Alginate Oligosaccharides modify hyphal infiltration of Candida albicans in an in vitro model of invasive Human Candidosis

AIMS: A novel alginate oligomer (OligoG CF-5/20) has been shown to potentiate antifungal therapy against a range of fungal pathogens. The current study assessed the effect of this oligomer on in vitro virulence factor expression and epithelial invasion by Candida species. METHODS AND RESULTS: Plate substrate assays and epithelial models were used to assess Candida albicans (CCUG 39343 and ATCC 90028) invasion, in conjunction with confocal laser scanning microscopy and histochemistry. Expression of candidal virulence factors was determined biochemically and by quantitative PCR (qPCR). Changes in surface charge of C. albicans following OligoG treatment were analysed using electrophoretic light scattering. OligoG induced marked alterations in hyphal formation in the substrate assays and reduced invasion in the epithelial model (P 0·05), qPCR demonstrated a reduction in phospholipase B (PLB2) and SAPs (SAP4 and SAP6) expression. CONCLUSION: OligoG CF-5/20 reduced in vitro virulence factor expression and invasion by C. albicans. SIGNIFICANCE AND IMPACT OF THE STUDY: These results, and the previously described potentiation of antifungal activity, define a potential therapeutic opportunity in the treatment of invasive candidal infections

Towards a better understanding of the benefits and risks of country food consumption using the case of walruses in Nunavik (Northern Quebec, Canada)

Food insecurity affects Inuit communities. One solution is to consume locally harvested foods, named country foods. However, some country foods are not eaten as often as before, and pressures including contaminants and environmental changes threaten the health of Arctic fauna, thus its suitability for local consumption. By combining Inuit Knowledge with laboratory data, our study assessed the benefits and risks of walrus consumption by Inuit in Nunavik, Québec, Canada. It aimed to increase understanding of: 1) the hunt of healthy Atlantic walruses (Odobenus rosmarus rosmarus); 2) the safe preparation of walruses; 3) the nutritional benefits and risks of consuming walruses. To do so, we interviewed 34 hunters and Elders from Nunavik. Levels of mercury, omega-3 polyunsaturated fatty acids and selenium were evaluated from locally harvested walruses. Through the Nunavik Trichinellosis Prevention Program, a total of 755 Atlantic walrus samples, collected between 1994 and 2013, were tested for Trichinella nativa. Information on botulism was reviewed. While interviews informed on how to select healthy walruses and prepare them for consumption, laboratory analyses revealed that walruses had elevated levels of omega-3 fatty acids and selenium but low levels of mercury compared to some other wildlife. Only 3% of the 755 walruses were infected with T. nativa. Most walruses' infections were found within individuals from the South East Hudson Bay stock, where Inuit have thus decided to stop hunting since mid-2000s. Finally, although the number of outbreaks of trichinellosis related to the consumption of walruses has significantly reduced in Nunavik, botulism could continue to be an issue when igunaq (i.e. aged walrus) is not properly prepared. With the support of the Nunavik Trichinellosis Prevention Program and transmission of Inuit knowledge on igunaq preparation, the consumption of Atlantic walruses has the potential to help address issues related to food insecurity in Nunavik in the future

Capturing systemic interrelationships by an impact analysis to help reduce production diseases in dairy farms

Production diseases, such asmetabolic and reproductive disorders,mastitis, and lameness,emerge from complex interactions between numerous factors (or variables) but can be controlled by the right management decisions. Since animal husbandry systems in practice are very diverse, it is difficult to identify the most influential components in the individual farm context. However, it is necessary to do this to control disease, since farmers are severely limited in their access to resources, and need to invest in management measures most likely to have an effect. In this study, systemic impact analyses were conducted on 192 organic dairy farms in France, Germany, Spain, and Sweden in the context of reducing the prevalence of production diseases. The impact analyses were designed to evaluate the interrelationships between farm variables and determine the systemic roles of these variables. In particular, the aim was to identify the most influential variables on each farm. The impact analysis consisted of a stepwise process: (i) in a participatory process 13 relevant system variables affecting the emergence of production diseases on organic dairy farms were defined; (ii) the interrelationships between these variables were evaluated by means of an impact matrix on the farm-level, involving the perspectives of the farmer, an advisor and the farm veterinarian; and (iii) the results were then used to identify general system behaviour and to classify variables by their level of influence on other system variables and their susceptibility to influence. Variables were either active (high influence, lowsusceptibility), reactive (low influence, high susceptibility), critical (both high), or buffering (both low). An overall active tendency was found for feeding regime, housing conditions, herd health monitoring, and knowledge and skills, while milk performance and financial resources tended to be reactive. Production diseases and labour capacity had a tendency for being critical while reproduction management, dry cow management, calf and heifer management, hygiene and treatment tended to have a buffering capacity. While generalised tendencies for variables emerged, the specific role of variables could vary widely between farms. The strength of this participatory impact assessment approach is its ability, through filling in the matrix and discussion of the output between farmer, advisor and veterinarian, to explicitly identify deviations from general expectations, thereby supporting a farm-specific selection of health management strategies and measures

Mass distributions of stars and cores in young groups and clusters

We investigate the relation of the stellar initial mass function (IMF) and the dense core mass function (CMF), using stellar masses and positions in 14 well-studied young groups. Initial column density maps are computed by replacing each star with a model initial core having the same star formation efficiency (SFE). For each group the SFE, core model, and observational resolution are varied to produce a realistic range of initial maps. A clumpfinding algorithm parses each initial map into derived cores, derived core masses, and a derived CMF. The main result is that projected blending of initial cores causes derived cores to be too few and too massive. The number of derived cores is fewer than the number of initial cores by a mean factor 1.4 in sparse groups and 5 in crowded groups. The mass at the peak of the derived CMF exceeds the mass at the peak of the initial CMF by a mean factor 1.0 in sparse groups and 12.1 in crowded groups. These results imply that in crowded young groups and clusters, the mass distribution of observed cores may not reliably predict the mass distribution of protostars which will form in those cores.Comment: 48 pages, 17 figures, accepted for publication in Astrophysical Journa

Correction:Kinome-wide analysis of the effect of statins in colorectal cancer (British Journal of Cancer, (2021), 124, 12, (1978-1987), 10.1038/s41416-021-01318-9)

The original version of this article unfortunately contained a mistake in an author name. Lucas J. A. C. Hawinkels should be Lukas J. A. C. Hawinkels. The authors apologize for the oversight. The original article has been corrected

Kinome-wide analysis of the effect of statins in colorectal cancer

Background Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome. Methods CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin. Results Kinome analysis can distinguish between non-specific, toxic effects caused by 10 mu M of Lovastatin and specific effects on cell signalling caused by 2 mu M Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling. Conclusions Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC

Early clinical experience with cabozantinib for advanced renal cell carcinoma in the UK: real-world treatment pathways and clinical outcomes

BACKGROUND: Cabozantinib monotherapy is approved in the UK for patients with treatment-naïve intermediate- or poor-risk advanced renal cell carcinoma (aRCC), or patients who received prior vascular endothelial growth factor-targeted therapy. Data are limited on the real-world use of cabozantinib for aRCC. PATIENTS AND METHODS: CERES (NCT03696407) was a retrospective study of patients with aRCC who received cabozantinib through the UK managed access programme (MAP; August 2016-July 2017), at which time cabozantinib had European regulatory approval for second- or later-line use only. The study objectives were to characterize aRCC treatment patterns and evaluate cabozantinib effectiveness. Outcomes were stratified by cabozantinib treatment line, MAP treatment date (months 0-7 vs. 8-12) and (post hoc) Charlson Comorbidity Index (CCI; ≥ 6 vs. < 6). RESULTS: Of 100 patients included, 99% had stage IV disease, 63% had a CCI ≥ 6 and 81% had an Eastern Cooperative Oncology Group Performance Status 0-1. Median (range) duration of follow-up was 10.8 (0.4-33.5) months. Cabozantinib was administered as second-line, third-line and fourth- or later-line in 41%, 31% and 28% of patients, respectively. Most patients (84%) initiated cabozantinib at 60 mg. Average (range) cabozantinib dose was 45.5 (19.6-59.8) mg/day; 66% of patients had ≥ 1 dose reduction. Disease progression was the most common reason for discontinuation (65.1%). Median (95% confidence interval) progression-free survival (PFS) and overall survival (OS) were 6.01 (5.16-7.85) and 10.84 (7.92-16.85) months, respectively. Overall response rate was 34.5%; disease control rate 70.1% and duration of response 6.9 (1.8-26.9) months. No significant differences in survival estimates were observed between treatment line or treatment date subgroups. Total CCI score ≤ 6 (vs. > 6) was associated with prolonged median PFS and OS. CONCLUSION: Cabozantinib demonstrated clinical activity in this UK real-world aRCC population. The results provide a benchmark for future real-world studies in aRCC

Potential contribution of surface-dwelling Sargassum algae to deep-sea ecosystems in the southern North Atlantic

Deep-sea ecosystems, limited by their inability to use primary production as a source of carbon, rely on other sources to maintain life. Sedimentation of organic carbon into the deep sea has been previously studied, however, the high biomass of sedimented Sargassum algae discovered during the VEMA Transit expedition in 2014/2015 to the southern North Atlantic, and its potential as a regular carbon input, has been an underestimated phenomenon. To determine the potential for this carbon flux, a literature survey of previous studies that estimated the abundance of surface water Sargassum was conducted. We compared these estimates with quantitative analyses of sedimented Sargassum appearing on photos taken with an autonomous underwater vehicle (AUV) directly above the abyssal sediment during the expedition. Organismal communities associated to Sargassum fluitans from surface waters were investigated and Sargassum samples collected from surface waters and the deep sea were biochemically analyzed (fatty acids, stable isotopes, C:N ratios) to determine degradation potential and the trophic significance within deep-sea communities. The estimated Sargassum biomass (fresh weight) in the deep sea (0.07 − 3.75 g/m2) was several times higher than that estimated from surface waters in the North Atlantic (0.024 – 0.84 g/m2). Biochemical analysis showed degradation of Sargassum occurring during sedimentation or in the deep sea, however, fatty acid and stable isotope analysis did not indicate direct trophic interactions between the algae and benthic organisms. Thus, it is assumed that components of the deep-sea microbial food web form an important link between the macroalgae and larger benthic organisms. Evaluation of the epifauna showed a diverse nano- micro-, meio, and macrofauna on surface Sargassum and maybe transported across the Atlantic, but we had no evidence for a vertical exchange of fauna components. The large-scale sedimentation of Sargassum forms an important trophic link between surface and benthic production and has to be further considered in the future as a regular carbon input to the deep-sea floor in the North Atlantic

Plasmodium falciparum adapts its investment into replication versus transmission according to the host environment

The malaria parasite life cycle includes asexual replication in human blood, with a proportion of parasites differentiating to gametocytes required for transmission to mosquitoes. Commitment to differentiate into gametocytes, which is marked by activation of the parasite transcription factor ap2-g, is known to be influenced by host factors but a comprehensive model remains uncertain. Here, we analyze data from 828 children in Kilifi, Kenya with severe, uncomplicated, and asymptomatic malaria infection over 18 years of falling malaria transmission. We examine markers of host immunity and metabolism, and markers of parasite growth and transmission investment. We find that inflammatory responses associated with reduced plasma lysophosphatidylcholine levels are associated with markers of increased investment in parasite sexual reproduction (i.e. transmission investment) and reduced growth (i.e. asexual replication). This association becomes stronger with falling transmission and suggests that parasites can rapidly respond to the within-host environment, which in turn is subject to changing transmission

Balancing mcr-1 expression and bacterial survival is a delicate equilibrium between essential cellular defence mechanisms

MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin. Here, we analyse the impact of MCR-1 expression on E. coli morphology, fitness, competitiveness, immune stimulation and virulence. Increased expression of mcr-1 results in decreased growth rate, cell viability, competitive ability and significant degradation in cell membrane and cytoplasmic structures, compared to expression of catalytically inactive MCR-1 (E246A) or MCR-1 soluble component. Lipopolysaccharide (LPS) extracted from mcr-1 strains induces lower production of IL-6 and TNF, when compared to control LPS. Compared to their parent strains, high-level colistin resistance mutants (HLCRMs) show reduced fitness (relative fitness is 0.41–0.78) and highly attenuated virulence in a Galleria mellonella infection model. Furthermore, HLCRMs are more susceptible to most antibiotics than their respective parent strains. Our results show that the bacterium is challenged to find a delicate equilibrium between expression of MCR-1-mediated colistin resistance and minimalizing toxicity and thus ensuring cell survival