Ray et al. (Reports, 14 February 2020, p. 800) report apparent transcriptional circadian rhythms in mouse tissues lacking the core clock component BMAL1. To better understand these surprising results, we reanalyzed the associated data. We were unable to reproduce the original findings, nor could we identify reliably cycling genes. We conclude that there is insufficient evidence to support circadian transcriptional rhythms in the absence of Bmal1.
Animals in the wild are able to subsist on pathogen-infected and poisonous food and show immunity to various diseases. These may be due to their microbiota, yet we have a poor understanding of animal microbial diversity and function. We used metagenomics to analyze the gut microbiota of more than 180 species in the wild, covering diverse classes, feeding behaviors, geographies, and traits. Using de novo metagenome assembly, we constructed and functionally annotated a database of more than 5000 genomes, comprising 1209 bacterial species of which 75% are unknown. The microbial composition, diversity, and functional content exhibit associations with animal taxonomy, diet, activity, social structure, and life span. We identify the gut microbiota of wild animals as a largely untapped resource for the discovery of therapeutics and biotechnology applications.
Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.
Protocadherin-19 (PCDH19) mutations cause early-onset seizures and cognitive impairment. The PCDH19 gene is on the X-chromosome. Unlike most X-linked disorders, PCDH19 mutations affect heterozygous females (PCDH19HET) but not hemizygous males (PCDH19HEMI); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19HET but not Pcdh19HEMI mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19HET but not Pcdh19HEMI mice exhibit reduced pattern completion and separation abilities, which require mossy fiber synaptic function. Furthermore, PCDH19 appears to interact with N-cadherin at mossy fiber synapses. In Pcdh19HET conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin–dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19HET phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.
Quantum computing hardware technologies have advanced during the past two decades, with the goal of building systems that can solve problems that are intractable on classical computers. The ability to realize large-scale systems depends on major advances in materials science, materials engineering, and new fabrication techniques. We identify key materials challenges that currently limit progress in five quantum computing hardware platforms, propose how to tackle these problems, and discuss some new areas for exploration. Addressing these materials challenges will require scientists and engineers to work together to create new, interdisciplinary approaches beyond the current boundaries of the quantum computing field.
Abruzzi et al. argue that transcriptome oscillations found in our study in the absence of Bmal1 are of low amplitude, statistical significance, and consistency. However, their conclusions rely solely on a different statistical algorithm than we used. We provide statistical measures and additional analyses showing that our original analyses and observations are accurate. Further, we highlight independent lines of evidence indicating Bmal1-independent 24-hour molecular oscillations.
Ness-Cohn et al. claim that our observations of transcriptional circadian rhythms in the absence of the core clock gene Bmal1 in mouse skin fibroblast cells are supported by inadequate evidence. They claim that they were unable to reproduce some of the original findings with their reanalysis. We disagree with their analyses and outlook.
The intestinal mucus layer, an important element of epithelial protection, is produced by goblet cells. Intestinal goblet cells are assumed to be a homogeneous cell type. In this study, however, we delineated their specific gene and protein expression profiles and identified several distinct goblet cell populations that form two differentiation trajectories. One distinct subtype, the intercrypt goblet cells (icGCs), located at the colonic luminal surface, produced mucus with properties that differed from the mucus secreted by crypt-residing goblet cells. Mice with defective icGCs had increased sensitivity to chemically induced colitis and manifested spontaneous colitis with age. Furthermore, alterations in mucus and reduced numbers of icGCs were observed in patients with both active and remissive ulcerative colitis, which highlights the importance of icGCs in maintaining functional protection of the epithelium.
Ray et al. (Reports, 14 February 2020, p. 800) recently claimed temperature-compensated, free-running mRNA oscillations in Bmal1–/– liver slices and skin fibroblasts. We reanalyzed these data and found far fewer reproducible mRNA oscillations in this genotype. We also note errors and potentially inappropriate analyses.
Extensive global sampling and sequencing of the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have enabled researchers to monitor its spread and to identify concerning new variants. Two important determinants of variant spread are how frequently they arise within individuals and how likely they are to be transmitted. To characterize within-host diversity and transmission, we deep-sequenced 1313 clinical samples from the United Kingdom. SARS-CoV-2 infections are characterized by low levels of within-host diversity when viral loads are high and by a narrow bottleneck at transmission. Most variants are either lost or occasionally fixed at the point of transmission, with minimal persistence of shared diversity, patterns that are readily observable on the phylogenetic tree. Our results suggest that transmission-enhancing and/or immune-escape SARS-CoV-2 variants are likely to arise infrequently but could spread rapidly if successfully transmitted.
The study of deep-time ecological dynamics has the ability to inform conservation decisions by anticipating the behavior of ecosystems millions of years into the future. Using network analysis and an exceptional fossil dataset spanning the past 21 million years, we show that mammalian ecological assemblages undergo long periods of functional stasis, notwithstanding high taxonomic volatility due to dispersal, speciation, and extinction. Higher functional richness and diversity promoted the persistence of functional faunas despite species extinction risk being indistinguishable among these different faunas. These findings, and the large mismatch between functional and taxonomic successions, indicate that although safeguarding functional diversity may or may not minimize species losses, it would certainly enhance the persistence of ecosystem functioning in the face of future disturbances.
Technologies that can efficiently purify nontraditional water sources are needed to meet rising global demand for clean water. Water treatment plants typically require a series of costly separation units to achieve desalination and the removal of toxic trace contaminants such as heavy metals and boron. We report a series of robust, selective, and tunable adsorptive membranes that feature porous aromatic framework nanoparticles embedded within ion exchange polymers and demonstrate their use in an efficient, one-step separation strategy termed ion-capture electrodialysis. This process uses electrodialysis configurations with adsorptive membranes to simultaneously desalinate complex water sources and capture diverse target solutes with negligible capture of competing ions. Our methods are applicable to the development of efficient and selective multifunctional separations that use adsorptive membranes.
Gene-regulatory networks achieve complex mappings of inputs to outputs through mechanisms that are poorly understood. We found that in the galactose-responsive pathway in Saccharomyces cerevisiae, the decision to activate the transcription of genes encoding pathway components is controlled independently from the expression level, resulting in behavior resembling that of a mechanical dimmer switch. This was not a direct result of chromatin regulation or combinatorial control at galactose-responsive promoters; rather, this behavior was achieved by hierarchical regulation of the expression and activity of a single transcription factor. Hierarchical regulation is ubiquitous, and thus dimmer switch regulation is likely a key feature of many biological systems. Dimmer switch gene regulation may allow cells to fine-tune their responses to multi-input environments on both physiological and evolutionary time scales.
Nutrient supply regulates the activity of phytoplankton, but the global biogeography of nutrient limitation and co-limitation is poorly understood. Prochlorococcus adapt to local environments by gene gains and losses, and we used genomic changes as an indicator of adaptation to nutrient stress. We collected metagenomes from all major ocean regions as part of the Global Ocean Ship-based Hydrographic Investigations Program (Bio-GO-SHIP) and quantified shifts in genes involved in nitrogen, phosphorus, and iron assimilation. We found regional transitions in stress type and severity as well as widespread co-stress. Prochlorococcus stress genes, bottle experiments, and Earth system model predictions were correlated. We propose that the biogeography of multinutrient stress is stoichiometrically linked by controls on nitrogen fixation. Our omics-based description of phytoplankton resource use provides a nuanced and highly resolved description of nutrient stress in the global ocean.
Although much can be deduced from fossils alone, estimating abundance and preservation rates of extinct species requires data from living species. Here, we use the relationship between population density and body mass among living species combined with our substantial knowledge of Tyrannosaurus rex to calculate population variables and preservation rates for postjuvenile T. rex. We estimate that its abundance at any one time was ~20,000 individuals, that it persisted for ~127,000 generations, and that the total number of T. rex that ever lived was ~2.5 billion individuals, with a fossil recovery rate of 1 per ~80 million individuals or 1 per 16,000 individuals where its fossils are most abundant. The uncertainties in these values span more than two orders of magnitude, largely because of the variance in the density–body mass relationship rather than variance in the paleobiological input variables.
In boreal forests, climate warming is shifting the wildfire disturbance regime to more frequent fires that burn more deeply into organic soils, releasing sequestered carbon to the atmosphere. To understand the destabilization of carbon storage, it is necessary to consider these effects in the context of long-term ecological change. In Alaskan boreal forests, we found that shifts in dominant plant species catalyzed by severe fire compensated for greater combustion of soil carbon over decadal time scales. Severe burning of organic soils shifted tree dominance from slow-growing black spruce to fast-growing deciduous broadleaf trees, resulting in a net increase in carbon storage by a factor of 5 over the disturbance cycle. Reduced fire activity in future deciduous-dominated boreal forests could increase the tenure of this carbon on the landscape, thereby mitigating the feedback to climate warming.
Geometrical frustration, quantum entanglement, and disorder may prevent long-range ordering of localized spins with strong exchange interactions, resulting in an exotic state of matter. -(BEDT-TTF)2Cu2(CN)3 is considered the prime candidate for this elusive quantum spin liquid state, but its ground-state properties remain puzzling. We present a multifrequency electron spin resonance (ESR) study down to millikelvin temperatures, revealing a rapid drop of the spin susceptibility at 6 kelvin. This opening of a spin gap, accompanied by structural modifications, is consistent with the formation of a valence bond solid ground state. We identify an impurity contribution to the ESR response that becomes dominant when the intrinsic spins form singlets. Probing the electrons directly manifests the pivotal role of defects for the low-energy properties of quantum spin systems without magnetic order.
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