bluuebunny/crossref_metadata_2025 huggingface dataset:
Rheb signaling and tumorigenesis: mTORC1 and new horizons
Authors: Armijo Marisol E. , Campos Tania , Fuentes‐Villalobos Francisco , Palma Mario E. , Pincheira Roxana , Castro Ariel F.
Published: August 2015

Rheb is a conserved small GTPase that belongs to the Ras superfamily, and is mainly involved in activation of cell growth through stimulation of mTORC1 activity. Because deregulation of the Rheb/mTORC1 signaling is associated with proliferative disorders and cancer, inhibition of mTORC1 has been therapeutically approached. Although this therapy has proven antitumor activity, its efficacy is not as expected. Here, we will review the main work on the identification of the role of Rheb in cell growth, and on the relevance of Rheb in proliferative disorders, including cancer. We will also review the Rheb functions that could explain tumor resistance to therapies with mTORC1 inhibitors, and will mainly focus our discussion on mTORC1‐independent Rheb functions that could also be implicated in cancer cell survival and tumorigenesis. The current progress on the understanding of the noncanonical Rheb functions prompts future studies to establish their relevance in cancer and in the context of current cancer therapies.
Prospective, longitudinal assessment of quality of life in children from diagnosis to 3 months off treatment for standard risk acute lymphoblastic leukemia: Results of Children's Oncology Group study AALL0331
Authors: Mitchell Hannah‐Rose , Lu Xiaomin , Myers Regina M. , Sung Lillian , Balsamo Lyn M. , Carroll William L. , Raetz Elizabeth , Loh Mignon L. , Mattano Leonard A. , Winick Naomi J. , Devidas Meenakshi , Hunger Stephen P. , Maloney Kelly , Kadan‐Lottick Nina S.
Published: August 2015

Standard risk acute lymphoblastic leukemia (SR‐ALL) has high cure rates, but requires 2–3 years of therapy. We aimed to (i) prospectively evaluate health‐related quality of life (HRQOL) during and after SR‐ALL therapy, and (ii) identify associated predictors. Parents of 160 SR‐ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device‐General Functioning (FAD‐GF) at 1, 6 and 12 months after diagnosis, and 3 months post‐therapy. Mean PedsQL scores in physical, emotional and social functioning were impaired 1 month after diagnosis but steadily improved. Three months post‐therapy, impaired physical and social functioning was observed in 27.8 and 25.8% of patients, respectively. In repeated‐measures analysis, problematic family functioning predicted emotional (OR = 1.85, 95% CI 1.03–3.34) and social (OR = 1.99, 95% CI 1.21–3.27) impairment. Larger household size was associated with social impairment (OR = 1.21, 95% CI 1.02–1.45). Adverse neurological event(s) during therapy predicted post‐therapy physical (OR = 5.17, 95% CI 1.61–16.63) and social (OR = 8.17, 95% CI 1.19–56.16) impairment. HRQOL 1 month after diagnosis was not predictive of HRQOL 3 months after therapy completion. In conclusion, children with SR‐ALL experience considerable impairment in HRQOL at the end of induction, but rapidly improve. However, many still experience physical and social impairment 3 months post‐therapy, suggesting a role for continued family and physical functioning support. Longer follow‐up is needed to determine if post‐therapy deficits change over time.
A prospective cohort study on poor oral hygiene and pancreatic cancer risk
Authors: Huang Jiaqi , Roosaar Ann , Axéll Tony , Ye Weimin
Published: August 2015

Poor oral hygiene has been proposed to increase the risk for pancreatic cancer. We aim to assess this hypothesis, using number of teeth, dental plaque and oral mucosal lesions examined at baseline as a proxy for oral hygiene. During 1973–74 a population‐based prevalence study of oral mucosal lesions was carried out in Uppsala County in central Sweden. We followed the study population through linkages with the Swedish Cancer and Total Population registers. A total of 19,924 participants were included, and 126 pancreatic cancer cases were identified during an average of 28.7 years of follow‐up. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for pancreatic cancer were estimated using Cox proportional hazards regression models. Overall, subjects with fewer teeth at baseline tended to have an increased risk for pancreatic cancer, although the estimates were not statistically significant. Among subjects with more than 10 teeth, those with unacceptable dental plaque had an HR of 2.1 (95% CI: 1.0, 4.7), compared with those without dental plaque after adjustment for potential confounding factors. Individuals with Candida‐related or denture‐related oral mucosal lesions, or tongue lesions, compared with those without any of the three studied lesions, had a 70, 30 and 80% excess risk of developing pancreatic cancer, respectively. Presence of more than one type of studied lesions further increased the risk for pancreatic cancer. In conclusion, our findings provide evidence to support the hypothesis that poor oral hygiene plays an important role in the development of pancreatic cancer.
Single agent carboplatin for pediatric low‐grade glioma: A retrospective analysis shows equivalent efficacy to multiagent chemotherapy
Authors: Dodgshun Andrew J. , Maixner Wirginia J. , Heath John A. , Sullivan Michael J. , Hansford Jordan R.
Published: August 2015

Pediatric low‐grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small Phase II studies have suggested equivalent efficacy of single agent 4‐weekly carboplatin. A single‐institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multiagent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560 mg/m2, four‐weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m–16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3‐year progression free survival (PFS) 66% (95% CI 57–76%), and 5‐year PFS was 51% (95% CI 41–63%). 5‐year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up‐front treatment of unresectable LGG.
True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo
Authors: Allen Matthew R , McNerny Erin MB , Organ Jason M , Wallace Joseph M
Published: August 2015

Although the gold standard for determining bones' mechanical integrity is the direct measure of mechanical properties, clinical evaluation has long relied on surrogates of mechanical properties for assessment of fracture risk. Nearly a decade ago, reference point indentation (RPI) emerged as an innovative way to potentially assess mechanical properties of bone in vivo. Beginning with the BioDent device, and then followed by the newer generation OsteoProbe, this RPI technology has been utilized in several publications. In this review we present an overview of the technology and some important details about the two devices. We also highlight select key studies, focused specifically on the in vivo application of these devices, as a way of synthesizing where the technology stands in 2015. The BioDent machine has been shown, in two clinical reports, to be able to differentiate fracture versus nonfracture patient populations and in preclinical studies to detect treatment effects that are consistent with those quantified using traditional mechanical tests. The OsteoProbe appears able to separate clinical cohorts yet there exists a lack of clarity regarding details of testing, which suggests more rigorous work needs to be undertaken with this machine. Taken together, RPI technology has shown promising results, yet much more work is needed to determine if its theoretical potential to assess mechanical properties in vivo can be realized. © 2015 American Society for Bone and Mineral Research.
Site-Dependent Reference Point Microindentation Complements Clinical Measures for Improved Fracture Risk Assessment at the Human Femoral Neck
Authors: Jenkins Thomas , Coutts Louise V , D'Angelo Stefania , Dunlop Douglas G , Oreffo Richard OC , Cooper Cyrus , Harvey Nicholas C , Thurner Phillipp J ,   and the Observational Study Examining Osteoporosis (OStEO) group
Published: August 2015

In contrast to traditional approaches to fracture risk assessment using clinical risk factors and bone mineral density (BMD), a new technique, reference point microindentation (RPI), permits direct assessment of bone quality; in vivo tibial RPI measurements appear to discriminate patients with a fragility fracture from controls. However, it is unclear how this relates to the site of the most clinically devastating fracture, the femoral neck, and whether RPI provides information complementary to that from existing assessments. Femoral neck samples were collected at surgery after low-trauma hip fracture (n = 46; 17 male; aged 83 [interquartile range 77–87] years) and compared, using RPI (Biodent Hfc), with 16 cadaveric control samples, free from bone disease (7 male; aged 65 [IQR 61–74] years). A subset of fracture patients returned for dual-energy X-ray absorptiometry (DXA) assessment (Hologic Discovery) and, for the controls, a micro-computed tomography setup (HMX, Nikon) was used to replicate DXA scans. The indentation depth was greater in femoral neck samples from osteoporotic fracture patients than controls (p < 0.001), which persisted with adjustment for age, sex, body mass index (BMI), and height (p < 0.001) but was site-dependent, being less pronounced in the inferomedial region. RPI demonstrated good discrimination between fracture and controls using receiver-operating characteristic (ROC) analyses (area under the curve [AUC] = 0.79 to 0.89), and a model combining RPI to clinical risk factors or BMD performed better than the individual components (AUC = 0.88 to 0.99). In conclusion, RPI at the femoral neck discriminated fracture cases from controls independent of BMD and traditional risk factors but dependent on location. The clinical RPI device may, therefore, supplement risk assessment and requires testing in prospective cohorts and comparison between the clinically accessible tibia and the femoral neck. © 2015 American Society for Bone and Mineral Research.
FGF23 Regulates Bone Mineralization in a 1,25(OH)2D3 and Klotho-Independent Manner
Authors: Murali Sathish Kumar , Roschger Paul , Zeitz Ute , Klaushofer Klaus , Andrukhova Olena , Erben Reinhold G
Published: August 2015

Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH)2D3) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23-/- or Klotho-/- mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho-/- mice the mineralization defect is solely driven by 1,25(OH)2D3-induced upregulation of the mineralization-inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23-/- mice, the mineralization defect has two components, a 1,25(OH)2D3-driven component similar to Klotho-/- mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization. © 2015 American Society for Bone and Mineral Research.
Nonenzymatic Glycation and Degree of Mineralization Are Higher in Bone From Fractured Patients With Type 1 Diabetes Mellitus
Authors: Farlay Delphine , Armas Laura AG , Gineyts Evelyne , Akhter Mohammed P , Recker Robert R , Boivin Georges
Published: August 2015

Low-energy fractures are frequent complications in type 1 diabetes mellitus patients (T1DM). Modifications of bone intrinsic composition might be a potential cause of fragility observed in diabetic subjects. Advanced glycation end products (AGEs) were found in numerous connective tissues from T1DM patients. However, whether AGEs are present at high levels in bone matrix from diabetic subjects is unknown. Moreover, whether elevated AGEs in the bone matrix impair mineralization has not been addressed in humans. The purposes of this study were 1) to determine whether bone matrix from fracturing and nonfracturing T1DM contained more AGEs than bone from healthy patients (CTL), and 2) to compare the degree of mineralization of bone and hardness between fracturing and nonfracturing T1DM versus CTL. We analyzed iliac crest bone biopsies from 5 fracturing T1DM patients, 5 nonfracturing T1DM patients, and 5 healthy subjects, all age- and sex-matched. AGEs (pentosidine) in bone matrix was measured by high-performance liquid chromatography separately in trabecular and cortical bone. The degree of mineralization of bone (DMB) was assessed by digitized microradiography, and mechanical properties by micro- and nanohardness tests. Trabecular bone from fracturing T1DM exhibited significantly higher levels of pentosidine than CTL (p = 0.04) and was more mineralized than nonfracturing T1DM (p = 0.04) and CTL (p = 0.04). Trabecular bone was not significantly different in pentosidine between nonfracturing T1DM and CTL. Cortical bone from nonfracturing T1DM was not significantly different from CTL. Positive correlations were found between HbA1c and pentosidine (r' = 0.79, p < 0.003) and between HbA1c and DMB (r' = 0.64, p < 0.02). Both modifications could lead to less flexible bone (reduced modulus of elasticity) and a tendency toward low-energy fractures in T1DM patients. © 2015 American Society for Bone and Mineral Research.
Long-Term Exercise and Bone Mineral Density Changes in Postmenopausal Women—Are There Periods of Reduced Effectiveness?
Authors: Kemmler Wolfgang , Engelke Klaus , von Stengel Simon
Published: August 2015

There is increasing evidence that physical exercise can prevent fractures in postmenopausal women. However, even with careful adaptation of the exercise program to subjects' changing bone, health, and fitness status, effectivity may still decrease over the time. This could be specifically the case where the limitations of higher age collide with the specification of the exercise program. Thus, the aim of this study was to monitor bone mineral density (BMD) changes over a 16-year period of supervised exercise. Our hypothesis was that BMD differences at lumbar spine (LS) and femoral neck (FN) between exercisers (EG) and nontraining controls (CG) increased throughout the intervention with significant differences for each of the four 4-year observation periods. Sixty-seven (EG, n = 39 versus CG, n = 28) initially early-postmenopausal osteopenic women of the Erlangen Fitness and Osteoporosis Prevention Study (EFOPS) with complete BMD data sets for baseline (1998) and 4-, 8-, 12-, and 16-year follow-up were included in the analysis. The exercise protocol initially focused on a high-intensity strategy that addressed bone but increasingly shifted to a more comprehensive intervention. LS-BMD differences between the EG and CG continuously increased (year 4: 2.4% (95%- Confidence Interval 1.0% to 3.8%), year 8: 3.1% (1.6% to 4.7%), year 12: 3.9% (1.9% to 5.8), year 16: 4.5% (2.5% to 6.6%). Correspondingly, rising differences for FN-BMD (0.9% (–0.2% to 2.1%) versus 1.9% (0.4% to 3.3%) versus 2.0% (0.5% to 3.8%) versus 3.0% (1.0% to 5.0%)) were observed. However, in contrast to our hypothesis, group differences within the four 4-year periods were not consistently significant (LS, p = 0.001 to 0.097; FN, p = 0.026 to 0.673); further, BMD kinetics among the groups varied between LS and FN. Of particular importance, significant differences (p ≤ 0.030) for both regions were still found in the final period. We conclude that exercise—even when adapted for subjects' decreasing bone, health, and fitness status—is consistently effective in favorably affecting BMD in (initially) early-postmenopausal osteopenic women without any leveling-off effect after 16 years of exercise. © 2015 American Society for Bone and Mineral Research.
Noninvasive Assessment of Skeletal Microstructure and Estimated Bone Strength in Hypoparathyroidism
Authors: Cusano Natalie E , Nishiyama Kyle K , Zhang Chengchen , Rubin Mishaela R , Boutroy Stephanie , McMahon Donald J , Guo X Edward , Bilezikian John P
Published: August 2015

In hypoparathyroidism, areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is above average, and skeletal indices by bone biopsy are abnormal. We used high-resolution peripheral quantitative computed tomography (HRpQCT) and finite element analyses (FEA) to further investigate skeletal microstructure and estimated bone strength. We studied 60 hypoparathyroid subjects on conventional therapy using DXA, HRpQCT, and FEA of the distal radius and tibia compared with normative controls from the Canadian Multicentre Osteoporosis Study. In hypoparathyroid women and men, areal BMD was above average at the lumbar spine and hip sites by DXA; radial BMD was also above average in hypoparathyroid women. Using HRpQCT, cortical volumetric BMD was increased in the hypoparathyroid cohort compared with controls at both the radius and tibia. Cortical porosity was reduced at both sites in pre- and postmenopausal women and at the tibia in young men with a downward trend at the radius in men. At the tibia, trabecular number was increased in premenopausal women and men and trabecular thickness was lower in women. Ultimate stress and failure load at both sites for the hypoparathyroid subjects were similar to controls. Using a linear regression model, at both radius and tibia, each increment in age decreased ultimate stress and failure load, whereas each increment in duration of hypoparathyroidism increased these same indices. These results provide additional evidence for the critical role of parathyroid hormone in regulating skeletal microstructure. Longer disease duration may mitigate the adverse effects of age on estimated bone strength in hypoparathyroidism. © 2015 American Society for Bone and Mineral Research.
A 3D Cosserat point element (CPE) for nonlinear orthotropic solids: Generalization for an initially distorted mesh and an arbitrary orientation of material orthotropy
Authors: Jabareen M. , Mtanes E.
Published: August 2015

The objective of the present paper is to develop a Cosserat point element (CPE) formulation for the numerical solution of three‐dimensional problems of general hyperelastic orthotropic materials under finite deformations with initially distorted element shapes. Generally speaking, the accuracy of the CPE depends on the constitutive coefficients of the strain energy function that controls the inhomogeneous deformations. In the present study, a new methodology for the determination of the constitutive coefficients is presented, which allows the CPE to model any elastic material including isotropic, orthotropic, and anisotropic materials and with initially distorted element geometry. A number of example problems are considered, which verify and compare the performance of the developed CPE with other 3D brick elements that exist in the commercial finite element package ABAQUS. These examples demonstrate that the developed CPE is accurate, robust, free of hourglass instabilities, and can be used for modeling both 3D and thin structures that undergo large deformations. Copyright © 2015 John Wiley & Sons, Ltd.
Computer‐assisted surgical planning and intraoperative guidance in fetal surgery: a systematic review
Authors: Pratt Rosalind , Deprest Jan , Vercauteren Tom , Ourselin Sebastien , David Anna L.
Published: August 2015

Fetal surgery has become a clinical reality, with interventions for twin‐to‐twin transfusion syndrome (TTTS) and spina bifida demonstrated to improve outcome. Fetal imaging is evolving, with the use of 3D ultrasound and fetal MRI becoming more common in clinical practise. Medical imaging analysis is also changing, with technology being developed to assist surgeons by creating 3D virtual models that improve understanding of complex anatomy, and prove powerful tools in surgical planning and intraoperative guidance.

We introduce the concept of computer‐assisted surgical planning, and present the results of a systematic review of image reconstruction for fetal surgical planning that identified six articles using such technology.

Indications from other specialities suggest a benefit of surgical planning and guidance to improve outcomes. There is therefore an urgent need to develop fetal‐specific technology in order to improve fetal surgical outcome. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
Intestinal, portal, and peripheral profiles of daikenchuto (TU‐100)'s active ingredients after oral administration
Authors: Watanabe Junko , Kaifuchi Noriko , Kushida Hirotaka , Matsumoto Takashi , Fukutake Miwako , Nishiyama Mitsue , Yamamoto Masahiro , Kono Toru
Published: August 2015

A pharmaceutical grade Japanese traditional medicine, daikenchuto (TU‐100), consisting of Japanese pepper, processed ginger, and ginseng, has been widely used for various intestinal disorders in Japan and now under development as a new therapeutic drug in the US. It is suggested that TU‐100 ingredients exert pharmacological effects on intestines via two routes, from the luminal side before absorption and the peripheral blood stream after absorption. Therefore, in order to fully understand the pharmacological actions of TU‐100, it is critically important to know the intraluminal amounts and forms of ingested TU‐100 ingredients. In the present study, after administrating TU‐100 to rats, the concentrations of TU‐100 ingredients and their conjugates in the peripheral and portal blood and ileal contents were determined by LC‐MS/MS. Next, TU‐100 was administered to patients with ileostomy bags, but whose small intestines are diagnosed as healthy, and the ingredients/conjugates in the ileal effluent were analyzed. The results suggest that: (1) Pepper ingredients hydroxysanshools are rapidly absorbed and enter systemic circulation, (2) Ginseng ingredients ginsenosides are transported to the colon with the least absorption, (3) Ginger ingredients gingerols are absorbed and some conjugated in the small intestine and transported via the portal vein. While only a small amount of gingerols/gingerol conjugates enter systemic circulation, considerable amounts reappear in the small intestine. Thus, the effect of TU‐100 on the intestines is believed to be a composite of multiple actions by multiple compounds supplied via multiple routes.
Comparing α7 nicotinic acetylcholine receptor binding, amyloid‐β deposition, and mitochondria complex‐I function in living brain: A PET study in aged monkeys
Authors: Nishiyama Shingo , Ohba Hiroyuki , Kanazawa Masakatsu , Kakiuchi Takeharu , Tsukada Hideo
Published: August 2015

This study was aimed to assess the correlations among α7 nicotinic acetylcholine receptor (α7‐nAChR) binding, amyloid‐β (Aβ) deposition, and mitochondrial complex I (MC‐I) activity in the brain of aged monkeys (Macaca mulatta). Positron emission tomography (PET) measurements with [11C](R)‐MeQAA, [11C]PIB, and [18F]BCPP‐EF were conducted in monkeys in a conscious condition. [11C](R)‐MeQAA binding was analyzed by a simplified reference tissue model to calculate nondisplaceable binding potential (BPND), [11C]PIB uptake was calculated by standard uptake value ratio (SUVR), and [18F]BCPP‐EF binding was determined by Logan graphical analysis to calculate total distribution volume (VT) with arterial blood sampling. Higher brain uptake was determined in the thalamus, hippocampus, striatum, and cortical regions for [11C](R)‐MeQAA, while being lower in the cerebellum. Significant age‐related reduction of [11C](R)‐MeQAA binding to α7‐nAChR was determined only in the occipital cortex. The plot of Vt of [18F]BCPP‐EF against BPND of [11C](R)‐MeQAA indicated a significant negative correlation in the hippocampus and cortical regions in aged animals. Plotting of SUVR of [11C]PIB against BPND of [11C](R)‐MeQAA showed a positive correlation. The in vivo binding of [11C](R)‐MeQAA could reflect the upregulation of α7‐nAChR induced by neurodegenerative damage determined by Aβ deposition as well as impaired MC‐I activity in living brain. Synapse 69:475–483, 2015. © 2015 Wiley Periodicals, Inc.
Life‐Cycle Assessment of Construction in a Developing Country
Authors: Asadollahfardi G. , Asadi M. , Karimi S.
Published: August 2015

The construction industry plays a great role in a country's or an area's economy. Construction activities also have significant and increasing effects on the environment. Life‐cycle assessment (LCA) is one of the environmental management techniques that can be used to evaluate the environmental burdens of construction. The authors of this study applied the LCA approach and SimaPro 7.1 software within the framework of the International Organization of Standardization's (ISO) 14040 series of standards and analyzed the global warming potential (GWP) and acidification potential (AP) of the materials acquisition and construction phases of the Parand residential apartment complex located in the southwest part of Tehran province, Iran.
Effects of Temperature and Anion on the Copper(II) Complexes based on 2‐(Carboxyphenyl)iminodiacetic Acid and 1,10‐Phenanthroline
Authors: Ma Jie , Jiang Fei‐Long , Zhou Kang , Chen Lian , Wu Ming‐Yan , Hong Mao‐Chun
Published: August 2015

Using Cu(NO3)2 as metal salt, [Cu3(cpida)(phen)2(H2O)5]·3NO3·2H2O (1) and {[Cu2(cpida)(phen)(NO3)]·2H2O}n (2a) were synthesized from an identical starting mixture with 2‐(carboxyphenyl)iminodiacetic acid (H3cpida) and 1,10‐phenanthroline (phen) at 5 °C and 25 °C, respectively. Additionally, complexes 2b–2d, which are isostructural to 2a, were obtained using Cu(ClO4)2, Cu(BF4)2, and Cu(CF3SO3)2 instead of Cu(NO3)2 in the temperature range 0–65 °C. 1 is characterized by a V‐shaped trinuclear CuII monomer, whereas 2a–2d features a one‐dimensional (1D) Δ CuII chain. Abundant hydrogen bonds constructed by the nitrate anion are observed in 1. A structural transformation study was undertaken and revealed that 1 could completely transform into 2a from the reaction solution at 25 °C and the temperature plays a crucial role in the process. Magnetic measurements revealed that 1 exhibits dominant antiferromagnetic behavior, whereas 2a presents dominant ferromagnetic behavior.
Bridging Nonaselenium Ring in [Se9(IrBr3)2], and Three Modifications of the Mononuclear Complex [IrBr3(SeBr2)3]
Authors: Stolze Karoline , Ruck Michael
Published: August 2015

The reaction of iridium powder with an excess of selenium and SeBr4 yielded lustrous, vermillion crystals of the mononuclear iridium complex [IrBr3(SeBr2)3]. The transition metal is coordinated octahedrally by three SeBr2 and three bromide ligands with facial or meridional configuration. Three different modifications were obtained under similar conditions: a‐fac‐IrBr3(SeBr2)3, space group P$\bar{1}$, with a = 789.4(1) pm, b = 830.4(1) pm, c = 1334.4(1) pm, α = 81.634(5)°, β = 84.948(5)°, γ = 67.616(4)°; m‐fac‐IrBr3(SeBr2)3, space group P21/n, with a = 1205.3(1) pm, b = 962.4(1) pm, c = 1383.9(1) pm, β = 91.114(3)°; mer‐IrBr3(SeBr2)3, space group P21/n with a = 859.7(1) pm, b = 1284.3(1) pm, c = 1437.5(1) pm, β = 94.427(3)°. A lower bromine content in the starting composition resulted in shiny, deep‐red crystals of [Se9(IrBr3)2]. X‐ray diffraction on a single‐crystal revealed a tetragonal lattice (space group I41/a) with a = 1245.4(1) pm and c = 2486.8(1) pm at 296(1) K. In the [Se9(IrBr3)2] complex, a crown‐shaped uncharged Se9 ring coordinates two iridium(III) cations as a bridging bis‐tridentate ligand. Three terminal bromide ions complete the distorted octahedral coordination of each transition metal atom.
Biosynthetic enhancement of single-stage Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) production by manipulating the substrate mixtures
Authors: Huong Kai-Hee , Kannusamy Shantini , Lim Sumithda Yeong Hui , Amirul A A
Published: August 2015

Two-stage fermentation was normally employed to achieve a high poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] productivity with higher 4HB molar fraction. Here, we demonstrated single-stage fermentation method which is more industrial feasible by implementing mixed-substrate cultivation strategy. Studies on bioreactor scale show a remarkably high PHA accumulation of 73 wt%, contributing to a high PHA concentration and product yield of 8.6 g/L and 2.7 g/g, respectively. This fermentation strategy has resulted in copolymers with wider range of 4HB monomer composition, which ranges from 12 to 55 mol%. These copolymers show a broad range of weight average molecular weight (M  w) from 119.5 to 407.0 kDa. The copolymer characteristics were found to be predominantly affected by the nature of the substrates and the mixture strategies, regardless of the 4HB monomer compositions. This was supported by the determination of copolymer randomness using 13C-NMR analysis. The study warrants significantly in the copolymer scale-up and modeling at industrial level.
The modeling of ethanol production by Kluyveromyces marxianus using whey as substrate in continuous A-Stat bioreactors
Authors: Gabardo Sabrina , Pereira Gabriela Feix , Rech Rosane , Ayub Marco Antônio Záchia
Published: August 2015

We investigated the kinetics of whey bioconversion into ethanol by Kluyveromyces marxianus in continuous bioreactors using the “accelerostat technique” (A-stat). Cultivations using free and Ca-alginate immobilized cells were evaluated using two different acceleration rates (a). The kinetic profiles of these systems were modeled using four different unstructured models, differing in the expressions for the specific growth (μ) and substrate consumption rates (r  s), taking into account substrate limitation and product inhibition. Experimental data showed that the dilution rate (D) directly affected cell physiology and metabolism. The specific growth rate followed the dilution rate (μ≈D) for the lowest acceleration rate (a = 0.0015 h−2), condition in which the highest ethanol yield (0.52 g g−1) was obtained. The highest acceleration rate (a = 0.00667 h−2) led to a lower ethanol yield (0.40 g g−1) in the system where free cells were used, whereas with immobilized cells ethanol yields increased by 23 % (0.49 g g−1). Among the evaluated models, Monod and Levenspiel combined with Ghose and Tyagi models were found to be more appropriate for describing the kinetics of whey bioconversion into ethanol. These results may be useful in scaling up the process for ethanol production from whey.
Attitudes Toward Genetic Testing for Celiac Disease
Authors: Roy Abhik , Pallai Michele , Lebwohl Benjamin , Taylor Annette K. , Green Peter H.
Published: August 2015

HLA molecular typing for celiac disease (CD) is a genetic test with a high negative predictive value. The aim of this study is to explore knowledge of and attitudes towards genetic testing (GT). A 25‐item questionnaire was developed by a multidisciplinary team and distributed to members of CD support groups across the United States. Respondents (n = 1835) were mainly female (88 %), married (76 %), and college‐educated (55 %), with a median age range of 31–50 years. Those who were married (82 vs 75 %, p = 0.002), had children (82 vs 74 %, p < 0.001), and had pursued education beyond high school (81 vs 68 %, p = 0.004) were more likely to be aware of the availability of GT. On multivariable analysis, adjusting for age, sex, education, marital status, region of residence, and having children, college‐education (OR 2.05, 95 % CI: 1.33–3.16) and having children (OR 1.56, 95 % CI: 1.15–2.11) remained significant predictors of GT awareness. A majority of patients with a personal or family history of CD planned GT for their children, and the most common concerns regarding GT were cost and impact on health care and/or insurance. In conclusion, awareness of GT is high among CD support group members. Efforts should be made to increase knowledge of GT in those with a lower educational level, and healthcare professionals should attempt to address concerns regarding GT cost and the impact of results on health care and insurance status.
Catalysts for the Ethoxylation of Esters
Authors: Di Serio Martino , Tesser Riccardo , Russo Vincenzo , Turco Rosa , Vitiello Rosa , Sun Yongqiang , Hreczuch Wiesław
Published: August 2015

The intermediates for the production of nonionic surfactants can be derived from petrochemicals and/or from renewable raw materials. In both, the role of catalysis is fundamental. In this paper the main results reported in the literature related with the catalysis for ethoxylation of fatty esters will be reviewed. The main open challenges for these technologies will be outlined.
Milk Phospholipids Enhance Lymphatic Absorption of Dietary Sphingomyelin in Lymph‐Cannulated Rats
Authors: Morifuji Masashi , Higashi Seiichiro , Oba Chisato , Ichikawa Satomi , Kawahata Keiko , Yamaji Taketo , Itoh Hiroyuki , Manabe Yuki , Sugawara Tatsuya
Published: August 2015

Supplementation with sphingomyelin has been reported to have beneficial effects on disease prevention and health maintenance. However, compared with glycerolipids, intact sphingomyelin and ceramides are poorly absorbed. Therefore, if the bioavailability of dietary sphingomyelin is increased, then the dose administered can be reduced. This study was designed to identify molecular species of ceramide in rat lymph after the ingestion of milk sphingomyelin, and to compare the effect of purified sphingomyelin with milk phospholipids concentrate (MPL, 185 mg sphingomyelin/g) on lymphatic absorption of milk sphingomyelin. Lymph was collected hourly for 6 h from lymph‐cannulated rats (n = 8/group) after the administration of a control emulsion (triolein, bovine serum albumin, and sodium taurocholate), a sphingomyelin emulsion (control + purified sphingomyelin), or a MPL emulsion (control + MPL). Molecular species of ceramide in lymph were analyzed using high‐performance liquid chromatography‐tandem mass spectrometry (HPLC–MS/MS). Molecular species of ceramide, containing not only d18:1, but also d17:1 and d16:1 sphingosine with 16:0, 22:0, 23:0, and 24:0 fatty acids (specific to milk sphingomyelin), were increased in rat lymph after the administration of milk sphingomyelin. Their molecular species were similar to those of dietary milk sphingomyelin. Recovery of ceramide moieties from dietary sphingomyelin was 1.28‐ to 1.80‐fold significantly higher in the MPL group than in the sphingomyelin group. Our results demonstrated that dietary sphingomyelin from milk was transported to lymph as molecular species of ceramide hydrolyzed from milk sphingomyelin and co‐ingestion of sphingomyelin with glycerophospholipids enhanced the bioavailability of dietary sphingomyelin.
Mass Spectrometric Confirmation of γ‐Linolenic Acid Ester‐Linked Ceramide 1 in the Epidermis of Borage Oil Fed Guinea Pigs
Authors: Shin Kyong‐Oh , Kim Kunpyo , Jeon Sanghun , Seo Cho‐Hee , Lee Yong‐Moon , Cho Yunhi
Published: August 2015

Ceramide 1 (Cer1), a Cer species with eicosasphingenine (d20:1) amide‐linked to two different ω‐hydroxy fatty acids (C30wh:0:C32wh:1), which are, in turn, ester‐linked to linoleic acid (LNA; 18:2n‐6), plays a critical role in maintaining the structural integrity of the epidermal barrier. Prompted by the recovery of a disrupted epidermal barrier with dietary borage oil [BO: 36.5 % LNA and 23.5 % γ‐linolenic acid (GLA; 18:3n‐6)], in essential fatty acid (EFA)‐deficient guinea pigs, we further investigated the effects of BO on the substitution of ester‐linked GLA for LNA in these two epidermal Cer1 species by LC–MS in positive and negative modes. Dietary supplementation of BO for 2 weeks in EFA‐deficient guinea pigs increased LNA ester‐linked to C32wh:1/d20:1 and C30wh:0/d20:1 of Cer1. Moreover, GLA ester‐linked to C32wh:1/d20:1, but not to C30wh:0/d20:1, of Cer1 was detected, which was further confirmed by the product ions of m/z 277.2 for ester‐linked GLA and m/z 802.3 for the deprotonated C32wh:1/d20:1. C20‐Metabolized fatty acids of LNA or GLA were not ester‐linked to these Cer1 species. Dietary BO induced GLA ester‐linked to C32wh:1/d20:1 of epidermal Cer1.
Modulation of the Expression of Components of the Stress Response by Dietary Arachidonic Acid in European Sea Bass (Dicentrarchus labrax) Larvae
Authors: Montero Daniel , Terova Genciana , Rimoldi Simona , Betancor Mónica B. , Atalah Eyad , Torrecillas Silvia , Caballero María J. , Zamorano María J. , Izquierdo Marisol
Published: August 2015

This study reports for the first time on European sea bass, Dicentrarchus labrax (L.), larvae, the effect of different levels of dietary arachidonic acid (ARA; 20:4n‐6) on the expression of genes related to the fish stress response. Copies of mRNA from genes related to steroidogenesis [StAR (steroidogenic acute regulatory protein), c‐Fos, and CYP11β (11β‐hydroxylase gene)], glucocorticoid receptor complex [GR (glucocorticoid receptor) and HSP (heat shock proteins) 70 and 90) and antioxidative stress (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase] were quantified. Eighteen day‐old larvae were fed for 14 days with three experimental diets with increasing levels of ARA (0.3, 0.6 and 1.2 % d.w.) and similar levels of docosahexaenoic (22:6n‐3) and eicosapentaenoic (20:5n‐3) acids (5 and 3 %, respectively). The quantification of stress‐related genes transcripts was conducted by One‐Step TaqMan real time RT‐PCR with the standard curve method (absolute quantification). Increase dietary levels of ARA induced a significantly (p < 0.05) down‐regulation of genes related to cortisol synthesis, such as StAR and CYP11β and up‐regulated genes related to glucocorticoid receptor complex, such as HSP70 and GR. No effects were observed on antioxidant enzymes gene expression. These results revealed the regulatory role of dietary ARA on the expression of stress‐related genes in European sea bass larvae.
The Fatty Acid Profile and Phenolic Composition of Descurainia sophia Seeds Extracted by Supercritical CO2
Authors: HadiNezhad Mehri , Rowland Owen , Hosseinian Farah
Published: August 2015

Oil and phenolics were extracted from Descurainia sophia (Sophia) seeds by a supercritical CO2 system. Extractions were conducted in two sequential steps, first using 100 % CO2 and then adding 10 % ethanol as co‐solvent. The extracts were collected in each step using two separate collectors operating at different pressures. The extraction run was 3 and 4 h for the first period, and 2 h for the second period. The majority of the oil was collected in the first extraction period while phenolic compounds were obtained in the second extraction period. A combined mode of static/dynamic extraction (3 h running and 1 h soaking in CO2) was also used in the first extraction period, which enhanced the total extraction yield (29.3 ± 0.5 %) and was comparable to the 4 h extraction yield (31.4 ± 0.1 %). The total fatty acid (FA) content of oil in collector 1 (0.94 g) was nearly twice that in collector 2 (0.60 g). The oil contained 14 FAs with α‐linolenic being predominant (48.5 %), with a total 91.1 % unsaturated FAs, a ω3/ω6 ratio of 2.7, and an erucic acid content of 6.2 %. More than 10 phenolic compounds were detected by HPLC in the Sophia seed extracts of which sinapic acid was the dominant compound. Sophia seed extracts showed high levels of antioxidant activity. These results suggest that Sophia seed oil and phenolics have the potential for functional food and pharmaceutical applications.
13‐Hydroxy‐9Z,11E‐Octadecadienoic Acid Production by Recombinant Cells Expressing Burkholderia thailandensis 13‐Lipoxygenase
Authors: Sim Dong‐Hyun , Shin Kyung‐Chul , Oh Deok‐Kun
Published: August 2015

Linoleate 13‐lipoxygenase from Burkholderia thailandensis was expressed in Escherichia coli for the production of 13‐hydroxyoctadecadienoic acid (13‐HODE), an antiseptic emulsifier. Linoleate 13‐lipoxygenase in cells had higher thermal stability than the purified enzyme. To increase 13‐HODE production, recombinant cells were permeabilized by solvents, detergents, salts, and other chemicals. The enzymatic activity in cells was the highest for permeabilized cells treated with 0.5 M NaCl among the permeabilizers tested. The optimal reaction conditions for the production of 13‐HODE from linoleic acid by permeabilized cells treated with 0.5 M NaCl were at pH 7.5, 25 °C, 20 g/l linoleic acid, 15 g/l cells, 0.15 mM Cu2+, and 6 % (v/v) methanol in a 100‐ml baffled flask containing a 5‐ml working volume with agitation at 200 rpm. Under these conditions, permeabilized cells produced 15.8 g/l 13‐HODE after 30 min with a conversion yield of 79 % (w/w) and a productivity of 31.6 g/l/h. The conversion yield and productivity of permeabilized cells for 13‐HODE production were higher than those of purified and crude enzymes as well as nonpermeabilized cells. Therefore, permeabilized cells were efficient biocatalysts for 13‐HODE production. To the best of our knowledge, this is the first report of the production of 13‐HODE using cells.
A Simple Standardization Method for the Biodiesel Cold Soak Filtration Apparatus
Authors: Haas Michael J. , Barr Meredith R. , Phillips John , Wagner Karen M.
Published: August 2015

Commercially available refined vegetable oils were investigated as calibration standards for the filtration device and protocol specified by ASTM D7501 for conducting the biodiesel cold soak filtration test. Filtration time was determined to be a function of the amount of vacuum applied during filtration, with an 8 % change in the filtration time of soybean oil occurring across the vacuum range specified by ASTM D7501. At a constant vacuum of 57 cm Hg the mean filtration time of 150 mL of soybean oil was independent of operator, device, and oil lot number. Mean filtration time was also largely independent of brand: the average of the mean filtration times of replicate samples of seven brands of soybean oil was 396 s with a minimum significant difference (MSD) of 28 s, and the filtration times of seven of eight brands of soybean oil tested fell within this MSD. Refined edible‐grade corn, canola, peanut, safflower and sunflower oils gave reliable filtration times and would be suitable standards. Each oil exhibited a characteristic filtration time, all greater than that for soy oil. Filtration times were an approximately linear function of kinematic viscosities, as predicted by Darcy's Law. Edible vegetable oils can serve as reliable, affordable, consistent and generally available materials for confirming the operability of the filtration device used in the biodiesel cold soak filtration test.
Isolation of Gamma and Delta Tocotrienols from Rice Bran Oil Deodorizer Distillate Using Flash Chromatography
Authors: Kordsmeier Mary , Howard Luke R. , Brownmiller Cindi , Proctor Andy , Hauer‐Jensen Martin
Published: August 2015

Gamma (γ‐T3) and delta (δ‐T3) tocotrienols are the most potent natural protective agents against harmful effects of radiation exposure and there is substantial interest in advancing these tocols toward Food and Drug Administration approval. However, co‐administration with alpha tocopherol is reported to interfere with the radioprotective properties of the tocotrienols. The objective of this study was to test various flash chromatography conditions for the purification of fractions with a high proportion of γ‐T3 or δ‐T3 and a minimal amount of alpha isomers from tocol extract obtained from rice bran oil deodorizer distillate (RBODD). Load size (0.125, 0.250, 0.500 and 1.000 g), sample cartridge type (pre‐packed silica cartridge, empty cartridge+Celite 545) and mobile phase gradient [varying proportions of hexane–acetic acid (99.1:0.9 v/v) and ethyl acetate–acetic acid (99.1:0.9 v/v)] were evaluated. Peak resolution was best with a load size of ~1 % column capacity and a 5‐g silica sample cartridge coupled with a 12‐g silica column. A linear gradient of 0.8 % ethyl acetate–acetic acid (99.1:0.9 v/v) to hexane–acetic acid (99.1:0.9 v/v) (50 min) → 100 % ethyl acetate–acetic acid (99.1:0.9 v/v) (5 min) resulted in the best separation of tocols. The method developed was used to isolate tocols from samples of crude RBODD, tocol concentrate and tocol‐rich extract. The use of these conditions with a tocol‐rich extract resulted in several fractions containing 100 % purities of both γ‐T3 and δ‐T3.
Identifying amyloid pathology–related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study
Authors: Leung Yuk Yee , Toledo Jon B. , Nefedov Alexey , Polikar Robi , Raghavan Nandini , Xie Sharon X. , Farnum Michael , Schultz Tim , Baek Young , Van Deerlin Vivianna M. , Hu William T. , Holtzman David M. , Fagan Anne M. , Perrin Richard J. , Grossman Murray , Soares Holly D. , Kling Mitchel A. , Mailman Matthew , Arnold Steven E. , Narayan Vaibhav A. , Lee Virginia M‐Y. , Shaw Leslie M. , Baker David , Wittenberg Gayle M. , Trojanowski John Q. , Wang Li‐San ,   Alzheimer's Disease Neuroimaging Initiative
Published: August 2015

Introduction

The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1–42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important.

Methods

Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP‐RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of apolipoprotein E (APOE) e4 alleles, and cohort variable) to identify amyloid‐related proteins for symptomatic AD subjects in this largest ever CSF–based MAP‐RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini‐mental state examination (MMSE).

Results

Seven proteins were significantly associated with Aβ1–42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD.

Discussion

Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF–based MAP‐RBM studies. Although some of our reported analytes are related to AD pathophysiology, other's roles in symptomatic AD samples worth further explorations.