Background There is general consensus that consumption of dietary fermentable fiber improves cardiometabolic health, in part by promoting mutualistic microbes and by increasing production of beneficial metabolites in the distal gut. However, human studies have reported variations in the observed benefits among individuals consuming the same fiber. Several factors likely contribute to this variation, including host genetic and gut microbial differences. We hypothesized that gut microbial metabolism of dietary fiber represents an important and differential factor that modulates how dietary fiber impacts the host. Results We examined genetically identical gnotobiotic mice harboring two distinct complex gut microbial communities and exposed to four isocaloric diets, each containing different fibers: (i) cellulose, (ii) inulin, (iii) pectin, (iv) a mix of 5 fermentable fibers (assorted fiber). Gut microbiome analysis showed that each transplanted community preserved a core of common taxa across diets that differentiated it from the other community, but there were variations in richness and bacterial taxa abundance within each community among the different diet treatments. Host epigenetic, transcriptional, and metabolomic analyses revealed diet-directed differences between animals colonized with the two communities, including variation in amino acids and lipid pathways that were associated with divergent health outcomes. Conclusion This study demonstrates that interindividual variation in the gut microbiome is causally linked to differential effects of dietary fiber on host metabolic phenotypes and suggests that a one-fits-all fiber supplementation approach to promote health is unlikely to elicit consistent effects across individuals. Overall, the presented results underscore the importance of microbe-diet interactions on host metabolism and suggest that gut microbes modulate dietary fiber efficacy.

Ribonuclease inhibitor (RNH1) is a cytosolic protein that binds with femtomolar affinity to human ribonuclease 1 (RNase 1) and homologous secretory ribonucleases. RNH1 contains 32 cysteine residues and has been implicated as an anti-oxidant. Here, we use CRISPR–Cas9 to knockout RNH1 in HeLa cells. We find that cellular RNH1 affords marked protection from the lethal ribonucleolytic activity of RNase 1 but not from oxidants. We conclude that RNH1 protects cytosolic RNA from invading ribonucleases.

Angiogenin (ANG) is a secretory ribonuclease that promotes the proliferation of endothelial cells, leading to angiogenesis. This function relies on its ribonucleolytic activity, which is low for simple RNA substrates. Upon entry into the cytosol, ANG is sequestered by the ribonuclease inhibitor protein (RNH1). We find that ANG is a potent cytotoxin for -knockout HeLa cells, belying its inefficiency as a nonspecific catalyst. The toxicity does, however, rely on the ribonucleolytic activity of ANG and a cytosolic localization, which lead to the accumulation of particular tRNA fragments (tRFs), such as tRF-5 Gly-GCC. These up-regulated tRFs are highly cytotoxic at physiological concentrations. Although ANG is well-known for its promotion of cell growth, our results reveal that ANG can also cause cell death.

Despite the increasing availability of tandem mass spectrometry (MS/MS) community spectral libraries for untargeted metabolomics over the past decade, the majority of acquired MS/MS spectra remain uninterpreted. To further aid in interpreting unannotated spectra, we created a nearest neighbor suspect spectral library, consisting of 87,916 annotated MS/MS spectra derived from hundreds of millions of public MS/MS spectra. Annotations were propagated based on structural relationships to reference molecules using MS/MS-based spectrum alignment. We demonstrate the broad relevance of the nearest neighbor suspect spectral library through representative examples of propagation-based annotation of acylcarnitines, bacterial and plant natural products, and drug metabolism. Our results also highlight how the library can help to better understand an Alzheimer’s brain phenotype. The nearest neighbor suspect spectral library is openly available through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.

Short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are produced in large quantities by the gut microbiome and contribute to a wide array of physiological processes. While the underlying mechanisms are largely unknown, many effects of SCFAs have been traced to changes in the cell’s epigenetic state. Here, we systematically investigate how SCFAs alter the epigenome. Using quantitative proteomics of histone modification states, we identified rapid and sustained increases in histone acetylation after addition of butyrate or propionate, but not acetate. While decades of prior observations would have suggested that hyperacetylation induced by SCFAs are attributed to inhibition of histone deacetylases (HDACs), we found that propionate and butyrate instead activate the acetyltransferase p300. Propionate and butyrate are rapidly converted to the corresponding acyl-CoAs which are then used by p300 to catalyze auto-acylation of the autoinhibitory loop, activating the enzyme for histone/protein acetylation. This data challenges the long-held belief that SCFAs mainly regulate chromatin by inhibiting HDACs, and instead reveals a previously unknown mechanism of HAT activation that can explain how an influx of low levels of SCFAs alters global chromatin states.

We present the results of a model-based search for continuous gravitational waves from the low-mass X-ray binary Scorpius X-1 using LIGO detector data from the third observing run of Advanced LIGO and Advanced Virgo. This is a semicoherent search that uses details of the signal model to coherently combine data separated by less than a specified coherence time, which can be adjusted to balance sensitivity with computing cost. The search covered a range of gravitational-wave frequencies from 25 to 1600 Hz, as well as ranges in orbital speed, frequency, and phase determined from observational constraints. No significant detection candidates were found, and upper limits were set as a function of frequency. The most stringent limits, between 100 and 200 Hz, correspond to an amplitude h 0 of about 10−25 when marginalized isotropically over the unknown inclination angle of the neutron star’s rotation axis, or less than 4 × 10−26 assuming the optimal orientation. The sensitivity of this search is now probing amplitudes predicted by models of torque balance equilibrium. For the usual conservative model assuming accretion at the surface of the neutron star, our isotropically marginalized upper limits are close to the predicted amplitude from about 70 to 100 Hz; the limits assuming that the neutron star spin is aligned with the most likely orbital angular momentum are below the conservative torque balance predictions from 40 to 200 Hz. Assuming a broader range of accretion models, our direct limits on gravitational-wave amplitude delve into the relevant parameter space over a wide range of frequencies, to 500 Hz or more.

No abstract

Short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are produced in large quantities by the gut microbiome and contribute to a wide array of physiological processes. While the underlying mechanisms are largely unknown, many effects of SCFAs have been traced to changes in the cell’s epigenetic state. Here, we systematically investigate how SCFAs alter the epigenome. Using quantitative proteomics of histone modification states, we identified rapid and sustained increases in histone acetylation after addition of butyrate or propionate, but not acetate. While decades of prior observations would have suggested that hyperacetylation induced by SCFAs are attributed to inhibition of histone deacetylases (HDACs), we found that propionate and butyrate instead activate the acetyltransferase p300. Propionate and butyrate are rapidly converted to the corresponding acyl-CoAs which are then used by p300 to catalyze auto-acylation of the autoinhibitory loop, activating the enzyme for histone/protein acetylation. This data challenges the long-held belief that SCFAs mainly regulate chromatin by inhibiting HDACs, and instead reveals a previously unappreciated mechanism of HAT activation that can explain how even low levels of SCFAs alter global chromatin states.