Accelerating the search for global minima on potential energy surfaces using machine learning.

Controlling molecule-surface interactions is key for chemical applications ranging from catalysis to gas sensing. We present a framework for accelerating the search for the global minimum on potential surfaces, corresponding to stable adsorbate-surface structures. We present a technique using Bayesian inference that enables us to predict converged density functional theory potential energies with fewer self-consistent field iterations. We then discuss how this technique fits in with the Bayesian Active Site Calculator, which applies Bayesian optimization to the problem. We demonstrate the performance of our framework using a hematite (Fe2O3) surface and present the adsorption sites found by our global optimization method for various simple hydrocarbons on the rutile TiO2 (110) surface.

Heterogeneous nuclear ribonucleoproteins F and K mediate insulin inhibition of renal angiotensinogen gene expression and prevention of hypertension and kidney injury in diabetic mice.

AIMS/HYPOTHESIS: We investigated whether heterogeneous nuclear ribonucleoproteins F and K (hnRNP F, hnRNP K) mediate insulin inhibition of renal Agt expression and prevention of hypertension and kidney injury in an Akita mouse model of type 1 diabetes. METHODS: Adult male Akita mice (12 weeks old) were treated with insulin implants and killed at week 16. Untreated non-Akita littermates served as controls. The effects of insulin on blood glucose, systolic BP (SBP), renal proximal tubular cell (RPTC) gene expression and interstitial fibrosis were studied. We also examined immortalised rat RPTCs stably transfected with control plasmid or with plasmid containing rat Agt promoter in vitro. RESULTS: Insulin treatment normalised blood glucose levels and SBP, inhibited renal AGT expression but enhanced hnRNP F, hnRNP K and angiotensin-converting enzyme-2 expression, attenuated renal hypertrophy and glomerular hyperfiltration and decreased urinary albumin/creatinine ratio, as well as AGT and angiotensin II levels, in Akita mice. In vitro, insulin inhibited Agt but stimulated Hnrnpf and Hnrnpk expression in high-glucose media via p44/42 mitogen-activated protein kinase signalling in RPTCs. Transfection with Hnrnpf or Hnrnpk small interfering RNAs prevented insulin inhibition of Agt expression in RPTCs. CONCLUSIONS/INTERPRETATION: These data indicate that insulin prevents hypertension and attenuates kidney injury, at least in part, through suppressing renal Agt transcription via upregulation of hnRNP F and hnRNP K expression in diabetic Akita mice. HnRNP F and hnRNP K may be potential targets in the treatment of hypertension and kidney injury in diabetes.

Unilateral segmentally arranged basaloid follicular hamartomas with osteoma cutis and hypodontia: a case of Happle-Tinschert syndrome.

Happle-Tinschert syndrome (HTS) is a rare syndrome characterized by segmentally arranged basaloid follicular hamartomas (BFH) associated with ipsilateral osseous, dental and cerebral abnormalities. Happle and Tinschert first reported this disorder in 2008, and three cases with similar presentations have since been reported. We report another case, that of a 40-year-old man, presenting with the characteristic clinical features of HTS.

Sugar transport by intestine. Escape of galactose from preloaded mucosa of hamster jejunum.

Everted hamster jejunum was loaded with D-galactose and then escape into an initially galactose-free mucosal solution was followed. Mucosal anaerobiosis greatly increased the rate of escape, an effect which might have been caused by inhibiting reuptake from the unstirred layer and/or by augmenting the ease of unidirectional efflux across the brush border membrane. The former effect was expected because of our previous results from influx studies, and the main object here was to find out if the ease of efflux is affected by anaerobiosis. With phlorizin present in the mucosal solution during escape, information about unidirectional efflux was obtainable. We estimated that 10(-4) M phlorizin inhibited the ease of efflux via the phlorizin-sensitive pathway by about 65%. Apparently the reason why mucosal phlorizin accelerates escape of sugar from loaded mucosa, an effect which has been reported previously by others, is that it inhibits unidirectional efflux less effectively than it inhibits reuptake from the unstirred layer. Residual efflux via the phlorizin-sensitive pathway was markedly increased by mucosal anaerobiosis. This increase did not require an elevation of intracellular Na+ concentration. These results, together with those of our previous study, show that mucosal anaerobiosis abolishes uphill transport of galactose across the brush border of hamster jejunum by inhibiting unidirectional influx and by increasing the ease of unidirectional efflux. Neither of these effects requires a rise in intracellular Na+ concentration.

Cardiotoxin from cobra venom increases the level of phosphatidylinositol 4-monophosphate and phosphatidylinositol kinase activity in two cell lines.

In rat basophilic leukemia-2H3 (RBL-2H3) and Madin-Darby canine kidney (MDCK) cells, cardiotoxin from cobra venom induced a marked decrease in the level of [3H] phosphatidylinositol and a corresponding increase in the level of [3H]phosphatidylinositol 4-monophosphate over the course of 20 min as demonstrated in cells that had been labeled to equilibrium with [3H]inositol. The effect was dependent on the concentration (5-30 micrograms/ml) of the toxin. In plasma membrane-enriched fractions isolated from the two cell lines, the cardiotoxin enhanced the endogenous activity of phosphatidylinositol kinase especially at temperatures above 14 degrees C. In RBL-2H3 cells, cardiotoxin also induced release of substantial amounts of histamine and lactate dehydrogenase. The release of histamine, but not of lactate dehydrogenase, was totally dependent on external calcium and this release probably represented an exocytotic response of the cells to cardiotoxin. Although, initially, treatment with the toxin did not impair antigen-induced hydrolysis of inositol phospholipids or prevent the antigen-induced rise in the concentration of cytosol Ca2+, prolonged exposure to the toxin did result in a progressive loss of responsiveness of RBL-2H3 cells to antigen.

Doppler ultrasound recognition of preclinical changes in arterial wall in diabetic subjects: compliance and pulse-wave damping.

Doppler ultrasound was used to detect early changes in arteries of the legs by two independent techniques. Pulse-wave velocity was measured to calculate arterial wall compliance and Fourier analysis was used to measure damping of the pulse-wave forms. Ten non-insulin-dependent diabetic men with no clinical evidence of peripheral arterial disease had significantly lower compliance and greater pulse-wave damping than 10 matched nondiabetic control subjects. There was a good correlation between the results for the two different techniques.

Putative determinants of arterial wall compliance in NIDDM.

Aortoiliac arterial wall compliance was measured in apparently healthy subjects and in patients with non-insulin-dependent diabetes (NIDDM), on diet alone, who had no clinical evidence of peripheral arterial disease. Compliance was significantly lower in patients with diabetes. The two clinical groups were combined to provide as wide a range of blood glucose values as possible. After allowing for the influence of age, there were significant negative correlations between compliance and free fatty acid and insulin levels. These were almost completely accounted for by differences in blood glucose levels. Therefore, arterial compliance was best predicted on the basis of age and the area under the blood glucose curve.

Triiodothyronine augments the number of membrane-bound (Na+-K+)-adenosine triphosphatase units, but does not affect the sedimentation properties of plasma membrane components.

We have previously demonstrated that T3 enhanced the de novo synthesis of renal cortical (Na+-K+)-dependent ATPase (NaK-ATPase) in the rat. A purified membrane fraction obtained from successive centrifugation of renal cortical crude homogenate was used in the above studies. To rule out a possible effect of T3 on plasma membrane properties, such as the sedimentation characteristic of NaK-ATPase, we have presently observed T3-dependent increases in the activity and number of NaK-ATPase units in a crude homogenate of rat renal cortex. The following results were obtained which substantiate a specific effect of T3 on the membrane-bound NaK-ATPase system. 1) Compared to the hypothyroid state, 43% and 44% increases in the activity and number of NaK-ATPase units, respectively, were observed in crude renal cortical homogenate of T3-treated hypothyroid rats. 2) In comparison with the crude homogenate prepared from hypothyroid rats, 4.8- and 113-fold increases in the specific activity of NaK-ATPase were obtained in the L and J fractions, respectively. Increases of similar relative magnitude in the L and J fractions were also shown in T3-treated hypothyroid and euthyroid rats. 3) No difference in the recovery of the number of NaK-ATPase units was observed from successive steps of the purification under different thyroid states. 4) Treatment of renal cortices from hypothyroid, T3-treated hypothyroid, and euthyroid rats with deoxycholate increased to the same extent NaK-ATPase activity and phosphorylated intermediate formation.

Regulation of rat renal (Na+ + K+)-adenosine triphosphatase activity by triiodothyronine and corticosterone.

The present study concerns the effects of corticosterone and T3 on renal cortical and outer medullary NaK-ATPase activities in the rat. The results show that corticosterone increases cortical and outer medullary NaK-ATPase activities when administered as either a single or multiple doses. Corticosterone and T3 are known to enhance NaK-ATPase activity. We investigate the possibility of interaction between the effects of corticosterone and T3 on renal NaK-ATPase activity. Our studies indicate that corticosterone and T3 regulate renal cortical NaK-ATPase activity via parallel independent pathways, and that corticosterone appears to regulate medullary NaK-ATPase activity without participation by thyroid hormone.

Regulation of NaK-ATPase by Platelet-Derived Growth Factors in Cultured Rat Thoracic Aortic Smooth Muscle Cells.

Regulation of (Na(+) + K(+))-adenosine triphosphatase (NaK-ATPase) by platelet-derived growth factor (PDGF) in cultured rat thoracic aortic smooth muscle cells (SMC) was examined. PDGF-BB enhances SMC proliferation and NaK-ATPase activity. Ouabain, an inhibitor of NaK-ATPase activity, prevents PDGF-BB-induced SMC proliferation. As shown by Western blot and immunochemiluminescence analysis, PDGF-BB also enhances alpha(1), truncated alpha(1), and beta(1) NaK-ATPase subunit levels. PDGF-AA and PDGF-AB show no effect on alpha(1) and truncated alpha(1) levels in slot blot analysis. Induction of NaK-ATPase subunit levels by PDGF-BB could be one of the initial events in vascular SMC proliferation. Copyright 1996 S. Karger AG, Basel

Regulation of Fibronectin by Platelet-Derived Growth Factors in Cultured Rat Thoracic Aortic Smooth Muscle Cells.

Induction of fibronectin (FN) gene expression by platelet-derived growth factor (PDGF) isoforms in rat thoracic aortic smooth muscle cells (SMC) was examined. PDGF-BB enhances FN levels in SMC cultures in a time- and concentration-response fashion. PDGF-AA and PDGF-AB show no effect on FN levels. The effects of insulin and insulin-like growth factor-I (IGF-I) on PDGF-BB-induced FN levels were examined. No additivity of FN levels is observed between PDGF-BB and insulin and/or IGF-I. Experiments also show that PDGF-BB enhances FN mRNA levels, implying that acquisition of additional FN mRNA units accounts for the increase in FN levels. Induction of FN and FN mRNA levels by PDGF-BB could be one of the initial events in vascular SMC proliferation and extracellular matrix expansion, leading to atherosclerosis and hypertension. Copyright 1995 S. Karger AG, Basel

Mastoparan increases membrane bound phosphatidylinositol kinase and phosphatidylinositol 4-monophosphate kinase activities in Madin-Darby canine kidney cells.

Synthetic wasp venom Mastoparan induced an increase of [3H] inositol phosphates levels and a corresponding decrease of [3H]inositol phospholipids levels in Madin-Darby canine kidney (MDCK) cells. The effect was dose (5-100 micrograms/ml) and time (1 to 15 min) dependent. Mastoparan also enhanced the endogenous activity of phosphatidylinositol kinase and phosphatidylinositol 4-monophosphate kinase. The effect was dose (25-75 micrograms/ml) and time dependent (1 to 15 min).

Mastoparan inhibits rat renal NaK-ATPase activity.

Rat renal NaK-ATPase was inhibited by mastoparan in a dose dependent fashion. This inhibition reached completion within 30 seconds. Due to mastoparan's rapid effects on NaK-ATPase activity, this inhibition does not appear to involve either a decrease in the rate of synthesis or an increase in their degradation of NaK-ATPase since these processes require a latency period of at least several minutes. In addition, the phosphoenzyme intermediate formed in the presence of mastoparan was greater than that formed in its absence further indicating that inhibition of NaK-ATPase by mastoparan is not due to a decrease in the number of NaK-ATPase. A possible mechanism for the inhibition is that mastoparan stabilizes the phosphoenzyme intermediate and reduces the Vmax of the enzyme by decreasing the rate of turnover of existing enzyme sites. Neomycin, an inhibitor of inositol phospholipid metabolism, was also found to attenuate the inhibition of Na,K-ATPase by mastoparan, suggesting that the mechanism of this inhibition may involve degradation of the phosphatidylinositol "pool".

Inhibition of alpha-aminoisobutyric acid uptake by mastoparan in Madin-Darby Canine Kidney cells.

Mastoparan, a wasp venom, was found to inhibit Na(+)-dependent net alpha-aminoisobutyric acid (AIB) uptake in Madin Darby Canine Kidney (MDCK) cells. Mastoparan also produced a significant increase in AIB efflux when compared to controls. Pretreatment of MDCK cells with 2 mM neomycin attenuated mastoparan's inhibition of net AIB uptake and completely suppressed mastoparan-mediated increases in AIB efflux when compared to controls. These data suggest that mastoparan's inhibition of net AIB uptake involves more than a single basic mechanism.

Body composition changes following laparoscopic gastric banding for morbid obesity.

Most reports of outcome following obesity surgery report weight and co-morbidity changes only. We studied body composition changes in 17 adult patients (15 F, 2 M, age 43+/-2 years, range 28-58 years), with morbid obesity (initial BMI 40.4+/-4.9 kg/m(2), range 34.7-48.8) who were managed surgically by laparoscopically inserting an adjustable gastric band. Body composition was studied before and after surgery (mean interval of 909+/-51 days, range 441-1155 days) using anthropometry (abdominal circumference, AC, sum of four skinfold thicknesses, SFSUM), whole-body potassium counting (TBK), in vivo neutron activation analysis total body nitrogen (TBProtein) and whole-body dual-energy ray absorptiometry (total body percent fat TBF%, and total body bone mineral density TBBMD). Weight loss over the study period was 23.4+/-2.5 kg. ( p<0.0003) with an AC reduction of 20.0+/-4.5 cm ( p<0.008). Both SFSUM and TBF% were significantly reduced ( p<0.02 and p<0.0005 respectively). Both TBK and TBProtein after normalization for sex and height, were significantly ( p<0.0054 and p<0.001 respectively) reduced, but the ratio of loss of fat mass to fat-free mass, at 4.4:1 was usual for weight loss, and there was no significant changes in the ratio of potassium to protein. TBBMD, after normalization relative to a young same sex adult, was not significantly changed. In this group of patients, most of the substantial weight loss over a 2- to 3-year period was due to loss of fat mass, with relatively less reduction in the components of fat-free mass. Adjustable laparoscopic gastric banding induces fat loss without significant other deleterious effects on body composition.

Orthogonal subspace projection-based approaches to classification of MR image sequences.

Orthogonal subspace projection (OSP) approach has shown success in hyperspectral image classification. Recently, the feasibility of applying OSP to multispectral image classification was also demonstrated via SPOT (Satellite Pour 1'Observation de la Terra) and Landsat (Land Satellite) images. Since an MR (magnetic resonance) image sequence is also acquired by multiple spectral channels (bands), this paper presents a new application of OSP in MR image classification. The idea is to model an MR image pixel in the sequence as a linear mixture of substances (such as white matter, gray matter, cerebral spinal fluid) of interest from which each of these substances can be classified by a specific subspace projection operator followed by a desired matched filter. The experimental results show that OSP provides a promising alternative to existing MR image classification techniques.

Riboflavin status of adolescents in southern China. Average intake of riboflavin and clinical findings.

The average riboflavin intake of 11 200 schoolchildren, aged 12-19 years, in Guangdong Province, China, was measured. Food intake was measured by weighing, and riboflavin intake was calculated by means of food tables. The average intake of riboflavin was 0.45 mg/day. In addition, clinical observations were made in 1313 adolescents in the dietary survey. The findings were consistent with the low intake of riboflavin. The observed clinical signs of riboflavin deficiency were scrotal dermatitis (7.9% of boys), angular stomatitis (5.8% of boys, 2.7% of girls), cheilosis (8.0% of boys, 5.6% of girls) and magenta tongue (36.0% of boys, 40.8% of girls). Corneal vascularization was found only in two of the 1313 children. Scrotal lesions resolved within three to six days after the oral administration of riboflavin (15 mg/day); the resolution of tongue and lip signs progressed more slowly.

Riboflavin status of adolescent southern Chinese: riboflavin saturation studies.

Riboflavin saturation studies were done on 36 high-school boys in Canton whose mean daily intake of riboflavin was 0.45 mg and who showed clinical evidence of deficiency. The boys were given a 2 mg load of riboflavin orally followed by supplements of 0.5, 1.0 and 1.5 mg riboflavin to three groups; a control group received no supplement. After 14 days' supplementation, excretion of riboflavin had increased significantly in all supplemented groups, but not in the control group. The 4-h excretion of riboflavin after the 2 mg load averaged 8.6 per cent of the load for all groups before supplementation. After 14 days' supplementation it was significantly increased only in the groups receiving 1.0 and 1.5 mg daily. This suggests that tissue saturation may not be achieved until the background intake of 0.45 mg/d is increased by between a further 0.5-1.0 mg daily. After 17 days' supplementation with 1.0 and 1.5 mg riboflavin, scrotal dermatitis disappeared. However, even in the 0.5 mg supplemented group, eight out of ten boys with scrotal dermatitis had responded and a total intake of 0.95 mg/d may be enough to prevent clinical deficiency.

PDGF-BB and IGF-I use different signaling pathways to induce fibronectin synthesis in cultured rat thoracic aortic smooth muscle cells.

Fibronectin, an extracellular matrix protein, acts as an early signal in initiating cell proliferation. Results have indicated that platelet-derived growth factor BB (PDGF-BB) and insulin-like growth factor-I (IGF-I) both enhance fibronectin gene expression. Genistein inhibits PDGF-BB-induced fibronectin levels without inhibiting IGF-I-induced fibronectin levels. It indicates that PDGF-BB and IGF-I utilize separate signaling pathways to induce the synthesis of fibronectin.