20 research outputs found

    Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection

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    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2–host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism

    Effects of shoreline armouring and overwater structures on coastal and estuarine fish: opportunities for habitat improvement

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    Nearshore ecosystems are increasingly recognized as critical habitats for fish of cultural, ecological and economic significance. These ecosystems are often densely inhabited by juvenile fish, highly productive and refuges from predation, leading ecologists to characterize them as nurseries. However, nearshore ecosystems are being transformed globally to support demands of growing coastal populations. Many shorelines are modified by armouring (e.g. seawalls, riprap) that minimizes erosion, and overwater structures (e.g. piers, docks) that facilitate waterfront use. These modifications affect the ecology of nearshore systems by restructuring, eliminating and shading shallow waters. Here, we review literature examining effects of armouring and overwater structures on coastal and estuarine fishes, and discuss how research and management can coordinate to minimize negative effects. Along armoured shorelines, fish assemblages differed from unarmoured sites, fish consumed less epibenthic and terrestrial prey, beach spawning was less successful and fish were larger. Under large overwater structures, visually oriented fish were less abundant and they fed less. Shade from overwater structures also interrupted localized movements of migratory fish. Thus, shoreline modifications impaired habitats by limiting feeding, reproduction, ontogenetic habitat shifts from shallow to deeper waters and connectivity. Research suggests that restoring shallow waters and substrate complexity, and minimizing shading underneath overwater structures, can rehabilitate habitats compromised by shoreline modifications. Synthesis and applications. Shoreline armouring and overwater structures often compromis e fish habitats. These threats to nearshore fish habitats will become more severe as growing coastal populations and rising sea levels increase demands for shoreline infrastructure. Our ability to assess and rehabilitate nearshore fish habitats along modified shorelines will be enhanced by: focusing research attention on metrics that directly indicate fish habitat quality; implementing and evaluating shoreline features that repair compromised habitat functions within human-use constraints; collating natural history knowledge of nearshore ecosystems; and embracing the socio-ecological nature of habitat improvements by educating the public about conservation efforts and fostering appreciation of local nearshore ecosystems. Actions to reduce impacts of shoreline modifications on fish are particularly feasible when they align with societal goals, such as improving flood protection and providing spaces that facilitate recreation, education, and connections between people and nature

    Supplementary Material for: Impairment in Natural Killer Cells Editing of Immature Dendritic Cells by Infection with a Virulent <b><i>Trypanosoma cruzi</i></b> Population

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    Early interactions between natural killer (NK) and dendritic cells (DC) shape the immune response at the frontier of innate and adaptive immunity. Activated NK cells participate in maturation or deletion of DCs that remain immature. We previously demonstrated that infection with a high virulence (HV) population of the protozoan parasite <i>Trypanosoma cruzi</i> downmodulates DC maturation and T-cell activation capacity. Here, we evaluated the role of NK cells in regulating the maturation level of DCs. Shortly after infection with HV <i>T. cruzi</i>, DCs in poor maturation status begin to accumulate in mouse spleen. Although infection induces NK cell cytotoxicity and cytokine production, NK cells from mice infected with HV <i>T. cruzi</i> exhibit reduced ability to lyse and fail to induce maturation of bone marrow-derived immature DCs (iDCs). NK-mediated lysis of iDCs is restored by in vitro blockade of the IL-10 receptor during NK-DC interaction or when NK cells are obtained from <i>T. cruzi</i>-infected IL-10 knockout mice. These results suggest that infection with a virulent <i>T. cruzi</i> strain alters NK cell-mediated regulation of the adaptive immune response induced by DCs. This regulatory circuit where IL-10 appears to participate might lead to parasite persistence but can also limit the induction of a vigorous tissue-damaging T-cell response

    Mortality and utilisation of Sclerocarya birrea subsp. caffra between 2001 and 2008 in the Kruger National Park, South Africa

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    A resurvey of a sample of marula trees (n=474) in the Kruger National Park (KNP) originally documented in 2001, was conducted in 2008 to determine the response of this population segment to the conditions prevalent during that time. These included an increasing elephant population and changes to the KNP fire policy. The overall mortality rate was estimated to be 2.6% per annum, with the mortality rate for individuals N5 m in height being 3.7% per annum. The highest level of mortality was found in the 5–8 m height class (7.1% per annum), while the highest number of dead individuals occurred in the 11–15 m height class (25). In addition minimal recruitment into the seedling size class was observed (n=6). No growth of saplings less than 2 m in height to heights greater than 2 m was observed. Almost half the individuals that were heavily damaged in 2001 had died by 2008. Heavy elephant utilisation and tree mortality was concentrated in the Sabie thorn thickets ecozone on granites where marula density was highest. Utilisation levels on the surviving individuals throughout the sampled area had almost tripled between 2001 and 2008, with individuals between 5 and 8 m in height accumulating the most additional elephant utilisation. It was concluded that the sampled marula population was not sustaining itself under the conditions prevalent between 2001 and 2008. Since sampled trees N5 m in height were strongly biased towards the Sabie thorn thickets, any projections for the likely fate of marulas in terms of adult mortality would mainly apply to this ecozone. The spatial variability described in this study suggests that further sampling is needed to adequately represent trends elsewherePeer reviewe

    Antibacterial activity of indole alkaloids from Aspidosperma ramiflorum

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    We evaluated the antibacterial activities of the crude methanol extract, fractions (I-V) obtained after acid-base extraction and pure compounds from the stem bark of Aspidosperma ramiflorum. The minimum inhibitory concentration (MIC) was determined by the microdilution technique in Mueller-Hinton broth. Inoculates were prepared in this medium from 24-h broth cultures of bacteria (10(7) CFU/mL). Microtiter plates were incubated at 37ºC and the MICs were recorded after 24 h of incubation. Two susceptibility endpoints were recorded for each isolate. The crude methanol extract presented moderate activity against the Gram-positive bacteria B. subtilis (MIC = 250 µg/mL) and S. aureus (MIC = 500 µg/mL), and was inactive against the Gram-negative bacteria E. coli and P. aeruginosa (MIC > 1000 µg/mL). Fractions I and II were inactive against standard strains at concentrations of <=1000 µg/mL and fraction III displayed moderate antibacterial activity against B. subtilis (MIC = 500 µg/mL) and S. aureus (MIC = 250 µg/mL). Fraction IV showed high activity against B. subtilis and S. aureus (MIC = 15.6 µg/mL) and moderate activity against E. coli and P. aeruginosa (MIC = 250 µg/mL). Fraction V presented high activity against B. subtilis (MIC = 15.6 µg/mL) and S. aureus (MIC = 31.3 µg/mL) and was inactive against Gram-negative bacteria (MIC > 1000 µg/mL). Fractions III, IV and V were then submitted to bioassay-guided fractionation by silica gel column chromatography, yielding individual purified ramiflorines A and B. Both ramiflorines showed significant activity against S. aureus (MIC = 25 µg/mL) and E. faecalis (MIC = 50 µg/mL), with EC50 of 8 and 2.5 µg/mL for ramiflorines A and B, respectively, against S. aureus. These results are promising, showing that these compounds are biologically active against Gram-positive bacteria

    A research agenda for malaria eradication: vaccines.

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    Contains fulltext : 97591.pdf (publisher's version ) (Open Access)Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented
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