From calibration to parameter learning: Harnessing the scaling effects of big data in geoscientific modeling.

The behaviors and skills of models in many geosciences (e.g., hydrology and ecosystem sciences) strongly depend on spatially-varying parameters that need calibration. A well-calibrated model can reasonably propagate information from observations to unobserved variables via model physics, but traditional calibration is highly inefficient and results in non-unique solutions. Here we propose a novel differentiable parameter learning (dPL) framework that efficiently learns a global mapping between inputs (and optionally responses) and parameters. Crucially, dPL exhibits beneficial scaling curves not previously demonstrated to geoscientists: as training data increases, dPL achieves better performance, more physical coherence, and better generalizability (across space and uncalibrated variables), all with orders-of-magnitude lower computational cost. We demonstrate examples that learned from soil moisture and streamflow, where dPL drastically outperformed existing evolutionary and regionalization methods, or required only ~12.5% of the training data to achieve similar performance. The generic scheme promotes the integration of deep learning and process-based models, without mandating reimplementation.

Impact of cathodic electron acceptor on microbial fuel cell internal resistance.

Ferricyanide is often used in microbial fuel cells (MFCs) to avoid oxygen intrusion that occurs with air cathodes. However, MFC internal resistances using ferricyanide can be larger than those with air cathodes even though ferricyanide results in higher power densities. Using a graphite fiber brush cathode and a ferricyanide catholyte (FC-B) the internal resistance was 62 ± 4 mΩ m2, with 84 ± 8 mΩ m2 obtained using ferricyanide and a flat carbon paper cathode (FC-F) and only 51 ± 1 mΩ m2 using a 70% porosity air cathode (A-70). The FC-B MFCs produced the highest maximum power density of all configurations examined: 2.46 ± 0.26 W/m2, compared to 1.33 ± 0.14 W/m2 for the A-70 MFCs. The electrode potential slope (EPS) analysis method showed that electrode resistances were similar for ferricyanide and air-cathode MFCs, and that higher power was due to the larger experimental working potential (500 ± 12 mV) of ferricyanide compared to the air cathode (233 ± 5 mV).

The perspectives of obese women receiving antenatal care: A qualitative study of women's experiences.

BACKGROUND: The prevalence of overweight and obesity is increasing amongst women of child bearing age. Maternal obesity has implications for both mother and baby including increased health risks from gestational hypertensive disorders, caesarean section and stillbirth. Despite the increasing prevalence of maternal obesity little is known of the experiences of these women within the health care system. The aim of this research was to investigate the perspectives of pregnant women with a body mass index (BMI) of ≥30kg/m(2) receiving antenatal care. METHODS: A qualitative study using individual interviews was undertaken. Sixteen pregnant women with a BMI ≥30kg/m(2) participated. Interviews were audio recorded, transcribed, cross checked for consistency and then entered into a word processing document for analysis. Data was analysed using Interpretative Phenomenological Analysis. In any phenomenological study the researcher's objective is to elicit the participant's views on their lived experiences. FINDINGS: Four major themes emerged: (1) obese during pregnancy as part of a long history of obesity; (2) lack of knowledge of the key complications of obesity for both mother and child; (3) communication about weight and gestational weight gain can be conflicting, confusing and judgmental; (4) most women are motivated to eat well during pregnancy and want help to do so. CONCLUSION: Specialist lifestyle interventions for obese women should be a priority in antenatal care. Extra support is required to assist obese women in pregnancy achieve recommended nutritional and weight goals. Health professionals should approach the issue of maternal obesity in an informative but non-judgmental way.

P-cadherin potentiates ligand-dependent EGFR and IGF-1R signaling in dysplastic and malignant oral keratinocytes.

Oral and oropharyngeal cancer together constitute the sixth most common cancer worldwide, with over 400,000 new cases diagnosed each year. Early detection is paramount, as the 5-year survival rate for these cancers decreases markedly once tumors have become regionally invasive. In many tissues, including oral epithelia, neoplastic progression is accompanied by alterations in expression of the epithelial cell adhesion molecules E-cadherin and P-cadherin. Oral epithelia is one of only a few tissues in which P-cadherin levels have been noted to increase in dysplasia and well-differentiated carcinomas and decrease in advanced malignancies. In the present study, P-cadherin was overexpressed in both dysplastic and malignant oral keratinocytes to characterize the mechanisms by which aberrantly expressed P-cadherin may modulate tumor progression. We found that P-cadherin was able to potentiate ligand-dependent signaling of insulin-like growth factor 1 receptor (IGF-1R) in malignant keratinocytes and epidermal growth factor receptor (EGFR) in dysplastic cells. P-cadherin prolonged activation of the mitogen-activated protein kinase (MAPK) in both cell lines and also increased the magnitude of AKT phosphorylation in dysplastic cells. P-cadherin overexpression alone was sufficient to increase steady-state levels of the mesenchymal transcription factor Snail, increase cell motility and also induce morphological changes in dysplastic keratinocytes. Taken together, these data suggest that the aberrantly elevated levels of P-cadherin which occur in early oral tumor development may play a critical role in the augmentation of neoplastic signaling networks and in the further acquisition of aggressive phenotypes.

The cytoplasmic domain of N-cadherin modulates MMP­9 induction in oral squamous carcinoma cells.

Oral squamous carcinoma is the sixth most common cancer worldwide, and one of the most common cancers in developing countries. Regional and distant metastases comprise the majority of cases at initial diagnosis and correlate with poor patient outcomes. Oral epithelia is one of many tissue types to exhibit a cadherin switch during tumor progression, in which endogenous cell adhesion proteins, such as E-cadherin, give way to those of mesenchymal origin. The mesenchymal cell adhesion protein N-cadherin is found at the invading front of oral squamous carcinomas and has been strongly correlated with poor patient prognosis. The goal of the present study was to elucidate the mechanism by which N-cadherin may increase extracellular matrix-associated proteolytic activity to facilitate invasiveness in oral tumor development. The overexpression of N-cadherin in two oral squamous carcinoma cell lines increased motility, invasive capacity and synthesis of matrix metalloproteinase-9 (MMP-9) in a manner that was independent of E-cadherin downregulation. The use of EN and NE chimeric cadherin molecules with reciprocally substituted cytoplasmic domains revealed that optimal induction of MMP-9 synthesis required the cytoplasmic region, but not the extracellular region, of N-cadherin. Utilizing an N-cadherin mutant with impaired p120 binding ability, we found that such mutation resulted in a 4-fold decrease in motility compared to wild-type N-cadherin, but did not affect either MMP-9 expression or motility-normalized invasion. Overexpression of wild-type N-cadherin produced a 27-fold increase in the transcriptional activity of ß-catenin, concomitant with increases in MMP-9 transcription. These results suggest that N-cadherin may promote motility and invasiveness through distinct mechanisms, and that ß-catenin may be an integral mediator of N-cadherin-dependent invasive signaling in oral epithelia.

Resolving genetic functions within microbial populations: in situ analyses using rRNA and mRNA stable isotope probing coupled with single-cell raman-fluorescence in situ hybridization.

Prokaryotes represent one-half of the living biomass on Earth, with the vast majority remaining elusive to culture and study within the laboratory. As a result, we lack a basic understanding of the functions that many species perform in the natural world. To address this issue, we developed complementary population and single-cell stable isotope ((13)C)-linked analyses to determine microbial identity and function in situ. We demonstrated that the use of rRNA/mRNA stable isotope probing (SIP) recovered the key phylogenetic and functional RNAs. This was followed by single-cell physiological analyses of these populations to determine and quantify in situ functions within an aerobic naphthalene-degrading groundwater microbial community. Using these culture-independent approaches, we identified three prokaryote species capable of naphthalene biodegradation within the groundwater system: two taxa were isolated in the laboratory (Pseudomonas fluorescens and Pseudomonas putida), whereas the third eluded culture (an Acidovorax sp.). Using parallel population and single-cell stable isotope technologies, we were able to identify an unculturable Acidovorax sp. which played the key role in naphthalene biodegradation in situ, rather than the culturable naphthalene-biodegrading Pseudomonas sp. isolated from the same groundwater. The Pseudomonas isolates actively degraded naphthalene only at naphthalene concentrations higher than 30 muM. This study demonstrated that unculturable microorganisms could play important roles in biodegradation in the ecosystem. It also showed that the combined RNA SIP-Raman-fluorescence in situ hybridization approach may be a significant tool in resolving ecology, functionality, and niche specialization within the unculturable fraction of organisms residing in the natural environment.

Platelet thromboxane A2 secretion in patients with major depression responsive to electroconvulsive therapy.

OBJECTIVE: To determine a) whether clinical response to electroconvulsive therapy (ECT) is associated with decreased platelet activation in patients with major depressive disorder (MDD) and b) if any medical/demographic characteristics predict response to ECT or changes in platelet activation. Increased platelet activation may underlie the increased risk of coronary artery disease (CAD) in patients with MDD. METHODS: Before their first and sixth ECT treatments, study patients (n = 44) completed the Beck Depression Inventory (BDI) to assess the severity of depressive symptoms. Activity of the platelet thromboxane (TBX) A(2) pathway was assessed by measuring the morning spot urinary concentrations of 11-dehydroxy-thromboxane B(2) (11-D-TBX B(2)), a major metabolite of platelet-derived TBX A(2). RESULTS: Multivariate logistic regression analyses revealed that improvement on the BDI was significantly more likely in patients without a history of hypertension (p = .02) and in patients who were prescribed a greater number of "platelet-altering" medications (p = .03). During a course of ECT, a decrease in urinary 11-D-TBX B(2) was significantly more likely to occur in ECT nonresponders (p = .01) and younger patients (p = .02). CONCLUSIONS: Clinical response to ECT coadministered may not be associated with decreases in platelet-derived TBX. Future studies will confirm which somatic "antidepression" treatments offer optimal thrombovascular benefits for depressed patients with multiple risk factors for, or clinically evident, cerebral disease or CAD.

The diagnosis of major depression in patients with cancer: a comparative approach.

Depressive symptoms not only impair quality of life in cancer patients but constitute an independent risk factor for increased mortality. In order to accurately and efficiently identify depression in cancer patients, the authors developed a biostatistical strategy to identify items of the 21-item, observer-rated Hamilton Rating Scale for Depression (Ham-D) that would optimize the diagnosis of depression among cancer patients. Exhibiting a relatively high sensitivity and specificity, our most optimal diagnostic tool contained six Ham-D items (late insomnia, agitation, psychic anxiety, diurnal mood variation, depressed mood, and genital symptoms). This study may serve as a prototype to generate valid instruments accurate for the diagnosis of major depression in other populations of cancer patients.

A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression.

OBJECTIVE: This study compared the efficacy and safety of paroxetine and desipramine with those of placebo in the treatment of depressive disorders in adult women with breast cancer, stages I-IV. METHOD: In a double-blind, placebo-controlled study, 35 female outpatients with breast cancer and DSM-III-R major depression or adjustment disorder with depressed mood were randomly assigned to treatment with paroxetine (N=13), desipramine (N=11), or placebo (N=11) for 6 weeks. Primary efficacy was assessed by change from baseline in score on the 21-item Hamilton Rating Scale for Depression (HAM-D), and the secondary outcome measure was change from baseline in the Clinical Global Impressions-Severity of Illness scale (CGI-S) score. RESULTS: Mean changes in the total HAM-D and CGI-S scores from baseline to 6-week endpoint for the paroxetine and desipramine groups were not significantly different than those for the placebo-treated group. An unusually high rate of response (defined as >or=50% improvement in the HAM-D score) in the placebo group was observed (55% [N=6]); adverse events precipitated patient discontinuation in the active treatment groups (9% [N=1] for desipramine, 15% [N=2] for paroxetine) similar to that in the placebo-treated patients (18% [N=2]). Improvement on symptom dimensions within the HAM-D and Hamilton Rating Scale for Anxiety (depressive, anxiety, cognitive, neurovegetative, or somatic) was also similar between groups. CONCLUSION: The small number of women in this study most likely contributed to the lack of observed differences in efficacy observed during the 6 weeks of treatment. Randomized, placebo-controlled trials of adequate power seeking to determine efficacy of antidepressants in the United States for the treatment of women with breast cancer and comorbid depression remain of paramount importance.

A novel protein kinase CK2 substrate indicates CK2 is not directly stimulated by polyamines in vivo.

The activity of the protein kinase (CK2) is enhanced in vitro by the binding of polyamines to the CK2beta regulatory subunit. The overexpression of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, also elevates CK2 kinase activity in primary keratinocytes and tissues of K6/ODC transgenic mice. In an effort to better characterize the mechanisms by which polyamines may affect CK2 in vivo, we constructed a transfectable CK2 substrate cDNA consisting of the enhanced green fluorescence protein appended with a canonical CK2 phosphorylation sequence (EGFP-S). In contrast to unmodified EGFP, the EGFP-S protein was extensively phosphorylated by CK2, and this phosphorylation was stimulated by the polyamine spermine in a dose-dependent manner. The in vivo phosphorylation of EGFP-S was examined in cell lines which inducibly express either wild-type CK2 holoenzyme or a CK2 holoenzyme which contains activating mutations in the polyamine-binding region of its CK2beta regulatory subunit. Neither the overexpression of ODC in either cell line nor the mutation of the CK2beta subunit conferred an increase in CK2 kinase activity as measured by the in vivo phosphorylation of EGFP-S. Rather, our data indicate that polyamines increase total CK2 kinase activity through increases in steady-state levels of both CK2alpha and CK2beta subunits. The overexpression of ODC resulted in a 3-fold increase in steady-state levels of both exogenous and endogenous CK2 transcripts but did not increase the half-life of wild-type or mutated CK2 protein. These data suggest that the regulation of intracellular CK2 by the polyamines may occur through mechanisms distinct from the direct stimulation of CK2 by polyamines in vitro as previously described.

B23 is a downstream target of polyamine-modulated CK2.

Our previous studies have shown that the overexpression of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, increases the enzymatic activity of the polyamine-responsive enzyme casein kinase 2 (CK2). Because CK2 is known to preferentially associate with the nuclear matrix in response to other trophic stimuli, we investigated the effects of ODC overexpression on CK2 localisation and on the CK2-mediated phosphorylation of a known CK2 substrate, the nucleolar phosphoprotein B23. Immunofluorescence analysis of CK2 and B23 in primary keratinocytes revealed that ODC overexpression resulted in the colocalisation of CK2 with B23 at the nucleolar borders. ODC overexpression also increased CK2 kinase activity 2-fold at the nuclear matrix, a response which could be abrogated by treatment of K6/ODC transgenic keratinocytes with the ODC inhibitor alpha-difluoromethylornithine (DFMO). Levels of B23 protein were also elevated in ODC-overexpressing cells compared to normal cells or transgenic cells treated with DFMO. This increase in protein level was neither due to an increase in steady-state mRNA levels, nor was it due to increased stability of B23 protein. Phosphorylation of B23 was also increased in ODC-overexpressing cells, and this increased phosphorylation could be blocked by treatment of the cells with the CK2 kinase inhibitors apigenin or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). These data suggest that B23 may be a downstream effector of polyamines via phosphorylation by the protein kinase CK2.

Digestion of mu- and m-calpain by trypsin and chymotrypsin.

Proteolytic digestion by trypsin and chymotrypsin was used to probe conformation and domain structure of the mu- and m-calpain molecules in the presence and the absence of Ca(2+). Both calpains have a compact structure in the absence of Ca(2+); incubation with either protease for 120 min results in only three or four major fragments. A 24-kDa fragment was produced by removal of the Gly-rich area in domain V of the 28-kDa subunit. The other fragments were from the 80-kDa subunit. Except for trypsin digestion of m-calpain, the region between amino acids 245 and 265 (human sequence) was very susceptible to cleavage by both proteases in the absence of Ca(2+); this region is in domain II (IIb of the crystallographic structure). Although no proteolytically active fragments could be isolated from either tryptic or chymotryptic digests, the calpain molecule can remain assembled in a proteolytically active complex even after the 80-kDa subunit has been completely degraded. The results suggest that interaction among different regions of the entire calpain molecule is required for its full proteolytic activity. In the presence of 1 mM Ca(2+), both calpains are degraded to fragments less than 40-kDa in less than 5 min. The C-terminal ends of both subunits, from amino acids 503 to 506 to the end of the 80-kDa subunit and from amino acids 85 to 88 to the end of the 28-kDa subunit, were resistant to degradation by either protease in the presence or in the absence of Ca(2+). Hence, this part of the calpain molecule is in a compact structure that does not change significantly in the presence of Ca(2+).

Detoxification of the polyamine analogue N1-ethyl-N11-[(cycloheptyl)methy]-4,8-diazaundecane (CHENSpm) by polyamine oxidase.

PURPOSE: Analogues of the naturally occurring polyamines, alkylated on both terminal amines, are being developed as anticancer drugs. Because bisalkylated derivatives of putrescine (1,4-diaminobutane) are potent inhibitors of the flavin adenine dinucleotide-dependent polyamine oxidase (PAO), we asked whether PAO could detoxify synthetic bisalkylated polyamines with chain lengths longer than putrescine. EXPERIMENTAL DESIGN: We investigated the effects of one polyamine analogue in Chinese hamster ovary (CHO) and HCT116 human colon tumor-derived cells, which express dramatically different levels of PAO activity, and in these same cells treated with an inhibitor of PAO. RESULTS: Concentrations of N1-ethyl-N11-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm), ranging from 0.3 to 10 microM, caused growth arrest and reduced cell survival in HCT116 cells but not in CHO cells. This cell line-specific difference in CHENSpm toxicity was not attributable to differences in analogue uptake, because intracellular levels of the drug were similar in CHO and HCT116 cells treated with equivalent concentrations of CHENSpm in the presence of MDL 72,527, a specific inhibitor of PAO. The PAO inhibitor, in combination with CHENSpm, caused a significant increase in intracellular CHENSpm levels and increased growth inhibition and cell damage in CHO cells but not in HCT116 cells. CHO cells, but not HCT116 cells, produced two primary amine-containing metabolites from CHENSpm that were suppressed by MDL 72,527. CONCLUSIONS: These data demonstrate that CHENSpm is detoxified in PAO-expressing CHO cells, but not in PAO-deficient HCT116 cells, by a mechanism yielding products containing free primary amine groups and implicate PAO as the detoxification enzyme. Because other studies suggest that PAO may be self-regulated in some tumors, differential expression of PAO may be the basis for selective toxicity of CHENSpm and other N-substituted polyamine analogues in certain cancers.