Individual based modeling of North Atlantic common minke whale (Balaenoptera acutorostrata) migratory and foraging behaviour in the Nordic Seas

The North Atlantic common minke whale (Balaenoptera Acutorostrata) is an abundant, top-level marine predator in the Nordic Seas and Barents Sea ecosystems whose large-scale migratory and foraging behaviors are widely unknown. Understanding these behaviors may offer important insight into their life-history and management-unit structuring as defined by the International Whaling Commission. Existing modeling do not incorporate spatially-explicit movements of individual minkes, limiting our ability to investigate their large- scale behaviors. In this study, an individual based model (IBM) for minke whales is developed as an extension of the NORWECOM.E2E ecosystem model to identify behaviors that may contribute to minke distribution in the Nordic Seas. The energetic reward of both their use of migration within predominant currents and four large-scale foraging strategies are investigated. First, the effect on minke migration from ocean circulation and migration path selection are tested by running simulations with variation in activation of currents and paths (into and out of the Nordic Seas) along the Norwegian coast, the Norwegian Sea center, and the Greenland coast. Simulations are then run with variation in foraging strategies: random-walk, migration only, and periodic searching for maximum prey density with either random-walk or migration along the route determined to be optimal. NORWECOM.E2E model output of Norwegian spring-spawning herring, blue whiting, and mackerel are used as prey-fields. The optimal migration route is found to be in along the Norwegian coast and out through the Norwegian Sea center, with mean migration durations of 24.611 ± 0.051 d and 24.997 ± 0.041 d. Foraging that incorporates migration and 10 d periods of maximum prey density searching is found to have the highest foraging efficiency index (2.381 ± 0.435). Random- walk movement with maximum prey density searching had similarly high in- dex (2.256 ± 0.444), along with an increase in mean individual whale movement of 14.159 km d^_1 whale^_1 . The development of a minke IBM is an important addition of a high-level predator in Nordic Seas and Barents Sea modeling efforts, and the results from this study could have implications for minke population structuring and success in these areas. With migration throughout the Nordic Seas being energetically viable, interaction between whales categorized as separate sub-stocks could be possible. As an unvalidated model with key improvements necessary, further development of individual based modeling of minkes with more dynamic data is encouraged.JMAMN-MCLIMCLI39

Effect of using internal teat sealant with or without antibiotic therapy at dry-off on subsequent somatic cell count and milk production

peer-reviewedThe objective of this study was to assess the effect of treating cows with teat sealant only compared with antibiotic plus teat sealant at drying off on weekly somatic cell count, potential intramammary infection, and milk production across the entire subsequent lactation. In 3 research herds in the south of Ireland, cows with SCC that did not exceed 200,000 cells/mL in the previous lactation (LowSCC) were randomly assigned to 1 of 2 treatments at drying off: internal teat sealant alone (ITS) or antibiotic plus teat sealant (AB+ITS). Cows with SCC that exceeded 200,000 cells/mL in the previous lactation were treated with AB+ITS and included in the analyses as a separate group (HighSCC). Weekly individual animal composite SCC records were available for 654 cow lactations and were transformed to somatic cell scores (SCS) for the purpose of analysis. Data were divided into 3 data sets to represent records obtained (1) up to 35 DIM, (2) up to 120 DIM, and (3) across the lactation. Foremilk secretions were taken from all quarters at drying off, at calving, 2 wk after calving, and in mid-lactation and were cultured to detect the presence of bacteria. The LowSCC cows treated with ITS alone had higher daily milk yield (0.67 kg/d) across lactation compared with LowSCC cows treated with AB+ITS. The LowSCC cows treated with ITS alone had higher SCS in early, up to mid, and across lactation compared with LowSCC cows treated with AB+ITS. We detected no difference in weekly SCS of LowSCC cows treated with ITS alone and SCS of HighSCC cows. The least squares means back-transformed SCC across lactation of the LowSCC cows treated with ITS alone, LowSCC cows treated with AB+ITS, and HighSCC cows were 41,523, 34,001, and 38,939 cells/mL respectively. The odds of LowSCC cows treated with ITS alone having bacteria present in their foremilk across lactation was 2.7 (95% confidence interval: 1.91 to 3.85) and 1.6 (1.22 to 2.03) times the odds of LowSCC cows treated with AB+ITS and of HighSCC cows treated with AB+ITS, respectively. In this study, Staphylococcus aureus was the most prevalent pathogen isolated from the population. Recategorizing the threshold for LowSCC cows as ≤150,000 cells/mL or ≤100,000 cells/mL in the previous lactation had no effect on the results. The results indicate that herds with good mastitis control programs may use ITS alone at dry-off in cows with SCC <200,000 cells/mL across lactation with only a small effect on herd SCC

Effect of using internal teat sealant with or without antibiotic therapy at dry-off on subsequent somatic cell count and milk production

peer-reviewedThe objective of this study was to assess the effect of treating cows with teat sealant only compared with antibiotic plus teat sealant at drying off on weekly somatic cell count, potential intramammary infection, and milk production across the entire subsequent lactation. In 3 research herds in the south of Ireland, cows with SCC that did not exceed 200,000 cells/mL in the previous lactation (LowSCC) were randomly assigned to 1 of 2 treatments at drying off: internal teat sealant alone (ITS) or antibiotic plus teat sealant (AB+ITS). Cows with SCC that exceeded 200,000 cells/mL in the previous lactation were treated with AB+ITS and included in the analyses as a separate group (HighSCC). Weekly individual animal composite SCC records were available for 654 cow lactations and were transformed to somatic cell scores (SCS) for the purpose of analysis. Data were divided into 3 data sets to represent records obtained (1) up to 35 DIM, (2) up to 120 DIM, and (3) across the lactation. Foremilk secretions were taken from all quarters at drying off, at calving, 2 wk after calving, and in mid-lactation and were cultured to detect the presence of bacteria. The LowSCC cows treated with ITS alone had higher daily milk yield (0.67 kg/d) across lactation compared with LowSCC cows treated with AB+ITS. The LowSCC cows treated with ITS alone had higher SCS in early, up to mid, and across lactation compared with LowSCC cows treated with AB+ITS. We detected no difference in weekly SCS of LowSCC cows treated with ITS alone and SCS of HighSCC cows. The least squares means back-transformed SCC across lactation of the LowSCC cows treated with ITS alone, LowSCC cows treated with AB+ITS, and HighSCC cows were 41,523, 34,001, and 38,939 cells/mL respectively. The odds of LowSCC cows treated with ITS alone having bacteria present in their foremilk across lactation was 2.7 (95% confidence interval: 1.91 to 3.85) and 1.6 (1.22 to 2.03) times the odds of LowSCC cows treated with AB+ITS and of HighSCC cows treated with AB+ITS, respectively. In this study, Staphylococcus aureus was the most prevalent pathogen isolated from the population. Recategorizing the threshold for LowSCC cows as ≤150,000 cells/mL or ≤100,000 cells/mL in the previous lactation had no effect on the results. The results indicate that herds with good mastitis control programs may use ITS alone at dry-off in cows with SCC <200,000 cells/mL across lactation with only a small effect on herd SCC

Characterization of cellulolytic activity in the gut of the terrestrial land slug Arion ater : Biochemical identification of targets for intensive study

The level of cellulolytic activity in different areas of the gut of the terrestrial slug Arion ater was assayed at different temperatures and pH values. To do this, crude gut proteins were isolated and assayed using modified dinitrosalicylic acid reducing sugar assay. Crude protein samples were also separated and cellulolytic activity identified using in gel CMC zymography and esculin hydrate activity gel assays. pH and temperature profiling revealed optimum cellulolytic activity between pH5.0 and 6.0 for different gut regions and retention of up to 90% of activity at temperatures up to 50°C. Zymograms and activity gels revealed multiple endoglucanase and β-glucosidase enzymes. To further investigate the source of this cellulolytic activity bacterial isolates from the gut were tested for endoglucanase and β-glucosidase activity using growth plate assays. 12 cellulolytic microbes were identified using 16S rDNA gene sequencing. These include members of the genera Buttiauxella, Enterobacter, Citrobacter, Serratia and Klebsiella. Gut metagenomic DNA was then subjected to PCR, targeting a 400bp region of the 16SrDNA gene which was subsequently separated and individuals identified using DGGE. This identified members of the genera Citrobacter, Serratia, Pectobacterium, Acinetobacter, Mycoplasma, Pantoea and Erwinia. In summary, multiple glycoside hydrolase enzymes active over a broad range of temperature and pH values in a relatively under studied organism were detected, indicating that the gut of A. ater is a viable target for intensive study to identify novel carbohydrate active enzymes that may be used in the biofuel industry

Venous access devices for the delivery of long-term chemotherapy: the CAVA three-arm RCT

Background: Venous access devices are used for patients receiving long-term chemotherapy. These include centrally inserted tunnelled catheters or Hickman-type devices (Hickman), peripherally inserted central catheters (PICCs) and centrally inserted totally implantable venous access devices (PORTs). Objectives: To evaluate the clinical effectiveness, safety, cost-effectiveness and acceptability of these devices for the central delivery of chemotherapy. Design: An open, multicentre, randomised controlled trial to inform three comparisons: (1) peripherally inserted central catheters versus Hickman, (2) PORTs versus Hickman and (3) PORTs versus peripherally inserted central catheters. Pre-trial and post-trial qualitative research and economic evaluation were also conducted. Setting: This took place in 18 UK oncology centres. Participants: Adult patients (aged ≥ 18 years) receiving chemotherapy (≥ 12 weeks) for either a solid or a haematological malignancy were randomised via minimisation. Interventions: Hickman, peripherally inserted central catheters and PORTs. Primary outcome: A composite of infection (laboratory confirmed, suspected catheter related and exit site infection), mechanical failure, venous thrombosis, pulmonary embolism, inability to aspirate blood and other complications in the intention-to-treat population. Results: Overall, 1061 participants were recruited to inform three comparisons. First, for the comparison of peripherally inserted central catheters (n = 212) with Hickman (n = 212), it could not be concluded that peripherally inserted central catheters were significantly non-inferior to Hickman in terms of complication rate (odds ratio 1.15, 95% confidence interval 0.78 to 1.71). The use of peripherally inserted central catheters compared with Hickman was associated with a substantially lower cost (–£1553) and a small decrement in quality-adjusted life-years gained (–0.009). Second, for the comparison of PORTs (n = 253) with Hickman (n = 303), PORTs were found to be statistically significantly superior to Hickman in terms of complication rate (odds ratio 0.54, 95% confidence interval 0.37 to 0.77). PORTs were found to dominate Hickman with lower costs (–£45) and greater quality-adjusted life-years gained (0.004). This was alongside a lower complications rate (difference of 14%); the incremental cost per complication averted was £1.36. Third, for the comparison of PORTs (n = 147) with peripherally inserted central catheters (n = 199), PORTs were found to be statistically significantly superior to peripherally inserted central catheters in terms of complication rate (odds ratio 0.52, 95% confidence interval 0.33 to 0.83). PORTs were associated with an incremental cost of £2706 when compared with peripherally inserted central catheters and a decrement in quality-adjusted life-years gained (–0.018) PORTs are dominated by peripherally inserted central catheters: alongside a lower complications rate (difference of 15%), the incremental cost per complication averted was £104. The qualitative work showed that attitudes towards all three devices were positive, with patients viewing their central venous access device as part of their treatment and recovery. PORTs were perceived to offer unique psychological benefits, including a greater sense of freedom and less intrusion in the context of personal relationships. The main limitation was the lack of adequate power (54%) in the non-inferiority comparison between peripherally inserted central catheters and Hickman. Conclusions: In the delivery of long-term chemotherapy, peripherally inserted central catheters should be considered a cost-effective option when compared with Hickman. There were significant clinical benefits when comparing PORTs with Hickman and with peripherally inserted central catheters. The health economic benefits were less clear from the perspective of incremental cost per quality-adjusted life-years gained. However, dependent on the willingness to pay, PORTs may be considered to be cost-effective from the perspective of complications averted. Future work: The deliverability of a PORTs service merits further study to understand the barriers to and methods of improving the service. Trial registration: This trial is registered as ISRCTN44504648. Funding: This project was funded by the National Institute for Health Research (NHIR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 47. See the NIHR Journals Library website for further project information

Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance

BACKGROUND: Creatine monohydrate (CrM) and nitrate are popular supplements for improving exercise performance; yet have not been investigated in combination. We performed two studies to determine the safety and exercise performance-characteristics of creatine nitrate (CrN) supplementation. METHODS: Study 1 participants (N = 13) ingested 1.5 g CrN (CrN-Low), 3 g CrN (CrN-High), 5 g CrM or a placebo in a randomized, crossover study (7d washout) to determine supplement safety (hepatorenal and muscle enzymes, heart rate, blood pressure and side effects) measured at time-0 (unsupplemented), 30-min, and then hourly for 5-h post-ingestion. Study 2 participants (N = 48) received the same CrN treatments vs. 3 g CrM in a randomized, double-blind, 28d trial inclusive of a 7-d interim testing period and loading sequence (4 servings/d). Day-7 and d-28 measured Tendo™ bench press performance, Wingate testing and a 6x6-s bicycle ergometer sprint. Data were analyzed using a GLM and results are reported as mean ± SD or mean change ± 95 % CI. RESULTS: In both studies we observed several significant, yet stochastic changes in blood markers that were not indicative of potential harm or consistent for any treatment group. Equally, all treatment groups reported a similar number of minimal side effects. In Study 2, there was a significant increase in plasma nitrates for both CrN groups by d-7, subsequently abating by d-28. Muscle creatine increased significantly by d-7 in the CrM and CrN-High groups, but then decreased by d-28 for CrN-High. By d-28, there were significant increases in bench press lifting volume (kg) for all groups (PLA, 126.6, 95 % CI 26.3, 226.8; CrM, 194.1, 95 % CI 89.0, 299.2; CrN-Low, 118.3, 95 % CI 26.1, 210.5; CrN-High, 267.2, 95 % CI 175.0, 359.4, kg). Only the CrN-High group was significantly greater than PLA (p < 0.05). Similar findings were observed for bench press peak power (PLA, 59.0, 95 % CI 4.5, 113.4; CrM, 68.6, 95 % CI 11.4, 125.8; CrN-Low, 40.9, 95 % CI −9.2, 91.0; CrN-High, 60.9, 95 % CI 10.8, 111.1, W) and average power. CONCLUSIONS: Creatine nitrate delivered at 3 g was well-tolerated, demonstrated similar performance benefits to 3 g CrM, in addition, within the confines of this study, there were no safety concerns

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

An Atlas for Schistosoma mansoni Organs and Life-Cycle Stages Using Cell Type-Specific Markers and Confocal Microscopy

Schistosomiasis (bilharzia) is a tropical disease caused by trematode parasites (Schistosoma) that affects hundreds of millions of people in the developing world. Currently only a single drug (praziquantel) is available to treat this disease, highlighting the importance of developing new techniques to study Schistosoma. While molecular advances, including RNA interference and the availability of complete genome sequences for two Schistosoma species, will help to revolutionize studies of these animals, an array of tools for visualizing the consequences of experimental perturbations on tissue integrity and development needs to be made widely available. To this end, we screened a battery of commercially available stains, antibodies and fluorescently labeled lectins, many of which have not been described previously for analyzing schistosomes, for their ability to label various cell and tissue types in the cercarial stage of S. mansoni. This analysis uncovered more than 20 new markers that label most cercarial tissues, including the tegument, the musculature, the protonephridia, the secretory system and the nervous system. Using these markers we present a high-resolution visual depiction of cercarial anatomy. Examining the effectiveness of a subset of these markers in S. mansoni adults and miracidia, we demonstrate the value of these tools for labeling tissues in a variety of life-cycle stages. The methodologies described here will facilitate functional analyses aimed at understanding fundamental biological processes in these parasites

The Gravity Collective: A Search for the Electromagnetic Counterpart to the Neutron Star-Black Hole Merger GW190814

We present optical follow-up imaging obtained with the Katzman Automatic Imaging Telescope, Las Cumbres Observatory Global Telescope Network, Nickel Telescope, Swope Telescope, and Thacher Telescope of the LIGO/Virgo gravitational wave (GW) signal from the neutron star-black hole (NSBH) merger GW190814. We searched the GW190814 localization region (19 deg$^{2}$ for the 90th percentile best localization), covering a total of 51 deg$^{2}$ and 94.6% of the two-dimensional localization region. Analyzing the properties of 189 transients that we consider as candidate counterparts to the NSBH merger, including their localizations, discovery times from merger, optical spectra, likely host-galaxy redshifts, and photometric evolution, we conclude that none of these objects are likely to be associated with GW190814. Based on this finding, we consider the likely optical properties of an electromagnetic counterpart to GW190814, including possible kilonovae and short gamma-ray burst afterglows. Using the joint limits from our follow-up imaging, we conclude that a counterpart with an $r$-band decline rate of 0.68 mag day$^{-1}$, similar to the kilonova AT 2017gfo, could peak at an absolute magnitude of at most $-17.8$ mag (50% confidence). Our data are not constraining for ''red'' kilonovae and rule out ''blue'' kilonovae with $M>0.5 M_{\odot}$ (30% confidence). We strongly rule out all known types of short gamma-ray burst afterglows with viewing angles $<$17$^{\circ}$ assuming an initial jet opening angle of $\sim$$5.2^{\circ}$ and explosion energies and circumburst densities similar to afterglows explored in the literature. Finally, we explore the possibility that GW190814 merged in the disk of an active galactic nucleus, of which we find four in the localization region, but we do not find any candidate counterparts among these sources.Comment: 86 pages, 9 figure