Effects of Changing Meteoric Precipitation Patterns on Groundwater Temperature in Karst Environments.

Climate predictions indicate that precipitation patterns will change and average air temperatures will increase across much of the planet. These changes will alter surface water and groundwater temperatures which can significantly affect the local and regional environment. Here, we examine the role of precipitation timing in changes to groundwater temperature in carbonate-karst aquifers using measured groundwater level and temperature data from the Konza Prairie Long-Term Ecological Research Site, Kansas. We demonstrate that shifts to increased cool-season precipitation may mitigate the increases in groundwater temperature produced by increases in average annual air temperature. In karst, the solution-enlarged conduits allow faster and focused recharge, and the recharge-event temperature can strongly influence the groundwater temperature in the aquifer. Our field data and analysis show that predictions of future groundwater conditions in karst aquifers need to consider changes in precipitation patterns, in addition to changes to average annual air temperature.

Pituicytoma, spindle cell oncocytoma, and granular cell tumor: clarification and meta-analysis of the world literature since 1893.

BACKGROUND AND PURPOSE: Pituicytoma, SCO, and GCT are poorly understood entities with confusing nomenclature and undetermined imaging characteristics. Our purpose was to confirm published cases of pituicytoma, SCO, and GCT with the newest 2007 World Health Organization criteria and elucidate imaging findings that distinguish these tumors from common entities such as pituitary adenoma. MATERIALS AND METHODS: A literature search identified 145 published cases (81 GCTs, 48 pituicytomas, and 16 SCOs). Case diagnoses were blindly reviewed by a neuropathologist according to the latest WHO criteria, resulting in 112 pathologically documented cases (64 GCTs, 35 pituicytomas, and 13 SCOs). Imaging illustrations from proved cases were reviewed to determine location, configuration, attenuation and signal intensity, and enhancement characteristics. RESULTS: Only pituicytomas presented as purely intrasellar lesions (7/33). Most GCTs were purely suprasellar (28/45). All SCOs were both intra- and suprasellar (13/13). Twenty-five percent of pituicytomas (6/22) and GCTs (7/30) appeared separate from the pituitary gland. All SCOs were infiltrating. Seventy-nine percent of entities appeared isointense to brain on T1-weighted image (34/43). Seventy-four percent of pituicytomas enhanced homogeneously (14/19). Twelve of 23 GCTs and 5/7 SCOs enhanced heterogeneously. Most GCTs were hyperattenuated to brain on CT (18/20). Eleven of 13 cases enhanced homogeneously. Visual disturbances were common symptoms for all entities (67/112). Diabetes insipidus was rare (4/112). CONCLUSIONS: Pituicytoma may be considered for purely intrasellar masses that are clearly separate from the pituitary gland. GCT should receive consideration for purely suprasellar lesions that are hyperattenuated to brain on CT. SCO should be considered for infiltrating pituitary masses with a mixed intra- and suprasellar location. A history of diabetes insipidus helps to exclude these tumors.

The financial costs of healthcare treatment for people with Type 1 or Type 2 diabetes in the UK with particular reference to differing severity of peripheral neuropathy.

AIMS: To characterize symptom severity of diabetic peripheral neuropathy (DPN) in people with diabetes and to characterize its association with healthcare resource use. METHODS: The study was undertaken in Cardiff and the Vale of Glamorgan, UK. A postal survey was posted to subjects identified as having diabetes. Demography, quality of life (EQ-5D and SF-36) and symptoms of neuropathy (NTSS-6 and QOL-DN) data were collected. These data were linked to routine healthcare data coded into healthcare resource groups (HRGs) and subsequently costed according to UK National reference costs. RESULTS: Survey responses were received from 1298 patients, a 32% response rate. For patients with a clinically confirmed diagnosis of DPN, the mean NTSS-6-SA score was 6.16 vs. 3.19 (P < 0.001). Duration of diabetes did not change across groups defined by severity of neuropathy symptoms, but mean HbA(1c) and body mass index values did increase with symptom severity (range 7.6-8.1%, P = 0.023; and 28.0-30.9 kg/m(2), P < 0.001, respectively). General linear modelling showed that the NTSS-6-SA score was a significant predictor of both annual health resource costs and yearly prescribed drug costs. On average, each 1-point increase in NTSS-6-SA score predicted a 6% increase in primary and secondary care costs and a 3% increase in log transformed drug costs. CONCLUSION: This study demonstrated that severity of DPN symptoms was associated with increased healthcare resource use, thus costs.

The health-related utility and health-related quality of life of hospital-treated subjects with type 1 or type 2 diabetes with particular reference to differing severity of peripheral neuropathy.

AIMS/HYPOTHESIS: We characterised symptom severity of diabetic peripheral neuropathy (DPN) in people with diabetes, and correlated this with health-related utility and health-related quality of life. MATERIALS AND METHODS: The study was undertaken in Cardiff and the Vale of Glamorgan, Wales. A postal survey was mailed to a random sample of subjects identified as having diabetes. Data were collected on the symptoms of neuropathy using the Neuropathic Total Symptom Score (self-administered) (NTSS-6-6A) and on quality of life using the Quality of Life in Diabetes Neuropathy Instrument (QoL-DN), EueroQoL five dimensions (EQ5D) and Short Form 36 (SF36). Other information, such as demographics and self-reported drug use, was also collected. The anonymised data were linked to routine inpatient and outpatient healthcare data. RESULTS: Responses were received from 1,298 patients. For patients with a clinically confirmed diagnosis of DPN, the mean NTSS-6-SA score was 6.16 vs 3.19 in patients without DPN (p<0.001). Four categories of severity were defined, ranging from none to severe. All quality of life measures showed a deterioration between these groups: the EQ5D(index) fell from an average of 0.81 in those without symptoms to 0.25 in those with severe symptoms, the SF36 general health profile fell from 59.9 to 25.5 (p<0.001) and the QoL-DN increased from 25.8 to 48.1 (p<0.001). Multivariate models also demonstrated that this relationship remained after controlling for other factors. CONCLUSIONS/INTERPRETATION: This study demonstrated that severity of DPN symptoms was predictive of poor health-related utility and decreased quality of life. Furthermore, it provides detailed utility data for economic evaluation of treatment of typical diabetes-related morbidity states. Reducing DPN morbidity should be a priority.

Time-resolved measurement of propagating spin waves in ferromagnetic thin films.

We measure the propagation of spatially localized spin waves in NiFe thin films through local inductive detection of the dynamic magnetization. A pulsed magnetic field excites a linear superposition of spin wave modes with a distribution that is predominantly driven by the spatial dependence of the in-plane excitation field. The results of numerical micromagnetic calculations exhibit excellent agreement with experiment and show that a comprehensive account of spatial nonuniformity and propagation is necessary to accurately measure the intrinsic damping rate.

Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors.

A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.

Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release.

SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.

Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.

To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of

ELF3 encodes a circadian clock-regulated nuclear protein that functions in an Arabidopsis PHYB signal transduction pathway.

Many aspects of plant development are regulated by photoreceptor function and the circadian clock. Loss-of-function mutations in the Arabidopsis EARLY FLOWERING 3 (ELF3) and PHYTOCHROME B (PHYB) genes cause early flowering and influence the activity of circadian clock-regulated processes. We demonstrate here that the relative abundance of the ELF3 protein, which is a novel nucleus-localized protein, displays circadian regulation that follows the pattern of circadian accumulation of ELF3 transcript. Furthermore, the ELF3 protein interacts with PHYB in the yeast two-hybrid assay and in vitro. Genetic analyses show that ELF3 requires PHYB function in early morphogenesis but not for the regulation of flowering time. This suggests that ELF3 is a component of a PHYB signaling complex that controls early events in plant development but that ELF3 and PHYB control flowering via independent signal transduction pathways.

ELF3 modulates resetting of the circadian clock in Arabidopsis.

The Arabidopsis early flowering 3 (elf3) mutation causes arrhythmic circadian output in continuous light, but there is some evidence of clock function in darkness. Here, we show conclusively that normal circadian function occurs with no alteration of period length in elf3 mutants in dark conditions and that the light-dependent arrhythmia observed in elf3 mutants is pleiotropic on multiple outputs normally expressed at different times of day. Plants overexpressing ELF3 have an increased period length in both constant blue and red light; furthermore, etiolated ELF3-overexpressing seedlings exhibit a decreased acute CAB2 response after a red light pulse, whereas the null mutant is hypersensitive to acute induction. This finding suggests that ELF3 negatively regulates light input to both the clock and its outputs. To determine whether ELF3's action is phase dependent, we examined clock resetting by using light pulses and constructed phase response curves. Absence of ELF3 activity causes a significant alteration of the phase response curve during the subjective night, and constitutive overexpression of ELF3 results in decreased sensitivity to the resetting stimulus, suggesting that ELF3 antagonizes light input to the clock during the night. The phase of ELF3 function correlates with its peak expression levels in the subjective night. ELF3 action, therefore, represents a mechanism by which the oscillator modulates light resetting.

Biology of TACE inhibition.

Studies conducted over the past decade have demonstrated a central role for tumour necrosis factor alpha (TNFalpha) in inflammatory diseases. As a result of this work, a number of biological agents that neutralise the activity of this cytokine have entered the clinic. The recent clinical data obtained with etanercept and infliximab highlight the relevance of this strategy. TNFalpha converting enzyme (TACE) is the metalloproteinase that processes the 26 kDa membrane bound precursor of TNFalpha (proTNFalpha) to the 17 kDa soluble component. Although a number of proteases have been shown to process proTNFalpha, none do so with the efficiency of TACE. A series of orally bioavailable, selective, and potent TACE inhibitors are currently in clinical development. These inhibitors effectively block TACE mediated processing of proTNFalpha and can reduce TNF production by lipopolysaccharide stimulated whole blood by >95%. Through a series of studies it is shown here that >80% of the unprocessed proTNFalpha is degraded intracellularly. The remainder appears to be transiently expressed on the cell surface. Although, in vitro, TACE inhibition has also been implicated in shedding of p55 and p75 surface TNFalpha receptors, the in vivo data cast doubt on the consequences of this finding. In a mouse model of collagen-induced arthritis, the inhibitors are efficacious both prophylactically and therapeutically. The efficacy seen is equivalent to strategies that neutralise TNFalpha. In many studies greater efficacy is observed with the TACE inhibitors, presumably owing to greater penetration to the site of TNFalpha production.

Photon-assisted tunneling in electron pumps

We measure photon-assisted tunneling in 4- and 6-junction electron pumps at photon frequencies up to 60 GHz. We determine the microwave voltage at the pumps using noise thermometry. The standard theory of leakage in the electron pump, modified to include photon-assisted tunneling, describes our experiments well. From this test of theory we argue that, in the absence of external microwaves, photon-assisted tunneling driven by 1/f noise is an important error mechanism in electron pumps.

Goal theory, motivation, and school achievement: an integrative review.

The purpose of this review is to document the directions and recent progress in our understanding of the motivational dynamics of school achievement. Based on the accumulating research it is concluded that the quality of student learning as well as the will to continue learning depends closely on an interaction between the kinds of social and academic goals students bring to the classroom, the motivating properties of these goals and prevailing classroom reward structures. Implications for school reform that follow uniquely from a motivational and goal-theory perspective are also explored.

P1, P2'-linked macrocyclic amine derivatives as matrix metalloproteinase inhibitors.

A novel series of 13- and 14-membered macrocyclic amines was developed by linking the P1 and P2' groups. The synthesis entails stereoselective Frater alkylation to install the anti-succinate configuration and macrocyclic amination via nucleophilic displacement. This strategy resulted in a new class of conformationally constrained inhibitors that are potent and selective for MMP-8 and 9 over MMP-1 and 3.

Macrocyclic hydroxamate inhibitors of matrix metalloproteinases and TNF-alpha production.

Several macrocyclic, hydroxamate derivatives were synthesized and evaluated as inhibitors of matrix metalloproteinases (MMPs) and tumour necrosis factor-alpha (TNF-alpha) production. These macrocycles are anti-succinate based inhibitors linked from P1 to P2'. A variety of functionality was installed at the P1-P2' linkage, which gave inhibitors that displayed excellent MMP inhibition and good TNF-alpha suppression.

Terphenyl cyclooxygenase-2 (COX-2) inhibitors: optimization of the central ring and o-biphenyl analogs.

The discovery of terphenyl derivatives as highly selective COX-2 inhibitors resulted from our efforts to overcome poor pharmacokinetics demonstrated by the COX-2 selective diarylthiophene DuP 697 [2-bromo-4-(4'-sulfonylmethyl)phenyl-5-(4'-fluoro)phenylthiophe ne]. Detailed SAR related to the ortho-biphenyls and variants of the central ring are described herein.

Inhibition of MAP kinase kinase prevents cytokine and prostaglandin E2 production in lipopolysaccharide-stimulated monocytes.

Activation of the extracellular signal-regulated kinase (ERK) pathway has been shown to occur in monocytes following stimulation with LPS. However, the importance of this event for monocyte function is not clear. To address this issue, we used the novel MAP/ERK kinase (MEK) inhibitor, U0126. Stimulation of monocytes with LPS resulted in activation of the mitogen-activated protein kinase (MAPK) family members ERK, Jun NH2-terminal kinase (JNK), and p38. Treatment of monocytes with LPS in the presence of U0126 blocked the activation of ERK1 and ERK2. However, the activation of Jun NH2-terminal kinase and p38 family members was not affected by the compound, confirming the selectivity of U0126. To examine the effects of MEK inhibition on monocyte function, we measured production of the cytokines IL-1, IL-8, and TNF, as well as PGE2. Monocytes treated with LPS in the presence of U0126 failed to release IL-1, IL-8, TNF, or PGE2. The failure to secrete IL-1 and TNF was due to decreased levels of mRNA. These results demonstrate that activation of MEK/ERK is critical for cytokine and PGE2 production by monocytes in response to LPS.