Investigation of the relationship between phenylalanine in venous plasma and capillary blood using volumetric blood collection devices

Measurement of plasma and dried blood spot (DBS) phenylalanine (Phe) is key to monitoring patients with phenylketonuria (PKU). The relationship between plasma and capillary DBS Phe concentrations has been investigated previously, however, differences in methodology, calibration approach and assumptions about the volume of blood in a DBS sub‐punch has complicated this. Volumetric blood collection devices (VBCDs) provide an opportunity to re‐evaluate this relationship. Paired venous and capillary samples were collected from patients with PKU (n = 51). Capillary blood was collected onto both conventional newborn screening (NBS) cards and VBCDs. Specimens were analysed by liquid‐chromatography tandem mass‐spectrometry (LC–MS/MS) using a common calibrator. Use of VBCDs was evaluated qualitatively by patients. Mean bias between plasma and volumetrically collected capillary DBS Phe was −13%. Mean recovery (SD) of Phe from DBS was 89.4% (4.6). VBCDs confirmed that the volume of blood typically assumed to be present in a 3.2 mm sub‐punch is over‐estimated by 9.7%. Determination of the relationship between plasma and capillary DBS Phe, using a single analytical method, common calibration and VBCDs, demonstrated that once the under‐recovery of Phe from DBS has been taken into account, there is no significant difference in the concentration of Phe in plasma and capillary blood. Conversely, comparison of plasma Phe with capillary DBS Phe collected on a NBS card highlighted the limitations of this approach. Introducing VBCDs for the routine monitoring of patients with PKU would provide a simple, acceptable specimen collection technique that ensures consistent sample quality and produces accurate and precise blood Phe results which are interchangeable with plasma Phe

Climate drives the geography of marine consumption by changing predator communities

Este artículo contiene 7 páginas, 3 figuras, 1 tabla.The global distribution of primary production and consumption by humans (fisheries) is well-documented, but we have no map linking the central ecological process of consumption within food webs to temperature and other ecological drivers. Using standardized assays that span 105° of latitude on four continents, we show that rates of bait consumption by generalist predators in shallow marine ecosystems are tightly linked to both temperature and the composition of consumer assemblages. Unexpectedly, rates of consumption peaked at midlatitudes (25 to 35°) in both Northern and Southern Hemispheres across both seagrass and unvegetated sediment habitats. This pattern contrasts with terrestrial systems, where biotic interactions reportedly weaken away from the equator, but it parallels an emerging pattern of a subtropical peak in marine biodiversity. The higher consumption at midlatitudes was closely related to the type of consumers present, which explained rates of consumption better than consumer density, biomass, species diversity, or habitat. Indeed, the apparent effect of temperature on consumption was mostly driven by temperature-associated turnover in consumer community composition. Our findings reinforce the key influence of climate warming on altered species composition and highlight its implications for the functioning of Earth’s ecosystems.We acknowledge funding from the Smithsonian Institution and the Tula Foundation.Peer reviewe

Search for high-energy neutrino emission from hard X-ray AGN with IceCube

Active Galactic Nuclei (AGN) are powerful astronomical objects with very high luminosities. Theoretical arguments suggest that these objects are capable of accelerating particles to energies of 1020 eV. In environments with matter or photon targets, cosmic-ray interactions transpire leading to the production of pionic gamma rays and neutrinos. Since the AGN environment is rich in gas, dust and photons, they are promising candidate sources of high-energy astrophysical neutrinos. While the neutrinos manage to escape, the gamma rays may further interact and cascade down to hard X-rays in environments with sufficiently large photon or gas targets. We have used 12 years of IceCube data to perform a stacked search and a point source search for high-energy neutrino emission from hard X-ray AGN sampled from Swift-BAT Spectroscopic Survey (BASS) and present the results of these two analyses

The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection

Background The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. Results Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. Conclusions These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Glamour and Honor: Going Online and Reading in West African Culture

In the fragile reading cultures of the developing world, will people abandon print as they embrace the Internet? Whether media compete or collaborate depends on place-specific factors. West Africans insert online practices into a local context of material circumstances, social roles, and cultural values. In Nigeria and Ghana these include (1) unreliable electricity and execrable telephone service; (2) overworked women, jobless young men, scammers, and ambitious teenagers; and (3) a reading culture of limited penetration but enormous prestige. Internet access via cybercafés has intensified personal communications, reinforced gender inequality, and enabled petty crooks to go global. It has not, however, encroached on reading's all-but-sacred status. Both netsavvy youth and the adult "reading class" protect reading practices through spatial and temporal separation, time management, and functional differentiation. These preserve the honored position of reading despite West Africans' enthusiasm for the glamour of going online. (c) 2007 by The Massachusetts Institute of Technology.

Investigation of the relationship between phenylalanine in venous plasma and capillary blood using volumetric blood collection devices

AbstractMeasurement of plasma and dried blood spot (DBS) phenylalanine (Phe) is key to monitoring patients with phenylketonuria (PKU). The relationship between plasma and capillary DBS Phe concentrations has been investigated previously, however, differences in methodology, calibration approach and assumptions about the volume of blood in a DBS sub‐punch has complicated this. Volumetric blood collection devices (VBCDs) provide an opportunity to re‐evaluate this relationship. Paired venous and capillary samples were collected from patients with PKU (n = 51). Capillary blood was collected onto both conventional newborn screening (NBS) cards and VBCDs. Specimens were analysed by liquid‐chromatography tandem mass‐spectrometry (LC–MS/MS) using a common calibrator. Use of VBCDs was evaluated qualitatively by patients. Mean bias between plasma and volumetrically collected capillary DBS Phe was −13%. Mean recovery (SD) of Phe from DBS was 89.4% (4.6). VBCDs confirmed that the volume of blood typically assumed to be present in a 3.2 mm sub‐punch is over‐estimated by 9.7%. Determination of the relationship between plasma and capillary DBS Phe, using a single analytical method, common calibration and VBCDs, demonstrated that once the under‐recovery of Phe from DBS has been taken into account, there is no significant difference in the concentration of Phe in plasma and capillary blood. Conversely, comparison of plasma Phe with capillary DBS Phe collected on a NBS card highlighted the limitations of this approach. Introducing VBCDs for the routine monitoring of patients with PKU would provide a simple, acceptable specimen collection technique that ensures consistent sample quality and produces accurate and precise blood Phe results which are interchangeable with plasma Phe.</jats:p

Establishing the Foundation for the Global Observing System for Marine Life

Maintaining healthy, productive ecosystems in the face of pervasive and accelerating human impacts including climate change requires globally coordinated and sustained observations of marine biodiversity. Global coordination is predicated on an understanding of the scope and capacity of existing monitoring programs, and the extent to which they use standardized, interoperable practices for data management. Global coordination also requires identification of gaps in spatial and ecosystem coverage, and how these gaps correspond to management priorities and information needs. We undertook such an assessment by conducting an audit and gap analysis from global databases and structured surveys of experts. Of 371 survey respondents, 203 active, long-term (>5 years) observing programs systematically sampled marine life. These programs spanned about 7% of the ocean surface area, mostly concentrated in coastal regions of the United States, Canada, Europe, and Australia. Seagrasses, mangroves, hard corals, and macroalgae were sampled in 6% of the entire global coastal zone. Two-thirds of all observing programs offered accessible data, but methods and conditions for access were highly variable. Our assessment indicates that the global observing system is largely uncoordinated which results in a failure to deliver critical information required for informed decision-making such as, status and trends, for the conservation and sustainability of marine ecosystems and provision of ecosystem services. Based on our study, we suggest four key steps that can increase the sustainability, connectivity and spatial coverage of biological Essential Ocean Variables in the global ocean: (1) sustaining existing observing programs and encouraging coordination among these; (2) continuing to strive for data strategies that follow FAIR principles (findable, accessible, interoperable, and reusable); (3) utilizing existing ocean observing platforms and enhancing support to expand observing along coasts of developing countries, in deep ocean basins, and near the poles; and (4) targeting capacity building efforts. Following these suggestions could help create a coordinated marine biodiversity observing system enabling ecological forecasting and better planning for a sustainable use of ocean resources

Effect of Buffer Conditions and Organic Cosolvents on the Rate of Strain-Promoted Azide–Alkyne Cycloaddition

We investigate the effect of buffer identity, ionic strength, pH, and organic cosolvents on the rate of strain-promoted azide–alkyne cycloaddition with the widely used DIBAC cyclooctyne. The rate of reaction between DIBAC and a hydrophilic azide is highly tolerant to changes in buffer conditions but is impacted by organic cosolvents. Thus, bioconjugation reactions using DIBAC can be carried out in the buffer that is most compatible with the biomolecules being labeled, but the use of organic cosolvents should be carefully considered

Establishing the Foundation for the Global Observing System for Marine Life

Maintaining healthy, productive ecosystems in the face of pervasive and accelerating human impacts including climate change requires globally coordinated and sustained observations of marine biodiversity. Global coordination is predicated on an understanding of the scope and capacity of existing monitoring programs, and the extent to which they use standardized, interoperable practices for data management. Global coordination also requires identification of gaps in spatial and ecosystem coverage, and how these gaps correspond to management priorities and information needs. We undertook such an assessment by conducting an audit and gap analysis from global databases and structured surveys of experts. Of 371 survey respondents, 203 active, long-term (>5 years) observing programs systematically sampled marine life. These programs spanned about 7% of the ocean surface area, mostly concentrated in coastal regions of the United States, Canada, Europe, and Australia. Seagrasses, mangroves, hard corals, and macroalgae were sampled in 6% of the entire global coastal zone. Two-thirds of all observing programs offered accessible data, but methods and conditions for access were highly variable. Our assessment indicates that the global observing system is largely uncoordinated which results in a failure to deliver critical information required for informed decision-making such as, status and trends, for the conservation and sustainability of marine ecosystems and provision of ecosystem services. Based on our study, we suggest four key steps that can increase the sustainability, connectivity and spatial coverage of biological Essential Ocean Variables in the global ocean: (1) sustaining existing observing programs and encouraging coordination among these; (2) continuing to strive for data strategies that follow FAIR principles (findable, accessible, interoperable, and reusable); (3) utilizing existing ocean observing platforms and enhancing support to expand observing along coasts of developing countries, in deep ocean basins, and near the poles; and (4) targeting capacity building efforts. Following these suggestions could help create a coordinated marine biodiversity observing system enabling ecological forecasting and better planning for a sustainable use of ocean resources