Stochastic Gravitational Waves from Early Structure Formation.

Early matter-dominated eras (EMDEs) are a natural feature arising in many models of the early Universe and can generate a stochastic gravitational wave background (SGWB) during the transition from an EMDE to the radiation-dominated universe required by the time of big bang nucleosynthesis. While there are calculations of the SGWB generated in the linear regime, no detailed study has been made of the nonlinear regime. We perform the first comprehensive calculation of gravitational wave (GW) production in EMDEs that are long enough that density contrasts grow to exceed unity, using a hybrid N-body and lattice simulation to study GW production from both a metastable matter species and the radiation produced in its decay. We find that nonlinearities significantly enhance GW production up to frequencies at least as large as the inverse light-crossing time of the largest halos that form prior to reheating. The resulting SGWB is within future observational reach for curvature perturbations as small as those probed in the cosmic microwave background, depending on the reheating temperature. Out-of-equilibrium dynamics could further boost the induced SGWB, while a fully relativistic gravitational treatment is required to resolve the spectrum at even higher frequencies.

Elevated drug overdose mortality among Americans who visit Florida, 2003-2020.

OBJECTIVE: Florida state has played a conspicuous role in the current U.S. drug epidemic. Reports suggest that even non-Florida residents may suffer excessive overdose fatalities while visiting the state, possibly in connection to two sets of events: (1) the overprescribing of controlled substances, and more recently, (2) the exploitation of patients' insurance benefits by unscrupulous operators of substance use treatment facilities in Florida. To date, however, no research has examined the overdose fatalities of non-Florida residents inside Florida. METHODS: Death certificate data were used to calculate proportionate mortality ratios for overdoses among Florida residents and visitors. Deaths occurring in the rest of the USA were used as reference populations. RESULTS: Between 2003 and 2020, overdose mortality was slightly elevated for Florida residents within their home counties (106.7 (95% CI 105.8 to 107.5)) and in other Florida counties (113.0 (95% CI 110.0 to 116.0)). Significantly, this mortality was much higher among out-of-state visitors in Florida (163.1 (95% CI 157.5 to 168.8)). When analysed by year, greater overdose mortality among visitors coincided with years when drug prescribing in Florida was rampant, and with the advent of expanded insurance coverage for substance use treatment. During this more recent period (since 2014), overdose mortality was exceptionally high for out-of-state visitors in Palm Beach County, where reports of malpractice in the Florida treatment industry have been concentrated. CONCLUSIONS: Overdose mortality was disproportionately high among out-of-state visitors in Florida. The results suggest that the regulatory policies in Florida may be implicated in drug-related casualties of people who live in other parts of the USA.

Encoded and updated spatial working memories share a common representational format in alpha activity.

Working memory (WM) flexibly updates information to adapt to the dynamic environment. Here, we used alpha-band activity in the EEG to reconstruct the content of dynamic WM updates and compared this representational format to static WM content. An inverted encoding model using alpha activity precisely tracked both the initially encoded position and the updated position following an auditory cue signaling mental updating. The timing of the update, as tracked in the EEG, correlated with reaction times and saccade latency. Finally, cross-training analyses revealed a robust generalization of alpha-band reconstruction of WM contents before and after updating. These findings demonstrate that alpha activity tracks the dynamic updates to spatial WM and that the format of this activity is preserved across the encoded and updated representations. Thus, our results highlight a new approach for measuring updates to WM and show common representational formats during dynamic mental updating and static storage.

Impact of a pyridazine derivative on tripartite synapse ultrastructure in hippocampus: a three-dimensional analysis.

Introduction: We previously discovered a pyridazine derivative compound series that can improve cognitive functions in mouse models of Alzheimer's disease. One of the advanced compounds from this series, LDN/OSU-0215111-M3, was selected as the preclinical development candidate. This compound activates local protein translation at the perisynaptic astrocytic process (PAP) and enhances synaptic plasticity sequentially. While biochemical evidence supports the hypothesis that the compound enhances the structural plasticity of the tripartite synapse, its direct structural impact has not been investigated. Methods: Volume electron microscopy was used to study the hippocampal tripartite synapse three-dimensional structure in 3-month-old wild-type FVB/NJ mice after LDN/OSU-0215111-M3 treatment. Results: LDN/OSU-0215111-M3 increased the size of tertiary apical dendrites, the volume of mushroom spines, the proportion of mushroom spines containing spine apparatus, and alterations in the spine distribution across the surface area of tertiary dendrites. Compound also increased the number of the PAP interacting with the mushroom spines as well as the size of the PAP in contact with the spines. Furthermore, proteomic analysis of the isolated synaptic terminals indicated an increase in dendritic and synaptic proteins as well as suggested a possible involvement of the phospholipase D signaling pathway. To further validate that LDN/OSU-0215111-M3 altered synaptic function, electrophysiological studies showed increased long-term potentiation following compound treatment. Discussion: This study provides direct evidence that pyridazine derivatives enhance the structural and functional plasticity of the tripartite synapse.

Higgsino Dark Matter Confronts 14 Years of Fermi γ-Ray Data.

Thermal Higgsino dark matter (DM), with mass around 1 TeV, is a well-motivated, minimal DM scenario that arises in supersymmetric extensions of the standard model. Higgsinos may naturally be the lightest superpartners in split-supersymmetry models that decouple the scalar superpartners while keeping Higgsinos and gauginos close to the TeV scale. Higgsino DM may annihilate today to give continuum γ-ray emission at energies less than a TeV in addition to a linelike signature at energies equal to the mass. Previous searches for Higgsino DM, for example with the H.E.S.S. γ-ray telescope, have not reached the necessary sensitivity to probe the Higgsino annihilation cross section. In this work we make use of 14 years of data from the Fermi Large Area Telescope at energies above ∼10 GeV to search for the continuum emission near the Galactic Center from Higgsino annihilation. We interpret our results using DM profiles from Milky Way analog galaxies in the FIRE-2 hydrodynamic cosmological simulations. We set the strongest constraints to date on Higgsino-like DM. Our results show a mild, ∼2σ preference for Higgsino DM with a mass near the thermal Higgsino mass and, depending on the DM density profile, the expected cross section.

Improving Single-Molecule Antibody Detection Selectivity through Optimization of Peptide Epitope Presentation in OmpG Nanopore.

Outer membrane protein G (OmpG) is a monomeric porin found in Escherichia coli, which possesses seven flexible loops. OmpG has been engineered as a nanopore sensor, where its loops can host affinity epitopes for selective detection of biological molecules. In this study, we investigated various loop positions to incorporate a FLAG peptide antigen epitope in the most flexible loop 6 and tested the efficacy and sensitivity of these nanopore constructs in antibody detection. We observed an OmpG construct containing inserted FLAG sequence, which exhibited strong interaction with anti-FLAG antibodies in flow cytometry; however, it could not translate molecule interactions into a readable signal in current recordings. Further optimization of the peptide presentation strategy by replacing specific sections of loop 6 sequences with the FLAG tag created a construct capable of generating unique and distinct signals when interacting with various monoclonal or polyclonal anti-FLAG clones IgG antibodies in the mixture. The peptide display scheme demonstrated in this study can be generalized for the engineering of OmpG sensors, which can be used for screening and validating positive clones during antibody development, as well as for real-time quality control of cell cultures in monoclonal antibody production.

Unidirectional single-file transport of full-length proteins through a nanopore.

The electrical current blockade of a peptide or protein threading through a nanopore can be used as a fingerprint of the molecule in biosensor applications. However, threading of full-length proteins has only been achieved using enzymatic unfolding and translocation. Here we describe an enzyme-free approach for unidirectional, slow transport of full-length proteins through nanopores. We show that the combination of a chemically resistant biological nanopore, α-hemolysin (narrowest part is ~1.4 nm in diameter), and a high concentration guanidinium chloride buffer enables unidirectional, single-file protein transport propelled by an electroosmotic effect. We show that the mean protein translocation velocity depends linearly on the applied voltage and translocation times depend linearly on length, resembling the translocation dynamics of ssDNA. Using a supervised machine-learning classifier, we demonstrate that single-translocation events contain sufficient information to distinguish their threading orientation and identity with accuracies larger than 90%. Capture rates of protein are increased substantially when either a genetically encoded charged peptide tail or a DNA tag is added to a protein.

The cost of divided attention for detection of simple visual features primarily reflects limits in post-perceptual processing.

Covert spatial attention allows us to prioritize processing at relevant locations. Perception is generally poorer when attention is distributed across multiple locations than when attention is focused on a single location. However, while divided attention typically impairs performance, recent work suggests that divided attention does not seem to impair detection of simple visual features. Here, we re-examined this possibility. In two experiments, observers detected a simple target (a vertical Gabor), and we manipulated whether attention was focused at one location (focal-cue condition) or distributed across two locations (distributed-cue condition). In Experiment 1, targets could appear independently at each location, such that observers needed to judge target presence for each location separately in the distributed-cue condition. Under these conditions, we found a robust cost of dividing attention. Next, we further probed what stage of processing gave rise to this cost. In Experiment 1, the cost of dividing attention could reflect a limit in the ability to make concurrent judgments about target presence. In Experiment 2, we simplified the task to test whether this was the case: just one target could appear on each trial, such that observers made a single judgment ("was a target present?") in both the focal-cue and distributed-cue conditions. Here, we found a marginal cost of dividing attention that was weaker than the cost in Experiment 1. Together, our results suggest that divided attention does impair detection of simple visual features, but that this cost is primarily due to a limit in post-perceptual processes.

An Engineered OmpG Nanopore with Displayed Peptide Motifs for Single-Molecule Multiplex Protein Detection.

Molecular detection via nanopore, achieved by monitoring changes in ionic current arising from analyte interaction with the sensor pore, is a promising technology for multiplex sensing development. Outer Membrane Protein G (OmpG), a monomeric porin possessing seven functionalizable loops, has been reported as an effective sensing platform for selective protein detection. Using flow cytometry to screen unfavorable constructs, we identified two OmpG nanopores with unique peptide motifs displayed in either loop 3 or 6, which also exhibited distinct analyte signals in single-channel current recordings. We exploited these motif-displaying loops concurrently to facilitate single-molecule multiplex protein detection in a mixture. We additionally report a strategy to increase sensor sensitivity via avidity motif display. These sensing schemes may be expanded to more sophisticated designs utilizing additional loops to increase multiplicity and sensitivity.

Distinguishing guesses from fuzzy memories: Further evidence for item limits in visual working memory.

There is consistent debate over whether capacity in working memory (WM) is subject to an item limit, or whether an unlimited number of items can be held in this online memory system. The item limit hypothesis clearly predicts guessing responses when capacity is exceeded, and proponents of this view have highlighted evidence for guessing in visual working memory tasks. Nevertheless, various models that deny item limits can explain the same empirical patterns by asserting extremely low fidelity representations that cannot be distinguished from guesses. To address this ambiguity, we employed a task for which guess responses elicited a qualitatively distinct pattern from low fidelity memories. Inspired by work from Rouder et al. (2014), we employed an orientation WM task that required subjects to recall the precise orientation of each of six memoranda presented 1 s earlier. The orientation stimuli were created by rotating the position of a "clock hand" inside a circular region that was demarcated by four colored quadrants. Critically, when observers guess with these stimuli, the distribution of responses is biased towards the center of these quadrants, creating a "banded" pattern that cannot be explained by a low precision memory. We confirmed the presence of this guessing pattern using formal model comparisons, and we show that the prevalence of this pattern matches observers' own reports of when they thought they were guessing. Thus, these findings provide further evidence for guessing behaviors predicted by item limit models of WM capacity.

Spinal premotor interneurons controlling antagonistic muscles are spatially intermingled.

Elaborate behaviours are produced by tightly controlled flexor-extensor motor neuron activation patterns. Motor neurons are regulated by a network of interneurons within the spinal cord, but the computational processes involved in motor control are not fully understood. The neuroanatomical arrangement of motor and premotor neurons into topographic patterns related to their controlled muscles is thought to facilitate how information is processed by spinal circuits. Rabies retrograde monosynaptic tracing has been used to label premotor interneurons innervating specific motor neuron pools, with previous studies reporting topographic mediolateral positional biases in flexor and extensor premotor interneurons. To more precisely define how premotor interneurons contacting specific motor pools are organized, we used multiple complementary viral-tracing approaches in mice to minimize systematic biases associated with each method. Contrary to expectations, we found that premotor interneurons contacting motor pools controlling flexion and extension of the ankle are highly intermingled rather than segregated into specific domains like motor neurons. Thus, premotor spinal neurons controlling different muscles process motor instructions in the absence of clear spatial patterns among the flexor-extensor circuit components.

The spinal cord contains circuits of nerve cells that control how the body moves. Within these networks are interneurons that project to motor neurons, which innervate different types of muscle to contract: flexors (such as the biceps), which bend, or 'flex', the body's joints, and extensors (such as the triceps), which lead to joint extension. These motor signals must be carefully coordinated to allow precise and stable control of the body's movements. Previous studies suggest that where interneurons are placed in the spinal cord depends on whether they activate the motor neurons responsible for flexion or extension. To test if these findings were reproducible, Ronzano, Skarlatou, Barriga, Bannatyne, Bhumbra et al. studied interneurons which flex and extend the ankle joint in mice. In collaboration with several laboratories, the team used a combination of techniques to trace how interneurons and motor neurons were connected in the mouse spinal cord. This revealed that regardless of the method used or the laboratory in which the experiments were performed, the distribution of interneurons associated with flexion and extension overlapped one another. This finding contradicts previously published results and suggests that interneurons in the spinal cord are not segregated based on their outputs. Instead, they may be positioned based on the signals they receive, similar to motor neurons. Understanding where interneurons in the spinal cord are placed will provide new insights on how movement is controlled and how it is impacted by injuries and disease. In the future, this knowledge could benefit work on how neural circuits in the spinal cord are formed and how they can be regenerated.

Characterization of adjacent charged residues near the agonist binding site of the nematode UNC-49 GABA receptor.

The UNC-49 receptor is a Cys-loop GABA receptor that is unique to the nematode phylum. The receptor differs from mammalian GABA receptors both in amino acid sequence and pharmacology which highlights its potential as a novel anthelmintic target. Sequence differences within and near the various ligand-binding loops of the nematode receptor suggest that there could be structural differences compared to mammalian receptors that result in different pharmacological and functional features. Here we investigated three residues in the UNC-49 receptor from the parasitic nematode Haemonchus contortus: K181, E183, and T230. Analysis of these residues was conducted via site-directed mutagenesis, electrophysiology, MD simulations, and mutant cycling analysis. In the UNC-49 receptor, E183 lies in close proximity to K181 where together they appear to play a role in GABA sensitivity and pharmacology, possibly interacting via an ionic bond. While the introduction of single alanine residues at each position separately had a negative impact on GABA EC50, the double alanine mutant (K181A/E183A) exhibited wildtype-level GABA EC50 and some differences in pharmacology. Overall, this study has revealed a potentially novel role for these two residues in nematode UNC-49 GABA receptors that could aid in understanding their function.

Feature-based attention multiplicatively scales the fMRI-BOLD contrast-response function.

Functional MRI (fMRI) plays a key role in the study of attention. However, there remains a puzzling discrepancy between attention effects measured with fMRI and with electrophysiological methods. While electrophysiological studies find that attention increases sensory gain, amplifying stimulus-evoked neural responses by multiplicatively scaling the contrast-response function (CRF), fMRI appears to be insensitive to these multiplicative effects. Instead, fMRI studies typically find that attention produces an additive baseline shift in the blood-oxygen-level-dependent (BOLD) signal. These findings suggest that attentional effects measured with fMRI reflect top-down inputs to visual cortex, rather than the modulation of sensory gain. If true, this drastically limits what fMRI can tell us about how attention improves sensory coding. Here, we examined whether fMRI is sensitive to multiplicative effects of attention using a feature-based attention paradigm designed to preclude any possible additive effects. We measured BOLD activity evoked by a probe stimulus in one visual hemifield while participants (6 male, 6 female) attended to the probe orientation (attended condition), or to an orthogonal orientation (unattended condition), in the other hemifield. To measure CRFs in visual areas V1-V3, we parametrically varied the contrast of the probe stimulus. In all three areas, feature-based attention increased contrast gain, improving sensitivity by shifting CRFs towards lower contrasts. In V2 and V3, we also found an increase in response gain, an increase in the responsivity of the CRF, that was greatest at inner eccentricities. These results provide clear evidence that the fMRI-BOLD signal is sensitive to multiplicative effects of attention.SIGNIFICANCE STATEMENTFunctional MRI (fMRI) plays a central role in the study of attention because it allows researchers to precisely and non-invasively characterize the effects of attention throughout the brain. Electrophysiological studies have shown that attention increases sensory gain, amplifying stimulus-evoked neural responses. However, a growing body of work suggests that the BOLD signal that is measured with fMRI is not sensitive to these multiplicative effects of attention, calling into question what we can learn from fMRI about how attention improves sensory codes. Here, using a feature-based attention paradigm, we provide evidence that the BOLD signal can pick up multiplicative effects of attention.

CaMKII binds both substrates and activators at the active site.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a signaling protein required for long-term memory. When activated by Ca2+/CaM, it sustains activity even after the Ca2+ dissipates. In addition to the well-known autophosphorylation-mediated mechanism, interaction with specific binding partners also persistently activates CaMKII. A long-standing model invokes two distinct S and T sites. If an interactor binds at the T-site, then it will preclude autoinhibition and allow substrates to be phosphorylated at the S site. Here, we specifically test this model with X-ray crystallography, molecular dynamics simulations, and biochemistry. Our data are inconsistent with this model. Co-crystal structures of four different activators or substrates show that they all bind to a single continuous site across the kinase domain. We propose a mechanistic model where persistent CaMKII activity is facilitated by high-affinity binding partners that kinetically compete with autoinhibition by the regulatory segment to allow substrate phosphorylation.

Upper Limit on the QCD Axion Mass from Isolated Neutron Star Cooling.

The quantum chromodynamics (QCD) axion may modify the cooling rates of neutron stars (NSs). The axions are produced within the NS cores from nucleon bremsstrahlung and, when the nucleons are in superfluid states, Cooper pair breaking and formation processes. We show that four of the nearby isolated magnificent seven NSs along with PSR J0659 are prime candidates for axion cooling studies because they are coeval, with ages of a few hundred thousand years known from kinematic considerations, and they have well-measured surface luminosities. We compare these data to dedicated NS cooling simulations incorporating axions, profiling over uncertainties related to the equation of state, NS masses, surface compositions, and superfluidity. Our calculations of the axion and neutrino emissivities include high-density suppression factors that also affect SN 1987A and previous NS cooling limits on axions. We find no evidence for axions in the isolated NS data, and within the context of the Kim-Shifman-Vainshtein-Zakharov QCD axion model, we constrain m_{a}≲16 meV at 95% confidence level. An improved understanding of NS cooling and nucleon superfluidity could further improve these limits or lead to the discovery of the axion at weaker couplings.

Perceptions of Divine Forgiveness, Religious Comfort, and Depression in Psychiatric Inpatients: A Mixed Methods Study.

Understanding how forgiveness relates to mental health outcomes may improve clinical care. This study assessed 248 adult psychiatric inpatients, testing associations of forgiveness, religious comfort (RC), religious strain (RS), and changes in depressive symptomatology from admission to discharge. Experiencing divine forgiveness and self-forgiveness was both directly associated with RC and inversely associated with RS. Using structural equation modeling, the path from divine forgiveness to depression through RC was significant, ß = - .106, SE = .046, z = - 2.290, p = .022, bootstrapped 95% CI = - .196 to - .015. Qualitative findings illustrated patients' changed perspectives on divine forgiveness during hospitalization.

Dark matter from axion strings with adaptive mesh refinement.

Axions are hypothetical particles that may explain the observed dark matter density and the non-observation of a neutron electric dipole moment. An increasing number of axion laboratory searches are underway worldwide, but these efforts are made difficult by the fact that the axion mass is largely unconstrained. If the axion is generated after inflation there is a unique mass that gives rise to the observed dark matter abundance; due to nonlinearities and topological defects known as strings, computing this mass accurately has been a challenge for four decades. Recent works, making use of large static lattice simulations, have led to largely disparate predictions for the axion mass, spanning the range from 25 microelectronvolts to over 500 microelectronvolts. In this work we show that adaptive mesh refinement simulations are better suited for axion cosmology than the previously-used static lattice simulations because only the string cores require high spatial resolution. Using dedicated adaptive mesh refinement simulations we obtain an over three order of magnitude leap in dynamic range and provide evidence that axion strings radiate their energy with a scale-invariant spectrum, to within ~5% precision, leading to a mass prediction in the range (40,180) microelectronvolts.

Extraterrestrial Axion Search with the Breakthrough Listen Galactic Center Survey.

Axion dark matter (DM) may efficiently convert to photons in the magnetospheres of neutron stars (NSs), producing nearly monochromatic radio emission. This process is resonantly triggered when the plasma frequency induced by the underlying charge distribution approximately matches the axion mass. We search for evidence of this process using archival Green Bank Telescope data collected in a survey of the Galactic Center in the C band by the Breakthrough Listen project. While Breakthrough Listen aims to find signatures of extraterrestrial life in the radio band, we show that their high-frequency resolution spectral data of the Galactic Center region is ideal for searching for axion-photon transitions generated by the population of NSs in the inner pc of the Galaxy. We use data-driven models to capture the distributions and properties of NSs in the inner Galaxy and compute the expected radio flux from each NS using state-of-the-art ray tracing simulations. We find no evidence for axion DM and set leading constraints on the axion-photon coupling, excluding values down to the level g_{aγγ}∼10^{-11} GeV^{-1} for DM axions for masses between 15 and 35 µeV.

The clashing nature of rebelliousness: Nontraditional attitudes and counter-normative behaviors show divergent associations with intelligence.

OBJECTIVE: Prior literature indicates that nontraditional attitudes are linked to higher intelligence. However, such attitudes in adolescence often accompany counter-normative, delinquent-type behaviors, which are themselves negatively linked with intelligence. This points to the possibility of suppression in the relationship between intelligence and nontraditional attitudes. METHOD: We analyzed a large community sample of 17 year olds (N = 3330) with data on intelligence, nontraditional attitudes, and a diverse collection of self- and teacher-reported counter-normative behaviors. Developmental questions for these relationships were examined through cross-sectional comparisons between the adolescents and their parents as well as longitudinal analysis of the adolescent sample across emerging adulthood. RESULTS: Youth who endorsed nontraditional attitudes had lower school grades, earlier age at first sex, heavier substance use, and were perceived as more oppositional by their teachers. Each of these problem behaviors was inversely related to intelligence. Accordingly, the positive correlation between nontraditional attitudes and intelligence was much weaker in adolescents as compared to their middle-aged parents. Longitudinal analyses revealed that the association between nontraditional attitudes and intelligence strengthens in early adulthood. CONCLUSIONS: Associations between intelligence and sociopolitical attitudes can be obscured even by seemingly distal psychological characteristics.