Effects of a saponin fraction extracted from Trigonella foenum-graecum L. and two commercially available saponins on sex ratio and gonad histology of Nile tilapa fry, Oreochromis niloticus (L.)

Over three million tonnes (t) of tilapia, mostly Nile tilapia (Oreochromis niloticus, L.), are produced annually making it the second most abundantly produced freshwater fish (FAO, 2010). Tilapia are mouthbreeders that often produce stunted populations under pond conditions; one means of prevention is to produce all-male fish with the additional advantage that males usually grow faster than females. All-male populations can be achieved by supplementing feed with androgens such as 17-α-Methyltestosterone (MT) during days 10–25 post-hatch (Pandian and Sheela, 1995). However, MT is considered to be carcinogenic (Velazquez and Alter, 2004), and Hulak et al. (2008) also showed that effluents of systems in which carp were fed diets containing MT caused masculinization of female fish. Furthermore, in aquaculture the application of hormones to fish destined for human consumption is prohibited in the European Union under directive 96/22/EC, article 5, which also prohibits import of animal products produced with hormones. Kwon et al. (2000) showed that Fadrozole, a non-steroidal compound, caused masculinization in tilapia by inhibiting aromatase, which is the enzyme responsible for the conversion of endogenous androgens to estrogens. Steinbronn et al. (2004) were able to show that a dose of 2000 ppm Quillaja saponins (Sigma S-2149) inhibited reproduction of tilapia after dietary application for 32 days to first-feeding fry, suggesting saponins as a possible alternative to MT. These secondary plant compounds consist of either a steroid or triterpenoid basic structure (aglycone or sapogenin) plus one or more sugar side chains (Francis et al., 2002a). In a previous experiment a saponin fraction from the soapbark tree (Quillaja saponaria M.) inhibited aromatase in vitro (Golan et al., 2008). The fenugreek plant (Trigonella foenum-graecum L), widely cultivated in the Middle East and Asia, also has a high saponin content. The experiment was therefore conducted to test whether saponin fractions from Q. saponaria and from T. foenum-graecum were able to influence the sex ratio and gonad histology of Nile tilapia

The unfolded protein response affects readthrough of premature termination codons

One-third of monogenic inherited diseases result from premature termination codons (PTCs). Readthrough of in-frame PTCs enables synthesis of full-length functional proteins. However, extended variability in the response to readthrough treatment is found among patients, which correlates with the level of nonsense transcripts. Here, we aimed to reveal cellular pathways affecting this inter-patient variability. We show that activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts carrying PTCs. Quantitative proteomic analyses showed substantial differences in UPR activation between patients carrying PTCs, correlating with their response. We further found a significant inverse correlation between the UPR and nonsense-mediated mRNA decay (NMD), suggesting a feedback loop between these homeostatic pathways. We uncovered and characterized the mechanism underlying this NMD-UPR feedback loop, which augments both UPR activation and NMD attenuation. Importantly, this feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Altogether, our study demonstrates the importance of the UPR and its regulatory network for genetic diseases caused by PTCs and for cell homeostasis under normal conditions

New approaches to genetic therapies for cystic fibrosis

Gene therapy offers great promise for cystic fibrosis which has never been quite fulfilled due to the challenges of delivering sufficient amounts of the CFTR gene and expression persistence for a sufficient period of time in the lungs to have any effect. Initial trials explored both viral and non-viral vectors but failed to achieve a significant breakthrough. However, in recent years, new opportunities have emerged that exploit our increased knowledge and understanding of the biology of CF and the airway epithelium. New technologies include new viral and non-viral vector approaches to delivery, but also alternative nucleic acid technologies including oligonucleotides and siRNA approaches for gene silencing and gene splicing, described in this review, as presented at the 2019 annual European CF Society Basic Science meeting (Dubrovnik, Croatia). We also briefly discuss other emerging technologies including mRNA and CRISPR gene editing that are advancing rapidly. The future prospects for genetic therapies for CF are now diverse and more promising probably than any time since the discovery of the CF gene

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

<div><p>Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in <i>Cftr^F508del</i> homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the <i>F508del-CFTR</i> mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from <i>F508del</i> homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both <i>in vivo</i>, in mice, and <i>in vitro</i>, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 <i>F508del-CFTR</i> homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells <i>in vivo</i>, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of <i>TNF/TNF-alpha (tumor necrosis factor)</i> and <i>CXCL8</i> (<i>chemokine [C-X-C motif] ligand 8</i>) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the <i>F508del-CFTR</i> mutation.</p></div

The Energetic Particle Detector (EPD) Investigation and the Energetic Ion Spectrometer (EIS) for the Magnetospheric Multiscale (MMS) Mission

Abstract The Energetic Particle Detector (EPD) Investigation is one of 5 fields-and-particles investigations on the Magnetospheric Multiscale (MMS) mission. MMS comprises 4 spacecraft flying in close formation in highly elliptical, near-Earth-equatorial orbits targeting understanding of the fundamental physics of the important physical process called magnetic reconnection using Earth’s magnetosphere as a plasma laboratory. EPD comprises two sensor types, the Energetic Ion Spectrometer (EIS) with one instrument on each of the 4 spacecraft, and the Fly’s Eye Energetic Particle Spectrometer (FEEPS) with 2 instruments on each of the 4 spacecraft. EIS measures energetic ion energy, angle and elemental compositional distributions from a required low energy limit of 20 keV for protons and 45 keV for oxygen ions, up to \u3e0.5 MeV (with capabilities to measure up to \u3e1 MeV). FEEPS measures instantaneous all sky images of energetic electrons from 25 keV to \u3e0.5 MeV, and also measures total ion energy distributions from 45 keV to \u3e0.5 MeV to be used in conjunction with EIS to measure all sky ion distributions. In this report we describe the EPD investigation and the details of the EIS sensor. Specifically we describe EPD-level science objectives, the science and measurement requirements, and the challenges that the EPD team had in meeting these requirements. Here we also describe the design and operation of the EIS instruments, their calibrated performances, and the EIS in-flight and ground operations. Blake et al. (The Flys Eye Energetic Particle Spectrometer (FEEPS) contribution to the Energetic Particle Detector (EPD) investigation of the Magnetospheric Magnetoscale (MMS) Mission, this issue) describe the design and operation of the FEEPS instruments, their calibrated performances, and the FEEPS in-flight and ground operations. The MMS spacecraft will launch in early 2015, and over its 2-year mission will provide comprehensive measurements of magnetic reconnection at Earth’s magnetopause during the 18 months that comprise orbital phase 1, and magnetic reconnection within Earth’s magnetotail during the about 6 months that comprise orbital phase 2

Mixed integer programming in production planning with backlogging and setup carryover : modeling and algorithms

This paper proposes a mixed integer programming formulation for modeling the capacitated multi-level lot sizing problem with both backlogging and setup carryover. Based on the model formulation, a progressive time-oriented decomposition heuristic framework is then proposed, where improvement and construction heuristics are effectively combined, therefore efficiently avoiding the weaknesses associated with the one-time decisions made by other classical time-oriented decomposition algorithms. Computational results show that the proposed optimization framework provides competitive solutions within a reasonable time

PTX3 genetic variations affect the risk of Pseudomonas aeruginosa airway colonization in cystic fibrosis patients

Cystic fibrosis (CF) is a common life-threatening autosomal recessive disorder in the Caucasian population, and the gene responsible is the CF transmembrane conductance regulator (CFTR). Patients with CF have repeated bacterial infection of the airways caused by Pseudomonas aeruginosa (PA), which is one of the predominant pathogen, and endobronchial chronic infection represents a major cause of morbidity and mortality. Pentraxin 3 (PTX3) is a gene that encodes the antimicrobial protein, PTX3, which is believed to have an important role in innate immunity of lung. To address the role of PTX3 in the risk of PA lung colonization, we investigated five single nucleotide polymorphisms of PTX3 gene in 172 Caucasian CF patients who were homozygous for the F508del mutation. We observed that PTX3 haplotype frequencies were significantly different between patients with PA colonization, as compared with noncolonized patients. Moreover, a protective effect was found in association with a specific haplotype (odds ratio 0.524). Our data suggest that variations within PTX3 affect lung colonization of Pseudomonas in patients with CF

Using leap motion to investigate the emergence of structure in speech and language

© 2016, The Author(s). In evolutionary linguistics, experiments using artificial signal spaces are being used to investigate the emergenceof speech structure. These signal spaces need to be continuous, non-discretized spaces from which discrete unitsand patterns can emerge. They need to be dissimilar from—but comparable with—the vocal tract, in order tominimize interference from pre-existing linguistic knowledge, while informing us about language. This is a hardbalance to strike. This article outlines a new approach that uses the Leap Motion, an infrared controller that canconvert manual movement in 3d space into sound. The signal space using this approach is more flexible than signalspaces in previous attempts. Further, output data using this approach is simpler to arrange and analyze. Theexperimental interface was built using free, and mostly open- source libraries in Python. We provide our sourcecode for other researchers as open source

Effects of saponin fractions from fenugreek and the soap bark tree in the diet on performance of Nile tilapia, Oreochromis niloticus (L.)

Saponins are generally regarded as anti-nutritional factors in aquaculture diets. However, previous experiments have shown that low dietary levels of saponins derived from Quillaja saponaria Molina do have growth promoting effects on common carp and Nile tilapia. Based on these experiments, we conducted an experiment in which we fed eluated saponin fractions from Q. saponaria and Trigonella foenum-graecum L. (fenugreek) to Nile tilapia in a respirometric system allowing for continuous measurement of oxygen consumption. Saponins were eluated with consecutive methanol/water concentrations (v/v, 40/60, 60/40, 80/20) resulting in three different eluates for each plant. Fractions chosen were the 80% methanol eluate from Q. saponaria (80QS) and all three eluates from T. foenum-graecum (40TS, 60TS and 80TS). Three fish each were fed with low levels (150 mg kg-1 diet) of saponins in the diet and a control diet without saponins. Growth, feed and nutrient utilization, proximate composition, oxygen consumption and metabolic performance were evaluated. The fish grew between 224% (40TS) and 266% (Control) over the eight week period. Feed conversion ratios were between 0.94 (80TS) and 1.15 (40TS) and protein efficiency ratios between 2.54 (80TS) and 2.16 (40TS). Due to low sample sizes, no statistical differences were found between control fish and saponin fed fish. However, numerically one of the tested saponin fractions (40TS) showed inferior performance (Table 1). It is concluded that the tested saponins in the tested concentrations are no potential growth promoter for Nile tilapia. On the contrary, one fraction appears to be a growth inhibitor