Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p> <p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p> <p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p&gt

Advancing nursing practice : the emergence of the role of Advanced Practice Nurse in Saudi Arabia

Background: The roots of advanced practice nursing can be traced back to the 1890s, but the Nurse Practitioner (NP) emerged in Western countries during the 1960s in response to the unmet health care needs of populations in rural areas. These early NPs utilized the medical model of care to assess, diagnose and treat. Nursing has since grown as a profession, with its own unique and distinguishable, holistic, science-based knowledge, which is complementary within the multidisciplinary team. Today Advanced Practice Nurses (APNs) demonstrate nursing expertise in clinical practice, education, research and leadership, and are no longer perceived as “physician replacements” or assistants. Saudi Arabia has yet to define, legislate or regulate Advanced Practice Nursing. Aims: This article aims to disseminate information from a Saudi Advanced Practice Nurse thought leadership meeting, to chronicle the history of Advanced Practice Nursing within the Kingdom of Saudi Arabia, while identifying strategies for moving forward. Conclusion: It is important to build an APN model based on Saudi health care culture and patient population needs, while recognizing global historical underpinnings. Ensuring that nursing continues to distinguish itself from other health care professions, while securing a seat at the multidisciplinary health care table will be instrumental in advancing the practice of nursing

Neutrinos

229 pages229 pages229 pagesThe Proceedings of the 2011 workshop on Fundamental Physics at the Intensity Frontier. Science opportunities at the intensity frontier are identified and described in the areas of heavy quarks, charged leptons, neutrinos, proton decay, new light weakly-coupled particles, and nucleons, nuclei, and atoms

Growth and ecophysiology of two Antarctic benthic predators; Isotealia antarctica and Urticinopsis antarctica

There is a dearth of basic life history and physiological data from Southern Ocean species, particularly from benthic vagile predators. This is an important data gap because species inhabiting the Southern Ocean live in a more temperature stable but seasonally varying environment than temperate and tropical counterparts. For many species living below 0 ◦C for a significant proportion of the year, bodily functions are slowed to disproportionately lower rates than would be predicted by temperature alone. Certain life history and physiological processes are often aligned with the short summer season of productivity. However, predators may behave differently because they are decoupled from the phytoplankton bloom and some have been shown to exhibit less seasonal physiological change. To further our understanding of Antarctic predator growth and seasonal ecophysiology, field growth rates were measured for two soft-bodied Antarctic anemone benthic predators, Isotealia antarctica and Urticinopsis antarctica, using in situ sampling of anemones on uniquely marked tiles. Ex situ measurements of oxygen consumption and seven-day faecal output were obtained from recently collected specimens in aquaria and compared between summer and winter. Winter physiological data for Antarctic species are rare, and we tested the hypothesis that generalist feeders or predators continue to feed during the winter. Growth rates differed between species and between years. I. antarctica and U. antarctica both exhibited overall positive field growth rates across a 15 month period between 2020 and 2021; with U. antarctica increasing 199.80% (± SE 25.8) in mass compared to a 16.85% (± SE 8.9) increase in I. antarctica. There was no significant difference in I. antarctica’s growth between 15 and 25 months field deployment. After 25 months, I. antarctica showed an average 7.96% (± SE 8.05) increase in buoyant weight. Ex situ oxygen consumption and faecal egestion did not differ seasonally, which, demonstrates that anemones fed at similar rates during the winter and summer. In contrast to some members of the Antarctica benthos, I. antarctica and U. antarctica actively feed all year round, whereas several other species have been reported to enter a state of torpor in winter

ACTIV-2: A Platform Trial for the Evaluation of Novel Therapeutics for the Treatment of Early COVID-19 in Outpatients

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410

A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex

Dysregulated pre-mRNA splicing is an emerging Achilles heel of cancers and myelodysplasias. To expand the currently limited portfolio of small-molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties. Cells expressing a cancer-associated U2AF1 mutant are preferentially killed by treatment with the compound. Altogether, our results highlight the potential of trapping early spliceosome assembly as an effective pharmacological means to manipulate pre-mRNA splicing. By extension, we suggest that stabilizing assembly intermediates may offer a useful approach for small-molecule inhibition of macromolecular machines

Species abundance distributions: moving beyond single prediction theories to integration within an ecological framework

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75247/1/j.1461-0248.2007.01094.x.pd