The production of artificial fertilizers, fossil fuel use and leguminous agriculture worldwide has increased the amount of reactive nitrogen in the natural environment by an order of magnitude since ...the Industrial Revolution1. This reorganization of the nitrogen cycle has led to an increase in food production2, but increasingly causes a number of environmental problems1, 3. One such problem is the accumulation of nitrate in both freshwater and coastal marine ecosystems. Here we establish that ecosystem nitrate accrual exhibits consistent and negative nonlinear correlations with organic carbon availability along a hydrologic continuum from soils, through freshwater systems and coastal margins, to the open ocean. The trend also prevails in ecosystems subject to substantial human alteration. Across this diversity of environments, we find evidence that resource stoichiometry (organic carbon:nitrate) strongly influences nitrate accumulation by regulating a suite of microbial processes that couple dissolved organic carbon and nitrate cycling. With the help of a meta-analysis we show that heterotrophic microbes maintain low nitrate concentrations when organic carbon:nitrate ratios match the stoichiometric demands of microbial anabolism. When resource ratios drop below the minimum carbon:nitrogen ratio of microbial biomass4, however, the onset of carbon limitation appears to drive rapid nitrate accrual, which may then be further enhanced by nitrification. At low organic carbon:nitrate ratios, denitrification appears to constrain the extent of nitrate accretion, once organic carbon and nitrate availability approach the 1:1 stoichiometry5 of this catabolic process. Collectively, these microbial processes express themselves on local to global scales by restricting the threshold ratios underlying nitrate accrual to a constrained stoichiometric window. Our findings indicate that ecological stoichiometry can help explain the fate of nitrate across disparate environments and in the face of human disturbance.
Tropical forests dominate global terrestrial carbon (C) exchange, and recent droughts in the Amazon Basin have contributed to short‐term declines in terrestrial carbon dioxide uptake and storage. ...However, the effects of longer‐term climate variability on tropical forest carbon dynamics are still not well understood. We synthesised field data from more than 150 tropical forest sites to explore how climate regulates tropical forest aboveground net primary productivity (ANPP) and organic matter decomposition, and combined those data with two existing databases to explore climate – C relationships globally. While previous analyses have focused on the effects of either temperature or rainfall on ANPP, our results highlight the importance of interactions between temperature and rainfall on the C cycle. In cool forests (< 20 °C), high rainfall slowed rates of C cycling, but in warm tropical forests (> 20 °C) it consistently enhanced both ANPP and decomposition. At the global scale, our analysis showed an increase in ANPP with rainfall in relatively warm sites, inconsistent with declines in ANPP with rainfall reported previously. Overall, our results alter our understanding of climate – C cycle relationships, with high precipitation accelerating rates of C exchange with the atmosphere in the most productive biome on earth.
Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α ...and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8+ T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8+ cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8+ CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8+ OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.
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•GSK-3 is a key upstream kinase that contributes to inhibition of PD-1 transcription•GSK-3 siRNAs or inhibitors block PD-1 transcription to thereby enhance CTL function•GSK-3 inhibition enhances Tbx21 transcription, which represses PD-1 transcription•Use of GSK-3 inhibitors in vivo downregulates PD-1 and enhances viral clearance
The upstream pathway regulating PD-1 expression is not clear. Rudd and colleagues show that inhibition of the serine/threonine kinase GSK-3 upregulates T-bet expression, which decreases PD-1 expression and enhances CTL function. They demonstrate that the use of GSK-3 inhibitors in vivo inhibits PD-1 and enhances T cell clearance of viral infections.
Global changes such as variations in plant net primary production are likely to drive shifts in leaf litterfall inputs to forest soils, but the effects of such changes on soil carbon (C) cycling and ...storage remain largely unknown, especially in C‐rich tropical forest ecosystems. We initiated a leaf litterfall manipulation experiment in a tropical rain forest in Costa Rica to test the sensitivity of surface soil C pools and fluxes to different litter inputs. After only 2 years of treatment, doubling litterfall inputs increased surface soil C concentrations by 31%, removing litter from the forest floor drove a 26% reduction over the same time period, and these changes in soil C concentrations were associated with variations in dissolved organic matter fluxes, fine root biomass, microbial biomass, soil moisture, and nutrient fluxes. However, the litter manipulations had only small effects on soil organic C (SOC) chemistry, suggesting that changes in C cycling, nutrient cycling, and microbial processes in response to litter manipulation reflect shifts in the quantity rather than quality of SOC. The manipulation also affected soil CO ₂ fluxes; the relative decline in CO ₂ production was greater in the litter removal plots (−22%) than the increase in the litter addition plots (+15%). Our analysis showed that variations in CO ₂ fluxes were strongly correlated with microbial biomass pools, soil C and nitrogen (N) pools, soil inorganic P fluxes, dissolved organic C fluxes, and fine root biomass. Together, our data suggest that shifts in leaf litter inputs in response to localized human disturbances and global environmental change could have rapid and important consequences for belowground C storage and fluxes in tropical rain forests, and highlight differences between tropical and temperate ecosystems, where belowground C cycling responses to changes in litterfall are generally slower and more subtle.
Geomorphic position often correlates with nutrient cycling across landscapes. In tropical forests, topography is known to influence phosphorus (P) availability, but its effect on nitrogen (N) cycling ...has received less exploration, especially in lowland forests where widespread N richness is frequently assumed. Here, we report significant effects of topographic slope and landscape position on multiple aspects of the N cycle across a highly dissected lowland tropical forest on the Osa Peninsula, Costa Rica. A suite of N cycle metrics measured along a topographic sequence revealed a distinct gradient in N availability. Values of soil δ
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N, inorganic N pools, net nitrification rates, and nitrification potentials were all substantially lower on a flanking steep hillslope (~28°) compared to a relatively flat ridge top (~6°), indicating lower N availability and a less open N cycle in steep parts of the landscape. Slope soils also hosted smaller total carbon and nitrogen stocks and notably less weathered soil minerals than did ridge soils. These latter findings suggest that elevated N loss resulting from high rates of soil and particulate organic matter erosion could underpin the spatial variation in N cycling and availability. Expanding our analysis to the larger study landscape, a strong negative linear relationship between soil δ
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N values and surface slope angles was observed. N isotope mass balance models suggest that this pattern is most plausibly explained by an increase in N loss via erosive, non-fractioning pathways from steep zones, as most other variables commonly assumed to affect soil δ
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N values (such as temperature, precipitation, and vegetation type) did not vary across the sampled region. Together, these results reveal notable hillslope-scale variation in N richness and suggest an important role for non-fractionating N loss in the maintenance of this pattern. Such findings highlight the importance of geomorphology and the significant capacity of erosion to influence N availability in steepland ecosystems.
The third Fermi Large Area Telescope γ-ray source catalog (3FGL) contains over 1000 objects for which there is no known counterpart at other wavelengths. The physical origin of the γ-ray emission ...from those objects is unknown. Such objects are commonly referred to as unassociated and mostly do not exhibit significant γ-ray flux variability. We performed a survey of all unassociated γ-ray sources found in 3FGL using the Australia Telescope Compact Array and Very Large Array in the range 4.0-10.0 GHz. We found 2097 radio candidates for association with γ-ray sources. The follow-up with very long baseline interferometry for a subset of those candidates yielded 142 new associations with active galactic nuclei that are γ-ray sources, provided alternative associations for seven objects, and improved positions for another 144 known associations to the milliarcsecond level of accuracy. In addition, for 245 unassociated γ-ray sources we did not find a single compact radio source above 2 mJy within 3 of their γ-ray localization. A significant fraction of these empty fields, 39%, are located away from the Galactic plane. We also found 36 extended radio sources that are candidates for association with a corresponding γ-ray object, 19 of which are most likely supernova remnants or H ii regions, whereas 17 could be radio galaxies.
We hypothesized that dinitrogen (N2)- and non-N2-fixing tropical trees would have distinct phosphorus (P) acquisition strategies allowing them to exploit different P sources, reducing competition.
We ...measured root phosphatase activity and arbuscular mycorrhizal (AM) colonization among two N2- and two non-N2-fixing seedlings, and grew them alone and in competition with different inorganic and organic P forms to assess potential P partitioning.
We found an inverse relationship between root phosphatase activity and AM colonization in field-collected seedlings, indicative of a trade-off in P acquisition strategies. This correlated with the predominantly exploited P sources in the seedling experiment: the N2 fixer with high N2 fixation and root phosphatase activity grew best on organic P, whereas the poor N2 fixer and the two non-N2 fixers with high AM colonization grew best on inorganic P. When grown in competition, however, AM colonization, root phosphatase activity and N2 fixation increased in the N2 fixers, allowing them to outcompete the non-N2 fixers regardless of P source.
Our results indicate that some tropical trees have the capacity to partition soil P, but this does not eliminate interspecific competition. Rather, enhanced P and N acquisition strategies may increase the competitive ability of N2 fixers relative to non-N2 fixers.
Autosomal dominant optic atrophy (DOA) is a major cause of visual impairment in young adults that is characterized by selective retinal ganglion cell loss. To define the prevalence and natural ...history of this optic nerve disorder, we performed a population-based epidemiologic and molecular study of presumed DOA cases in the north of England.
Case series.
Seventy-six affected probands with a clinical diagnosis of DOA were identified from our neuro-ophthalmology and neurogenetics database.
OPA1 genetic testing was performed using a polymerase chain reaction-based sequencing strategy. OPA1-negative cases were then screened for large-scale OPA1 rearrangements and OPA3 mutations. Additional affected family members identified through contact tracing were examined, and longitudinal visual data were analyzed.
The prevalence and molecular characteristics of DOA in the north of England. Visual function and disease progression among patients with OPA1-positive mutations.
The detection rate of OPA1 mutations was 57.6% among probands with a positive family history of optic atrophy (19/33) and 14.0% among singleton cases (6/43). Approximately two thirds of our families with DOA harbored OPA1 mutations (14/22, 63.6%), and 5 novel OPA1 mutations were identified. Only 1 family carried a large-scale OPA1 rearrangement, and no OPA3 mutations were found in our optic atrophy cohort. The minimum point prevalence of DOA in the north of England was 2.87 per 100,000 (95% confidence interval CI, 2.54-3.20), or 2.09 per 100,000 (95% CI, 1.95-2.23) when only OPA1-positive cases were considered. Snellen visual acuity varied markedly between OPA1-positive cases with a mean of 20/173 (range 20/20 to hand movements), and visual function worsened in 67.4% of patients during follow-up. The mean rate of visual loss was 0.032 logarithm of the minimum angle of resolution per year, but some patients experienced faster visual decline (range = 0-0.171 logarithm of the minimum angle of resolution/year). OPA1 missense mutations were associated with a significantly worse visual outcome compared with other mutational subtypes (P=0.0001).
Dominant optic atrophy causes significant visual morbidity and affects at least 1 in 35,000 of the general population.
This study examined the relationship between terminal referral source and subsequent urgent health service use in a Canadian early intervention service (EIS) for psychosis. Administrative health ...record data of emergency and inpatient mental health service use over a 2-year follow up from entry to EIS were retrospectively analyzed (n = 515). Negative binomial regression models were used to assess for the relationship between referral source and care outcomes. Compared to those referred from primary care services, the rate of urgent health care use was significantly greater for individuals referred to early intervention services from urgent care services while accounting for social and occupational functioning and psychotic symptom severity. Findings suggest that those referred from urgent services may be at an increased risk for subsequent urgent health care use while attending EIS for psychosis. Further research examining this relationship while incorporating additional relevant predictors is needed.
Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to ...antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.
To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites.
The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.
In total, 45 1H-MRS studies contributed data.
Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor.
Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).
In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean SD age, 30.3 10.4 years) and 1197 healthy volunteers (mean SD age, 27.5 8.8 years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose.
Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.
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