bluuebunny/crossref_metadata_2025 huggingface dataset:
Isotopic and hydrochemistry spatial variation of sulfate for groundwater characterization in karstic aquifers
Authors: González‐Ramón Antonio , López‐Chicano Manuel , Gázquez Fernando , Durán‐Valsero Juan José , Pedrera Antonio , Ruiz‐Constán Ana , González‐Egea Elena
Published: June 2017

The Sierra Gorda aquifer is one of the most extensive of southern Spain. The main groundwater discharge is produced at its northern boundary through several high‐flow springs. In this study, stable isotopes of dissolved sulfate (δ34S and δ18O) and groundwater chemistry were used to determine the origin of the sulfate and to characterize the groundwater flow. We sampled the main springs, as well as other minor outlets related to perched water tables, in order to determine the different sources of SO42− (e.g., dissolution of evaporites and atmospheric deposition). The substantial difference in the amount of dissolved SO42− between the springs located in its northwestern part (≈25 mg/L) and those elsewhere in the northern part (≈60 mg/L) suggests zones with separate groundwater flow systems. A third group of springs, far from the northeastern boundary of the permeable outcrops, shows higher SO42− content than the rest (≈125 mg/L). The isotopic range of sulfate (−0.3‰ to 14.82‰ V‐CTD) points to several sources, including dissolution of Triassic or Miocene evaporites, atmospheric deposition, and decomposition of organic material in the soil. Among these, the dissolution of Triassic gypsum—which overlies the saturated zone as a consequence of the folds and faults that deform the aquifer—is the main source of SO42− (range from 12.79‰ to 14.82‰ V‐CTD). This range is typical for Triassic gypsum. The higher karstification in the western sector, together with important differences in the saturated thickness between the western and eastern sectors, would also be due to the tectonic structure and could explain the difference in SO42− contents in the water. This singular arrangement may cause a higher residence time of groundwater in the eastern sector; thus, a higher contact time with Triassic evaporitic rocks is inferred. Accordingly, the stable isotopes of SO42− are found to be a valuable tool for identifying areas with different flow systems in the saturated zone of karstic aquifers, as well as for evaluating aspects such as the degree of karstification.
Hydrological cycle and water balance estimates for the megadune–lake region of the Badain Jaran Desert, China
Authors: Ma Yan‐Dong , Zhao Jing‐Bo , Luo Xiao‐Qing , Shao Tian‐Jie , Dong Zhi‐Bao , Zhou Qi
Published: June 2017

The hydrology and water balance of megadunes and lakes have been investigated in the Badain Jaran Desert of China. Field observations and analyses of sand layer water content, field capacity, secondary salt content, and grain size reveal 3 types of important natural phenomenon: (a) vegetation bands on the leeward slope of the megadunes reflect the hydrological regime within the sandy vadose zone; (b) seepage, wet sand deposits, and secondary salt deposits indicate the pattern of water movement within the sandy vadose zone; (c) zones of groundwater seeps and descending springs around the lakes reflect the influence of the local topography on the hydrological regime of the megadunes. The seepage exposed on the sloping surface of the megadunes and gravity water contained within the sand layer confirm the occurrence of preferential flow within the vadose zone of the megadunes. Alternating layers of coarse and fine sand create the conditions for the formation of preferential flows. The preferential flows promote movement of water within the sand layer water that leads to deep penetration of water within the megadunes and ultimately to the recharging of groundwater and lake water. Our results indicate that a positive water balance promotes recharge of the megadunes, which depends on the high permeability of the megadune material, the shallow depth of the surface sand layer affected by evaporation, the occurrence of rainfall events exceeding 15 mm, and the sparse vegetation cover. Water balance estimates indicate that the annual water storage of the megadunes is about 7.5 mm, accounting for only 8% of annual precipitation; however, the shallow groundwater per unit area under the megadunes receives only 3.6% of annual precipitation, but it is still able to maintain a dynamic balance of the lake water. From a water budget perspective, the annual water storage in the megadunes is sufficient to serve as a recharge source for lake water, thereby enabling the long‐term persistence of the lakes. Overall, our findings demonstrate that precipitation is a significant component of the hydrological cycle in arid deserts.
Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF‐1/IGF‐1R signaling
Authors: Shi Haojun , Fang Winston , Liu Minda , Fu Deliang
Published: June 2017

Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor‐induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin‐like growth factor‐1 (IGF‐1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF‐1‐dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF‐1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF‐1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF‐1/IGF‐1R‐induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF‐1/IGF‐1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies.
Spatial clustering of childhood leukaemia in Switzerland: A nationwide study
Authors: Konstantinoudis Garyfallos , Kreis Christian , Ammann Roland A. , Niggli Felix , Kuehni Claudia E. , Spycher Ben D. ,   for the Swiss Paediatric Oncology Group and the Swiss National Cohort Study Group
Published: June 2017

The aetiology of childhood leukaemia remains largely unknown. Several hypotheses involve environmental exposures that could implicate spatial clustering of cases. The evidence from previous clustering studies is inconclusive. Most of them used areal data and thus had limited spatial resolution. We investigated whether childhood leukaemia tends to cluster in space using exact geocodes of place of residence both at the time of birth or diagnosis. We included 1,871 leukaemia cases diagnosed between 1985 and 2015 at age 0–15 years from the Swiss Childhood Cancer Registry. For each case, we randomly sampled 10 age and sex matched controls from national censuses closest in time. We used the difference ofk‐functions, Cuzick‐Edwards' test and Tango's index for point data to assess spatial clustering and Kulldorff's circular scan to detect clusters. We separately investigated acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), different age groups at diagnosis (0–4, 5–15 years) and adjusted for multiple testing. After adjusting for multiple testing, we found no evidence of spatial clustering of childhood leukaemia neither around time of birth (p = 0.52) nor diagnosis (p = 0.51). Individual tests indicated spatial clustering for leukaemia diagnosed at age 5–15 years,p k‐functions = 0.05 andpCuzick‐Edwards' = 0.04 and a cluster of ALL cases diagnosed at age 0–4 years in a small rural area (p = 0.05). This study provides little evidence of spatial clustering of childhood leukaemia in Switzerland and highlights the importance of accounting for multiple testing in clustering studies.
Effect of extended oral contraception use on the prevalence of fetal trisomy 21 in women aged at least 35 years
Authors: Horányi Dániel , Babay Lilla Éva , Rigó János , Győrffy Balázs , Nagy Gyula R.
Published: June 2017

Objective

To study factors influencing the number of ovulations in reproductive life as risk factors for common trisomies.

Methods

The present observational study examined data from genetic counseling sessions performed at the 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary, between September 1, 2013, and September 1, 2015, and retrieved data on patients of advanced maternal age (≥35 years) who had fetal trisomy 21, 18, or 13 confirmed. Consecutive patients of advanced maternal age with genetic amniocentesis‐confirmed healthy fetal karyotypes were also included as a control group. Medical record details were confirmed through telephone interviews with patients; the estimated ovulation number was calculated and compared among patients, as were factors contributing to the number of ovulations each patient had.

Results

Data from 12 776 genetic counseling situations were examined; 35 patients with fetal trisomies and 100 patients in the control group were interviewed. Shorter mean length of oral contraceptive pill use before trisomic pregnancy (P<0.001) and a lower estimated ovulation number (P=0.012) were identified among patients with pregnancies with fetal trisomies.

Conclusion

Fewer ovulatory cycles, potentially resulting from longer oral contraceptive pill use, was associated with healthy fetal karyotypes among patients of advanced reproductive age.
Use of lecithin to control fiber morphology in electrospun poly (ɛ‐caprolactone) scaffolds for improved tissue engineering applications
Authors: Coverdale Benjamin D.M. , Gough Julie E. , Sampson William W. , Hoyland Judith A.
Published: June 2017

We elucidate the effects of incorporating surfactants into electrospun poly (ɛ‐caprolactone) (PCL) scaffolds on network homogeneity, cellular adherence and osteogenic differentiation. Lecithin was added with a range of concentrations to PCL solutions, which were electrospun to yield functionalized scaffolds. Addition of lecithin yielded a dose‐dependent reduction in scaffold hydrophobicity, whilst reducing fiber width and hence increasing specific surface area. These changes in scaffold morphology were associated with increased cellular attachment of Saos‐2 osteoblasts 3‐h postseeding. Furthermore, cells on scaffolds showed comparable proliferation over 14 days of incubation to TCP controls. Through model‐based interpretation of image analysis combined with gravimetric estimates of porosity, lecithin is shown to reduce scaffold porosity and mean pore size. Additionally, lecithin incorporation is found to reduce fiber curvature, resulting in increased scaffold specific elastic modulus. Low concentrations of lecithin were found to induce upregulation of several genes associated with osteogenesis in primary mesenchymal stem cells. The results demonstrate that functionalization of electrospun PCL scaffolds with lecithin can increase the biocompatibility and regenerative potential of these networks for bone tissue engineering applications. © 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2865–2874, 2017.
Purification and partial characterization of an anticoagulant PLA2 from the venom of Indian Daboia russelii that induces inflammation through upregulation of proinflammatory mediators
Authors: Deka Archana , Sharma Maitreyee , Sharma Manoj , Mukhopadhyay Rupak , Doley Robin
Published: June 2017

The present study describes the purification and partial characterization of a basic anticoagulant PLA2 enzyme named as Rv(i) PLA2 from the venom of Indian Daboia russelii. The molecular mass of the protein was found to be 13,659.65 Da, and peptide mass fingerprinting revealed that it belongs to group II PLA2 family. The peptide sequence showed similarity to uncharacterized basic PLA2 enzyme having an accession no. of P86368 reported from Sri Lankan D. russelii. Rv(i) PLA2 exhibited strong phospholipase A2 and anticoagulant activity. It also induced expression of COX‐2 and TNF‐α mRNA in a dose‐dependent manner in phorbol 12‐myristate 13‐acetate differentiated THP‐1 cells, which play a crucial role during inflammation. Chemical modification of His residue in Rv(i) PLA2 with p‐bromophenacyl bromide abolished the enzymatic, anticoagulant, and inflammatory activities. The result indicates that the catalytic site of Rv(i) PLA2 might play a vital role in inducing inflammation at the bite site during D. russelii envenomation.
Comparison of the CELLEX™ and UVAR‐XTS™ closed‐system extracorporeal photopheresis devices in the treatment of chronic graft‐versus‐host disease
Authors: Whittle Robert M. , Denney Helen , Chantry Andrew D. , Alfred Arun , Taylor Peter C.
Published: June 2017

Extracorporeal Photopheresis (ECP) is a cellular immunotherapy frequently used for steroid‐refractory graft‐versus‐host disease (GVHD). Chronic GVHD (cGVHD), response to ECP is associated with survival benefit. The UVAR‐XTSTM system and the more recently developed CELLEXTM device (both TherakosTM) are the mainstay for ECP‐delivery in the UK and US. No comparison of treatment outcomes has been reported. We retrospectively compared cGVHD response and steroid reduction and withdrawal in patients treated exclusively over 12 months with either the XTS (n = 51) or CELLEX (n = 50). Our hypothesis was that there would be no difference in clinical outcome or steroid changes in the 2 matched cohorts. We also compared infection incidence, infection‐related death (IRD), and treatment time. Significant clinical improvement and regular capacity to reduce or cease steroids was encountered in both cohorts; at 6 months of ECP 70% of cutaneous cGvHD patients had partial or complete responses and 85% of patients receiving steroids pre‐ECP had reduced dosage. In the XTS group we unexpectedly encountered both superior steroid reduction (86% dose at least halved vs. 61% for CELLEX, P = 0.01) and withdrawal (15 vs. 5 CELLEX, P = 0.01) and a trend for superior skin disease response in the CELLEX‐treated cohort at 3 months. No inter‐relationship was evident. Halving or greater reduction of steroid dose by 3 or 6 months was associated with reduced risk of IRD in the XTS cohort as was withdrawal at 6 months for the combined cohorts. By 6 months, XTS‐treated patients had experienced fewer antibiotic‐requiring infections (mean 1.9 vs. 2.8, P = 0.025). Origins for the disparities are unclear and warrant investigation.
Membrane‐based therapeutic plasma exchange (mTPE): Technical and clinical experience
Authors: Gashti Casey N. , Andreoli Daniel C. , Patel Dipal
Published: June 2017

Therapeutic plasma exchange (TPE) has long been utilized to manage a variety of immune‐mediated diseases. The basic principle relies on removal of circulating pathogenic substances from the bloodstream. Methods of plasma separation include centrifuge (cTPE) and membrane (mTPE). Although mTPE has existed for a few decades, recent advances in developing highly permeable filters that are compatible with currently existing dialysis machines has opened a new frontier. Published data in the area of technical and clinical experience with mTPE is lacking. We report our single center experience of 998 inpatient mTPE treatments performed in 237 patients at a large tertiary care academic center. The most common treatment indication was neurologic. We found a very low incidence of patient‐reported complications. Filter clotting without the use of anticoagulation occurred in 7.7% of treatments. Laboratory parameters that significantly changed during the course of therapy included serum potassium, platelet count, and partial thromboplastin time. We found that mTPE can be safely and efficiently performed as an alternative to cTPE, and suggest an individualized approach when prescribing this therapy.
Efficacy and Toxicity of Different Chemotherapy Regimens in the Treatment of Advanced or Metastatic Pancreatic Cancer: A Network Meta‐Analysis
Authors: Liu Gui‐Feng , Li Gui‐Jie , Zhao Hang
Published: June 2017

Objective A network meta‐analysis was conducted to compare the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic pancreatic cancer (PC). PubMed, Cochrane Library and EMBASE databases from inception to June 2016 were searched. A combination of direct and indirect evidences was referred to for calculating the weighted mean difference (WMD) or the odds ratio (OR) and to establish surface under the cumulative ranking (SUCRA) curves, so as to evaluate the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic PC. Twenty randomized controlled trials were enrolled. Twelve chemotherapy regimens included Gemcitabine, S‐1 (Tegafur), Gemcitabine + Cisplatin, Gemcitabine + Capecitabine, Gemcitabine + S‐1, Gemcitabine + 5‐FU (5‐fluorouracil), Gemcitabine + Exatecan, Gemcitabine + Irinotecan, Gemcitabine + Nab‐paclitaxel, FOLFIRINOX (Oxaliplatin + Irinotecan + Fluorouracil + Leucovorin), Gemcitabine + Oxaliplatin, and Gemcitabine + Pemetrexed. Higher overall response rate (ORR) was observed in patients treated with the gemcitabine + S‐1 and FOLFIRINO regimens. Thrombocytopenia reduced in patients treated with the S‐1 regimen. The Gemcitabine + S‐1 and FOLFIRINO regimens had better short‐ and long‐term efficacies than the other regimens; S‐1 regimen had the lowest hematologic toxicity, while Gemcitabine + Nab‐paclitaxel, FOLFIRINOX, and Gemcitabine + Pemetrexed regimens had higher incidence of non‐hematologic toxicity among twelve chemotherapy regimens. The efficacy of Gemcitabine + S‐1 and FOLFIRINOX regimens may be better in treating patients with advanced or metastatic pancreatic cancer, while FOLFIRINOX and Gemcitabine + Pemetrexed regimens may have relatively higher incidence of toxicity than other regimens. J. Cell. Biochem. 119: 511–523, 2018. © 2017 Wiley Periodicals, Inc.
Angiogenic and Restorative Abilities of Human Mesenchymal Stem Cells Were Reduced Following Treatment With Serum From Diabetes Mellitus Type 2 Patients
Authors: Rezaie Jafar , Mehranjani Malek S. , Rahbarghazi Reza , Shariatzadeh Mohammad A.
Published: June 2017

This experiment investigated the impact of serum from patients with type 2 diabetes mellitus on the angiogenic behavior of human mesenchymal stem cells in vitro. Changes in the level of Ang‐1, Ang‐2, cell migration, and trans‐differentiation into pericytes and endothelial lineage were monitored after 7 days. The interaction of mesenchymal stem cells with endothelial cells were evaluated using surface plasmon resonance technique. Paracrine restorative effect of diabetic stem cells was tested on pancreatic β cells. Compared to data from FBS and normal serum, diabetic serum reduced the stem cell survival and chemotaxis toward VEGF and SDF‐1α (P < 0.05). Diabetic condition were found to decline cell migration rate and the activity of MMP‐2 and ‐9 (P < 0.05). The down‐regulation of VEGFR‐2 and CXCR‐4 was observed with an increase in the level of miR‐1‐3p and miR‐15b‐5p at the same time. The paracrine angiogenic potential of diabetic stem cells was disturbed via the changes in the dynamic of Ang‐1, Ang‐2, and VEGF. Surface plasmon resonance analysis showed that diabetes could induce an aberrant increase in the interaction of stem cells with endothelial cells. After treatment with diabetic serum, the expression of VE‐cadherin and NG2 and ability for uptake of Dil‐Ac‐LDL were reduced (P < 0.01). Conditioned media prepared from diabetic stem cells were unable to decrease fatty acid accumulation in β‐cells (P < 0.05). The level of insulin secreted by β‐cells was not affected after exposure to supernatant from diabetic or non‐diabetic mesenchymal stem cells. Data suggest diabetes could decrease angiogenic and restorative effect of stem cells in vitro. J. Cell. Biochem. 119: 524–535, 2018. © 2017 Wiley Periodicals, Inc.
Retracted: The Role of MicroRNA‐143‐5p in the Differentiation of Dental Pulp Stem Cells into Odontoblasts by Targeting Runx2 via the OPG/RANKL Signaling Pathway
Authors: Zhan Fu‐Liang , Liu Xin‐Yang , Wang Xing‐Bo
Published: June 2017

This study aims to elucidate the mechanisms by which microRNA‐143‐5p (miR‐143‐5p) targets runt‐related transcription factor 2 (Runx2) in the differentiation of dental pulp stem cells (DPSCs) into odontoblasts, through regulating the osteoprotegerin receptor activator of the nuclear factor‐κB ligand (OPG/RANKL) signaling pathway. Following transfection, DPSCs were divided into blank, control, miR‐143‐5p mimics, miR‐143‐5p inhibitors, miR‐143‐5p inhibitors + siRunx2 and siRunx2 groups. Alkaline phosphatase (ALP) activity and mineralized nodules were detected using ALP kit and alizarin red staining. Quantitative reverse transcriptase real time PCR (qRT‐PCR) was conducted to measure mRNA expressions of miR‐143‐5p, Runx2, OPG, and RANKL. Western blotting was used to assess protein expression of odontoblast differentiation‐related proteins. Transwell assay and an extracellular matrix (ECM) adhesion cell assay were employed to examine cell migration and cell adhesion. Compared with the blank group, the miR‐143‐5p mimics and siRunx2 groups showed decreased ALP activity, decreased mineralized nodules and displays of calcium. Fewer migrated cells, weakened cell adhesion, decreased protein expression of dentin phosphoprotein (DPP), dentin sialoprotein (DSP), dentin matrix protein 1 (DMP1), osteopontin (OPN), bone sialoprotein (BSP), osteocalcin (OCN), OPG and Runx2, and increased RANKL protein expressions were observed. Additionally, opposite results were observed in the miR‐143‐5p inhibitors group, demonstrating that down‐regulated miR‐143‐5p promotes the differentiation of DPSCs into odontoblasts by enhancing Runx2 expression via the OPG/RANKL signaling pathway. Based on findings in this study, it is postulated that the enhancement of Runx2 expression via the regulation of the OPG/RANKL signaling pathway could be a beneficial approach for dental pulp regeneration. J. Cell. Biochem. 119: 536–546, 2018. © 2017 Wiley Periodicals, Inc.
CDK9 Regulates Apoptosis of Myoblast Cells by Modulation of microRNA‐1 Expression
Authors: Tarhriz Vahideh , Wagner Kay‐Dietrich , Masoumi Zahra , Molavi Ommoleila , Hejazi Mohammad Saeid , Ghanbarian Hossein
Published: June 2017

Cdk9 is the catalytic core of the positive transcription elongation factor b (P‐TEFb) and regulates transcriptional elongation factors by phosphorylation of RNA pol II. Apart from its role on myogenic gene expression, Cdk9 regulation of muscle‐specific microRNAs in the early stage of cardiomyogenesis is poorly understood. Here we demonstrate that Cdk9 not only regulates myogenic transcription factors, but also controls muscle‐specific microRNAs. During cardiac differentiation of mouse embryonic stem cells, high Cdk9 expression preceded up‐regulation of miR‐1. To investigate potential regulatory roles of Cdk9 on cardiac microRNAs and myogenesis genes, we overexpressed Cdk9 in myoblast C2C12 cells, which resulted in significant induction of miR‐1 and miR‐206, while miR‐133 was downregulated. Moreover, expression levels of MyoD and Srf, key regulators of myogenesis, also increased in cells with overexpression of Cdk9. We further observed Cdk9‐mediated apoptosis in C2C12 cells corresponding to induction of miR‐1 expression levels. Thus, Cdk9 plays a complex role in myocyte progenitor differentiation and apoptosis by regulating myogenic protein and muscle‐specific microRNA expression. J. Cell. Biochem. 119: 547–554, 2018. © 2017 Wiley Periodicals, Inc.
Lipoprotein(a): A missing culprit in the management of athero‐thrombosis?
Authors: Ferretti Gianna , Bacchetti Tiziana , Johnston Thomas P. , Banach Maciej , Pirro Matteo , Sahebkar Amirhossein
Published: June 2017

Lipoprotein(a) Lp(a) is a cholesterol‐rich, LDL‐like particle that is independently associated with an increased risk for ischemic heart disease, atherosclerosis, thrombosis, and stroke. Genetic variation in the Lp(a) locus and some other genes related to Lp(a) synthesis and metabolism play a critical role in regulating plasma Lp(a) levels. The pathophysiological potential of Lp(a) is related to proatherogenic and prothrombotic effects on the vasculature. Different molecular mechanisms underlying the atherothrombotic potential of Lp(a), free apolipoprotein(a), and oxidized‐Lp(a) have been proposed. However, plasma Lp(a) assay is complicated by problems associated with quantification and standardization owing to the polymorphic nature of this lipoprotein. This review has focused on the physicochemical properties of Lp(a), the genetic aspects of Lp(a), the need for accurate determination of Lp(a), the synthesis, and recent findings on metabolism of Lp(a). Lastly, the patho‐physiological mechanisms by which Lp(a) may increase athero‐thrombosis and an overview on the therapeutic modalities to interfere with Lp(a) are summarized.
A randomized clinical trial investigating the efficacy of targeted nutrition as adjunct to exercise training in COPD
Authors: van de Bool Coby , Rutten Erica P.A. , van Helvoort Ardy , Franssen Frits M.E. , Wouters Emiel F.M. , Schols Annemie M.W.J.
Published: June 2017

Background

Evidence regarding the efficacy of nutritional supplementation to enhance exercise training responses in COPD patients with low muscle mass is limited.

The objective was to study if nutritional supplementation targeting muscle derangements enhances outcome of exercise training in COPD patients with low muscle mass.

Methods

Eighty‐one COPD patients with low muscle mass, admitted to out‐patient pulmonary rehabilitation, randomly received oral nutritional supplementation, enriched with leucine, vitamin D, and omega‐3 fatty acids (NUTRITION) or PLACEBO as adjunct to 4 months supervised high intensity exercise training.

Results

The study population (51% males, aged 43–80) showed moderate airflow limitation, low diffusion capacity, normal protein intake, low plasma vitamin D, and docosahexaenoic acid. Intention‐to‐treat analysis revealed significant differences after 4 months favouring NUTRITION for body mass (mean difference ± SEM) (+1.5 ± 0.6 kg, P = 0.01), plasma vitamin D (+24%, P = 0.004), eicosapentaenoic acid (+91%,P < 0.001), docosahexaenoic acid (+31%, P < 0.001), and steps/day (+24%, P = 0.048). After 4 months, both groups improved skeletal muscle mass (+0.4 ± 0.1 kg, P < 0.001), quadriceps muscle strength (+12.3 ± 2.3 Nm,P < 0.001), and cycle endurance time (+191.4 ± 34.3 s, P < 0.001). Inspiratory muscle strength only improved in NUTRITION (+0.5 ± 0.1 kPa, P = 0.001) and steps/day declined in PLACEBO (−18%,P = 0.005).

Conclusions

High intensity exercise training is effective in improving lower limb muscle strength and exercise performance in COPD patients with low muscle mass and moderate airflow obstruction. Specific nutritional supplementation had additional effects on nutritional status, inspiratory muscle strength, and physical activity compared with placebo.
Smallest graphs with given generalized quaternion automorphism group
Authors: Graves Christina , Graves Stephen J. , Lauderdale L.‐K.
Published: June 2017

For , a smallest graph whose automorphism group is isomorphic to the generalized quaternion group is constructed. If , then such a graph has vertices and edges. In the special case when , a smallest graph has 16 vertices but 44 edges.
Syntheses of Symmetric and Unsymmetric Bis‐imidazole Derivatives Using Phase‐Transfer Catalysis
Authors: Zhang Kun‐Peng , Jin Tian‐Qi , Zhou Jun‐Qiang , Ma Ting‐Ting , Jin Chuan‐Ming
Published: June 2017

A convenient method for the preparation of symmetric and unsymmetric bisimidazole derivatives was established. The symmetric bisimidazolylmethane derivatives 1a–9a was prepared with 2‐substituted imidazole derivatives 1–9 as reaction materials. However, the symmetric and unsymmetric bisimidazolylmethane derivatives 10a–12a and 10b–12b was obtained, respectively. With 4‐position with the azo‐groups imidazole derivatives 10–12 were used as reaction materials. All these compounds have been structurally characterized by the NMR, ESI‐MS, and EA. And 8a and 12a were also characterized by the X‐ray single crystal diffusion.
Cantharidin inhibits competitively heme‐Fe(III) binding to the FA1 site of human serum albumin
Authors: Polticelli Fabio , Leboffe Loris , Tortosa Valentina , Trezza Viviana , Fanali Gabriella , Fasano Mauro , Ascenzi Paolo
Published: June 2017

Cantharidin, a monoterpene isolated from the insect blister beetle, has long been used as a medicinal agent in the traditional Chinese medicine. Cantharidin inhibits a subgroup of serine/threonine phosphatases, thus inducing cell growth inhibition and cytotoxicity. Cantharidin has anticancer activity in vitro, since it is able of inducing p53‐dependent apoptosis and double‐strand breakage of DNA in cancer cells. Although the toxicity of cantharidin to the gastrointestinal and urinary tracts prevents its medical use, it is a promising lead compound for chemical modification to develop new anticancer therapeutics. In fact, cantharidin does not cause myelosuppression and displays anticancer activity against cells with a multidrug resistance phenotype. Here, the competitive inhibitory effect of cantharidin on heme‐Fe(III) binding to the fatty acid site 1 (FA1) of human serum albumin (HSA) is reported. Docking and molecular dynamics simulations support functional data indicating the preferential binding of cantharidin to the FA1 site of HSA. Present results may be relevant in vivo as HSA could transport cantharidin, which in turn could affect heme‐Fe(III) scavenging by HSA.
Computational modeling of the bat HKU4 coronavirus 3CLpro inhibitors as a tool for the development of antivirals against the emerging Middle East respiratory syndrome (MERS) coronavirus
Authors: Abuhammad Areej , Al‐Aqtash Rua'a A. , Anson Brandon J. , Mesecar Andrew D. , Taha Mutasem O.
Published: June 2017

The Middle East respiratory syndrome coronavirus (MERS‐CoV) is an emerging virus that poses a major challenge to clinical management.

The 3C‐like protease (3CLpro) is essential for viral replication and thus represents a potential target for antiviral drug development. Presently, very few data are available on MERS‐CoV 3CLpro inhibition by small molecules. We conducted extensive exploration of the pharmacophoric space of a recently identified set of peptidomimetic inhibitors of the bat HKU4‐CoV 3CLpro. HKU4‐CoV 3CLpro shares high sequence identity (81%) with the MERS‐CoV enzyme and thus represents a potential surrogate model for anti‐MERS drug discovery. We used 2 well‐established methods: Quantitative structure‐activity relationship (QSAR)‐guided modeling and docking‐based comparative intermolecular contacts analysis. The established pharmacophore models highlight structural features needed for ligand recognition and revealed important binding‐pocket regions involved in 3CLpro‐ligand interactions. The best models were used as 3D queries to screen the National Cancer Institute database for novel nonpeptidomimetic 3CLpro inhibitors. The identified hits were tested for HKU4‐CoV and MERS‐CoV 3CLpro inhibition. Two hits, which share the phenylsulfonamide fragment, showed moderate inhibitory activity against the MERS‐CoV 3CLpro and represent a potential starting point for the development of novel anti‐MERS agents. To the best of our knowledge, this is the first pharmacophore modeling study supported by in vitro validation on the MERS‐CoV 3CLpro.

Highlights

MERS‐CoV is an emerging virus that is closely related to the bat HKU4‐CoV.

3CLpro is a potential drug target for coronavirus infection.

HKU4‐CoV 3CLpro is a useful surrogate model for the identification of MERS‐CoV 3CLpro enzyme inhibitors.

dbCICA is a very robust modeling method for hit identification.

The phenylsulfonamide scaffold represents a potential starting point for MERS coronavirus 3CLpro inhibitors development.
Molecular basis for the recognition of CCN1 by monoclonal antibody 093G9
Authors: Zhong Chen , Huo Rongfen , Hu Kuan , Shen Jinlong , Li Dangsheng , Li Ningli , Ding Jianping
Published: June 2017

CCN1, also named Cyr61 (cysteine‐rich protein 61), is the first identified member of the CCN family that is composed of 6 secreted extracellular matrix‐associated glycoproteins. CCN1 has been demonstrated to participate in pathogenesis of rheumatoid arthritis through various pathways. A monoclonal antibody, namely, 093G9, is effective to antagonize the effects of CCN1 and hence has potential therapeutic benefits against rheumatoid arthritis. Here, we show that the epitope recognized by 093G9 is mapped to residues 77 to 80 of CCN1, and a cyclic peptide encompassing residues 75 to 81 of CCN1 displays high binding affinity for 093G9. The crystal structure of the 093G9 Fab in complex with the cyclic peptide was determined at 2.7 Å resolution, which reveals the intensive interactions between CCN1 and 093G9. Particularly, residues Asn79 and Phe80 of CCN1 are inserted into cavities mainly formed by residues of complementarity‐determining region loop L3 and framework region L2 and by residues of complementarity‐determining region loops H2 and H3, respectively, which contribute most of the interactions and therefore are critical for the recognition by 093G9. Together, these findings not only identify the epitope of CCN1 for 093G9 but also reveal the molecular mechanism of recognition and binding of CCN1 by 093G9.
Experimental and computational characterization on the binding of two fluoroquinolones to bovine hemoglobin
Authors: Qin Pengfei , Pan Xingren , Liu Rutao , Qiu Jicai , Fang Xiaoyan
Published: June 2017

Ciprofloxacin (CPFX) and enrofloxacin (ENFX) are 2 representatives of widely used fluoroquinolones (FQs) with many human and veterinary applications. The residues of FQs in the environment are potentially harmful. Recently, great concern has been paid to their persistence and fate in the environment because of the potential adverse effects on humans and ecosystem functions. In the present study, we examined the interactions of bovine hemoglobin (BHb) with these 2 FQs by means of multiple spectroscopic and molecular docking methods under physiological conditions. The experimental results revealed that both FQs could bind with BHb to form complexes mainly through electrostatic interactions. And CPFX posed more of an affinity threat to BHb than ENFX. On the basis of molecular docking, both FQs could bind into the central cavity of BHb and interact with the residue Trp 37, resulting in the remarkable fluorescence quenching of protein. Additionally, as shown by the synchronous fluorescence, UV‐visible absorption and circular dichroism data, both CPFX and ENFX could lead to the conformational and microenvironmental changes of BHb, which may affect its physiological functions. The work is beneficial for understanding the biological toxicity of FQs in vivo.
Tailoring the volatility and stability of oligopeptides
Authors: Schätti J. , Sezer U. , Pedalino S. , Cotter J. P. , Arndt M. , Mayor M. , Köhler V.
Published: June 2017

Amino acids are essential building blocks of life, and fluorinated derivatives have gained interest in chemistry and medicine. Modern mass spectrometry has enabled the study of oligo‐ and polypeptides as isolated entities in the gas phase, but predominantly as singly or even multiply charged species. While laser desorption of neutral peptides into adiabatically expanding supersonic noble gas jets is possible, UV–VIS spectroscopy, electric or magnetic deflectometry as well as quantum interferometry would profit from the possibility to prepare thermally slow molecular beams. This has typically been precluded by the fragility of the peptide bond and the fact that a peptide would rather ‘fry’, i.e. denature and fragment than ‘fly’. Here, we explore how tailored perfluoroalkyl functionalization can reduce the intermolecular binding and thus increase the volatility of peptides and compare it to previously explored methylation, acylation and amidation of peptides. We show that this strategy is essential and enables the formation of thermal beams of intact neutral tripeptides, whereas only fragments were observed for an extensively fluoroalkyl‐decorated nonapeptide. © 2017 The Authors. Journal of Mass Spectrometry Published by John Wiley & Sons Ltd.
Influence of universal HBV vaccination on chronic HBV infection in Italy: Results of a cross‐sectional multicenter study
Authors: Sagnelli Evangelista , Stroffolini Tommaso , Sagnelli Caterina , Morisco Filomena , Coppola Nicola , Smedile Antonina , Pisaturo Mariantonietta , Colloredo Guido , Babudieri Sergio , Licata Anna , Brancaccio Giuseppina , Andriulli Angelo , Almasio Piero L. , Gaeta Giovani B. ,   on behalf of the EPACRON study group
Published: June 2017

Background and Aim

The universal hepatitis B vaccination for infants and 12‐year‐old adolescents (the latter limited to the first 12 years of application) was launched in Italy in 1991. Twenty‐three years later we evaluated the impact of the vaccination campaign on the burden of HBsAg‐positive chronic liver diseases (CLD).

Material and Methods

A total of 513 HBsAg‐positive chronic carriers referring to 16 Italian liver units were investigated and compared with HBsAg carriers enrolled in previous surveys.

Results

The proportion of inactive carriers decreased from 20.0% in 2001 to 3.3% in 2014, while that of cirrhotic patients increased from 22.6% to 33.2%. Regarding the age class 0‐33 (fully covered by HBV vaccination in 2014), the rate of inactive carriers decreased from the 21.7% in 2001 to 5.9% in 2014, that of chronic hepatitis from 17.5% to 5.2% and that of cirrhosis cases from 26.4% to 4.1%. Instead, in the over‐60 age group the rate of inactive carriers increased from 22.8% to 41.2% and that of chronic hepatitis from 16.8% to 46%; the rate of patients with cirrhosis ranged from 5% to 8% in different studies.

Conclusion

Twenty‐three years after the introduction universal HBV vaccination in Italy, the clinical presentation of CLD had shown a shift toward older ages and more severe diseases.
Diffusion MRI and the detection of alterations following traumatic brain injury
Authors: Hutchinson Elizabeth B. , Schwerin Susan C. , Avram Alexandru V. , Juliano Sharon L. , Pierpaoli Carlo
Published: June 2017

This article provides a review of brain tissue alterations that may be detectable using diffusion magnetic resonance imaging MRI (dMRI) approaches and an overview and perspective on the modern dMRI toolkits for characterizing alterations that follow traumatic brain injury (TBI). Noninvasive imaging is a cornerstone of clinical treatment of TBI and has become increasingly used for preclinical and basic research studies. In particular, quantitative MRI methods have the potential to distinguish and evaluate the complex collection of neurobiological responses to TBI arising from pathology, neuroprotection, and recovery. dMRI provides unique information about the physical environment in tissue and can be used to probe physiological, architectural, and microstructural features. Although well‐established approaches such as diffusion tensor imaging are known to be highly sensitive to changes in the tissue environment, more advanced dMRI techniques have been developed that may offer increased specificity or new information for describing abnormalities. These tools are promising, but incompletely understood in the context of TBI. Furthermore, model dependencies and relative limitations may impact the implementation of these approaches and the interpretation of abnormalities in their metrics. The objective of this paper is to present a basic review and comparison across dMRI methods as they pertain to the detection of the most commonly observed tissue and cellular alterations following TBI.
The loss of a fellow service member: Complicated grief in post‐9/11 service members and veterans with combat‐related posttraumatic stress disorder
Authors: Simon Naomi M. , O'Day Emily B. , Hellberg Samantha N. , Hoeppner Susanne S. , Charney Meredith E. , Robinaugh Donald J. , Bui Eric , Goetter Elizabeth M. , Baker Amanda W. , Rogers Andrew H. , Nadal‐Vicens Mireya , Venners Margaret R. , Kim Hyungjin M. , Rauch Sheila A.M.
Published: June 2017

Bereavement is a potent and highly prevalent stressor among service members and veterans. However, the psychological consequences of bereavement, including complicated grief (CG), have been minimally examined. Loss was assessed in 204 post‐9/11, when service members and veterans with combat‐related posttraumatic stress disorder (PTSD) took part in a multicenter treatment study. Those who reported the loss of an important person completed the inventory of complicated grief (ICG; n = 160). Over three quarters (79.41%) of the sample reported an important lifetime loss, with close to half (47.06%) reporting the loss of a fellow service member (FSM). The prevalence of CG was 24.75% overall, and nearly one third (31.25%) among the bereaved. CG was more prevalent among veterans who lost a fellow service member (FSM) (41.05%, n = 39) compared to those bereaved who did not (16.92%, n = 11; OR = 3.41, 95% CI: 1.59, 7.36). CG was associated with significantly greater PTSD severity, functional impairment, trauma‐related guilt, and lifetime suicide attempts. Complicated grief was prevalent and associated with adverse psychosocial outcomes in veterans and service members with combat‐related PTSD. Clinicians working with this population should inquire about bereavement, including loss of a FSM, and screen for CG. Additional research examining CG in this population is needed.
Resolving the contributions of anaesthesia, surgery, and nerve injury on brain derived neurotrophic factor expression in the medial prefrontal cortex of male rats in the CCI model of neuropathic pain
Authors: Kang James W.M. , Keay Kevin A. , Mor David
Published: June 2017

The medial prefrontal cortex (mPFC) is critical for selecting and shaping complex behavioral responses. In rodent models of neuropathic pain there is evidence for both structural and functional changes in the mPFC. Brain derived neurotrophic factor (BDNF) plays a critical role in the normal functioning of the mPFC. It has been suggested that the disruption of complex behaviors and mood seen in some neuropathic pain patients is mediated in part by alterations of BDNF in this cortical region. In Sprague‐Dawley rats, mPFC levels of BDNF and TrkB mRNA and protein, were quantified and compared to controls (n = 24) 6 days after either: (a) halothane (1.5%) anaesthesia (n = 12), (b) sham surgery under halothane (n = 12), (c) sciatic nerve chronic constriction injury under halothane (n = 48). The social behaviors of the rats were quantified daily during the experimental period. Halothane anaesthesia increased BDNF and TrkB mRNA bilaterally. These increases were reversed in rats that underwent sham surgical and nerve injury procedures. Further, halothane anaesthesia, surgical procedures, and nerve injury each decreased BDNF protein levels. These results reveal a marked and distinct BDNF expression profile in the mPFC of rats that have undergone each stage of the procedure to produce neuropathic pain by chronic constriction injury of the sciatic nerve. The highly sensitive nature of neurotrophic signalling to general anaesthesia in the mature neuronal circuit of the adult rat brain highlights the importance of careful evaluation and interpretation of data evaluating the effects of experimental procedures on neural substrates.
Acute glucose and lactate metabolism are associated with cognitive recovery following traumatic brain injury
Authors: Mannino Christina , Glenn Thomas C. , Hovda David A. , Vespa Paul M. , McArthur David L. , Van Horn John D. , Wright Matthew J.
Published: June 2017

Traumatic brain injury (TBI) is associated with acute cerebral metabolic crisis (ACMC). ACMC‐related atrophy appears to be prominent in frontal and temporal lobes following moderate‐to‐severe TBI. This atrophy is correlated with poorer cognitive outcomes in TBI. The current study investigated ability of acute glucose and lactate metabolism to predict long‐term recovery of frontal‐temporal cognitive function in participants with moderate‐to‐severe TBI. Cerebral metabolic rate of glucose and lactate were measured by the Kety‐Schmidt method on days 0–7 post‐injury. Indices of frontal‐temporal cognitive processing were calculated for six months post‐injury; 12 months post‐injury; and recovery (the difference between the six‐ and 12‐month scores). Glucose and lactate metabolism were included in separate regression models, as they were highly intercorrelated. Also, glucose and lactate values were centered and averaged and included in a final regression model. Models for the prediction frontal‐temporal cognition at six and 12 months post‐injury were not significant. However, average glucose and lactate metabolism predicted recovery of frontal‐temporal cognition, accounting for 23% and 22% of the variance, respectively. Also, maximum glucose metabolism, but not maximum lactate metabolism, was an inverse predictor in the recovery of frontal‐temporal cognition, accounting for 23% of the variance. Finally, the average of glucose and lactate metabolism predicted frontal‐temporal cognitive recovery, accounting for 22% of the variance. These data indicate that acute glucose and lactate metabolism both support cognitive recovery from TBI. Also, our data suggest that control of endogenous fuels and/or supplementation with exogenous fuels may have therapeutic potential for cognitive recovery from TBI.
Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat
Authors: Han Xiaowen , Min Mengjun , Wang Juan , Bao Zejun , Fan Hongbin , Li Xinyu , Adelusi Temitope Isaac , Zhou Xueyan , Yin Xiaoxing
Published: June 2017

Diabetic encephalopathy (DE), one of the most prevalent chronic complications of diabetes mellitus, is short of effective prevention and formidable therapeutic strategies. The aim of the present study is to reveal the imbalance of tryptophan (Trp) and its metabolites in streptozotocin (STZ)‐induced experimental DE rats to underscore their critical values in clinical diagnosis of the disease. For this purpose, we first developed an accurate and appropriate simultaneous method for measuring Trp and its metabolites using liquid chromatography–tandem mass spectrometry, which was in accordance with the requirements of biological sample analysis. Secondly, a single STZ intraperitoneal injection was administered to male Sprague–Dawley rats, and their cognitive function was detected by Morris water maze tests. Cerebrospinal fluid (CSF), serum, and brain tissue were then collected for the determination of Trp and its metabolites. Compared with age‐matched control rats, the levels of neuroprotective serotonin decreased significantly in the samples of cortices, hippocampi, striatum, CSF, and serums in the STZ‐induced DE rats, while the levels of neurotoxic 3‐hydroxykynurenine increased significantly. Moreover, analogous changes of both compounds were found in the central nervous system and peripheral blood of the STZ‐induced DE rats. In conclusion, we established a quantitative method for the simultaneous detection of Trp and its metabolites, and we also present a critical elucidation of the nervous system dysfunction in DE.