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A simplified open culture chain elongation process with ethanol and acetate to produce renewable n -caprylate without adding yeast extract showed a trophic hierarchy between aerobic, facultative anaerobic, and fully anaerobic microbial species.
Consumption of ergot alkaloids during the second half of gestation has been shown to decrease umbilical artery vasoactivity resulting in decreased birth weights. Negative vascular effects of ergot alkaloids are mediated predominantly through serotonergic and adrenergic receptors in other tissues. Vasoactivity of serotonin (5-HT) receptors 5-HT 2A and 5-HT 1B/1D in umbilical artery and vein from ewes receiving endophyte-infected seed (E + 1.77 mg ergovaline/hd/d) or a control total mixed ration (CON; 0 mg ergovaline/hd/d) tall fescue seed at d-110 and d-133 of gestation was evaluated. Gravid reproduction tracts were collected from ewes. Two-mm sections of umbilical artery and vein were exposed to increasing concentrations of a 5-HT 1B/1D agonist and 5-HT 2A agonist. The 5-HT 1B/1D agonist did not stimulate a contractile response in artery or vein or either gestation time point. 5-HT 2A agonist caused large responses in artery with greatest occurring at d-110 and decreasing in magnitude as days of gestation increased ( p < 0.05). On d-110 and 133 of gestation, arteries from CON ewes had greater contractile response than arteries collected from E+ ewes ( p < 0.05). Veins responded to increasing concentrations of the 5-HT 2A agonist. Maximal d-110 vein response was greater than d-133 when exposed to 5-HT 2A agonist ( p < 0.05). Unlike the artery, veins from E+ ewes had greater d-133 contractile response than CON ( p < 0.05). Vascular contractions of umbilical artery and vein are induced by 5-HT 2A receptor activity and not 5-HT 1B/1D . Umbilical artery 5-HT 2A receptor activity was more sensitive to seed treatment and could be responsible for ergot alkaloid-induced intra-uterine growth restriction.
The extensin (EXT) network is elaborated by the covalent intermolecular crosslinking of EXT glycoprotein monomers, and its proper assembly is important for numerous aspects of basic wall architecture and cellular defense. In this review, we discuss new advances in the secretion of EXT monomers and the molecular drivers of EXT network self-assembly. Many of the functions of EXTs are conferred through covalent crosslinking into the wall, so we also discuss the different types of known intermolecular crosslinks, the enzymes that are involved, as well as the potential for additional crosslinks that are yet to be identified. EXTs also function in wall architecture independent of crosslinking status, and therefore, we explore the role of non-crosslinking EXTs. As EXT crosslinking is upregulated in response to wounding and pathogen infection, we discuss a potential regulatory mechanism to control covalent crosslinking and its relationship to the subcellular localization of the crosslinking enzymes.
African swine fever virus (ASFV) is the etiological agent of a frequently lethal disease, ASF, affecting domestic and wild swine. Currently, ASF is causing a pandemic affecting pig production in Eurasia. There are no vaccines available, and therefore control of the disease is based on culling infected animals. We report here that deletion of the ASFV gene A104R, a virus histone-like protein, from the genome of the highly virulent ASFV-Georgia2010 (ASFV-G) strain induces a clear decrease in virus virulence when experimentally inoculated in domestic swine. A recombinant virus lacking the A104R gene, ASFV-G-ΔA104R, was developed to assess the role of the A104R gene in disease production in swine. Domestic pigs were intramuscularly inoculated with 10 2 HAD 50 of ASFV-G-ΔA104R, and compared with animals that received a similar dose of virulent ASFV-G. While all ASFV-G inoculated animals developed a fatal form of the disease, animals receiving ASFV-G-ΔA104R survived the challenge, remaining healthy during the 28-day observational period, with the exception of only one showing a protracted but fatal form of the disease. ASFV-G-ΔA104R surviving animals presented protracted viremias with reduced virus titers when compared with those found in animals inoculated with ASFV-G, and all of them developed a strong virus-specific antibody response. This is the first report demonstrating that the A104R gene is involved in ASFV virulence in domestic swine, suggesting that A104R deletion may be used to increase the safety profile of currently experimental vaccines.
Digestion of red blood cell (RBC) hemoglobin by the malaria parasite results in the formation of paramagnetic hemazoin crystals inside the parasite body. A number of reports suggest that magnetic field interaction with hamazoin crystals significantly reduces the number of infected cells in culture, and thus magnetic field can be used to combat malaria. We studies the effects of magnetic filed on the Plasmodium falciparum asexual life cycle inside RBCs under various experimental conditions. No effect was found during prolonged exposure of infected RBCs to constant magnetic fields up to 6000 Gauss. Infected RBCs were also exposed, under temperature-controlled conditions, to oscillating magnetic fields with frequencies in the range of 500-20000 kHz, and field strength 30-600 Gauss. This exposure often changed the proportion of different parasite stages in treated culture compared to controls. However, no significant effect on parasitemia was observed in treated cultures. This result indicates that the magnetic field effect on Plasmodium falciparum is negligible, or that hypothetical negative and positive effects on different stages within one 48-hour compensate each other.
Malaria control in sub-Saharan Africa has stagnated despite widespread adoption of control measures such as long-lasting insecticidal nets (LLINs). Progress has stalled, in part, because of pyrethroid insecticide resistance, driving the need for retooling to increase the effectiveness of bed nets. Consequently, LLINs have been treated with the chemical synergist piperonyl butoxide (PBO). Piperonyl butoxide LLINs have been shown to be efficacious in controlled settings; however, their effectiveness in real-world settings warrants investigation. In Bungoma County, Western Kenya, a cohort of 768 participants was followed from June 2017 to December 2023 via active and passive surveillance. Household visits were conducted monthly, during which LLIN use for nets distributed in 2017 and 2021 was recorded, and symptomatic malaria cases were identified using rapid diagnostic tests (RDTs). The comparative effectiveness of PBO versus conventional LLINs was assessed in terms of malaria infections. A multilevel logistic regression model was fit with monthly RDT results as the dependent variable. The study results indicate that PBO LLINs provide greater protection against malaria at the individual level than conventional LLINs (odds ratio: 0.70; 95% CI: 0.47–1.03), although the findings were not statistically significant. The added protection against malaria infections provided by PBO LLINs compared with conventional LLINs observed in the current study aligns with findings from most previous studies, although this finding was not statistically significant. In areas with documented pyrethroid resistance, the use of LLINs with an added synergist, such as PBO, can provide additional protection against malaria infections (compared with pyrethroid-only LLINs) and should be considered for scaled-up scenarios despite the additional cost.
The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)–infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Furthermore, upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb–treated macaques. Viral control was correlated with the reprogramming of CD8 + T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.
OBJECTIVE: To assess the frequency of shedding of polyomavirus JC virus (JCV) genotypes in urine of HIV-infected patients receiving highly active antiretroviral therapy (HAART). METHODS: Single samples of urine and blood were collected prospectively from 70 adult HIV-infected patients and 68 uninfected volunteers. Inclusion criteria for HIV-infected patients included an HIV RNA viral load < 1000 copies, CD4 cell count of 200-700 x 106 cells/l, and stable HAART regimen. PCR assays and sequence analysis were carried out using JCV-specific primers against different regions of the virus genome. RESULTS: JCV excretion in urine was more common in HIV-positive patients but not significantly different from that of the HIV-negative group [22/70 (31%) versus 13/68 (19%); P = 0.09]. HIV-positive patients lost the age-related pattern of JCV shedding (P = 0.13) displayed by uninfected subjects (P = 0.01). Among HIV-infected patients significant differences in JCV shedding were related to CD4 cell counts (P = 0.03). Sequence analysis of the JCV regulatory region from both HIV-infected patients and uninfected volunteers revealed all to be JCV archetypal strains. JCV genotypes 1 (36%) and 4 (36%) were the most common among HIV-infected patients, whereas type 2 (77%) was the most frequently detected among HIV-uninfected volunteers. CONCLUSION: These results suggest that JCV shedding is enhanced by modest depressions in immune function during HIV infection. JCV shedding occurred in younger HIV-positive persons than in the healthy controls. As the common types of JCV excreted varied among ethnic groups, JCV genotypes associated with progressive multifocal leukoencephalopathy may reflect demographics of those infected patient populations.
Abstract The development of new antibiotics has stalled, and novel strategies are needed as we enter the age of antibiotic resistance. Certain naturally occurring clays have been shown to be effective in killing antibiotic resistant bacteria. However, these natural clays are too variable to be used in clinical settings. Our study shows that synthetic antibacterial minerals exhibit potent antibacterial activity against topical MRSA infections and increase the rate of wound closure relative to controls. The antibacterial minerals maintain a redox cycle between Fe 2+ /Fe 3+ and the surfaces of pyrite minerals, which act as a semiconductor and produce reactive oxygen species (ROS), while smectite minerals act as a cation exchange reservoir. Acidic conditions are maintained throughout the application of the hydrated minerals and can mitigate the alkaline pH conditions observed in chronic non-healing wounds. These results provide evidence for the strategy of ‘iron overload’ to combat antibiotic resistant infections through the maintained release of Fe 2+ and generation of ROS via distinct geochemical reactions that can break the chronic wound damage cycle.
We previously identified a Plasmodium falciparum (Pf) protein of unknown function encoded by a single-copy gene, PF3D7_1134300, as a target of antibodies in plasma of Tanzanian children in a whole-proteome differential screen. Here we characterize this protein as a blood-stage antigen that localizes to the surface membranes of both parasitized erythrocytes and merozoites, hence its designation as Pf erythrocyte membrane and merozoite antigen 1 (PfEMMA1). Mouse anti-PfEMMA1 antisera and affinity-purified human anti-PfEMMA1 antibodies inhibited growth of P. falciparum strains by up to 68% in growth inhibition assays. Following challenge with uniformly fatal Plasmodium berghei (Pb) ANKA, up to 40% of mice immunized with recombinant PbEMMA1 self-cured, and median survival of lethally infected mice was up to 2.6-fold longer than controls (21 vs. 8 d, P = 0.005). Furthermore, high levels of naturally acquired human anti-PfEMMA1 antibodies were associated with a 46% decrease in parasitemia over 2.5 yr of follow-up of Tanzanian children. Together, these findings suggest that antibodies to PfEMMA1 mediate protection against malaria.
Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.
Early and accurate diagnosis of respiratory pathogens and associated outbreaks can allow for the control of spread, epidemiological modeling, targeted treatment, and decision making–as is evident with the current COVID-19 pandemic. Many respiratory infections share common symptoms, making them difficult to diagnose using only syndromic presentation. Yet, with delays in getting reference laboratory tests and limited availability and poor sensitivity of point-of-care tests, syndromic diagnosis is the most-relied upon method in clinical practice today. Here, we examine the variability in diagnostic identification of respiratory infections during the annual infection cycle in northern New Mexico, by comparing syndromic diagnostics with polymerase chain reaction (PCR) and sequencing-based methods, with the goal of assessing gaps in our current ability to identify respiratory pathogens. Of 97 individuals that presented with symptoms of respiratory infection, only 23 were positive for at least one RNA virus, as confirmed by sequencing. Whereas influenza virus (n = 7) was expected during this infection cycle, we also observed coronavirus (n = 7), respiratory syncytial virus (n = 8), parainfluenza virus (n = 4), and human metapneumovirus (n = 1) in individuals with respiratory infection symptoms. Four patients were coinfected with two viruses. In 21 individuals that tested positive using PCR, RNA sequencing completely matched in only 12 (57%) of these individuals. Few individuals (37.1%) were diagnosed to have an upper respiratory tract infection or viral syndrome by syndromic diagnostics, and the type of virus could only be distinguished in one patient. Thus, current syndromic diagnostic approaches fail to accurately identify respiratory pathogens associated with infection and are not suited to capture emerging threats in an accurate fashion. We conclude there is a critical and urgent need for layered agnostic diagnostics to track known and unknown pathogens at the point of care to control future outbreaks.
This project was funded by DOE under Grant no. DE-SC0016108. Originally approved for the 2016-2019 period, two no-cost extensions were solicited and approved, which prolonged the lifespan through July 2021. This final report informs on the results obtained so far from the research implemented. The research hinged on integrating genomics (genomic selection, RNAseq, virus-plant interactions) with classical genetics (conventional breeding) to incorporate durable resistance to fungal (rust) and viral (mosaic) diseases in switchgrass (Panicum virgatum) populations being bred for bioenergy. Higher biomass yield, higher quality (low lignin content), and durable disease resistance are key features to make lignocellulosic switchgrass feedstocks economically competitive and sustainable. Genomic selection is being applied on three generations of a switchgrass population derived from crossing two ecotypes (Kanlow as lowland female and Summer as upland male) with differential performance in terms of biomass yield and quality, disease resistance, and winter survivability. Target populations were screened for rust and mosaic in field and/or lab and phenotyped for biomass yield and quality traits. Genetic analyses were applied across generations to capture the joint inheritance of the targeted traits and predict breeding values for parents and progeny with greater accuracy. Parental and a panel of different switchgrass populations were genotyped with the DArTseq technology to develop SNP (0, 1, 2) and in-silico (presence/absence) DArT markers. Rust inoculations techniques were developed and applied successfully on switchgrass. The original populations (Kanlow and Summer) were sequenced with RNAseq to capture the gene expression profiles across sequential time-points and appraise the basis of greater resistance in the Kanlow vs the Summer ecotype. Constructs of PMV and sPMV mosaic virus were assembled and tested first on proso millet to find the best protocol to use later on switchgrass. Results from the preliminary analyses indicate that 1) ample additive genetic variation is available for selection and improving this inter-ecotypic population for yield, quality, and disease traits, 2) significant gains are to be expected with the genetic correlations being favorable between yield and lignin content and between yield and disease ratings, 3) substantial differences exist in the genetic regions controlling rust resistance in the two ecotypes, 4) co-infection with PMV isolates from Nebraska and its satellite from Kansas elicit severe mosaic symptoms, and 5) two different genetic systems are responsible for imparting resistance to rust and virus in switchgrass.
SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.
Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed—some animals exhibited large fluctuations in viral load after cART cessation—the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.
Both rodents and men returning from spaceflight have exhibited alterations in immune responses and, in particular, interferon production. This work utilizes a model for antiorthostatic (20-deg head-down tilt), hypokinetic, hypodynamic suspension of mice that simulates some aspects of weightlessness. Female Swiss/Webster mice that are normally resistant to infection with the D variant of encephalomyocarditis virus showed a marked increase in susceptibility to infection when suspended. This correlated with a drop in interferom production. Control, orthostatically suspended mice (no tilt) showed no increase in susceptibility to the virus.
Abstract Wetlands store 20–30% of the world’s soil carbon, and identifying the microbial controls on these carbon reserves is essential to predicting feedbacks to climate change. Although viral infections likely play important roles in wetland ecosystem dynamics, we lack a basic understanding of wetland viral ecology. Here 63 viral size-fraction metagenomes (viromes) and paired total metagenomes were generated from three time points in 2021 at seven fresh- and saltwater wetlands in the California Bodega Marine Reserve. We recovered 12,826 viral population genomic sequences (vOTUs), only 4.4% of which were detected at the same field site two years prior, indicating a small degree of population stability or recurrence. Viral communities differed most significantly among the seven wetland sites and were also structured by habitat (plant community composition and salinity). Read mapping to a new version of our reference database, PIGEONv2.0 (515,763 vOTUs), revealed 196 vOTUs present over large geographic distances, often reflecting shared habitat characteristics. Wetland vOTU microdiversity was significantly lower locally than globally and lower within than between time points, indicating greater divergence with increasing spatiotemporal distance. Viruses tended to have broad predicted host ranges via CRISPR spacer linkages to metagenome-assembled genomes, and increased SNP frequencies in CRISPR-targeted major tail protein genes suggest potential viral eco-evolutionary dynamics in response to both immune targeting and changes in host cell receptors involved in viral attachment. Together, these results highlight the importance of dispersal, environmental selection, and eco-evolutionary dynamics as drivers of local and global wetland viral biogeography.
Shifts in surface climate may have changed the dynamic of zoonotic cutaneous leishmaniasis (ZCL) in the pre-Saharan zones of North Africa. Caused by Leishmania major, this form multiplies in the body of rodents serving as reservoirs of the disease. The parasite is then transmitted to human hosts by the bite of a Phlebotomine sand fly (Diptera: Psychodidae) that was previously fed by biting an infected reservoir. We examine the seasonal and interannual dynamics of the incidence of this ZCL as a function of surface climate indicators in two regions covering a large area of the semi-arid Pre-Saharan North Africa. Results suggest that in this area, changes in climate may have initiated a trophic cascade that resulted in an increase in ZCL incidence. We find the correlation between the rainy season precipitation and the same year Normalized Difference Vegetation Index (NDVI) to be strong for both regions while the number of cases of ZCL incidence lags the precipitation and NDVI by 2 years. The zoonotic cutaneous leishmaniasis seasonal dynamic appears to be controlled by minimum temperatures and presents a 2-month lag between the reported infection date and the presumed date when the infection actually occurred. The decadal increase in the number of ZCL occurrence in the region suggests that changes in climate increased minimum temperatures sufficiently and created conditions suitable for endemicity that did not previously exist. We also find that temperatures above a critical range suppress ZCL incidence by limiting the vector's reproductive activity.