C-3 Benzoic Acid Derivatives of C-3 Deoxybetulinic Acid and Deoxybetulin as HIV-1 Maturation Inhibitors

Publication date: Available online 2 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Zheng Liu, Jacob J. Swidorski, Beata Nowicka-Sans, Brian Terry, Tricia Protack, Zeyu Lin, Himadri Samanta, Sharon Zhang, Zhufang Li, Dawn D. Parker, Sandhya Rahematpura, Susan Jenkins, Brett R. Beno, Mark Krystal, Nicholas A. Meanwell, Ira B. Dicker, Alicia Regueiro-Ren
A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50 = 16 nM for 9a compared to 10 nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2^nd generation MI.

Graphical abstract

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In vivo phase II-enzymes inducers, as potential chemopreventive agents, based on the chalcone and furoxan skeletons

Publication date: Available online 2 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Mauricio Cabrera, Ignacio Mastandrea, Gabriel Otero, Hugo Cerecetto, Mercedes González
Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 S. typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes.

Graphical abstract

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Design, Synthesis of Phenstatin/isocombretastatin-Oxindole Conjugates as Antimitotic agents

Publication date: Available online 3 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): G. Bharath Kumar, V. Lakshma Nayak, Ibrahim Bin Sayeed, Vangala Santhosh Reddy, Anver Basha Shaik, Mirza Feroz Baig, Mohd Adil Shareef, A. Ravikumar, Rasala Mahesh, Ahmed Kamal
A series of phenstatin/isocombretasatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049-38.90 μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 μM and 1.01 μM respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin

Graphical abstract

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Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors

Publication date: Available online 3 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Rui Chen, Jie Xiao, Yong Ni, Han-Fei Xu, Min Zheng, Xu Tong, Tong-Tian Zhang, Chenzhong Liao, Wen-Jian Tang
Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a ∼ 3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50 = 221 nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50 = 321 nM), which is a commercial selective hMAO-B inhibitor used to Parkinson's disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors.

Graphical abstract

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Synthesis, and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Publication date: Available online 3 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Wufu Zhu, Wenhui Wang, Shan Xu, Jianqiang Wang, Qidong Tang, Chunjiang Wu, Yanfang Zhao, Pengwu Zheng
Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a–e, 15a–g, 16a–e and 17a–g) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a–b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit μM to nanomole range. Eleven of them are equal to or more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC50 values of 0.14±0.08 μM, 0.24±0.07 μM and 0.02±0.01 μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What's more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.

Graphical abstract

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Discovery of novel N,N-3-phenyl-3-benzylaminopropionanilides as potent inhibitors of cholesteryl ester transfer protein in vivo

Publication date: Available online 2 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Honglei Xie, Yiqun Li, Changlin Bai, Ruifeng Wang, Chunchi Liu, Chenzhou Hao, Bin Lin, Maosheng Cheng, Dongmei Zhao
Epidemiological studies have identified that the risk of cardiovascular events increases due to the decreased levels of high density lipoprotein-cholesterol and the elevated levels of low density lipoprotein-cholesterol. Herein, we report a novel series of N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which were identified as potent cholesteryl ester transfer protein (CETP) inhibitor. The initial lead compound L10 (IC50 8.06 μM) was found by pharmacophore-based virtual screening (Dong-Mei Zhao et al, Chin. Chem. Lett, 25, 299). After systematic structure variation and biological testing against CETP, two different series were identified as scaffolds for potent CETP inhibitors. One is N,N-3-phenyl-3-benzylaminopropanamide derivatives, which were investigated in our previous paper (Bioorganic & Medicinal Chemistry (2015), in press, doi: 10.1016/j.bmc.2015.12.010). The most potent compound HL16 in that series has the IC50 of 0.69 μM. The other series is N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which was investigated in current study. Further optimization of the structure-activity relationship (SAR) resulted in H16 (IC50 0.15 μM), which was discovered as a potent CETP inhibitor in vitro by BODIPY-CE fluorescence assay. In addition, the results of pharmacodynamics studies showed that H16 exhibited both favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. It also has an excellentstabilityin ratliver microsomal.

Graphical abstract

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Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations

Publication date: Available online 2 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Sofia Vasilakaki, Efrosini Barbayianni, Georgios Leonis, Manthos G. Papadopoulos, Thomas Mavromoustakos, Michael H. Gelb, George Kokotos
Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50 = 143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.

Graphical abstract

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Novel indole-based melatonin analogues: Evaluation of antioxidant activity and protective effect against amyloid β-induced damage

Publication date: Available online 2 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Hande Gurer-Orhan, Cigdem Karaaslan, Senem Ozcan, Omidreza Firuzi, Marjan Tavakkoli, Luciano Saso, Sibel Suzen
Oxidative stress has been recognized as a contributing factor in aging and various diseases including cancer and neuropathological disorders. Indole derivatives such as the neurohormone melatonin (MLT) constitute an important class of therapeutic agent in medicinal chemistry. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. As a part of our ongoing studies, a series of new indole-based hydrazide/hydrazone derivatives were synthesized as MLT analogues. Their antioxidant activity was investigated in human erythrocytes by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Possible inherent cytotoxicity of the compounds was investigated in CHO-K1 cells by lactate dehydrogenase leakage test. Protection of neuronal PC12 cells against amyloid β-induced damage was examined by MTT assay and their ability in reduction of ROS generation induced by amyloid β was tested. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any membrane-damaging effect. Moreover, derivatives having o-halogenated and dihalogenated aromatic side chain significantly protected neuronal cells at concentrations of 10 and 100 μM. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant and neuroprotective agents.

Graphical abstract

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Trimethoprim–Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess

Between 1993 and 2005, annual emergency department visits for skin and soft-tissue infections in the United States increased from 1.2 million to 3.4 million, primarily because of an increased incidence of abscesses. During this period, community-associated methicillin-resistant Staphylococcus…

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Declines in Unintended Pregnancy in the United States, 2008–2011

The rate of unintended pregnancy in a population is a central measure of reproductive health; it indicates the extent to which women and couples can determine freely whether and when they have children. In addition to supporting individual autonomy, there is also a clear public health justification…

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Randomized Trial of Labor Induction in Women 35 Years of Age or Older

The average age of women at childbirth in industrialized nations has been increasing steadily for approximately 30 years. Between 1996 and 2006, births to women 35 years of age or older in the United Kingdom increased from 12% to 20% of all births. In 2006, a total of 5.6% of live births in the…

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Changes in knee kinematics following total knee arthroplasty

Total knee arthroplasty (TKA) changes the knee joint in both intentional and unintentional, known and unknown, ways. Patellofemoral and tibiofemoral kinematics play an important role in postoperative pain, function, satisfaction and revision, yet are largely unknown. Preoperative kinematics, postoperative kinematics or changes in kinematics may help identify causes of poor clinical outcome. Patellofemoral kinematics are challenging to record since the patella is obscured by the metal femoral component in X-ray and moves under the skin. The purpose of this study was to determine the kinematic degrees of freedom having significant changes and to evaluate the variability in individual changes to allow future study of patients with poor clinical outcomes. We prospectively studied the 6 degrees of freedom patellofemoral and tibiofemoral weightbearing kinematics, tibiofemoral contact points and helical axes of rotation of nine subjects before and at least 1 year after total knee arthroplasty using clinically available computed tomography and radiographic imaging systems. Normal kinematics for healthy individuals were identified from the literature. Significant differences existed between pre–TKA and post–TKA kinematics, with the post-TKA kinematics being closer to normal. While on average the pre–total knee arthroplasty knees in this group displayed no pivoting (only translation), individually only five knees displayed this behaviour (of these, two showed lateral pivoting, one showed medial pivoting and one showed central pivoting). There was considerable variability postoperatively as well (five central, two lateral and two medial pivoting). Both preop and postop, flexion behaviour was more hinge-like medially and more rolling laterally. Helical axes were more consistent postop for this group. An inclusive understanding of the pre–TKA and post–TKA kinematics and changes in kinematics due to total knee arthroplasty could improve implant design, patient diagnosis and surgical technique.

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Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

Introduction

Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy.

Methods and analysis

Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years.

The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples.

Ethics and dissemination

The study will be conducted under International Conference on Harmonisation – Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications.

Trial registration number

NCT02040441; Pre-results.

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Lay support for pregnant women with social risk: a randomised controlled trial

Objectives

We sought evidence of effectiveness of lay support to improve maternal and child outcomes in disadvantaged families.

Design

Prospective, pragmatic, individually randomised controlled trial.

Setting

3 Maternity Trusts in West Midlands, UK.

Participants

Following routine midwife systematic assessment of social risk factors, 1324 nulliparous women were assigned, using telephone randomisation, to standard maternity care, or addition of referral to a Pregnancy Outreach Worker (POW) service. Those under 16 years and teenagers recruited to the Family Nurse Partnership trial were excluded.

Interventions

POWs were trained to provide individual support and case management for the women including home visiting from randomisation to 6 weeks after birth. Standard maternity care (control) included provision for referring women with social risk factors to specialist midwifery services, available to both arms.

Main outcome measures

Primary outcomes were antenatal visits attended and Edinburgh Postnatal Depression Scale (EPDS) 8–12 weeks postpartum. Prespecified, powered, subgroup comparison was among women with 2 or more social risks. Secondary outcomes included maternal and neonatal birth outcomes; maternal self-efficacy, and mother-to-infant bonding at 8–12 weeks; child development assessment at 6 weeks, breastfeeding at 6 weeks, and immunisation uptake at 4 months, all collected from routine child health systems.

Results

Antenatal attendances were high in the standard care control and did not increase further with addition of the POW intervention (10.1 vs 10.1 (mean difference; MD) –0.00, 95% CI (95% CI –0.37 to 0.37)). In the powered subgroup of women with 2 or more social risk factors, mean EPDS (MD –0.79 (95% CI –1.56 to –0.02) was significantly better, although for all women recruited, no significant differences were seen (MD –0.59 (95% CI –1.24 to 0.06). Mother-to-infant bonding was significantly better in the intervention group for all women (MD –0.30 (95% CI –0.61 to –0.00) p=0.05), and there were no differences in other secondary outcomes.

Conclusions

This trial demonstrates differences in depressive symptomatology with addition of the POW service in the powered subgroup of women with 2 or more social risk factors. Addition to existing evidence indicates benefit from lay interventions in preventing postnatal depression. This finding is important for women and their families given the known effect of maternal depression on longer term childhood outcomes.

Trial registration number

ISRCTN35027323; Results.

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Getting our house in order: an audit of the registration and publication of clinical trials supported by the National Institute for Health Research Oxford Biomedical Research Centre and the Musculoskeletal Biomedical Research Unit

Objectives

To audit the proportion of clinical trials that had been publically registered and, of the completed trials, the proportion published.

Setting

2 major research institutions supported by the National Institute of Health Research (NIHR).

Primary and secondary outcome measures

The proportion of trials reporting results within 12 months, 24 months and 'ever'. Factors associated with non-publication were analysed using logistic regression.

Inclusion criteria

Phases 2–4 clinical trials identified from internal documents and publication lists.

Results

In total, 286 trials were identified. We could not find registration for 4 (1.4%) of these, all of which were completed and published. Of the trials with a registered completion date pre-January 2015, just over half (56%) were published, and half of these were published within 12 months (36/147, 25%). For some trials, information on the public registers was found to be out-of-date and/or inaccurate. No clinical trial characteristics were found to be significantly associated with non-publication. We have produced resources to facilitate similar audits elsewhere.

Conclusions

It was feasible to conduct an internal audit of registration and publication in 2 major research institutions. Performance was similar to, or better than, comparable cohorts of trials sampled from registries. The major resource input required was manually seeking information: if all registry entries were maintained, then almost the entire process of audit could be automated—and routinely updated—for all research centres and funders.

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The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel

Abstract

The olfactory system is intricately linked with the endocrine system where it may serve as a detector of internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU-YFP mice that express a genetic reporter under the control of the preproglucagon reporter, suggested the presence of the gut hormone, glucagon-like peptide (GLP-1) in deep short axon cells (dSAC; Cajal cells) of the olfactory bulb and its neuromodulatory effect on the mitral cell (MC) first order neurons. A MC target for the peptide was determined using GLP-1R binding assays, immunocytochemistry for the receptor, and injection of fluorescently-labelled GLP-1 analog Exendin-4. Using patch-clamp recording of olfactory bulb slices in the whole-cell configuration, we report that GLP-1 and its stable analog Exendin-4 increase action potential (AP) firing frequency of MCs by decreasing the interburst interval rather than modifying the AP shape, train length, or interspike interval. GLP-1 decreases Kv1.3 channel contribution to outward currents in voltage-clamp recordings as determined by pharmacological block of Kv1.3 or utilizing mice with Kv1.3 gene-targeted deletion as a negative control. Because fluctuations in GLP-1 concentrations monitored by the olfactory bulb could modify firing frequency of MCs, olfactory coding could change depending upon nutritional or physiological state. As a regulator of neuronal activity, GLP-1 or its analog may be a new metabolic factor with potential therapeutic target to the olfactory bulb (i.e. intranasal delivery) to control an imbalance in energy homeostasis.

This article is protected by copyright. All rights reserved

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Novel Use for DOG1 in Discriminating Breast Invasive Carcinoma from Noninvasive Breast Lesions

Aims. DOG1 has proven to be a useful marker of gastrointestinal stromal tumors (GISTs). Recently, DOG1 expression has also been reported in some non-GIST malignant tumors, but the details related to DOG1 expression in breast tissue remain unclear. The aim of this study was to detect the expression of DOG1 in the human breast and to evaluate the feasibility of using DOG1 to discriminate between invasive breast carcinoma and noninvasive breast lesions. Methods and Results. A total of 210 cases, including both invasive and noninvasive breast lesions, were collected to assess DOG1 expression immunohistochemically. DOG1 expression was consistently positive in breast myoepithelial cells (MECs), which was similar to the results obtained for three other MEC markers: calponin, smooth muscle myosin heavy chain (SMMHC), and P63 ( in all). Importantly, DOG1 was useful in discriminating invasive breast carcinoma from noninvasive breast lesions (). Conclusions. DOG1 is a useful marker of breast MECs, and adding DOG1 to the MEC identification panel will provide more sophisticated information when diagnosing uncertain cases in the breast.

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IJMS, Vol. 17, Pages 247: Identification, Functional Study, and Promoter Analysis of HbMFT1, a Homolog of MFT from Rubber Tree (Hevea brasiliensis)

A homolog of MOTHER OF FT AND TFL1 (MFT) was isolated from Hevea brasiliensis and its biological function was investigated. Protein multiple sequence alignment and phylogenetic analysis revealed that HbMFT1 conserved critical amino acid residues to distinguish MFT, FLOWERING LOCUS T (FT) and TERMINAL FLOWER1 (TFL1)-like proteins and showed a closer genetic relationship to the MFT-like group. The accumulation of HbMFT1 was generally detected in various tissues except pericarps, with the highest expression in embryos and relatively higher expression in roots and stems of seedlings, flowering inflorescences, and male and female flowers. HbMFT1 putative promoter analysis showed that tissue-specific, environmental change responsive and hormone-signaling responsive elements were generally present. HbMFT1 was strongly induced under a short-day condition at 28 °C, with the highest expression after the onset of a day. Overexpression of HbMFT1 inhibited seed germination, seedling growth, and flowering in transgenic Arabidopsis. The qRT-PCR further confirmed that APETALA1 (AP1) and FRUITFULL (FUL) were drastically down-regulated in 35S::HbMFT1 plants. A histochemical β-glucuronidase (GUS) assay showed that HbMFT1::GUS activity was mainly detected in stamens and mature seeds coinciding with its original expression and notably induced in rosette leaves and seedlings of transgenic Arabidopsis by exogenous abscisic acid (ABA) due to the presence of ABA cis-elements in HbMFT1 promoter. These results suggested that HbMFT1 was mainly involved in maintenance of seed maturation and stamen development, but negatively controlled germination, growth and development of seedlings and flowering. In addition, the HbMFT1 promoter can be utilized in controlling transgene expression in stamens and seeds of rubber tree or other plant species.

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Sensors, Vol. 16, Pages 313: Radiometric Calibration of a Dual-Wavelength, Full-Waveform Terrestrial Lidar

Radiometric calibration of the Dual-Wavelength Echidna® Lidar (DWEL), a full-waveform terrestrial laser scanner with two simultaneously-pulsing infrared lasers at 1064 nm and 1548 nm, provides accurate dual-wavelength apparent reflectance (ρapp), a physically-defined value that is related to the radiative and structural characteristics of scanned targets and independent of range and instrument optics and electronics. The errors of ρapp are 8.1% for 1064 nm and 6.4% for 1548 nm. A sensitivity analysis shows that ρapp error is dominated by range errors at near ranges, but by lidar intensity errors at far ranges. Our semi-empirical model for radiometric calibration combines a generalized logistic function to explicitly model telescopic effects due to defocusing of return signals at near range with a negative exponential function to model the fall-off of return intensity with range. Accurate values of ρapp from the radiometric calibration improve the quantification of vegetation structure, facilitate the comparison and coupling of lidar datasets from different instruments, campaigns or wavelengths and advance the utilization of bi- and multi-spectral information added to 3D scans by novel spectral lidars.

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IJMS, Vol. 17, Pages 317: Molecular Mechanisms of Floral Boundary Formation in Arabidopsis

Boundary formation is a crucial developmental process in plant organogenesis. Boundaries separate cells with distinct identities and act as organizing centers to control the development of adjacent organs. In flower development, initiation of floral primordia requires the formation of the meristem-to-organ (M–O) boundaries and floral organ development depends on the establishment of organ-to-organ (O–O) boundaries. Studies in this field have revealed a suite of genes and regulatory pathways controlling floral boundary formation. Many of these genes are transcription factors that interact with phytohormone pathways. This review will focus on the functions and interactions of the genes that play important roles in the floral boundaries and discuss the molecular mechanisms that integrate these regulatory pathways to control the floral boundary formation.

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Climate, Vol. 4, Pages 13: The Relationships between Climate Variability and Crop Yield in a Mountainous Environment: A Case Study in Lamjung District, Nepal

Several studies have concluded that mountainous countries such as Nepal are more vulnerable to climate change; thus, a changing climate should have a significant impact on crop yields. This work aims to explore the impact of climate change on major crop yields in the mountainous parts of Nepal and to determine their relationships based on a regression model between historical climatic data and yield data for food crops. The study starts with an analysis of the last 30 years of climatic data from Lamjung district. Mann-Kendall and Sen's Slope methods have been used for the trend analysis and quantification. The results showed an increase in temperature of approximately 0.02 °C to 0.07 °C per year in different seasons and a mixed trend in precipitation. Although there was no significant impact of the climate variables on the yields of all crops, the regression analysis revealed negative relationships between maize yield and summer precipitation and between wheat yield and winter minimum temperature, and a positive relationship between millet yield and summer maximum temperature.

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IJMS, Vol. 17, Pages 328: Gleditsia sinensis Thorn Attenuates the Collagen-Based Migration of PC3 Prostate Cancer Cells through the Suppression of α2β1 Integrin Expression

Gleditsia sinensis thorns (GST) have been used as a traditional medicine for carbuncles and skin diseases. The purpose of this study was to decide whether non-toxicological levels of water extract of GST (WEGST) are effective in inhibiting the progress of prostate cancer formation and to identify the target molecule involved in the WEGST-mediated inhibitory process of prostate cancer cell migration and in vivo tumor formation. Through the Boyden chamber migration assay, we found that non-toxic levels of WEGST could not attenuate the PC3 migration to the bottom area coated with serum but significantly inhibited PC3 cell migration to the collagen-coated bottom area. We also found that non-toxic levels of WEGST significantly attenuated collagen against adhesion. Interestingly, ectopic administration of WEGST could not affect the expression of α2β1 integrin, which is known as a receptor of collagen. However, when the PC3 cells adhered to a collagen-coated plate, the expression of α2 integrin but not that of β1 integrin was significantly inhibited by the administration of non-toxic levels of WEGST, leading to the inhibition of focal adhesion kinase (FAK) phosphorylation. Furthermore, oral administration of WEGST (25 mg/kg/day) significantly inhibited the size of a PC3 cell-xenografted tumor. Taken together, these results suggest a novel molecular mechanism for WEGST to inhibit prostate cancer progression at particular stages, such as collagen-mediated adhesion and migration, and it might provide further development for the therapeutic use of WEGST in the treatment of prostate cancer progression.

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IJMS, Vol. 17, Pages 327: Endoplasmic Reticulum Stress and Associated ROS

The endoplasmic reticulum (ER) is a fascinating network of tubules through which secretory and transmembrane proteins enter unfolded and exit as either folded or misfolded proteins, after which they are directed either toward other organelles or to degradation, respectively. The ER redox environment dictates the fate of entering proteins, and the level of redox signaling mediators modulates the level of reactive oxygen species (ROS). Accumulating evidence suggests the interrelation of ER stress and ROS with redox signaling mediators such as protein disulfide isomerase (PDI)-endoplasmic reticulum oxidoreductin (ERO)-1, glutathione (GSH)/glutathione disuphide (GSSG), NADPH oxidase 4 (Nox4), NADPH-P450 reductase (NPR), and calcium. Here, we reviewed persistent ER stress and protein misfolding-initiated ROS cascades and their significant roles in the pathogenesis of multiple human disorders, including neurodegenerative diseases, diabetes mellitus, atherosclerosis, inflammation, ischemia, and kidney and liver diseases.

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IJMS, Vol. 17, Pages 325: Adjuvant Effect of Quillaja saponaria Saponin (QSS) on Protective Efficacy and IgM Generation in Turbot (Scophthalmus maximus) upon Immersion Vaccination

The adjuvant effect of Quillaja saponaria saponin (QSS) on protection of turbot fry was investigated with immersion vaccination of formalin-killed Vibrio anguillarum O1 and various concentrations of QSS (5, 25, 45 and 65 mg/L). Fish were challenged at days 7, 14 and 28 post-vaccination. Significantly high relative percent of survival (RPS) ((59.1 ± 13.6)%, (81.7 ± 8.2)%, (77.8 ± 9.6)%) were recorded in the fish that received bacterins immersion with QSS at 45 mg/L, which is comparable to the positive control group vaccinated by intraperitoneal injection (IP). Moreover, a remarkably higher serum antibody titer was also demonstrated after 28 days in the vaccinated fish with QSS (45 mg/L) than those vaccinated fish without QSS (p < 0.05), but lower than the IP immunized fish (p < 0.05). Significant upregulation of IgM gene expression has also been identified in the tissues of skin, gill, spleen and kidney from the immunized fish in comparison to the control fish. Taken together, the present study indicated that QSS was able to dramatically evoke systemic and mucosal immune responses in immunized fish. Therefore, QSS might be a promising adjuvant candidate for fish vaccination via an immersion administering route.

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Water, Vol. 8, Pages 77: Investigating Trends in Streamflow and Precipitation in Huangfuchuan Basin with Wavelet Analysis and the Mann-Kendall Test

This study aims to investigate trends in streamflow and precipitation in the period 1954–2010 in a semiarid region of the Yellow River watershed, Huangfuchuan basin, China. The combination of the wavelet transform and different Mann-Kendall (MK) tests were employed to figure out the basic trends structure in streamflow and precipitation and what time scales are affecting the observed trends. The comparative analysis with five MK test methods showed that the modified MK tests with full serial correlation structure performed better when significant autocorrelations exhibited for more than one lag. Three criteria were used to determine the optimal smooth mother wavelet, the decomposition level and the extension mode used in the discrete wavelet transform (DWT) procedure. The first criteria referred to the relative error of the wavelet approximated component and the original series. The second one was the relative error of MK Z-values of approximation component and the original series. Additionally, a new criterion (Er), based on the relative error of energy between the approximate component and the original series, was proposed in this study, with better performance than the previous two criteria. Further, a new powerful index, the energy of the hydrological time series, was proposed to verify the dominant periodic components for the observed trends. The analysis indicated that all monthly, seasonal and annual streamflow showed significant decreasing trends, while no significant trends were found in precipitation. Results from the DWT and MK tests revealed that the main factors influencing the trends in the monthly and seasonal series in Huangfuchuan watershed are intra-annual cycles, while the leading factors affecting the trends in the annual series are decadal events. Different driving factors (e.g., seasonal cycles, solar activities, etc.) related to the periodicities identified in these data types resulted in this discrepancy.

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Sustainability, Vol. 8, Pages 181: Factors Affecting Rural Households’ Resilience to Food Insecurity in Niger

Niger faces many natural and human constraints explaining the erratic evolution of its agricultural production over time. Unfortunately, this is likely to cause a decline in the food supply. This study attempts to identify factors affecting rural households' resilience to food insecurity in Niger. For this, we first create a resilience index by using principal component analysis and later apply structural equation modeling to identify its determinants. Data from the 2010 National Survey on Households' Vulnerability to Food Insecurity done by the National Institute of Statistics is used. The study shows that asset and social safety net indicators are significant and have a positive impact on households' resilience. Climate change approximated by long-term mean rainfall has a negative and significant effect on households' resilience. Therefore, to strengthen households' resilience to food insecurity, there is a need to increase assistance to households through social safety nets and to help them gather more resources in order to acquire more assets. Furthermore, early warning of climatic events could alert households, especially farmers, to be prepared and avoid important losses that they experience anytime an uneven climatic event occurs.

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Materials, Vol. 9, Pages 148: Seismic Performance of Composite Shear Walls Constructed Using Recycled Aggregate Concrete and Different Expandable Polystyrene Configurations

The seismic performance of recycled aggregate concrete (RAC) composite shear walls with different expandable polystyrene (EPS) configurations was investigated. Six concrete shear walls were designed and tested under cyclic loading to evaluate the effect of fine RAC in designing earthquake-resistant structures. Three of the six specimens were used to construct mid-rise walls with a shear-span ratio of 1.5, and the other three specimens were used to construct low-rise walls with a shear-span ratio of 0.8. The mid-rise and low-rise shear walls consisted of an ordinary recycled concrete shear wall, a composite wall with fine aggregate concrete (FAC) protective layer (EPS modules as the external insulation layer), and a composite wall with sandwiched EPS modules as the insulation layer. Several parameters obtained from the experimental results were compared and analyzed, including the load-bearing capacity, stiffness, ductility, energy dissipation, and failure characteristics of the specimens. The calculation formula of load-bearing capacity was obtained by considering the effect of FAC on composite shear walls as the protective layer. The damage process of the specimen was simulated using the ABAQUS Software, and the results agreed quite well with those obtained from the experiments. The results show that the seismic resistance behavior of the EPS module composite for shear walls performed better than ordinary recycled concrete for shear walls. Shear walls with sandwiched EPS modules had a better seismic performance than those with EPS modules lying outside. Although the FAC protective layer slightly improved the seismic performance of the structure, it undoubtedly slowed down the speed of crack formation and the stiffness degradation of the walls.

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Climate, Vol. 4, Pages 14: CMIP5 Projected Changes in the Annual Cycle of Indian Monsoon Rainfall

The annual cycle of Indian monsoon rainfall plays a critical role in the agricultural as well as the industrial sector. Thus, it is necessary to evaluate the behaviour of the monsoon annual cycle in a warming climate. There are several studies on the variability and uncertainty of the Indian monsoon. This study, examines the impact of climate change on the annual cycle of monsoon rainfall in India from 1871–2100 by applying 20 model simulations designed by the World Climate Research Programme (WCRP) coupled with the model inter-comparison Project 5 (CMIP5). It is found that the models MPI-ESM-LR, INM-CM4 and MRI-CGCM3 best capture the spatial patterns of the monsoon rainfall peak month (MRPM) of the winter monsoon compared to observations, whereas HadGEM2-AO and MIROC-ESM-CHEM best capture the MRPM of the summer monsoon. The MIROC, MIROC-ESM, and MIROC-ESM-CHEM models best capture the average rainfall intensity as well as the MRPM of all-India rainfall. This paper examines the future spatial distribution of the MRPM for meteorological sub-divisions of India, that can have crucial implications for water resources and management. Although the future projections as per the CMIP5 models indicate no changes in the MRPM of the all-India rainfall, a reduction in average intensity can be expected. The projections indicate a shift in the MRPM in some meteorological sub-divisions, particularly with regard to the summer monsoon but no significant change has been projected for the winter monsoon. For example, the summer monsoon MRPM is projected to move from July to August in northern and central India.

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Toxins, Vol. 8, Pages 62: Occurrence of Staphylococcus aureus on Farms with Small Scale Production of Raw Milk Cheeses in Poland

This paper describes the results of a 3-year study on the prevalence, enterotoxinogenicity and resistance to antimicrobials of S. aureus isolated on dairy farms with small scale production of raw cow milk cheeses. The samples of raw milk, semi-finished products and the final products as well as swabs were collected between 2011 and 2013 from nine dairy farms in Poland. A total of 244 samples were examined, of which 122 (50.0%) were contaminated with S. aureus including 18 of 26 (69.2%) mature cheese samples with log10 CFU g−1 between <1- and 7.41. In swabs collected from the staff and production environment the highest contamination rate with coagulase positive staphylococci (CPS) was detected on hands of cheese makers (4.34 log10 CFU/swab). None of the cheese samples contaminated with CPS contained staphylococcal enterotoxins (SEs). However, 55 of 122 (45.1%) S. aureus isolates possessed SEs genes, mainly (26 of 55; 47.3%) a combination of the sed, sej and ser genes. Furthermore, the sep (15 of 55; 27.3%) as well as seg and sei (9 of 55; 16.4%) genes were also identified. The remaining S. aureus isolates possessed the sea gene (one isolate), the combination of sec, seg and sei (three isolates) as well as the sed, sej, sep and ser markers together (one CPS). Resistance to penicillin (62 of 122 isolates; 50.8%) was the most common among the tested isolates. Some CPS were also resistant to chloramphenicol (7; 5.7%) and tetracycline (5; 4.1%). The obtained results indicated that the analyzed cheeses were safe for consumers. To improve the microbiological quality of traditional cheese products more attention should be paid to animal welfare and hygiene practices during the process of cheese manufacturing in some dairy farms.

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Technologies, Vol. 4, Pages 8: Droplet-Assisted Laser Direct Nanoscale Writing on Silicon

Nano-structuring using laser direct writing technology has shown great potential for industrial applications. A novel application of water droplets to this technology is proposed in this paper. With a hydrophobic layer and a controlled substrate temperature, a layer of randomly distributed water droplets with a high contact angle is formed on the substrate. These liquid droplets can be used as lenses to enhance the laser intensity at the bottom of the droplets. As a result, nanoscale holes can be fabricated on the substrate by controlling the laser energy density. We successfully fabricated holes with a diameter of 600 nm at a substrate temperature of 12 ∘C and a power density of 1.2 × 108 W/cm2 in our experiments. We also found that the hole diameter was around a ninth of the water droplet diameter. Meanwhile, the machined holes are not affected much by the focal length of the lens, but a hole with less than 100 nm in diameter at the center was observed.

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Sensors, Vol. 16, Pages 317: SHM-Based Probabilistic Fatigue Life Prediction for Bridges Based on FE Model Updating

Fatigue life prediction for a bridge should be based on the current condition of the bridge, and various sources of uncertainty, such as material properties, anticipated vehicle loads and environmental conditions, make the prediction very challenging. This paper presents a new approach for probabilistic fatigue life prediction for bridges using finite element (FE) model updating based on structural health monitoring (SHM) data. Recently, various types of SHM systems have been used to monitor and evaluate the long-term structural performance of bridges. For example, SHM data can be used to estimate the degradation of an in-service bridge, which makes it possible to update the initial FE model. The proposed method consists of three steps: (1) identifying the modal properties of a bridge, such as mode shapes and natural frequencies, based on the ambient vibration under passing vehicles; (2) updating the structural parameters of an initial FE model using the identified modal properties; and (3) predicting the probabilistic fatigue life using the updated FE model. The proposed method is demonstrated by application to a numerical model of a bridge, and the impact of FE model updating on the bridge fatigue life is discussed.

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IJMS, Vol. 17, Pages 273: The Immunology of Neuromyelitis Optica—Current Knowledge, Clinical Implications, Controversies and Future Perspectives

Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder which needs to be differentiated from MS. The discovery of autoantibodies against aquaporin-4 (AQP4-IgGs) changed our understanding of NMO immunopathogenesis and revolutionized the diagnostic process. AQP4-IgG is currently regarded as a specific biomarker of NMO and NMO spectrum disorders (NMOsd) and a key factor in its pathogenesis. Nevertheless, AQP4-IgG seronegativity in 10%–25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis, i.e., autoantibodies against aquaporin-1 (AQP1-Abs) and antibodies against myelin oligodendrocyte glycoprotein (MOG-IgGs). This manuscript reviews current knowledge about NMO immunopathogenesis, pointing out the controversial issues and showing potential directions for future research. Further efforts should be made to broaden our knowledge of NMO immunology which could have important implications for clinical practice, including the use of potential novel biomarkers to facilitate an early and accurate diagnosis, and modern treatment strategies improving long-term outcome of NMO patients.

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4-Chloro-6-pyrimidinylferrocene modified silica gel: A novel multiple-function stationary phase for mixed-mode chromatography

Publication date: 1 June 2016
Source:Talanta, Volume 153
Author(s): Lijun Qiao, Xiaohua Zhou, Yanhao Zhang, Ajuan Yu, Kai Hu, Shusheng Zhang, Yangjie Wu
A novel multi-function and mixed-mode stationary phase based on 4-chloro-6-pyrimidinylferrocene modified silica (NFcS) was synthesized and characterized by infrared spectroscopy, elemental analysis and thermogravimetric analysis. Linear solvation energy relationship method was successfully employed to evaluate the new phase with a set of 27 solutes including aromatic and aliphatic compounds. Multiple mechanisms including hydrophobic, π–π, hydrogen-bonding, charge-transfer, acid–base equilibrium and anion-exchange interactions are involved. Based on these interactions, successful separation could be achieved among polycyclic aromatic hydrocarbons, mono-substituted benzenes, aromatic amines, phenols, quinolines, pyridines and nucleosides in reversed-phase (RP) or normal-phase (NP) chromatography. Inorganic anions were also shown to be individually separated in anion-exchange chromatography by using the same column. Moreover, the results here also demonstrated that NFcS based stationary phase could effectively reduce the adverse effect of residual silanol in the separation process. Such stationary phase with characteristics of multi-interaction mechanism and mixed-mode separation is potential for the analysis of complex samples. The NFcS column was successfully employed for the analysis of plant growth regulators in Fruit.

Graphical abstract

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A new application of micellar liquid chromatography in the determination of free ampicillin concentration in the drug–human serum albumin standard solution in comparison with the adsorption method

Publication date: 1 June 2016
Source:Talanta, Volume 153
Author(s): Katarzyna E. Stępnik, Irena Malinowska, Małgorzata Maciejewska
The determination of free drug concentration is a very important issue in the field of pharmacology because only the unbound drug fraction can achieve a pharmacological effect.Due to the ability to solubilize many different compounds in micellar aggregates, micellar liquid chromatography (MLC) can be used for direct determination of free drug concentration. Proteins are not retained on the stationary phase probably due to the formation of protein – surfactant complexes which are excluded from the pores of stationary phase. The micellar method is simple and fast. It does not require any pre-preparation of the tested samples for analysis.The main aim of this paper is to demonstrate a completely new applicability of the analytical use of MLC concerning the determination of free drug concentration in the standard solution of human serum albumin. The well-known adsorption method using RP-HPLC and the spectrophotometric technique was applied as the reference method.The results show that the free drug concentration value obtained in the MLC system (based on the RP-8 stationary phase and CTAB) is similar to that obtained by the adsorption method: both RP-HPLC (95.83μgmL⁻¹, 79.86% of free form) and spectrophotometry (95.71μgmL⁻¹, 79.76%). In the MLC the free drug concentration was 93.98μgmL⁻¹ (78.3%). This indicates that the obtained results are within the analytical range of % of free ampicillin fraction and the MLC with direct sample injection can be treated like a promising method for the determination of free drug concentration.

Graphical abstract

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Nutrients, Vol. 8, Pages 128: An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity

In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher. This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity. Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation. Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity. Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity.

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Molecules, Vol. 21, Pages 267: Synthesis of Naphthalene-Based Push-Pull Molecules with a Heteroaromatic Electron Acceptor

Naphthalene derivatives bearing electron-accepting and electron-donating groups at the 2,6-positions belong to the family of D-π-A push-pull dyes. It has been found that these compounds, e.g., 2-(1-(6-((2-(fluoro)ethyl)(methyl)amino)naphthalen-2-yl)ethylidene)malononitrile (FDDNP), show not only interesting optical properties, such as solvatochromism, but they have the potential to label protein aggregates of different compositions formed in the brain of patients suffering from neurodegenerative diseases like Alzheimer's (AD). In continuation of our research we set our goal to find new FDDNP analogs, which would inherit optical and binding properties but hopefully show better specificity for tau protein aggregates, which are characteristic for neurodegeneration caused by repetitive mild trauma. In this work we report on the synthesis of new FDDNP analogs in which the acceptor group has been formally replaced with an aromatic five- or six-membered heterocycle. The heterocyclic moiety was annealed to the central naphthalene ring either by classical ring closure reactions or by modern transition metal-catalyzed coupling reactions. The chemical characterization, NMR spectra, and UV/vis properties of all new compounds are reported.

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Nutrients, Vol. 8, Pages 130: Effects of Cereal, Fruit and Vegetable Fibers on Human Fecal Weight and Transit Time: A Comprehensive Review of Intervention Trials

Cereal fibers are known to increase fecal weight and speed transit time, but far less data are available on the effects of fruits and vegetable fibers on regularity. This study provides a comprehensive review of the impact of these three fiber sources on regularity in healthy humans. We identified English-language intervention studies on dietary fibers and regularity and performed weighted linear regression analyses for fecal weight and transit time. Cereal and vegetable fiber groups had comparable effects on fecal weight; both contributed to it more than fruit fibers. Less fermentable fibers increased fecal weight to a greater degree than more fermentable fibers. Dietary fiber did not change transit time in those with an initial time of <48 h. In those with an initial transit time ≥48 h, transit time was reduced by approximately 30 min per gram of cereal, fruit or vegetable fibers, regardless of fermentability. Cereal fibers have been studied more than any other kind in relation to regularity. This is the first comprehensive review comparing the effects of the three major food sources of fiber on bowel function and regularity since 1993.

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Nutrients, Vol. 8, Pages 123: Impact of Genotype on EPA and DHA Status and Responsiveness to Increased Intakes

At a population level, cardioprotective and cognitive actions of the fish oil (FO) derived long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been extensively demonstrated. In addition to dietary intake, which is limited for many individuals, EPA and DHA status is dependent on the efficiency of their biosynthesis from α-linolenic acid. Gender and common gene variants have been identified as influencing the rate-limiting desaturase and elongase enzymes. Response to a particular intake or status is also highly heterogeneous and likely influenced by genetic variants which impact on EPA and DHA metabolism and tissue partitioning, transcription factor activity, or physiological end-point regulation. Here, available literature relating genotype to tissue LC n-3 PUFA status and response to FO intervention is considered. It is concluded that the available evidence is relatively limited, with much of the variability unexplained, though APOE and FADS genotypes are emerging as being important. Although genotype × LC n-3 PUFA interactions have been described for a number of phenotypes, few have been confirmed in independent studies. A more comprehensive understanding of the genetic, physiological and behavioural modulators of EPA and DHA status and response to intervention is needed to allow refinement of current dietary LC n-3 PUFA recommendations and stratification of advice to "vulnerable" and responsive subgroups.

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Nutrients, Vol. 8, Pages 135: The Non-Genomic Actions of Vitamin D

Since its discovery in 1920, a great deal of effort has gone into investigating the physiological actions of vitamin D and the impact its deficiency has on human health. Despite this intense interest, there is still disagreement on what constitutes the lower boundary of adequacy and on the Recommended Dietary Allowance. There has also been a major push to elucidate the biochemistry of vitamin D, its metabolic pathways and the mechanisms that mediate its action. Originally thought to act by altering the expression of target genes, it was realized in the mid-1980s that some of the actions of vitamin D were too rapid to be accounted for by changes at the genomic level. These rapid non-genomic actions have attracted as much interest as the genomic actions and they have spawned additional questions in an already busy field. This mini-review attempts to summarise the in vitro and in vivo work that has been conducted to characterise the rapid non-genomic actions, the mechanisms that give rise to these properties and the roles that these play in the overall action of vitamin D at the cellular level. Understanding the effects of vitamin D at the cellular level should enable the design of elegant human studies to extract the full potential of vitamin D to benefit human health.

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Nutrients, Vol. 8, Pages 133: Effects of Trigonelline, an Alkaloid Present in Coffee, on Diabetes-Induced Disorders in the Rat Skeletal System

Diabetes increases bone fracture risk. Trigonelline, an alkaloid with potential antidiabetic activity, is present in considerable amounts in coffee. The aim of the study was to investigate the effects of trigonelline on experimental diabetes-induced disorders in the rat skeletal system. Effects of trigonelline (50 mg/kg p.o. daily for four weeks) were investigated in three-month-old female Wistar rats, which, two weeks before the start of trigonelline administration, received streptozotocin (60 mg/kg i.p.) or streptozotocin after nicotinamide (230 mg/kg i.p.). Serum bone turnover markers, bone mineralization, and mechanical properties were studied. Streptozotocin induced diabetes, with significant worsening of bone mineralization and bone mechanical properties. Streptozotocin after nicotinamide induced slight glycemia increases in first days of experiment only, however worsening of cancellous bone mechanical properties and decreased vertebral bone mineral density (BMD) were demonstrated. Trigonelline decreased bone mineralization and tended to worsen bone mechanical properties in streptozotocin-induced diabetic rats. In nicotinamide/streptozotocin-treated rats, trigonelline significantly increased BMD and tended to improve cancellous bone strength. Trigonelline differentially affected the skeletal system of rats with streptozotocin-induced metabolic disorders, intensifying the osteoporotic changes in streptozotocin-treated rats and favorably affecting bones in the non-hyperglycemic (nicotinamide/streptozotocin-treated) rats. The results indicate that, in certain conditions, trigonelline may damage bone.

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Molecules, Vol. 21, Pages 300: Elucidation of Transport Mechanism of Paeoniflorin and the Influence of Ligustilide, Senkyunolide I and Senkyunolide A on Paeoniflorin Transport through Mdck-Mdr1 Cells as Blood–Brain Barrier in Vitro Model

The objectives of the present investigation were to: (1) elucidate the transport mechanism of paeoniflorin (PF) across MDCK-MDR1 monolayers; and (2) evaluate the effect of ligustilide (LIG), senkyunolide I (SENI) and senkyunolide A (SENA) on the transport of PF through blood–brain barrier so as to explore the enhancement mechanism. Transport studies of PF were performed in both directions, from apical to basolateral side (A→B) and from basolateral to apical sides (B→A). Drug concentrations were analyzed by LC-MS/MS. PF showed relatively poor absorption in MDCK-MDR1 cells, apparent permeability coefficients (Papp) ranging from 0.587 × 10−6 to 0.705 × 10−6 cm/s. In vitro experiments showed that the transport of PF in both directions was concentration dependent and not saturable. The B→A/A→B permeability ER of PF was more than 2 in the MDCK-MDR1 cells, which indicated that the transport mechanism of PF might be passive diffusion as the dominating process with the active transportation mediated mechanism involved. The increased Papp of PF in A→B direction by EDTA-Na2 suggested that PF was absorbed via the paracellular route. The P-gp inhibitor verapamil could significantly increase the transport of PF in A→B direction, and ER decreased from 2.210 to 0.690, which indicated that PF was P-gp substance. The transport of PF in A→B direction significantly increased when co-administrated with increasing concentrations of LIG, SENI and SENA. An increased cellular accumulation of Rho 123 and Western blot analysis indicated that LIG, SENI and SENA had increased the transport of PF in the BBB models attribute to down-regulate P-gp expression. A decrease in transepithelial electrical resistance (TEER) during the permeation experiment can be explained by the modulation and opening of the tight junctions caused by the permeation enhancer LIG, SENI and SENA.

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Can surface electromyography improve surgery planning? Electromyographic assessment and intraoperative verification of the nerve bundle entry point location of the gracilis muscle

Publication date: Available online 2 March 2016
Source:Journal of Electromyography and Kinesiology
Author(s): Michal Romaniszyn, Piotr Walega, Michal Nowakowski, Wojciech Nowak
PurposeTo verify the precision of surface electromyography (sEMG) in locating the innervation zone of the gracilis muscle, by comparing the location of the IZ estimated by means of sEMG with in vivo location of the nerve bundle entry point in patients before graciloplasty procedure due to fecal incontinence.MethodsNine patients who qualified for the graciloplasty procedure underwent sEMG on both gracilis muscle before their operations. During surgery the nerve bundle was identified by means of electrical stimulation. The distance between the proximal attachment and the nerve entry point into the muscle's body was measured. Both measurements (sEMG and in vivo identification) were compared for each subject.ResultsOn average, the IZ was located 65,5 mm from the proximal attachment. The mean difference in location of the innervation zones in each individual was 10 mm ±9,7 mm, maximal - 30 mm, the difference being statistically significant (p=0,017). It was intraoperatively confirmed, that the nerve entered the muscle an average of 62 mm from the proximal attachment. The largest difference between the EMG IZ estimation and nerve bundle entry point was 5 mm (mean difference 2,8 mm, p=0,767).ConclusionPreoperative surface electromyography of both gracilis muscles is a safe, precise and reliable method of assessing the location of the innervation zones of the gracilis muscles. The asymmetry of the IZ location in left and right muscles may be important in context of technical aspects of the graciloplasty procedure.



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