Abstract: The Sample Analysis at Mars (SAM) investigation on the Mars Science Laboratory (MSL) Curiosity rover has detected oxidized nitrogen-bearing compounds during pyrolysis of scooped aeolian sediments and drilled sedimentary deposits within Gale crater. Total N concentrations ranged from 20 to 250 nmol N per sample. After subtraction of known N sources in SAM, our results support the equivalent of 110–300 ppm of nitrate in the Rocknest (RN) aeolian samples, and 70–260 and 330–1,100 ppm nitrate in John Klein (JK) and Cumberland (CB) mudstone deposits, respectively. Discovery of indigenous martian nitrogen in Mars surface materials has important implications for habitability and, specifically, for the potential evolution of a nitrogen cycle at some point in martian history. The detection of nitrate in both wind-drifted fines (RN) and in mudstone (JK, CB) is likely a result of N 2 fixation to nitrate generated by thermal shock from impact or volcanic plume lightning on ancient Mars. Fixed nitrogen could have facilitated the development of a primitive nitrogen cycle on the surface of ancient Mars, potentially providing a biochemically accessible source of nitrogen.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 〈 70 y and in 〉 4% of those 〉 70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals 〈 70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals 〈 40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Abstract: Nitrogen (N) isotope ratios ( 15 N/ 14 N) provide integrative constraints on the N inventory of the modern ocean. Anaerobic ammonium oxidation (anammox), which converts ammonium and nitrite to dinitrogen gas (N 2 ) and nitrate, is an important fixed N sink in marine ecosystems. We studied the so far unknown N isotope effects of anammox in batch culture experiments. Anammox preferentially removes 14 N from the ammonium pool with an isotope effect of +23.5‰ to +29.1‰, depending on factors controlling reversibility. The N isotope effects during the conversion of nitrite to N 2 and nitrate are ( i ) inverse kinetic N isotope fractionation associated with the oxidation of nitrite to nitrate (−31.1 ± 3.9‰), ( ii ) normal kinetic N isotope fractionation during the reduction of nitrite to N 2 (+16.0 ± 4.5‰), and ( iii ) an equilibrium N isotope effect between nitrate and nitrite (−60.5 ± 1.0‰), induced when anammox is exposed to environmental stress, leading to the superposition of N isotope exchange effects upon kinetic N isotope fractionation. Our findings indicate that anammox may be responsible for the unresolved large N isotope offsets between nitrate and nitrite in oceanic oxygen minimum zones. Irrespective of the extent of N isotope exchange between nitrate and nitrite, N removed from the combined nitrite and nitrate (NO x ) pool is depleted in 15 N relative to NO x . This net N isotope effect by anammox is superimposed on the N isotope fractionation by the co-occurring reduction of nitrate to nitrite in suboxic waters, possibly enhancing the overall N isotope effect for N loss from oxygen minimum zones.

Abstract: Drought alters carbon (C) allocation within trees, thereby impairing tree growth. Recovery of root and leaf functioning and prioritized C supply to sink tissues after drought may compensate for drought-induced reduction of assimilation and growth. It remains unclear if C allocation to sink tissues during and following drought is controlled by altered sink metabolic activities or by the availability of new assimilates. Understanding such mechanisms is required to predict forests’ resilience to a changing climate. We investigated the impact of drought and drought release on C allocation in a 100-y-old Scots pine forest. We applied 13 CO 2 pulse labeling to naturally dry control and long-term irrigated trees and tracked the fate of the label in above- and belowground C pools and fluxes. Allocation of new assimilates belowground was ca. 53% lower under nonirrigated conditions. A short rainfall event, which led to a temporary increase in the soil water content (SWC) in the topsoil, strongly increased the amounts of C transported belowground in the nonirrigated plots to values comparable to those in the irrigated plots. This switch in allocation patterns was congruent with a tipping point at around 15% SWC in the response of the respiratory activity of soil microbes. These results indicate that the metabolic sink activity in the rhizosphere and its modulation by soil moisture can drive C allocation within adult trees and ecosystems. Even a subtle increase in soil moisture can lead to a rapid recovery of belowground functions that in turn affects the direction of C transport in trees.

Abstract: Microbially catalyzed back fluxes also have practical implications in the biogeochemical evaluation of habitat data. Microbial catabolic activity in natural habitats is usually measured by examining the flux of an isotope label added from the substrate to the product pool rather than by determining the net rate of product accumulation by chemical quantification. However, if back flux occurs, the label flux from the substrate is not identical to the microbial net rate. Accurate net rate determination by isotope labeling would have to include both forward and back flux measurement to yield the net rate. Moreover, detection of a reaction in situ by labeling does not necessarily indicate a net reaction occurring in the direction of label conversion; it may represent the back flux during the opposite reaction. Finally, the existence of reverse reactions may also be important for our understanding of stable isotope fractionation and the underlying mechanisms. Reversibility through an entire biochemical pathway (e.g., sulfate ⇌ sulfide) with particular consideration of low-energy conditions is usually not taken into account in the study of stable isotope patterns. The existence of the reverse reaction of all products through the entire catabolism has consequences for the study of not only AOM but also other biogeochemical processes with low-energy yields in natural habitats. A low-energy habitat of present interest is the deep biosphere where energy-rich substrates have been depleted. Because individual reactions within the catabolism are less exergonic than the overall catabolic process, the particular reactions constituting the overall catabolism of the consortia must be even more reversible than determined in this study. To determine the back flux of sulfide to sulfate and bicarbonate to methane, we added 35 S-H 2 S or 14 C-NaHCO 3 and measured the accumulated radioactivity of 35 SO 4 2− and 14 CH 4 , respectively. A refined formula for data evaluation yielded sulfur back fluxes ( Fig. P1 ) of 7% (HR) and 13% (MV) of the net AOM rate. The determined carbon back fluxes were 3.2% (HR) and 5.5% (MV) of the net AOM rate ( Fig. P1 ). The carbon back flux continued when AOM was prevented by omitting sulfate. In contrast, when AOM was prevented by omission of methane, the back flux from 35 S-H 2 S to the sulfate pool was negligible. To test and quantify back fluxes of both carbon and sulfur during AOM, we used marine AOM consortia that were essentially free of nonliving particulate organic matter and had been highly enriched in vitro from anoxic sediment of two marine methane seep areas: Hydrate Ridge (HR; Cascadia Margin, Oregon, Northeast Pacific) and Isis Mud Volcano sediment (MV; Eastern Mediterranean Sea). The 1:1 stoichiometric conversion of methane and sulfate, according to Fig. P1 , was confirmed by quantification of methane consumption and sulfide production as well as substrate-labeling experiments with 14 CH 4 and 35 SO 4 2− . In the absence of methane, methanogenesis and sulfate reduction because of use of endogenous compounds or dead cell carbon were not detectable. Hence, these cultures were ideally suited to study the flux of labeled inorganic carbon and sulfide into the pools of methane and sulfate, respectively. Here, we present a refined quantitative study of the back fluxes of the products derived from both the electron donor and the electron acceptor. As an ecologically relevant example, we chose the AOM with sulfate, which is catalyzed by evolutionarily unrelated microorganisms of the archaea and regular bacteria ( 5 ) that seem to cooperate in microaggregates (consortia) with an as yet unknown mode of coupling ( Fig. P1 ). AOM with sulfate is one of the least exergonic catabolic reactions sustaining life, the standard free energy change Δ G ° being only −16.6 kJ mol −1 ; free energy changes under in situ conditions can be only slightly more favorable ( Fig. P1 ). Moreover, the low-energy yield is apparently shared between the two members of the consortia. Although a catabolism with low-energy gain (a weakly exergonic catabolism) is common in strictly anaerobic microorganisms ( 1 , 2 ), the possibility of product back fluxes existing in anaerobes has been treated in very few studies. Known examples are the conversion of added 14 C-methane to 14 C-carbon dioxide during net methane formation by various methanogenic archaea ( 3 ) and the conversion of added 35 S-sulfide to sulfate during net sulfate reduction with lactate by Desulfovibrio ( 4 ), a genus of sulfate-reducing bacteria. In these cases, the back flux of one element (C or S, respectively) through the corresponding pathway in the respective organism was shown. Microbial redox processes such as the degradation of organic carbon to carbon dioxide in natural habitats are commonly believed to occur in a single direction. However, in the area of enzyme kinetics, bidirectionality is a long-established feature, with the reverse reaction being the more significant the closer the system operates to thermodynamic equilibrium (i.e., the lower the energy yield). Hence, the energy metabolism (catabolism) in organisms, viewed as a multiplicity of enzymatic systems, should, in principle, exhibit some reversibility if the overall energy yield is low—a situation common among strictly anaerobic microorganisms. Such reversibility should be expressed as a back flux from product to substrate. We tested this possibility using highly enriched consortia of marine archaea and bacteria that catalyze the anaerobic oxidation of methane (AOM) with sulfate. The energy gain from AOM (approximately −20 kJ mol −1 ) is one of the lowest among metabolic processes fueling life. Expectedly, product radiolabeling with 14 C-bicarbonate and 35 S-sulfide showed the presence of back fluxes to the methane and sulfate pools during net AOM. Refined data evaluation revealed back fluxes up to 5% and 13%, respectively, of the net AOM rate. The existence of such back fluxes through the entire catabolism is a commonly overlooked kinetic and energetic aspect of microbial ecophysiology. It also has implications on the interpretation of isotope labeling experiments in the determination of in situ degradation rates and understanding of natural isotope patterns in anoxic habitats.

Abstract: Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocyte-dependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.

Abstract: Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or patients with chronic inflammatory bowel diseases. GC not only limit inflammation but also promote its resolution although the underlying mechanisms are obscure. Here, we reveal reciprocal regulation of 15-lipoxygenase (LOX) isoform expression in human monocyte/macrophage lineages by GC with respective consequences for the biosynthesis of specialized proresolving mediators (SPM) and their 15-LOX-derived monohydroxylated precursors (mono-15-OH). Dexamethasone robustly up-regulated pre-mRNA, mRNA, and protein levels of ALOX15B/15-LOX-2 in blood monocyte–derived macrophage (MDM) phenotypes, causing elevated SPM and mono-15-OH production in inflammatory cell types. In sharp contrast, dexamethasone blocked ALOX15/15-LOX-1 expression and impaired SPM formation in proresolving M2-MDM. These dexamethasone actions were mimicked by prednisolone and hydrocortisone but not by progesterone, and they were counteracted by the GC receptor (GR) antagonist RU486. Chromatin immunoprecipitation (ChIP) assays revealed robust GR recruitment to a putative enhancer region within intron 3 of the ALOX15B gene but not to the transcription start site. Knockdown of 15-LOX-2 in M1-MDM abolished GC-induced SPM formation and mono-15-OH production. Finally, ALOX15B/15-LOX-2 upregulation was evident in human monocytes from patients with GC-treated COVID-19 or patients with IBD. Our findings may explain the proresolving GC actions and offer opportunities for optimizing GC pharmacotherapy and proresolving mediator production.