Quantitative relationships between ingested and intestinal flows of linoleic and alpha-linolenic acids, body weight and milk performance in mid-lactation dairy cows.

Linoleic acid (LA) and alpha-linolenic acid (ALA) are essential fatty acids found in variable quantities in ruminant feedstuffs. Revision of French feed unit systems in 2018 has proposed the reassessment of energy requirements through a between-experiment approach expressing metabolisable energy supply as a function of the energy expenditures for maintenance and production, with these expenditures that reflect homeorhetic regulations. Based on the same approach, LA and ALA intake can be related to animal characteristics (i.e., BW) reflecting maintenance expenditures and secretion characteristics (i.e., milk yield, milk fat content and contents of LA and ALA in milk fat). Therefore, the objective of this work was to analyse the between-experiment relationships between ingested, duodenal, or absorbed flows of LA and ALA, BW and milk LA and ALA secretion by meta-analysis in mid-lactation dairy cows. These relationships were analysed using LA and ALA subsets of 96 and 99 experiments, respectively. Between-experiment regressions of daily flows of ingested, duodenal or absorbed LA and ALA on BW and milk LA and ALA flows were studied, with statistical unit defined as the mean of within-experiment treatments. For LA, the BW-associated coefficient was 0.019 (±0.0034) g absorbed LA/d per kg BW and milk LA secretion-associated coefficient was 0.70 (±0.081) g absorbed LA/g of LA secreted into milk. For ALA, the BW-associated coefficient was 0.0058 (±0.00093) g absorbed ALA/d per kg BW and milk ALA secretion-associated coefficient was 0.57 (±0.097) g absorbed ALA/g of ALA secreted into milk. When coding the diets as either control or milk fat depression diets, the BW-associated coefficient for LA was 0.017 (±0.0032) g absorbed LA/d per kg BW for both diets. For milk fat depression diets, milk LA secretion-associated coefficient was 1.02 (±0.119) g absorbed LA/g of LA secreted into milk, whereas it was 0.70 (±0.075) g absorbed LA/g of LA secreted into milk for control diets. Significant BW and milk performance coefficients were obtained in all LA and ALA equations, allowing the calculation of ingested and intestinal flows of LA and ALA based on measured BW, milk fat yield and milk fat content of LA and ALA. The relationships between ingested and intestinal flows of LA and ALA, BW and milk performance obtained in the present work could be integrated into renewed feed unit systems for energy and protein in dairy cows.

Cortical Tracking of Complex Sound Envelopes: Modeling the Changes in Response with Intensity.

Characterizing how the brain responds to stimuli has been a goal of sensory neuroscience for decades. One key approach has been to fit linear models to describe the relationship between sensory inputs and neural responses. This has included models aimed at predicting spike trains, local field potentials, BOLD responses, and EEG/MEG. In the case of EEG/MEG, one explicit use of this linear modeling approach has been the fitting of so-called temporal response functions (TRFs). TRFs have been used to study how auditory cortex tracks the amplitude envelope of acoustic stimuli, including continuous speech. However, such linear models typically assume that variations in the amplitude of the stimulus feature (i.e., the envelope) produce variations in the magnitude but not the latency or morphology of the resulting neural response. Here, we show that by amplitude binning the stimulus envelope, and then using it to fit a multivariate TRF, we can better account for these amplitude-dependent changes, and that this leads to a significant improvement in model performance for both amplitude-modulated noise and continuous speech in humans. We also show that this performance can be further improved through the inclusion of an additional envelope representation that emphasizes onsets and positive changes in the stimulus, consistent with the idea that while some neurons track the entire envelope, others respond preferentially to onsets in the stimulus. We contend that these results have practical implications for researchers interested in modeling brain responses to amplitude modulated sounds.

Climate change and atopic dermatitis: is there a link?

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with a growing health concern, because of its high prevalence and associated low quality of life. The etiology of AD is multifactorial with interaction between various factors such as genetic predisposition, immune, and importantly, environmental factors. Since climate change is associated with a profound shift in environmental factors, we suggest that AD is being influenced by climate change. This review highlights the effects of ultraviolet light, temperature, humidity, pollens, air pollutants, and their interaction between them contributing to the epidemiology and pathophysiology of AD.

Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also.

PURPOSE: Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. PATIENTS AND METHODS: Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. RESULTS: Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). CONCLUSION: This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.

Glycine-containing flaxseed orbitides.

Five new orbitides, cyclolinopeptides 21-25, were identified in flaxseed oil (Linum usitatissimum) extracts. Their HPLC-ESIMS quasimolecular ion peaks at m/z 1097.7 (21), 1115.6 (22), 1131.6 (23), 1018.6 (24), and 1034.6 (25) [M + H](+) corresponded to the molecular formulae C59H89N10O10, C58H87N10O10S, C58H87N10O11S, C53H80N9O9S, and C53H80N9O10S, respectively. Their structures were elucidated by extensive HPLC-ESIMS/MS analyses, and their presence was confirmed by precursor proteins identified in flax genomic DNA sequence data. The amino acid sequences of these orbitides were confirmed as [1-10-NαC]-GILVPPFFLI, [1-10-NαC]-GMLIPPFFVI, [1-10-NαC]-GOLIPPFFVI, [1-9-NαC]-GMLVFPLFI, and [1-9-NαC]-GOLVFPLFI for cyclolinopeptides 21-25, respectively. Previously reported orbitides, [1-9-NαC]-ILVPPFFLI (1), [1-9-NαC]-MLIPPFFVI (2), [1-9-NαC]-OLIPPFFVI (3), [1-8-NαC]-MLVFPLFI (7), and [1-8-NαC]-OLVFPLFI (8), were also present in flaxseed oil. The precursors of orbitides 21, 22, and 24 also produced orbitides 1, 2, and 7 by alternative cyclization. Cyclolinopeptides 3, 8, 23, and 25 contain MetO (O) and are not directly encoded, but are products of post-translational modification of the Met present in 2, 7, 22, and 24, respectively. Sufficient cyclolinopeptide 23 was isolated for characterization via 1D ((1)H and (13)C) and 2D (NOESY and HMBC) NMR spectroscopy. These compounds have been named as cyclolinopeptides U, V, W, X, and Y for 21, 22, 23, 24, and 25, respectively.

Simulated moving bed purification of flaxseed oil orbitides: unprecedented separation of cyclolinopeptides C and E.

The purification and enrichment of most natural products with potential pharmaceutical applications has been performed mainly employing conventional batch-mode chromatographic processes. There is a growing interest in use of simulated moving bed (SMB) chromatography for natural product enrichment as this method enables conservation of mobile phase, while increasing productivity of chromatography medium. SMB increases yield while decreasing cost. Cyclolinopeptides C ([1-9-NaC],[1-MetO]-CLB, 3) and E ([1-8-NaC],[1-MetO]-CLE, 8) were extracted as a mixture from flaxseed oil and then enriched using a three-zone simulated moving bed. The current research extends the SMB technology to enrichment of cyclolinopeptides (CLs), a group of biologically active hydrophobic cyclic peptides that occur in flaxseed oil. Of interest are [1-9-NaC],[1-MetO]-CLB (3) and [1-8-NaC],[1-MetO]-CLE (8) that provide synthetic scaffolds for modified CLs. The influence of flow rate (feed, desorbent, and extract) on the separation of [1-9-NaC],[1-MetO]-CLB (3) and [1-8-NaC],[1-MetO]-CLE (8) was investigated.

Effect of cyclolinopeptides on the oxidative stability of flaxseed oil.

Polar compounds present in flaxseed oil increase its oxidative stability. Flaxseed oil becomes less stable to oxidation when filtered with silica. This observation may be linked to antioxidant compounds present in flaxseed oil. Flaxseed oil was passed over a silica adsorbent column to remove polar compounds. The polar compounds were then eluted from the silica absorbant using a series of increasingly polar solvents. The polar fractions from flaxseed oil were then added back to silica-treated flaxseed oil to determine the impact of fractions containing polar compounds on oxidative stability (induction time) at 100 °C. A polar fraction containing mainly cyclolinopeptide A (CLA, 1), but also containing ß/γ- and δ-tocopherol increased the induction time of silica-treated flaxseed oil from 2.36 ± 0.28 to 3.20 ± 0.41 h. When oxidative stability was determined immediately after addition of the polar fractions other flaxseed fractions and solvent controls did not affect oil stability. However, when the oxidative stability index (OSI) test was delayed for three days and oil samples were held at room temperature after the addition of the polar fractions to the flaxseed oil, it was observed that the control oil treated with silica had become highly sensitive to oxidation. A polar fraction containing a mixture of CLs (1, 5, 7, 9, 11), improved the oxidative stability of peptide-free oil with respect to the control when the OSI measurement was made three days after adding the fraction. In addition, effects of 1 on the oxidative stability of peptide-free oil containing divalent metal cations was investigated.

Effect of an active packaging with citrus extract on lipid oxidation and sensory quality of cooked turkey meat.

An antioxidant active packaging was prepared by coating a citrus extract, consisting of a mixture of carboxylic acids and flavanones, on polyethylene terephthalate trays. The effect of the packaging in reducing lipid oxidation in cooked turkey meat and on meat pH, colour characteristics and sensorial parameters was investigated. An untrained sensory panel evaluated the odour, taste, tenderness, juiciness and overall acceptability of the meat, using triangle, paired preference and quantitative response scale tests. A comparison between the antioxidant effects of the different components of the extract was also carried out. The packaging led to a significant reduction in lipid oxidation. After 2 days of refrigerated storage the sensory panel detected differences in odour and, after 4 days, rated the meat stored in the active packaging higher for tenderness and overall acceptability. Citric acid appeared to be the most important component of the extract with regard to its antioxidant potency.

Overall migration and kinetics of release of antioxidant compounds from citrus extract-based active packaging.

Overall migration (OM) tests were conducted on an antioxidant active packaging prepared by coating plasma pretreated and untreated polyethylene terepthalate (PET) trays with a citrus extract. The release of antioxidant compounds into food simulants was measured to permit their subtraction from OM values in line with active packaging legislation. The results demonstrated the compliance of the packaging with the limit for OM for plastic material in contact with food. The validity of the procedure for OM in aqueous food simulants was questioned, with the loss of volatile compounds during evaporation of the simulant resulting in an underestimation of total compounds released. The study showed a total release of 75% of the citrus extract coating into water and 25% into oil, which decreased to 45 and 12.5%, respectively, following plasma pretreatment of the trays.

Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity.

We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.

Rapid reversed-phase liquid chromatography separation of cyclolinopeptides with monolithic and microparticulate columns.

Three monolithic C(18)-bonded silica gel columns i.e. Chromolith SpeedROD (CSR), Chromolith Performance (CP), and Chromolith High Resolution (CHR), MerckKGaA Darmstadt, Germany and two particle-based columns i.e. ZORBAX Eclipse XDB-C(18) (ZEX), Agilent and POROS R1/20 (POR), Applied Biosystems were compared for their performance in separating a mixture of flaxseed cyclolinopeptides (CLs). Gradient mobile phases of acetonitrile and water were optimized for each column. The performance of CHR column in profiling CL standards, measured as the resolution of individual CL, selectivity, and peak asymmetry exceeded the performance of traditional particle-packed columns and the other monolithic columns. The profiling of CLs in aqueous methanolic flaxseed extract was optimized for high-throughput analysis. A total analysis time of 1.5 min at a flow rate of 3.0mLmin(-1) was achieved on a CSR column. Injection of over 2000 methanol extracts of flaxseed on a CSR column had no impact on backpressure or resolution of a standard CL mixture.

In vitro cytotoxic activity of Brazilian Middle West plant extracts

Cytotoxic activity of eight plant extracts, native from the Mid-West of Brazil comprising Cerrado, Pantanal and semideciduous forest, was evaluated for MDA-MB-435, SF-295, and HCT-8 cancer cell strains. A single 100 µg.mL-1 dose of each extract was employed with 72 h of incubation for all tests. Doxorubicin (1 µg.mL-1) was used as the positive control and the MTT method was used to detect the activity. Cytotoxicity of distinct polarities was observed in thirty extracts (46 percent), from different parts of the following species: Tabebuia heptaphylla (Vell.) Toledo, Bignoniaceae, Tapirira guianensis Aubl., Anacardiaceae, Myracrodruon urundeuva Allemão, Anacardiaceae, Schinus terebinthifolius Raddi, Anacardiaceae, Gomphrena elegans Mart., Amaranthaceae, Attalea phalerata Mart. ex Spreng., Arecaceae, Eugenia uniflora L., Myrtaceae, and Annona dioica A. St.-Hil., Annonaceae. Extracts of at least two tested cell strains were considered to be highly active since their inhibition rate was over 75 percent.

Characterization of a mutant of Chlamydomonas reinhardtii deficient in the molybdenum cofactor.

Molybdenum (Mo) is an essential micronutrient for almost all organisms. In eukaryotes, it forms a part of the molybdenum cofactor (Moco), which is required for numerous enzymes involved in carbon, nitrogen and sulfur metabolism. Mo is taken up by cells in the form of molybdate and recently molybdate transporters have been identified in Arabidopsis thaliana and Chlamydomonas reinhardtii. Here, we report the characterization of a novel mutant (DB6) of C. reinhardtii generated by random insertional mutagenesis that is unable to assimilate nitrate as a nitrogen source because it lacks functional nitrate reductase (NR). Besides lacking NR, DB6 also lacks xanthine dehydrogenase activity; a common requirement of both enzymes is Moco. DB6 displays a 'molybdate-repairable' phenotype--growth on nitrate is partially restored by supplementing media with high levels of molybdate. This phenotype is typically associated with mutants defective in either molybdate transport or insertion of Mo into the pterin precursor of Moco. Mo content was found to be significantly lower in DB6 than in the wild-type strain, AOXR1, which suggests that DB6 is defective in Mo uptake. Genetic complementation with a variety of candidate genes that include the known molybdate transporter MOT1 and DNA that spans the site of mutation was unable to recover the wild-type phenotype. Taken together, our results indicate that DB6 is a novel molybdate transport-deficient mutant.

Remarkable incorporation of the first sulfur containing indole derivative: another piece in the biosynthetic puzzle of crucifer phytoalexins.

The first sulfur labelled compound, [(2)H(4),(34)S]indolyl-3-acetothiohydroxamic acid, is incorporated into the phytoalexins cyclobrassinin and spirobrassinin and the indole glucosinolate glucobrassicin, indicating that both biosynthetic pathways are closely related.

A question of finding harmony: a grounded theory study of clinical psychologists' experience of addressing spiritual beliefs in therapy.

In spite of the increasing emphasis upon spirituality in the psychological literature, research continues to highlight concerns that issues relating to spirituality are regularly overlooked within a therapeutic setting. The aim of the current study was to develop an account of the way in which clinical psychologists understand and address spirituality within therapy. Semi-structured interviews were conducted with eight clinical psychologists. The transcripts were analysed using the qualitative methodology of grounded theory, which also informed the data collection process. Two core categories were developed and termed spirituality as an elusive concept and finding harmony with spiritual beliefs. The diversity of meaning surrounding spirituality and the relative lack of engagement was found to create difficulty for constructing spirituality coherently as a concept. When specifically considering methods for identifying and addressing spiritual beliefs, contrasting approaches were identified. This diversity in understanding and approach has implications for the process and outcome of therapy, which are discussed in detail. Recommendations are suggested for developing spirituality as a more coherent and accessible concept, both within professional dialogue and the therapeutic context.

[Circadian rhythm variations of intraocular pressure and therapeutic decisions: interpretation of clinical trial results based on a statistical model]. / Variations nycthémérales de la pression intraoculaire et décisions thérapeutiques: Interprétation des résultats d'essais cliniques à partir d'un modèle statistique.

Therapeutic decisions (treatment initiation, continuation, change, combination, etc.) based on intraocular pressure (IOP) monitoring require knowledge of both circadian IOP fluctuations and the pharmacological circadian rhythm of the active ingredients. A simple model was applied to data from two clinical trials to estimate the consequences of circadian IOP fluctuations on (1) ocular hypertension diagnosis, (2) therapeutic adjustments, and (3) the daily cumulative effect of marginally low therapeutic differences. A grid for clinical interpretation of the average IOP differences is presented. The probability of an IOP that exceeds the target value for the diagnosis or therapy varied to a large extent throughout the day. IOP was higher in the morning than in the evening. The IOP variance (measured by standard deviation) was an important factor in decision-making, regardless of the IOP value itself. Regular IOP monitoring over the entire day allowed minimization of the time spent above a target value. IOP differences that seemed low when expressed in average values in therapeutic trials could have clinically significant consequences in the practitioner's decisions. The data presented suggest that ocular hypertension diagnosis and therapeutic decisions should be made early in the morning, at least for most patients. In any case, the time of the measurement should be considered in the therapeutic approach.

Evidence of mitochondrial involvement in the transduction of signals required for the induction of genes associated with pathogen attack and senescence.

Using the mRNA differential display technique, seven cDNAs have been isolated that are rapidly induced when cultured tobacco (Nicotiana tabacum) cells are treated with the mitochondrial electron transport inhibitor antimycin A (AA). Interestingly, six of the cDNAs show distinct similarity to genes known to be induced by processes that involve programmed cell death (PCD), such as senescence and pathogen attack. All of the cDNAs as well as Aox1, a gene encoding the alternative oxidase, were found to also be strongly induced by H2O2 and salicylic acid (SA). AA, H2O2 and SA treatment of tobacco cells caused a rapid rise in intracellular ROS accumulation that, when prevented by antioxidant treatment, resulted in inhibition of gene induction. Besides AA, both H2O2 and SA were found to disrupt normal mitochondrial function resulting in decreased rates of electron transport and a lowering of cellular ATP levels. Furthermore, the pre-treatment of tobacco cells with bongkrekic acid, a known inhibitor of the mitochondrial permeability transition pore in animal cells, was found to completely block gene induction when AA, H2O2 or SA were subsequently added. These findings suggest that the mitochondrion may serve an important role in conveying intracellular stress signals to the nucleus, leading to alterations in gene expression.

Effect of sacral nerve stimulation in patients with fecal and urinary incontinence.

PURPOSE: Preliminary studies have shown improvement in fecal incontinence in several patients who received temporary or permanent stimulation. The purpose of this study was to report our experience in sacral nerve stimulation in the treatment of fecal incontinence and to target patients who would benefit most from stimulation. METHODS: Patients with fecal incontinence were studied clinically and manometrically before, during, and after temporary nerve stimulation. If temporary nerve stimulation was clinically successful, the patient was implanted and followed up for six months. RESULTS: Nine patients (6 female) with a mean age of 50.7 +/- 12.3 years underwent temporary nerve stimulation. Temporary nerve stimulation was successful in eight patients, six of whom were implanted. Of the patients who could be evaluated, three of five had improved at the six-month follow-up visit, particularly in relation to the number of urgency episodes and delay in postponing defecation. All implanted patients had urinary symptoms. Urinary urgency was also improved by stimulation. During temporary nerve stimulation, the maximal squeeze pressure amplitude increased. After implantation, only the duration of maximal squeeze pressure seemed to improve. CONCLUSION: Sacral nerve stimulation can be used in the management of fecal incontinence, particularly in cases of urge fecal incontinence associated with urinary urgency. This study seems to confirm the effect of sacral nerve stimulation on striated sphincter function.