, whereas acute care hospitalization costs increased by dollar 1.5 billion (in constant 2000 dollars). Increased mortality in uninsured children was associated with a dollar 3.76 billion loss in economic benefits.
More aggressive management of pediatric traumatic brain injury appears to have contributed to reduced mortality rates over time and saved thousands of lives. Additional lives could be saved if mortality rates could be equalized between insured and uninsured children.
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