Abiotic and Microbiotic Factors Controlling Biofilm Formation by Thermophilic Sporeformers

One of the major concerns in the production of dairy concentrates is the risk of contamination by heat-resistant spores from thermophilic bacteria. In order to acquire more insight in the composition of microbial communities occurring in the dairy concentrate industry, a bar-coded 16S amplicon sequencing analysis was carried out on milk, final products, and fouling samples taken from dairy concentrate production lines. The analysis of these samples revealed the presence of DNA from a broad range of bacterial taxa, including a majority of mesophiles and a minority of (thermophilic) spore-forming bacteria. Enrichments of fouling samples at 55°C showed the accumulation of predominantly Brevibacillus and Bacillus, whereas enrichments at 65°C led to the accumulation of Anoxybacillus and Geobacillus species. Bacterial population analysis of biofilms grown using fouling samples as an inoculum indicated that both Anoxybacillus and Geobacillus preferentially form biofilms on surfaces at air-liquid interfaces rather than on submerged surfaces. Three of the most potent biofilm-forming strains isolated from the dairy factory industrial samples, including Geobacillus thermoglucosidans, Geobacillus stearothermophilus, and Anoxybacillus flavithermus, have been characterized in detail with respect to their growth conditions and spore resistance. Strikingly, Geobacillus thermoglucosidans, which forms the most thermostable spores of these three species, is not able to grow in dairy intermediates as a pure culture but appears to be dependent for growth on other spoilage organisms present, probably as a result of their proteolytic activity. These results underscore the importance of abiotic and microbiotic factors in niche colonization in dairy factories, where the presence of thermophilic sporeformers can affect the quality of end products.     

Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors

CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.     

Conjugation of Oligonucleotides with Steroid Structures and Their Interaction with the Low-Density Lipoprotein

Abstract

To induce association with low-density lipoprotein (LDL), antisense oligonucleotides were derivatized at their 3′ terminus with several steroid structures. It was found that only highly lipidic steroids can complex the oligonucleotide with LDL.     

Site‐specific dynamics in remnant populations of Northern Wheatears Oenanthe oenanthe in the Netherlands

Dynamics of populations may be synchronized at large spatial scales, indicating driving forces acting beyond local scales, but may also vary locally as a result of site‐specific conditions. Conservation measures for fragmented and declining populations may need to address such local effects to avoid local extinction before measures at large spatial scales become effective. To assess differences in local population dynamics, we aimed to determine the demographic drivers controlling population trends in three remaining populations of the Northern Wheatear Oenanthe oenanthe in the Netherlands, as a basis for conservation actions. An integrated population model (IPM) was fitted to field data collected in each site in 2007–2011 to estimate fecundity, survival and immigration. Sites were 40–120 km apart, yet first‐year recruits were observed to move between some of the sites, albeit rarely. All three populations were equally sensitive to changes in fecundity and first‐year survival. One population was less sensitive to adult survival but more sensitive to immigration. A life table response experiment suggested that differences in immigration were important determinants of differences in population growth between sites. Given the importance of immigration for local dynamics along with high philopatry, resulting in low exchange between sites, creating a metapopulation structure by improving connectivity and the protection of local populations are important for the conservation of these populations. Site‐specific conservation actions will therefore be efficient and, for the short term, we propose different site‐specific conservation actions.     

Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium

Oxidatively modified low-density lipoprotein (oxLDL) plays a key role in the initiation of atherosclerosis by increasing monocyte adhesion. The mechanism that is responsible for the oxLDL-induced atherogenic monocyte recruitment in vivo, however, still remains unknown. Oxidation of LDL generates lysophosphatidylcholine, which is the main substrate for the lysophosphatidic acid (LPA) generating enzyme autotaxin. We show that oxLDL requires endothelial LPA receptors and autotaxin to elicit CXCL1-dependent arterial monocyte adhesion. Unsaturated LPA releases endothelial CXCL1, which is subsequently immobilized on the cell surface and mediates LPA-induced monocyte adhesion. Local and systemic application of LPA accelerates the progression of atherosclerosis in mice. Blocking the LPA receptors LPA(1) and LPA(3) reduced hyperlipidemia-induced arterial leukocyte arrest and atherosclerosis in the presence of functional CXCL1. Thus, atherogenic monocyte recruitment mediated by hyperlipidemia and modified LDL crucially depends on LPA, which triggers endothelial deposition of CXCL1, revealing LPA signaling as a target for cardiovascular disease treatments.     

Dose-dependent suppression of hunger by a specific alginate in a low-viscosity drink formulation

Addition of specific types of alginates to drinks can enhance postmeal suppression of hunger, by forming strong gastric gels in the presence of calcium. However, some recent studies have not demonstrated an effect of alginate/calcium on appetite, perhaps because the selected alginates do not produce sufficiently strong gels or because the alginates were not sufficiently hydrated when consumed. Therefore, the objective of the study was to test effects on appetite of a strongly gelling and fully hydrated alginate in an acceptable, low-viscosity drink formulation. In a balanced order crossover design, 23 volunteers consumed a meal replacement drink containing protein and calcium and either 0 (control), 0.6, or 0.8% of a specific high-guluronate alginate. Appetite (six self-report scales) was measured for 5 h postconsumption. Relevant physicochemical properties of the drinks were measured, i.e., product viscosity and strength of gel formed under simulated gastric conditions. Hunger was robustly reduced (20-30% lower area under the curve) with 0.8% alginate (P < 0.001, analysis of covariance), an effect consistent across all appetite scales. Most effects were also significant with 0.6% alginate, and a clear dose-response observed. Gastric gel strength was 1.8 and 3.8 N for the 0.6 and 0.8% alginate drinks, respectively, while product viscosity was acceptable (<0.5 Pa.s at 10 s(-1)). We conclude that strongly gastric-gelling alginates at relatively low concentrations in a low-viscosity drink formulation produced a robust reduction in hunger responses. This and other related studies indicate that the specific alginate source and product matrix critically impacts upon apparent efficacy.     

Attentional window set by expected relevance of environmental signals

The existence of an attentional window--a limited region in visual space at which attention is directed--has been invoked to explain why sudden visual onsets may or may not capture overt or covert attention. Here, we test the hypothesis that observers voluntarily control the size of this attentional window to regulate whether or not environmental signals can capture attention. We have used a novel approach to test this: participants eye-movements were tracked while they performed a search task that required dynamic gaze-shifts. During the search task, abrupt onsets were presented that cued the target positions at different levels of congruency. The participant knew these levels. We determined oculomotor capture efficiency for onsets that appeared at different viewing eccentricities. From these, we could derive the participant's attentional window size as a function of onset congruency. We find that the window was small during the presentation of low-congruency onsets, but increased monotonically in size with an increase in the expected congruency of the onsets. This indicates that the attentional window is under voluntary control and is set according to the expected relevance of environmental signals for the observer's momentary behavioral goals. Moreover, our approach provides a new and exciting method to directly measure the size of the attentional window.