Lateral variability of ichnological content in muddy contourites: Weak bottom currents affecting organisms’ behavior

Although bioturbation is commonly recognized in contourites, only a few studies have analyzed the ichnological content of these deposits in detail. These studies have mainly focused on meso-scale bigradational sequence (a coarsening upward followed by a fining-upward sequence resulting from variations in current velocity). Here we present data from gravitational cores collected along the NW Iberian Margin showing systematic variation in ichnological content across proximal to distal depocenters within a large-scale elongated contourite drift. Data demonstrate that tracemakers’ behavior varies depending on the distance relative to the bottom current core. Trace fossils are already known to be a useful tool for studying of contouritic deposits and are even used as criterion for differentiating associated facies (e.g., turbidites, debrites), though not without controversy. We propose a mechanism by which the distance to the bottom current core exerts tangible influence on specific macro-benthic tracemaker communities in contourite deposits. This parameter itself reflects other bottom current features, such as hydrodynamic energy, grain size, nutrient transport, etc. Ichnological analysis can thus resolve cryptic features of contourite drift depositional settings.The contribution and research by JD was funded through the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 792314 (ICON-SE). The research of FJR-T was funded by project CGL2015-66835-P (Secretaría de Estado de Investigacion, Desarrollo e Innovacion, Spain), Research Group RNM-178 (Junta de Andalucía), and Scientific Excellence Unit UCE-2016- 05 (Universidad de Granada). AM’s research is funded by the I2C program of the Xunta de Galicia Postdoctoral programme (ED481B 2016/029-0). The research was conducted as part of “The Drifters Research Group” (RHUL) and “Ichnology and Palaeoenvironment Research Group” (UGR) programs

Glutamate-Gated Chloride Channels of Haemonchus contortus Restore Drug Sensitivity to Ivermectin Resistant Caenorhabditis elegans

Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects of polymorphisms found in resistant parasites, but may be complicated by differences between the gene families of target and model organisms. We tested this using the glutamate-gated chloride channel (GluCl) gene family, which forms the ivermectin drug target and are candidate resistance genes. We expressed GluCl subunits from C. elegans and H. contortus in a highly resistant triple mutant C. elegans strain (DA1316) under the control of the avr-14 promoter; expression of GFP behind this promoter recapitulated the pattern previously reported for avr-14. Expression of ivermectin-sensitive subunits from both species restored drug sensitivity to transgenic worms, though some quantitative differences were noted between lines. Expression of an ivermectin-insensitive subunit, Hco-GLC-2, had no effect on drug sensitivity. Expression of a previously uncharacterised parasite-specific subunit, Hco-GLC-6, caused the transgenic worms to become ivermectin sensitive, suggesting that this subunit also encodes a GluCl that responds to the drug. These results demonstrate that both orthologous and paralogous subunits from C. elegans and H. contortus are able to rescue the ivermectin sensitivity of mutant C. elegans, though some quantitative differences were observed between transgenic lines in some assays. C. elegans is a suitable system for studying parasitic nematode genes that may be involved in drug resistance

Temporal allocation of foraging effort in female Australian fur seals (Arctocephalus pusillus doriferus)

Across an individual\u27s life, foraging decisions will be affected by multiple intrinsic and extrinsic drivers that act at differing timescales. This study aimed to assess how female Australian fur seals allocated foraging effort and the behavioural changes used to achieve this at three temporal scales: within a day, across a foraging trip and across the final six months of the lactation period. Foraging effort peaked during daylight hours (57% of time diving) with lulls in activity just prior to and after daylight. Dive duration reduced across the day (196 s to 168 s) but this was compensated for by an increase in the vertical travel rate (1500–1600 m•h−1) and a reduction in postdive duration (111–90 s). This suggests physiological constraints (digestive costs) or prey availability may be limiting mean dive durations as a day progresses. During short trips (<2.9 d), effort remained steady at 55% of time diving, whereas, on long trips (>2.9 d) effort increased up to 2–3 d and then decreased. Dive duration decreased at the same rate in short and long trips, respectively, before stabilising (long trips) between 4–5 d. Suggesting that the same processes (digestive costs or prey availability) working at the daily scale may also be present across a trip. Across the lactation period, foraging effort, dive duration and vertical travel rate increased until August, before beginning to decrease. This suggests that as the nutritional demands of the suckling pup and developing foetus increase, female effort increases to accommodate this, providing insight into the potential constraints of maternal investment in this specie

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

<div><p>Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in <i>Trypanosoma brucei</i>. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.</p></div

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Nanoscale stimulation of osteoblastogenesis from mesenchymal stem cells: nanotopography and nanokicking

AIM: Mesenchymal stem cells (MSCs) have large regenerative potential to replace damaged cells from several tissues along the mesodermal lineage. The potency of these cells promises to change the longer term prognosis for many degenerative conditions currently suffered by our aging population. We have endeavored to demonstrate our ability to induce osteoblatogenesis in MSCs using high-frequency (1000-5000 Hz) piezo-driven nanodisplacements (16-30 nm displacements) in a vertical direction. &lt;p&gt;&lt;/p&gt; MATERIALS and METHODS: Osteoblastogenesis has been determined by the upregulation of osteoblasic genes such as osteonectin (ONN), RUNX2 and Osterix, assessed via quantitative real-time PCR; the increase of osteocalcin (OCN) and osteopontin (OPN) at the protein level and the deposition of calcium phosphate determined by histological staining.&lt;p&gt;&lt;/p&gt; RESULTS: Intriguingly, we have observed a relationship between nanotopography and piezo-stimulated mechanotransduction and possibly see evidence of two differing osteogenic mechanisms at work. These data provide confidence in nanomechanotransduction for stem cell differentiation without dependence on soluble factors and complex chemistries.&lt;p&gt;&lt;/p&gt; CONCLUSION: In the future it is envisaged that this technology may have beneficial therapeutic applications in the healthcare industry, for conditions whose overall phenotype maybe characterized by weak or damaged bones (e.g., osteoporosis and bone fractures), and which can benefit from having an increased number of osteoblastic cells in vivo.&lt;p&gt;&lt;/p&gt

The actions of chloride channel blockers, barbiturates and a benzodiazepine on Caenorhabditis elegans glutamate- and ivermectin-gated chloride channel subunits expressed in Xenopus oocytes

The pharmacology of Caenorhabditis elegans glutamate-gated chloride (GluCl) channels was determined by making intracellular voltage-clamp recordings from Xenopus oocytes expressing GluCl subunits. As previously reported (Cully et al. 1994), GluClalpha1beta responded to glutamate (in a picrotoxin sensitive manner) and ivermectin, while GluClbeta responded only to glutamate and GluClalpha1 only to ivermectin. This assay was used to further investigate the action of chloride channel compounds. The arylaminobenzoate, NPPB, reduced the action of glutamate on the heteromeric GluClalpha1beta channel (IC(50) 6.03 ± 0.81 µM). The disulphonate stilbene, DNDS, blocked the effect of both glutamate and ivermectin on GluClalpha1beta channels, the action of glutamate on GluClbeta subunits, and the effect of ivermectin on GluClalpha1 subunits (IC(50)s 1.58-3.83 µM). Surprisingly, amobarbital and pentobarbital, otherwise known as positive allosteric modulators of ligand-gated chloride channels, acted as antagonists. Both compounds reduced the action of glutamate on the GluClalpha1beta heteromer (IC(50)s of 2.04 ± 0.5 and 17.56 ± 2.16 µM, respectively). Pentobarbital reduced the action of glutamate on the GluClbeta homomeric subunit with an IC(50) of 0.59 ± 0.09 µM, while reducing the responses to ivermectin on both GluClalpha1beta and GluClalpha1 with IC(50)s of 8.7 ± 0.5 and 12.9 ± 2.5 µM, respectively. For all the antagonists, the mechanism is apparently non-competitive. The benzodiazepine, flurazepam had no apparent effect on these glutamate- and ivermectin-gated chloride channel subunits. Thus, arylaminobenzoates, disulphonate stilbenes, and barbiturates are non-competitive antagonists of C. elegans GluCl channels