Using Genetic Diversity in Deep Root Systems of Perennial Forage Grasses and Rice to Capture Carbon in Tropical Soils

Agricultural soils have the potential not only to be sinks of carbon dioxide (CO2) but also to mitigate the emissions of this gas to the atmosphere, thus, alleviating global warming. Perennial tropical grasses and rice upland and lowland varieties exhibit a large untapped genetic diversity in their root systems (e.g., deep rooting ability, exudation rates and chemical composition) that, if unlocked, could contribute to increased food production in crop-livestock systems while enhancing soil organic carbon (SOC) in tropical regions. Naturebased solutions that improve crop adaptation and SOC storage in tropical soils could help to remove CO2 from the atmosphere and thereby benefit the global climate system. With the launch of Future Seeds, one of the world’s largest repositories of tropical crop varieties, the Bezos Earth Fund (BEF) granted a major project within the Program of Future of Food. The focus of this BEF funded project is to: (i) develop novel high-throughput phenotyping methods to evaluate genetic diversity of root systems of tropical grasses and rice; (ii) unravel the potential of root systems in crop-livestock systems to replenish soil organic carbon (SOC) in human-intervened areas in tropical soils; (iii) identify and target hotspots/agroecological niches for SOC storage in tropical soils; and (iv) build capacity in conducting research on root systems and SOC storage towards carbon farming in tropical regions. Implementation of land-based SOC storage practices/projects (through carbon markets) based on deep rooting ability of perennial tropical forage grasses and rice cultivars in crop-pasture rotational systems could significantly reduce net emissions from tropical soils

Differential Release and Phagocytosis of Tegument Glycoconjugates in Neurocysticercosis: Implications for Immune Evasion Strategies

Neurocysticercosis (NCC) is an infection of the central nervous system (CNS) by the metacestode of the helminth Taenia solium. The severity of the symptoms is associated with the intensity of the immune response. First, there is a long asymptomatic period where host immunity seems incapable of resolving the infection, followed by a chronic hypersensitivity reaction. Since little is known about the initial response to this infection, a murine model using the cestode Mesocestoides corti (syn. Mesocestoides vogae) was employed to analyze morphological changes in the parasite early in the infection. It was found that M. corti material is released from the tegument making close contact with the nervous tissue. These results were confirmed by infecting murine CNS with ex vivo–labeled parasites. Because more than 95% of NCC patients exhibit humoral responses against carbohydrate-based antigens, and the tegument is known to be rich in glycoconjugates (GCs), the expression of these types of molecules was analyzed in human, porcine, and murine NCC specimens. To determine the GCs present in the tegument, fluorochrome-labeled hydrazides as well as fluorochrome-labeled lectins with specificity to different carbohydrates were used. All the lectins utilized labeled the tegument. GCs bound by isolectinB4 were shed in the first days of infection and not resynthesized by the parasite, whereas GCs bound by wheat germ agglutinin and concavalinA were continuously released throughout the infectious process. GCs bound by these three lectins were taken up by host cells. Peanut lectin-binding GCs, in contrast, remained on the parasite and were not detected in host cells. The parasitic origin of the lectin-binding GCs found in host cells was confirmed using antibodies against T. solium and M. corti. We propose that both the rapid and persistent release of tegumental GCs plays a key role in the well-known immunomodulatory effects of helminths, including immune evasion and life-long inflammatory sequelae seen in many NCC patients

Suppression of HBV by Tenofovir in HBV/HIV coinfected patients : a systematic review and meta-analysis

Background: Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. Methods: A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. Results: Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. Interpretation: TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone

Design and Initial Performance of the Prototype for the BEACON Instrument for Detection of Ultrahigh Energy Particles

The Beamforming Elevated Array for COsmic Neutrinos (BEACON) is a planned neutrino telescope designed to detect radio emission from upgoing air showers generated by ultrahigh energy tau neutrino interactions in the Earth. This detection mechanism provides a measurement of the tau flux of cosmic neutrinos. We have installed an 8-channel prototype instrument at high elevation at Barcroft Field Station, which has been running since 2018, and consists of 4 dual-polarized antennas sensitive between 30-80 MHz, whose signals are filtered, amplified, digitized, and saved to disk using a custom data acquisition system (DAQ). The BEACON prototype is at high elevation to maximize effective volume and uses a directional beamforming trigger to improve rejection of anthropogenic background noise at the trigger level. Here we discuss the design, construction, and calibration of the BEACON prototype instrument. We also discuss the radio frequency environment observed by the instrument, and categorize the types of events seen by the instrument, including a likely cosmic ray candidate event.Comment: 21 pages, 20 figure

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

Replication in Cells of Hematopoietic Origin Is Necessary for Dengue Virus Dissemination

Dengue virus (DENV) is a mosquito-borne pathogen for which no vaccine or specific therapeutic is available. Although it is well established that dendritic cells and macrophages are primary sites of DENV replication, it remains unclear whether non-hematopoietic cellular compartments serve as virus reservoirs. Here, we exploited hematopoietic-specific microRNA-142 (miR-142) to control virus tropism by inserting tandem target sites into the virus to restrict replication exclusively in this cell population. In vivo use of this virus restricted infection of CD11b+, CD11c+, and CD45+ cells, resulting in a loss of virus spread, regardless of the route of administration. Furthermore, sequencing of the targeted virus population that persisted at low levels, demonstrated total excision of the inserted miR-142 target sites. The complete conversion of the virus population under these selective conditions suggests that these immune cells are the predominant sources of virus amplification. Taken together, this work highlights the importance of hematopoietic cells for DENV replication and showcases an invaluable tool for the study of virus pathogenesis

Mining Virulence Genes Using Metagenomics

When a bacterial genome is compared to the metagenome of an environment it inhabits, most genes recruit at high sequence identity. In free-living bacteria (for instance marine bacteria compared against the ocean metagenome) certain genomic regions are totally absent in recruitment plots, representing therefore genes unique to individual bacterial isolates. We show that these Metagenomic Islands (MIs) are also visible in bacteria living in human hosts when their genomes are compared to sequences from the human microbiome, despite the compartmentalized structure of human-related environments such as the gut. From an applied point of view, MIs of human pathogens (e.g. those identified in enterohaemorragic Escherichia coli against the gut metagenome or in pathogenic Neisseria meningitidis against the oral metagenome) include virulence genes that appear to be absent in related strains or species present in the microbiome of healthy individuals. We propose that this strategy (i.e. recruitment analysis of pathogenic bacteria against the metagenome of healthy subjects) can be used to detect pathogenicity regions in species where the genes involved in virulence are poorly characterized. Using this approach, we detect well-known pathogenicity islands and identify new potential virulence genes in several human pathogens

Bleeding in cardiac patients prescribed antithrombotic drugs: Electronic health record phenotyping algorithms, incidence, trends and prognosis

Background Clinical guidelines and public health authorities lack recommendations on scalable approaches to defining and monitoring the occurrence and severity of bleeding in populations prescribed antithrombotic therapy. Methods We examined linked primary care, hospital admission and death registry electronic health records (CALIBER 1998–2010, England) of patients with newly diagnosed atrial fibrillation, acute myocardial infarction, unstable angina or stable angina with the aim to develop algorithms for bleeding events. Using the developed bleeding phenotypes, Kaplan-Meier plots were used to estimate the incidence of bleeding events and we used Cox regression models to assess the prognosis for all-cause mortality, atherothrombotic events and further bleeding. Results We present electronic health record phenotyping algorithms for bleeding based on bleeding diagnosis in primary or hospital care, symptoms, transfusion, surgical procedures and haemoglobin values. In validation of the phenotype, we estimated a positive predictive value of 0.88 (95% CI 0.64, 0.99) for hospitalised bleeding. Amongst 128,815 patients, 27,259 (21.2%) had at least 1 bleeding event, with 5-year risks of bleeding of 29.1%, 21.9%, 25.3% and 23.4% following diagnoses of atrial fibrillation, acute myocardial infarction, unstable angina and stable angina, respectively. Rates of hospitalised bleeding per 1000 patients more than doubled from 1.02 (95% CI 0.83, 1.22) in January 1998 to 2.68 (95% CI 2.49, 2.88) in December 2009 coinciding with the increased rates of antiplatelet and vitamin K antagonist prescribing. Patients with hospitalised bleeding and primary care bleeding, with or without markers of severity, were at increased risk of all-cause mortality and atherothrombotic events compared to those with no bleeding. For example, the hazard ratio for all-cause mortality was 1.98 (95% CI 1.86, 2.11) for primary care bleeding with markers of severity and 1.99 (95% CI 1.92, 2.05) for hospitalised bleeding without markers of severity, compared to patients with no bleeding. Conclusions Electronic health record bleeding phenotyping algorithms offer a scalable approach to monitoring bleeding in the population. Incidence of bleeding has doubled in incidence since 1998, affects one in four cardiovascular disease patients, and is associated with poor prognosis. Efforts are required to tackle this iatrogenic epidemic

Evidence That Intracellular Stages of Leishmania major Utilize Amino Sugars as a Major Carbon Source

Intracellular parasites, such as Leishmania spp, must acquire suitable carbon sources from the host cell in order to replicate. Here we present evidence that intracellular amastigote stages of Leishmania exploit amino sugars in the phagolysosome of mammalian macrophages as a source of carbon and energy. L. major parasites are capable of using N-acetylglucosamine and glucosamine as primarily carbon sources and contain key enzymes required for conversion of these sugars to fructose-6-phosphate. The last step in this pathway is catalyzed by glucosamine-6-phosphate deaminase (GND), which was targeted to glycosomes via a canonical C-terminal targeting signal when expressed as a GFP fusion protein. Mutant parasites lacking GND were unable to grow in medium containing amino sugars as sole carbohydrate source and rapidly lost viability, concomitant with the hyper-accumulation of hexosamine-phosphates. Expression of native GND, but not a cytosolic form of GND, in Δgnd parasites restored hexosamine-dependent growth, indicating that toxicity is due to depletion of glycosomal pools of ATP. Non-lethal increases in hexosamine phosphate levels in both Δgnd and wild type parasites was associated with a defect in promastigote metacyclogenesis, suggesting that hexosamine phosphate levels may influence parasite differentiation. Promastigote and amastigote stages of the Δgnd mutant were unable to replicate within macrophages and were either completely cleared or exhibited reduced lesion development in highly susceptible Balb/c mice. Our results suggest that hexosamines are a major class of sugars in the macrophage phagolysosome and that catabolism of scavenged amino sugars is required to sustain essential metabolic pathways and prevent hexosamine toxicity

EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM

Background and Aims: To maximize cost/efficay of boceprevirbased triple therapy (BOC) in patients with HCV-related advanced fibrosis/cirrhosis. Methods: ITT SVR12, safety and futility rules value were evaluated in the multicenter national Italian and Spanish early access Name- Patient-Program which includes treatment-experienced patients with HCVG1-related advanced fibrosis/cirrhosis (Metavir F3/4) treated with BOC in both countries. Results: 402 patients (mean age 55 years; range 22–75), 316 (78.6%) G1b, 255 (63.4%) F4, 60 (30.9%) with oesophageal varices, 137 (34.1%) relapsers, 95 (23.6%) partial and 168 (41.8%) null responders were enrolled. Platelets count <100,000 and albumin levels <3.5 g/dl were present in 49 (12.2%) and 22 (6.3%) patients, respectively. 369 (91.8%) received at least 1 dose of BOC. Overall ITT SVR12 rates and according to prior response to P/R, fibrosis stage and TW8 HCV-RNA value to P/R/BOC are reported in the table. At multivariate analysis, the strongest predictors of SVR12 were TW8 HCV-RNA undetectability (RR, 30.8; 95% CI, 8.7–108.7) and HCV-RNA detectable but <1000 IU/mL (RR, 9.1; 95% CI, 2.6–31.8) compared to those with HCV-RNA ≥1000 IU/mL. Two patients (0.5%) died from multi-organ failure, 13 (3.2%) developed hepatic decompensation, 41 (10.2%) had severe anemia (<8.5 g/dl) and 31 (7.7%) required at least one blood transfusion. Conclusions: In treatment-experienced patients with advanced fibrosis/cirrhosis, SVR12 attained by BOC was satisfactory. Mortality, life-threatening adverse events and severe anemia rates were similar to those reported in other real-practice studies. A TW8 futility rule enables a safely discontinuation of BOC in patients who are extremely unlikely to achieve SVR, thus optimizing the effectiveness of treatment in this difficult-to-cure population