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Multi-level analysis of the gut–brain axis shows autism spectrum disorder-associated molecular and microbial profiles
No full textAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut–brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD
Toward the Next Frontiers of Vibrational Bioimaging
No full textChemical imaging based on vibrational contrasts can extract molecular information entangled in complex biological systems. To this end, nonlinear Raman scattering microscopy, mid-infrared photothermal (MIP) microscopy, and atomic force microscopy (AFM)-based force-detected photothermal microscopies are emerging with better chemical sensitivity, molecular specificity, and spatial resolution than conventional vibrational methods. Their utilization in bioimaging applications has provided biological knowledge in unprecedented detail. This Perspective outlines key methodological developments, bioimaging applications, and recent technical innovations of the three techniques. Representative biological demonstrations are also highlighted to exemplify the unique advantages of obtaining vibrational contrasts. With years of effort, these three methods compose an expanding vibrational bioimaging toolbox to tackle specific bioimaging needs, benefiting many biological investigations with rich information in both label-free and labeling manners. Each technique will be discussed and compared in the outlook, leading to possible future directions to accommodate growing needs in vibrational bioimaging
A selectivity filter in the ER membrane protein complex limits protein misinsertion at the ER
No full textTail-anchored (TA) proteins play essential roles in mammalian cells, and their accurate localization is critical for proteostasis. Biophysical similarities lead to mistargeting of mitochondrial TA proteins to the ER, where they are delivered to the insertase, the ER membrane protein complex (EMC). Leveraging an improved structural model of the human EMC, we used mutagenesis and site-specific crosslinking to map the path of a TA protein from its cytosolic capture by methionine-rich loops to its membrane insertion through a hydrophilic vestibule. Positively charged residues at the entrance to the vestibule function as a selectivity filter that uses charge-repulsion to reject mitochondrial TA proteins. Similarly, this selectivity filter retains the positively charged soluble domains of multipass substrates in the cytosol, thereby ensuring they adopt the correct topology and enforcing the “positive-inside” rule. Substrate discrimination by the EMC provides a biochemical explanation for one role of charge in TA protein sorting and protects compartment integrity by limiting protein misinsertion
An elusive dark central mass in the globular cluster M4
No full textRecent studies of nearby globular clusters have discovered excess dark mass in their cores, apparently in an extended distribution, and simulations indicate that this mass is composed mostly of white dwarfs (respectively stellar-mass black holes) in clusters that are core collapsed (respectively with a flatter core). We perform mass-anisotropy modelling of the closest globular cluster, M4, with intermediate slope for the inner stellar density. We use proper motion data from Gaia Early Data Release 3 (EDR3) and from observations by the Hubble Space Telescope. We extract the mass profile employing Bayesian Jeans modelling, and check our fits with realistic mock data. Our analyses return isotropic motions in the cluster core and tangential motions (β ≈ −0.4 ± 0.1) in the outskirts. We also robustly measure a dark central mass of roughly 800±300M⊙ , but it is not possible to distinguish between a point-like source, such as an intermediate-mass black hole (IMBH), and a dark population of stellar remnants of extent ≈0.016pc≃3300au. However, when removing a high-velocity star from the cluster centre, the same mass excess is found, but more extended (∼0.034pc≈7000au). We use Monte Carlo N-body models of M4 to interpret the second outcome, and find that our excess mass is not sufficiently extended to be confidently associated with a dark population of remnants. Finally, we discuss the feasibility of these two scenarios (i.e. IMBH versus remnants), and propose new observations that could help to better grasp the complex dynamics in M4’s core
Clusters, clouds, and correlations: relating young clusters to giant molecular clouds in M33 and M31
No full textWe use young clusters and giant molecular clouds (GMCs) in the galaxies M33 and M31 to constrain temporal and spatial scales in the star formation process. In M33, we compare the Panchromatic Hubble Andromeda Treasury: Triangulum Extended Region (PHATTER) catalogue of 1214 clusters with ages measured via colour–magnitude diagram (CMD) fitting to 444 GMCs identified from a new 35 pc resolution Atacama Large Millimeter/submillimeter Array (ALMA) ¹²CO(2–1) survey. In M31, we compare the Panchromatic Hubble Andromeda Treasury (PHAT) catalogue of 1249 clusters to 251 GMCs measured from a Combined Array for Research in Millimeter-wave Astronomy (CARMA) ¹²CO(1–0) survey with 20 pc resolution. Through two-point correlation analysis, we find that young clusters have a high probability of being near other young clusters, but correlation between GMCs is suppressed by the cloud identification algorithm. By comparing the positions, we find that younger clusters are closer to GMCs than older clusters. Through cross-correlation analysis of the M33 cluster data, we find that clusters are statistically associated when they are ≤10 Myr old. Utilizing the high precision ages of the clusters, we find that clusters older than ≈18 Myr are uncorrelated with the molecular interstellar medium (ISM). Using the spatial coincidence of the youngest clusters and GMCs in M33, we estimate that clusters spend ≈4–6 Myr inside their parent GMC. Through similar analysis, we find that the GMCs in M33 have a total lifetime of ≈11–15 Myr. We also develop a drift model and show that the above correlations can be explained if the clusters in M33 have a 5–10 km s⁻¹ velocity dispersion relative to the molecular ISM
Earthquake focal mechanisms with distributed acoustic sensing
No full textEarthquake focal mechanisms provide critical in-situ insights about the subsurface faulting geometry and stress state. For frequent small earthquakes (magnitude < 3.5), their focal mechanisms are routinely determined using first-arrival polarities picked on the vertical component of seismometers. Nevertheless, their quality is usually limited by the azimuthal coverage of the local seismic network. The emerging distributed acoustic sensing (DAS) technology, which can convert pre-existing telecommunication cables into arrays of strain/strain-rate meters, can potentially fill the azimuthal gap and enhance constraints on the nodal plane orientation through its long sensing range and dense spatial sampling. However, determining first-arrival polarities on DAS is challenging due to its single-component sensing and low signal-to-noise ratio for direct body waves. Here, we present a data-driven method that measures P-wave polarities on a DAS array based on cross-correlations between earthquake pairs. We validate the inferred polarities using the regional network catalog on two DAS arrays, deployed in California and each comprising ~ 5000 channels. We demonstrate that a joint focal mechanism inversion combining conventional and DAS polarity picks improves the accuracy and reduces the uncertainty in the focal plane orientation. Our results highlight the significant potential of integrating DAS with conventional networks for investigating high-resolution earthquake source mechanisms
Discounting future reward in an uncertain world
No full textHumans discount delayed relative to more immediate reward. A plausible explanation is that impatience arises partly from uncertainty, or risk, implicit in delayed reward. Existing theories of discounting-as-risk focus on a probability that delayed reward will not materialize. By contrast, we examine how uncertainty in the magnitude of delayed reward contributes to delay discounting. We propose a model wherein reward is discounted proportional to the rate of random change in its magnitude across time, termed volatility. We find evidence to support this model across three experiments (total N = 158). First, using a task where participants chose when to sell products, whose price dynamics they previously learned, we show discounting increases in line with price volatility. Second, we show that this effect pertains over naturalistic delays of up to 4 months. Using functional magnetic resonance imaging, we observe a volatility-dependent decrease in functional hippocampal–prefrontal coupling during intertemporal choice. Third, we replicate these effects in a larger online sample, finding that volatility discounting within each task correlates with baseline discounting outside of the task. We conclude that delay discounting partly reflects time-dependent uncertainty about reward magnitude, that is volatility. Our model captures how discounting adapts to volatility, thereby partly accounting for individual differences in impatience. Our imaging findings suggest a putative mechanism whereby uncertainty reduces prospective simulation of future outcomes
The kinetics and potential dependence of the hydrogen evolution reaction optimized for the basal-plane Te vacancy site of MoTe₂
No full textElectrocatalysis at the edge sites of transition-metal dichalcogenides has been well studied, particularly for the hydrogen evolution reaction (HER). Here, we explore instead the HER activity on the basal plane of MoTe₂ by creating anion vacancies via computational predictions followed by experimental validation. Using the grand canonical potential kinetics method, we predict that overpotentials of 535 and 565 mV can achieve a current density of 10 mA cm⁻² for 1T′-MoTe₂ and 2H-MoTe₂ containing 1.14 x 10¹⁴ cm⁻² and 3.45 x 10¹³ cm⁻² Te vacancies, respectively. This is in good agreement with experimental overpotentials of 561 and 634 mV for 1T′-MoTe₂ and 2H-MoTe₂ containing similar vacancies (
1.28 x 10¹⁴ cm⁻² and 3.54 x 10¹³ cm⁻², respectively). Furthermore, we used Ar plasma treatment to increase the Te vacancy on the basal plane and found an optimal vacancy concentration of 3.18 x 10¹⁴ cm⁻² for 1T′-MoTe₂ and 1.02 x 10¹⁴ cm⁻² for 2H-MoTe₂. Increasing or decreasing the vacancy concentrations from this level further reduces HER performance
Long-lived heavy neutral leptons with a displaced shower signature at CMS
No full textWe study the LHC discovery potential in the search for heavy neutral leptons (HNL) with a new signature: a displaced shower in the CMS muon detector, giving rise to a large cluster of hits forming a displaced shower. A new Delphes module is used to model the CMS detector response for such displaced decays. We reinterpret a dedicated CMS search for neutral long-lived particles decaying in the CMS muon endcap detectors for the minimal HNL scenario. We demonstrate that this new strategy is particularly sensitive to active-sterile mixings with τ leptons, due to hadronic τ decays. HNL masses between ~ 1–6 GeV can be accessed for mixings as low as |V_(τN)|^(2) ~10^(−7), probing unique regions of parameter space in the τ sector
Spatial transcriptomics for profiling the tropism of viral vectors in tissues
No full textA barrier to advancing engineered adeno-associated viral vectors (AAVs) for precision access to cell subtypes is a lack of high-throughput, high-resolution assays to characterize in vivo transduction profiles. In this study, we developed an ultrasensitive, sequential fluorescence in situ hybridization (USeqFISH) method for spatial transcriptomic profiling of endogenous and viral RNA with a short barcode in intact tissue volumes by integrating hydrogel-based tissue clearing, enhanced signal amplification and multiplexing using sequential labeling. Using USeqFISH, we investigated the transduction and cell subtype tropisms across mouse brain regions of six systemic AAVs, including AAV-PHP.AX, a new variant that transduces robustly and efficiently across neurons and astrocytes. Here we reveal distinct cell subtype biases of each AAV variant, including a bias of AAV-PHP.N toward excitatory neurons. USeqFISH also enables profiling of pooled regulatory cargos, as we show for a 13-variant pool of microRNA target sites in AAV genomes. Lastly, we demonstrate potential applications of USeqFISH for in situ AAV profiling and multimodal single-cell analysis in non-human primates