How Landscape Filters Local Abundance: A Test of the Body Size-Foraging Range Hypothesis in Bumble Bees

For central place foragers, foraging range increases with body size. This is true for eusocial pollinators such as bumble bees, for whom body size dictates the maximum distance to which foragers can travel from their nest. Body size should therefore influence the size of landscape over which floral resources are accessible, and indirectly affect local abundance. Given this dispersal constraint, landscape should be an environmental filter for bees based on their body size, resulting in a size-based distribution of abundances in the local bee community reflecting the distance-based availability of resources. In this way, the abundance of bumble bees should reflect landscape composition. I found that the abundance of queens in Southern Alberta was related to an interaction between the amount of semi-natural land cover (a measure of foraging resources for bees) at two spatial scales: near the nest (local; 0 – 500 m) and further afield (broad; 500 – 2000 m). Small queens were more abundant when local availability of semi-natural land was moderate or high, and broad availability of semi-natural land was at low or moderate. The converse was not true: large queens were not more abundant when local resources were poor, and broad resources high. Worker abundance increased with local semi-natural land cover, but surprisingly showed no sign of this relationship being mediated by body size, suggesting that landscape composition influences the body size composition of bumble bee communities primarily during the nest establishment phase by queens. I conclude that the body size-foraging range hypothesis is generally unsupported in my system, but the hypothesis received partial support in the case of small-bodied queen bumble bees being more abundant when amount of local semi-natural habitat was high

Dual Pharmacological Inhibition of Angiopoietin-2 and VEGF-A in Murine Experimental Sepsis

BACKGROUND Sepsis is a pathological host response to infection leading to vascular barrier breakdown due to elevated levels of angiopoietin-2 (Angpt-2) and vascular endothelial growth factor-A (VEGF-A). Here, we tested a novel heterodimeric bispecific monoclonal IgG1-cross antibody of Angpt-2 and VEGF - termed "A2V." METHODS Cecal ligation and puncture was used to induce murine polymicrobial sepsis. Organs and blood were harvested for fluorescence immunohistochemistry and RT-PCR, and survival was recorded. In vitro endothelial cells were stimulated with plasma from septic shock patients costimulated with A2V or IgG antibody followed by immunocytochemistry and real-time transendothelial electrical resistance. RESULTS Septic mice treated with A2V had a reduced induction of the endothelial adhesion molecule ICAM-1, leading to a trend towards less transmigration of inflammatory cells (A2V: 42.2 ± 1.0 vs. IgG 48.5 ± 1.7 Gr-1+ cells/HPF, p = 0.08) and reduced tissue levels of inflammatory cytokines (e.g., IL-6 mRNA: A2V 9.4 ± 3.2 vs. IgG 83.9 ± 36.7-fold over control, p = 0.03). Endothelial permeability was improved in vivo and in vitro in stimulated endothelial cells with septic plasma. Survival was improved by 38% (p = 0.02). CONCLUSION Dual inhibition of Angpt-2 and VEGF-A improves murine sepsis morbidity and mortality, making it a potential therapeutic against vascular barrier breakdown

Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection leading to systemic inflammation and endothelial barrier breakdown. The vascular-destabilizing factor Angiopoietin-2 (Angpt-2) has been implicated in these processes in humans. Here we screened in an unbiased approach FDA-approved compounds with respect to Angpt-2 suppression in endothelial cells (ECs) in vitro. We identified Flunarizine – a well-known anti-migraine calcium channel (CC) blocker – being able to diminish intracellular Angpt-2 protein in a time- and dose-dependent fashion thereby indirectly reducing the released protein. Moreover, Flunarizine protected ECs from TNFα-induced increase in Angpt-2 transcription and vascular barrier breakdown. Mechanistically, we could exclude canonical Tie2 signalling being responsible but found that three structurally distinct T-type - but not L-type - CC blockers can suppress Angpt-2. Most importantly, experimental increase in intracellular calcium abolished Flunarizine’s effect. Flunarizine was also able to block the injurious increase of Angpt-2 in murine endotoxemia in vivo. This resulted in reduced pulmonary adhesion molecule expression (intercellular adhesion molecule-1) and tissue infiltration of inflammatory cells (Gr-1). Our finding could have therapeutic implications as side effects of Flunarizine are low and specific sepsis therapeutics that target the dysregulated host response are highly desirable

Molecular Regulation of Acute Tie2 Suppression in Sepsis

Objectives: Tie2 is a tyrosine kinase receptor expressed by endothelial cells that maintains vascular barrier function. We recently reported that diverse critical illnesses acutely decrease Tie2 expression and that experimental Tie2 reduction suffices to recapitulate cardinal features of the septic vasculature. Here we investigated molecular mechanisms driving Tie2 suppression in settings of critical illness. Design: Laboratory and animal research, postmortem kidney biopsies from acute kidney injury patients and serum from septic shock patients. Setting: Research laboratories and ICU of Hannover Medical School, Harvard Medical School, and University of Groningen. Patients: Deceased septic acute kidney injury patients (n = 16) and controls (n = 12) and septic shock patients (n = 57) and controls (n = 22). Interventions: Molecular biology assays (Western blot, quantitative polymerase chain reaction) + in vitro models of flow and transendothelial electrical resistance experiments in human umbilical vein endothelial cells; murine cecal ligation and puncture and lipopolysaccharide administration. Measurements and Main Results: We observed rapid reduction of both Tie2 messenger RNA and protein in mice following cecal ligation and puncture. In cultured endothelial cells exposed to tumor necrosis factor-, suppression of Tie2 protein was more severe than Tie2 messenger RNA, suggesting distinct regulatory mechanisms. Evidence of protein-level regulation was found in tumor necrosis factor--treated endothelial cells, septic mice, and septic humans, all three of which displayed elevation of the soluble N-terminal fragment of Tie2. The matrix metalloprotease 14 was both necessary and sufficient for N-terminal Tie2 shedding. Since clinical settings of Tie2 suppression are often characterized by shock, we next investigated the effects of laminar flow on Tie2 expression. Compared with absence of flow, laminar flow induced both Tie2 messenger RNA and the expression of GATA binding protein 3. Conversely, septic lungs exhibited reduced GATA binding protein 3, and knockdown of GATA binding protein 3 in flow-exposed endothelial cells reduced Tie2 messenger RNA. Postmortem tissue from septic patients showed a trend toward reduced GATA binding protein 3 expression that was associated with Tie2 messenger RNA levels (p <0.005). Conclusions: Tie2 suppression is a pivotal event in sepsis that may be regulated both by matrix metalloprotease 14-driven Tie2 protein cleavage and GATA binding protein 3-driven flow regulation of Tie2 transcript

The Emerging Global Tobacco Treatment Workforce: Characteristics of Tobacco Treatment Specialists Trained in Council-Accredited Training Programs from 2017 to 2019

Tobacco use is projected to kill 1 billion people in the 21st century. Tobacco Use Disorder (TUD) is one of the most common substance use disorders in the world. Evidence-based treatment of TUD is effective, but treatment accessibility remains very low. A dearth of specially trained clinicians is a significant barrier to treatment accessibility, even within systems of care that implement brief intervention models. The treatment of TUD is becoming more complex and tailoring treatment to address new and traditional tobacco products is needed. The Council for Tobacco Treatment Training Programs (Council) is the accrediting body for Tobacco Treatment Specialist (TTS) training programs. Between 2016 and 2019, = 7761 trainees completed Council-accredited TTS training programs. Trainees were primarily from North America (92.6%) and the Eastern Mediterranean (6.1%) and were trained via in-person group workshops in medical and academic settings. From 2016 to 2019, the number of Council-accredited training programs increased from 14 to 22 and annual number of trainees increased by 28.5%. Trainees have diverse professional backgrounds and work in diverse settings but were primarily White (69.1%) and female (78.7%) located in North America. Nearly two-thirds intended to implement tobacco treatment services in their setting; two-thirds had been providing tobacco treatment for 1 year or less; and 20% were sent to training by their employers. These findings suggest that the training programs are contributing to the development of a new workforce of TTSs as well as the development of new programmatic tobacco treatment services in diverse settings. Developing strategies to support attendance from demographically and geographically diverse professionals might increase the proportion of trainees from marginalized groups and regions of the world with significant tobacco-related inequities

The fatty acid biosynthesis enzyme fabi plays a key role in the development of liver stage malarial parasites

The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in &lt;i&gt;Plasmodium falciparum&lt;/i&gt; asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes Fab1. Here, we report synthetic chemistry and transfection studies concluding that &lt;i&gt;Plasmodium&lt;/i&gt; Fab1 is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial Fab1. Disruption of &lt;i&gt;fab1&lt;/i&gt; in &lt;i&gt;P. falciparum&lt;/i&gt; or the rodent parasite &lt;i&gt;P. berghei&lt;/i&gt; does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient &lt;i&gt;P. berghei&lt;/i&gt; sporozoites are markedly less infective for mice and typically fail to complete liver-stage development invitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions