Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease

OBJECTIVE: Current cerebrospinal fluid (CSF) tests for sporadic Creutzfeldt-Jakob disease (sCJD) are based on the detection of surrogate markers of neuronal damage such as CSF 14-3-3 which are not specific for sCJD. A number of prion protein conversion assays have been developed, including real-time quaking induced conversion (RT-QuIC). The objective of this study is to investigate whether CSF RT-QuIC analysis could be used as a diagnostic test in sCJD. METHODS: An exploratory study was undertaken which analysed 108 CSF samples from patients with neuropathologically confirmed sCJD or from control patients. Of the 108 CSF samples 56 were from sCJD patients (30 female, 26 male, aged 31–84 years; 62.3 ± 13.5 years) and 52 were from control patients (26 female, 26 male, aged 43–84 years; 67.8 ± 10.4 years). A confirmatory group of 118 patients were subsequently examined which consisted of 67 cases of neuropathologically confirmed sCJD (33 female, 34 male, aged 39–82 years; 67.5 ± 9.0 years) and 51 control cases (26 female, 25 male, aged 36–87 years; 63.5 ± 11.6 years). RESULTS: The exploratory study showed that RT-QuIC analysis had a sensitivity of 91% and a specificity of 98% for the diagnosis of sCJD. These results were confirmed in the confirmatory study which showed that CSF RT-QuIC analysis had a sensitivity and specificity of 87% and 100% respectively. INTERPRETATION: This study shows that CSF RT-QuIC analysis has the potential to be a more specific diagnostic test for sCJD than current CSF tests

Quantification of CO2 removal in a large-scale enhanced weathering field trial on an oil palm plantation in Sabah, Malaysia

Modeling studies show that large-scale deployment of enhanced rock weathering on croplands has the potential to reduce levels of atmospheric carbon dioxide by the end of the century. There is, however, a pressing need to verify model predictions through long-term field trials. Here we report results from the first 3 years of an ongoing enhanced weathering field trial, carried out on an oil palm plantation in Sabah, Malaysia. Crushed silicate rock was applied to three hydrologically isolated catchments, and three adjacent (paired) reference catchments were left untreated. The drawdown of atmospheric CO2 was quantified via the export of alkalinity in stream waters and changes in soil carbonate content. The amended and reference catchments were found to have a similar extent of CO2 drawdown via alkalinity export [respectively, 3.8 ± 0.8 (1 SD) and 3.7 ± 0.6 (1 SD) tCO2 ha−1] when all catchments were averaged over the study period (October 2018 to July 2021). However, differences were observed between the different catchment pairs (plots): two of the plots displayed a similar extent of CO2 removal for both the amended and reference catchments, but the third amended catchment had a higher extent of CO2 removal of ~1 tCO2 ha−1 relative to its adjacent reference catchment. The difference in CO2 removal rates determined for this plot can likely be attributed to increased weathering of silicate minerals in the amended catchment. Soil carbonate concentrations were on average < 0.2 wt% CaCO3, but we report a small increase of ~0.03 wt% CaCO3 in the top 30 cm of soil in the amended soils relative to the reference catchments. The magnitude of CO2 drawdown via alkalinity export determined for these agricultural catchments is around an order of magnitude higher than in natural forested catchments in Sabah and similar to that of basaltic catchments. We show that these high weathering rates are primarily driven by weathering of carbonate fertilizers. The data presented from this field trial provide vital contextual information on the real-world efficacy and practicalities associated with the implementation of enhanced weathering for atmospheric CO2 removal that will help to inform further trials as well as wider-scale deployment

Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

SummaryMetabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases

Analysis of a viral metagenomic library from 200 m depth in Monterey Bay, California constructed by direct shotgun cloning

<p>Abstract</p> <p>Background</p> <p>Viruses have a profound influence on both the ecology and evolution of marine plankton, but the genetic diversity of viral assemblages, particularly those in deeper ocean waters, remains poorly described. Here we report on the construction and analysis of a viral metagenome prepared from below the euphotic zone in a temperate, eutrophic bay of coastal California.</p> <p>Methods</p> <p>We purified viruses from approximately one cubic meter of seawater collected from 200m depth in Monterey Bay, CA. DNA was extracted from the virus fraction, sheared, and cloned with no prior amplification into a plasmid vector and propagated in <it>E. coli </it>to produce the MBv200m library. Random clones were sequenced by the Sanger method. Sequences were assembled then compared to sequences in GenBank and to other viral metagenomic libraries using BLAST analyses.</p> <p>Results</p> <p>Only 26% of the 881 sequences remaining after assembly had significant (E ≤ 0.001) BLAST hits to sequences in the GenBank nr database, with most being matches to bacteria (15%) and viruses (8%). When BLAST analysis included environmental sequences, 74% of sequences in the MBv200m library had a significant match. Most of these hits (70%) were to microbial metagenome sequences and only 0.7% were to sequences from viral metagenomes. Of the 121 sequences with a significant hit to a known virus, 94% matched bacteriophages (Families <it>Podo</it>-, <it>Sipho</it>-, and <it>Myoviridae</it>) and 6% matched viruses of eukaryotes in the Family <it>Phycodnaviridae </it>(5 sequences) or the Mimivirus (2 sequences). The largest percentages of hits to viral genes of known function were to those involved in DNA modification (25%) or structural genes (17%). Based on reciprocal BLAST analyses, the MBv200m library appeared to be most similar to viral metagenomes from two other bays and least similar to a viral metagenome from the Arctic Ocean.</p> <p>Conclusions</p> <p>Direct cloning of DNA from diverse marine viruses was feasible and resulted in a distribution of virus types and functional genes at depth that differed in detail, but were broadly similar to those found in surface marine waters. Targeted viral analyses are useful for identifying those components of the greater marine metagenome that circulate in the subcellular size fraction.</p

Quantification of CO2 removal in a large-scale enhanced weathering field trial on an oil palm plantation in Sabah, Malaysia

Modeling studies show that large-scale deployment of enhanced rock weathering on croplands has the potential to reduce levels of atmospheric carbon dioxide by the end of the century. There is, however, a pressing need to verify model predictions through long-term field trials. Here we report results from the first 3 years of an ongoing enhanced weathering field trial, carried out on an oil palm plantation in Sabah, Malaysia. Crushed silicate rock was applied to three hydrologically isolated catchments, and three adjacent (paired) reference catchments were left untreated. The drawdown of atmospheric CO2 was quantified via the export of alkalinity in stream waters and changes in soil carbonate content. The amended and reference catchments were found to have a similar extent of CO2 drawdown via alkalinity export [respectively, 3.8 ± 0.8 (1 SD) and 3.7 ± 0.6 (1 SD) tCO2 ha−1] when all catchments were averaged over the study period (October 2018 to July 2021). However, differences were observed between the different catchment pairs (plots): two of the plots displayed a similar extent of CO2 removal for both the amended and reference catchments, but the third amended catchment had a higher extent of CO2 removal of ~1 tCO2 ha−1 relative to its adjacent reference catchment. The difference in CO2 removal rates determined for this plot can likely be attributed to increased weathering of silicate minerals in the amended catchment. Soil carbonate concentrations were on average < 0.2 wt% CaCO3, but we report a small increase of ~0.03 wt% CaCO3 in the top 30 cm of soil in the amended soils relative to the reference catchments. The magnitude of CO2 drawdown via alkalinity export determined for these agricultural catchments is around an order of magnitude higher than in natural forested catchments in Sabah and similar to that of basaltic catchments. We show that these high weathering rates are primarily driven by weathering of carbonate fertilizers. The data presented from this field trial provide vital contextual information on the real-world efficacy and practicalities associated with the implementation of enhanced weathering for atmospheric CO2 removal that will help to inform further trials as well as wider-scale deployment

Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression

Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit+ neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression

Roadmap on structured light

Structured light refers to the generation and application of custom light fields. As the tools and technology to create and detect structured light have evolved, steadily the applications have begun to emerge. This roadmap touches on the key fields within structured light from the perspective of experts in those areas, providing insight into the current state and the challenges their respective fields face. Collectively the roadmap outlines the venerable nature of structured light research and the exciting prospects for the future that are yet to be realized

Cost-effectiveness of collaborative care for the treatment of major depressive disorder in primary care. A systematic review

Background. The effectiveness of collaborative care for patients with major depressive disorder in primary care has been established. Assessing its cost-effectiveness is important for deciding on implementation. This review therefore evaluates the cost-effectiveness of collaborative care for major depressive disorder in primary care. Methods. A systematic search on economic evaluations of collaborative care was conducted in Pubmed and PsychInfo. Quality of the studies was measured with the Cochrane checklist and the CHEC-list for economic evaluations. Cost-effectiveness and costs per depression-free days were reported. Results. 8 studies were found, involving 4868 patients. The quality of the cost effectiveness studies, according to the CHEC-list, could be improved. Generally, the studies did not include all relevant costs and did not perform sensitivity analysis. Only 4 out of 8 studies reported cost per QALY, 6 out of 8 reported costs per depression-free days. The highest costs per QALY reported were $49,500, the highest costs per depression-free day were$24. Conclusions. Although studies did not fulfil all criteria of the CHEC-list, collaborative care is a promising intervention and it may be cost-effective. However, to conclude on the cost-effectiveness, depression research should follow economic guidelines to improve the quality of the economic evaluations

Predicting growth rates and recessions: assessing US leading indicators under real-time conditions

In this paper we analyze the power of various indicators to predict growth rates of aggregate production using real-time data. In addition, we assess their ability to predict turning points of the economy. We consider four groups of indicators: survey data, composite indicators, real economic indicators, and financial data. Almost all indicators are found to improve short-run growth forecasts whereas the results for four-quarter-ahead growth forecasts and the prediction of recession probabilities in general are mixed. We can confirm the result that an indicator suited to improve growth forecasts does not necessarily help to produce more accurate recession forecasts. Only composite leading indicators perform generally well in both forecasting exercises