Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

An Amygdala-Hippocampus Subnetwork that Encodes Variation in Human Mood.

Human brain networks that encode variation in mood on naturalistic timescales remain largely unexplored. Here we combine multi-site, semi-chronic, intracranial electroencephalography recordings from the human limbic system with machine learning methods to discover a brain subnetwork that correlates with variation in individual subjects' self-reported mood over days. First we defined the subnetworks that influence intrinsic brain dynamics by identifying regions that showed coordinated changes in spectral coherence. The most common subnetwork, found in 13 of 21 subjects, was characterized by ß-frequency coherence (13-30 Hz) between the amygdala and hippocampus. Increased variability of this subnetwork correlated with worsening mood across these 13 subjects. Moreover, these subjects had significantly higher trait anxiety than the 8 of 21 for whom this amygdala-hippocampus subnetwork was absent. These results demonstrate an approach for extracting network-behavior relationships from complex datasets, and they reveal a conserved subnetwork associated with a psychological trait that significantly influences intrinsic brain dynamics and encodes fluctuations in mood.

Species-Independent Attraction to Biofilms through Electrical Signaling.

Bacteria residing within biofilm communities can coordinate their behavior through cell-to-cell signaling. However, it remains unclear if these signals can also influence the behavior of distant cells that are not part of the community. Using a microfluidic approach, we find that potassium ion channel-mediated electrical signaling generated by a Bacillus subtilis biofilm can attract distant cells. Integration of experiments and mathematical modeling indicates that extracellular potassium emitted from the biofilm alters the membrane potential of distant cells, thereby directing their motility. This electrically mediated attraction appears to be a generic mechanism that enables cross-species interactions, as Pseudomonas aeruginosa cells also become attracted to the electrical signal released by the B. subtilis biofilm. Cells within a biofilm community can thus not only coordinate their own behavior but also influence the behavior of diverse bacteria at a distance through long-range electrical signaling. PAPERCLIP.

PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation.

Targeted blockade of programmed cell death 1 (PD-1), an immune-checkpoint receptor that inhibits T cell activation, provides clinical benefits in various cancers. However, how PD-1 modulates gene expression in T cells remains enigmatic. Here we investigated how PD-1 affects transcriptome changes induced by T cell receptor (TCR) activation. Intriguingly, we identified a huge variance in PD-1 sensitivity among TCR-inducible genes. When we quantified the half maximal effective concentration (EC50) as the relationship between change in gene expression and TCR signal strength, we found that genes associated with survival and proliferation were efficiently expressed upon TCR activation and resistant to PD-1-mediated inhibition. Conversely, genes encoding cytokines and effector molecules were expressed less efficiently and sensitive to PD-1-mediated inhibition. We further demonstrated that transcription factor binding motifs and CpG frequency in the promoter region affect EC50 and thus the PD-1 sensitivity of genes. Our findings explain how PD-1, dependent on the TCR signal strength, calibrates cellular transcriptomes to shape functional properties of T cell populations.

Impact of specific electromagnetic radiation on wakefulness in mice.

Electromagnetic radiation (EMR) in the environment, particularly in the microwave range, may constitute a public health concern. Exposure to 2.4 GHz EMR modulated by 100 Hz square pulses was recently reported to markedly increase wakefulness in mice. Here, we demonstrate that a similar wakefulness increase can be induced by the modulation frequency of 1,000 Hz, but not 10 Hz. In contrast to the carrier frequency of 2.4 GHz, 935 MHz EMR of the same power density has little impact on wakefulness irrespective of modulation frequency. Notably, the replacement of the 100 Hz square-pulsed modulation by sinusoidal-pulsed modulation of 2.4 GHz EMR still allows a marked increase of wakefulness. In contrast, continuous sinusoidal amplitude modulation of 100 Hz with the same time-averaged power output fails to trigger any detectable change of wakefulness. Therefore, alteration of sleep behavior by EMR depends upon not just carrier frequency but also frequency and mode of the modulation. These results implicate biological sensing mechanisms for specific EMR in animals.

Pervasive mimicry in flight behavior among aposematic butterflies.

Flight was a key innovation in the adaptive radiation of insects. However, it is a complex trait influenced by a large number of interacting biotic and abiotic factors, making it difficult to unravel the evolutionary drivers. We investigate flight patterns in neotropical heliconiine butterflies, well known for mimicry of their aposematic wing color patterns. We quantify the flight patterns (wing beat frequency and wing angles) of 351 individuals representing 29 heliconiine and 9 ithomiine species belonging to ten color pattern mimicry groupings. For wing beat frequency and up wing angles, we show that heliconiine species group by color pattern mimicry affiliation. Convergence of down wing angles to mimicry groupings is less pronounced, indicating that distinct components of flight are under different selection pressures and constraints. The flight characteristics of the Tiger mimicry group are particularly divergent due to convergence with distantly related ithomiine species. Predator-driven selection for mimicry also explained variation in flight among subspecies, indicating that this convergence can occur over relatively short evolutionary timescales. Our results suggest that the flight convergence is driven by aposematic signaling rather than shared habitat between comimics. We demonstrate that behavioral mimicry can occur between lineages that have separated over evolutionary timescales ranging from <0.5 to 70 My.

The time course of feature-selective attention inside and outside the focus of spatial attention.

Research on attentional selection of stimulus features has yielded seemingly contradictory results. On the one hand, many experiments in humans and animals have observed a "global" facilitation of attended features across the entire visual field, even when spatial attention is focused on a single location. On the other hand, several event-related potential studies in humans reported that attended features are enhanced at the attended location only. The present experiment demonstrates that these conflicting results can be explained by differences in the timing of attentional allocation inside and outside the spatial focus of attention. Participants attended to fields of either red or blue randomly moving dots on either the left or right side of fixation with the task of detecting brief coherent motion targets. Recordings of steady-state visual evoked potentials elicited by the flickering stimuli allowed concurrent measurement of the time course of feature-selective attention in visual cortex on both the attended and the unattended sides. The onset of feature-selective attentional modulation on the attended side occurred around 150 ms earlier than on the unattended side. This finding that feature-selective attention is not spatially global from the outset but extends to unattended locations after a temporal delay resolves previous contradictions between studies finding global versus hierarchical selection of features and provides insight into the fundamental relationship between feature-based and location-based (spatial) attention mechanisms.

Sum rule comparison of narrowband and broadband sum frequency generation spectra and comparison with theory.

Earlier sum frequency generation (SFG) experiments involve one infrared and one visible laser, and a measurement of the intensity of the response, yielding data on the surface sensitive properties of the sample. Recently, both the real and imaginary components of the susceptibility were measured in two different sets of experiments. In one set, a broadband infrared laser was used, permitting observations at very short times, while in another set the infrared laser was narrowband, permitting higher spectral resolution. The differences in the spectrum obtained by the two will be most evident in studying narrow absorption bands, e.g., the band due to dangling OH bonds at a water interface. The direct comparisons in the integrated amplitude (sum rule) of the imaginary part of the dangling OH bond region differ by a factor of 3. Due to variations in experimental setup and data processing, corrections were made for the quartz reference, Fresnel factors, and the incident visible laser wavelength. After the corrections, the agreement differs now by the factors of 1.1 within broadband and narrowband groups and the two groups now differ by a factor of 1.5. The 1.5 factor may arise from the extra heating of the more powerful broadband laser system on the water surface. The convolution from the narrowband SFG spectrum to the broadband SFG spectrum is also investigated and it does not affect the sum rule. Theory and narrowband experiments are compared using the sum rule and agree to a factor of 1.3 with no adjustable parameters.

Frequencies of pharmacogenomic alleles across biogeographic groups in a large-scale biobank.

Pharmacogenomics (PGx) is an integral part of precision medicine and contributes to the maximization of drug efficacy and reduction of adverse drug event risk. Accurate information on PGx allele frequencies improves the implementation of PGx. Nonetheless, curating such information from published allele data is time and resource intensive. The limited number of allelic variants in most studies leads to an underestimation of certain alleles. We applied the Pharmacogenomics Clinical Annotation Tool (PharmCAT) on an integrated 200K UK Biobank genetic dataset (N = 200,044). Based on PharmCAT results, we estimated PGx frequencies (alleles, diplotypes, phenotypes, and activity scores) for 17 pharmacogenes in five biogeographic groups: European, Central/South Asian, East Asian, Afro-Caribbean, and Sub-Saharan African. PGx frequencies were distinct for each biogeographic group. Even biogeographic groups with similar proportions of phenotypes were driven by different sets of dominant PGx alleles. PharmCAT also identified "no-function" alleles that were rare or seldom tested in certain groups by previous studies, e.g., SLCO1B1∗31 in the Afro-Caribbean (3.0%) and Sub-Saharan African (3.9%) groups. Estimated PGx frequencies are disseminated via the PharmGKB (The Pharmacogenomics Knowledgebase: www.pharmgkb.org). We demonstrate that genetic biobanks such as the UK Biobank are a robust resource for estimating PGx frequencies. Improving our understanding of PGx allele and phenotype frequencies provides guidance for future PGx studies and clinical genetic test panel design, and better serves individuals from wider biogeographic backgrounds.

Demographic modeling of admixed Latin American populations from whole genomes.

Demographic models of Latin American populations often fail to fully capture their complex evolutionary history, which has been shaped by both recent admixture and deeper-in-time demographic events. To address this gap, we used high-coverage whole-genome data from Indigenous American ancestries in present-day Mexico and existing genomes from across Latin America to infer multiple demographic models that capture the impact of different timescales on genetic diversity. Our approach, which combines analyses of allele frequencies and ancestry tract length distributions, represents a significant improvement over current models in predicting patterns of genetic variation in admixed Latin American populations. We jointly modeled the contribution of European, African, East Asian, and Indigenous American ancestries into present-day Latin American populations. We infer that the ancestors of Indigenous Americans and East Asians diverged ∼30 thousand years ago, and we characterize genetic contributions of recent migrations from East and Southeast Asia to Peru and Mexico. Our inferred demographic histories are consistent across different genomic regions and annotations, suggesting that our inferences are robust to the potential effects of linked selection. In conjunction with published distributions of fitness effects for new nonsynonymous mutations in humans, we show in large-scale simulations that our models recover important features of both neutral and deleterious variation. By providing a more realistic framework for understanding the evolutionary history of Latin American populations, our models can help address the historical under-representation of admixed groups in genomics research and can be a valuable resource for future studies of populations with complex admixture and demographic histories.

Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals.

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in vivo evidence that regional identity in the embryonic cochlea acts as a framework upon which tonotopy-specific properties essential for frequency selectivity in the mature cochlea develop. We found that follistatin (FST) is required for the maintenance of apical cochlear identity, but dispensable for its initial induction. In a fate-mapping analysis, we found that FST promotes expansion of apical cochlear cells, contributing to the formation of the apical cochlear domain. SHH, in contrast, is required both for the induction and maintenance of apical identity. In the absence of FST or SHH, mice produce a short cochlea lacking its apical domain. This results in the loss of apex-specific anatomical and molecular properties and low-frequency-specific hearing loss.

Antibiotic perseverance increases the risk of resistance development.

The rise of antibiotic-resistant bacterial infections poses a global threat. Antibiotic resistance development is generally studied in batch cultures which conceals the heterogeneity in cellular responses. Using single-cell imaging, we studied the growth response of Escherichia coli to sub-inhibitory and inhibitory concentrations of nine antibiotics. We found that the heterogeneity in growth increases more than what is expected from growth rate reduction for three out of the nine antibiotics tested. For two antibiotics (rifampicin and nitrofurantoin), we found that sub-populations were able to maintain growth at lethal antibiotic concentrations for up to 10 generations. This perseverance of growth increased the population size and led to an up to 40-fold increase in the frequency of antibiotic resistance mutations in gram-negative and gram-positive species. We conclude that antibiotic perseverance is a common phenomenon that has the potential to impact antibiotic resistance development across pathogenic bacteria.

Surge of neurophysiological coupling and connectivity of gamma oscillations in the dying human brain.

The brain is assumed to be hypoactive during cardiac arrest. However, animal models of cardiac and respiratory arrest demonstrate a surge of gamma oscillations and functional connectivity. To investigate whether these preclinical findings translate to humans, we analyzed electroencephalogram and electrocardiogram signals in four comatose dying patients before and after the withdrawal of ventilatory support. Two of the four patients exhibited a rapid and marked surge of gamma power, surge of cross-frequency coupling of gamma waves with slower oscillations, and increased interhemispheric functional and directed connectivity in gamma bands. High-frequency oscillations paralleled the activation of beta/gamma cross-frequency coupling within the somatosensory cortices. Importantly, both patients displayed surges of functional and directed connectivity at multiple frequency bands within the posterior cortical "hot zone," a region postulated to be critical for conscious processing. This gamma activity was stimulated by global hypoxia and surged further as cardiac conditions deteriorated in the dying patients. These data demonstrate that the surge of gamma power and connectivity observed in animal models of cardiac arrest can be observed in select patients during the process of dying.

Assessing Spontaneous Categorical Processing of Visual Shapes via Frequency-Tagging EEG.

Categorization is an essential cognitive and perceptual process, which happens spontaneously. However, earlier research often neglected the spontaneous nature of this process by mainly adopting explicit tasks in behavioral or neuroimaging paradigms. Here, we use frequency-tagging (FT) during electroencephalography (EEG) in 22 healthy human participants (both male and female) as a direct approach to pinpoint spontaneous visual categorical processing. Starting from schematic natural visual stimuli, we created morph sequences comprising 11 equal steps. Mirroring a behavioral categorical perception discrimination paradigm, we administered a FT-EEG oddball paradigm, assessing neural sensitivity for equally sized differences within and between stimulus categories. Likewise, mirroring a behavioral category classification paradigm, we administered a sweep FT-EEG oddball paradigm, sweeping from one end of the morph sequence to the other, thereby allowing us to objectively pinpoint the neural category boundary. We found that FT-EEG can implicitly measure categorical processing and discrimination. More specifically, we could derive an objective neural index of the required level to differentiate between the two categories, and this neural index showed the typical marker of categorical perception (i.e., stronger discrimination across as compared with within categories). The neural findings of the implicit paradigms were also validated using an explicit behavioral task. These results provide evidence that FT-EEG can be used as an objective tool to measure discrimination and categorization and that the human brain inherently and spontaneously (without any conscious or decisional processes) uses higher-level meaningful categorization information to interpret ambiguous (morph) shapes.

Intracerebral Dynamics of Sleep Arousals: A Combined Scalp-Intracranial EEG Study.

As an intrinsic component of sleep architecture, sleep arousals represent an intermediate state between sleep and wakefulness and are important for sleep-wake regulation. They are defined in an all-or-none manner, whereas they actually present a wide range of scalp-electroencephalography (EEG) activity patterns. It is poorly understood how these arousals differ in their mechanisms. Stereo-EEG (SEEG) provides the unique opportunity to record intracranial activities in superficial and deep structures in humans. Using combined polysomnography and SEEG, we quantitatively categorized arousals during nonrapid eye movement sleep into slow wave (SW) and non-SW arousals based on whether they co-occurred with a scalp-EEG SW event. We then investigated their intracranial correlates in up to 26 brain regions from 26 patients (12 females). Across both arousal types, intracranial theta, alpha, sigma, and beta activities increased in up to 25 regions (p < 0.05; d = 0.06-0.63), while gamma and high-frequency (HF) activities decreased in up to 18 regions across the five brain lobes (p < 0.05; d = 0.06-0.44). Intracranial delta power widely increased across five lobes during SW arousals (p < 0.05 in 22 regions; d = 0.10-0.39), while it widely decreased during non-SW arousals (p < 0.05 in 19 regions; d = 0.10-0.30). Despite these main patterns, unique activities were observed locally in some regions such as the hippocampus and middle cingulate cortex, indicating spatial heterogeneity of arousal responses. Our results suggest that non-SW arousals correspond to a higher level of brain activation than SW arousals. The decrease in HF activities could potentially explain the absence of awareness and recollection during arousals.

Featural Representation and Internal Noise Underlie the Eccentricity Effect in Contrast Sensitivity.

Human visual performance for basic visual dimensions (e.g., contrast sensitivity and acuity) peaks at the fovea and decreases with eccentricity. The eccentricity effect is related to the larger visual cortical surface area corresponding to the fovea, but it is unknown if differential feature tuning contributes to this eccentricity effect. Here, we investigated two system-level computations underlying the eccentricity effect: featural representation (tuning) and internal noise. Observers (both sexes) detected a Gabor embedded in filtered white noise which appeared at the fovea or one of four perifoveal locations. We used psychophysical reverse correlation to estimate the weights assigned by the visual system to a range of orientations and spatial frequencies (SFs) in noisy stimuli, which are conventionally interpreted as perceptual sensitivity to the corresponding features. We found higher sensitivity to task-relevant orientations and SFs at the fovea than that at the perifovea, and no difference in selectivity for either orientation or SF. Concurrently, we measured response consistency using a double-pass method, which allowed us to infer the level of internal noise by implementing a noisy observer model. We found lower internal noise at the fovea than that at the perifovea. Finally, individual variability in contrast sensitivity correlated with sensitivity to and selectivity for task-relevant features as well as with internal noise. Moreover, the behavioral eccentricity effect mainly reflects the foveal advantage in orientation sensitivity compared with other computations. These findings suggest that the eccentricity effect stems from a better representation of task-relevant features and lower internal noise at the fovea than that at the perifovea.

Pre- versus Post-synaptic Forms of LTP in Two Branches of the Same Hippocampal Afferent.

There has been considerable controversy about pre- versus postsynaptic expression of memory-related long-term potentiation (LTP), with corresponding disputes about underlying mechanisms. We report here an instance in male mice, in which both types of potentiation are expressed but in separate branches of the same hippocampal afferent. Induction of LTP in the dentate gyrus (DG) branch of the lateral perforant path (LPP) reduces paired-pulse facilitation, is blocked by antagonism of cannabinoid receptor type 1, and is not affected by suppression of postsynaptic actin polymerization. These observations are consistent with presynaptic expression. The opposite pattern of results was obtained in the LPP branch that innervates the distal dendrites of CA3: LTP did not reduce paired-pulse facilitation, was unaffected by the cannabinoid receptor blocker, and required postsynaptic actin filament assembly. Differences in the two LPP termination sites were also noted for frequency facilitation of synaptic responses, an effect that was reproduced in a two-step simulation by small adjustments to vesicle release dynamics. These results indicate that different types of glutamatergic neurons impose different forms of filtering and synaptic plasticity on their afferents. They also suggest that inputs are routed to, and encoded by, different sites within the hippocampus depending upon the pattern of activity arriving over the parent axon.

Resting EEG Periodic and Aperiodic Components Predict Cognitive Decline Over 10 Years.

Measures of intrinsic brain function at rest show promise as predictors of cognitive decline in humans, including EEG metrics such as individual α peak frequency (IAPF) and the aperiodic exponent, reflecting the strongest frequency of α oscillations and the relative balance of excitatory/inhibitory neural activity, respectively. Both IAPF and the aperiodic exponent decrease with age and have been associated with worse executive function and working memory. However, few studies have jointly examined their associations with cognitive function, and none have examined their association with longitudinal cognitive decline rather than cross-sectional impairment. In a preregistered secondary analysis of data from the longitudinal Midlife in the United States (MIDUS) study, we tested whether IAPF and aperiodic exponent measured at rest predict cognitive function (N = 235; age at EEG recording M = 55.10, SD = 10.71) over 10 years. The IAPF and the aperiodic exponent interacted to predict decline in overall cognitive ability, even after controlling for age, sex, education, and lag between data collection time points. Post hoc tests showed that "mismatched" IAPF and aperiodic exponents (e.g., higher exponent with lower IAPF) predicted greater cognitive decline compared to "matching" IAPF and aperiodic exponents (e.g., higher exponent with higher IAPF; lower IAPF with lower aperiodic exponent). These effects were largely driven by measures of executive function. Our findings provide the first evidence that IAPF and the aperiodic exponent are joint predictors of cognitive decline from midlife into old age and thus may offer a useful clinical tool for predicting cognitive risk in aging.

Attention Drives Visual Processing and Audiovisual Integration During Multimodal Communication.

During communication in real-life settings, our brain often needs to integrate auditory and visual information and at the same time actively focus on the relevant sources of information, while ignoring interference from irrelevant events. The interaction between integration and attention processes remains poorly understood. Here, we use rapid invisible frequency tagging and magnetoencephalography to investigate how attention affects auditory and visual information processing and integration, during multimodal communication. We presented human participants (male and female) with videos of an actress uttering action verbs (auditory; tagged at 58 Hz) accompanied by two movie clips of hand gestures on both sides of fixation (attended stimulus tagged at 65 Hz; unattended stimulus tagged at 63 Hz). Integration difficulty was manipulated by a lower-order auditory factor (clear/degraded speech) and a higher-order visual semantic factor (matching/mismatching gesture). We observed an enhanced neural response to the attended visual information during degraded speech compared to clear speech. For the unattended information, the neural response to mismatching gestures was enhanced compared to matching gestures. Furthermore, signal power at the intermodulation frequencies of the frequency tags, indexing nonlinear signal interactions, was enhanced in the left frontotemporal and frontal regions. Focusing on the left inferior frontal gyrus, this enhancement was specific for the attended information, for those trials that benefitted from integration with a matching gesture. Together, our results suggest that attention modulates audiovisual processing and interaction, depending on the congruence and quality of the sensory input.

fastDFE: Fast and Flexible Inference of the Distribution of Fitness Effects.

Estimating the distribution of fitness effects (DFE) of new mutations is of fundamental importance in evolutionary biology, ecology, and conservation. However, existing methods for DFE estimation suffer from limitations, such as slow computation speed and limited scalability. To address these issues, we introduce fastDFE, a Python-based software package, offering fast, and flexible DFE inference from site-frequency spectrum (SFS) data. Apart from providing efficient joint inference of multiple DFEs that share parameters, it offers the feature of introducing genomic covariates that influence the DFEs and testing their significance. To further simplify usage, fastDFE is equipped with comprehensive VCF-to-SFS parsing utilities. These include options for site filtering and stratification, as well as site-degeneracy annotation and probabilistic ancestral-allele inference. fastDFE thereby covers the entire workflow of DFE inference from the moment of acquiring a raw VCF file. Despite its Python foundation, fastDFE incorporates a full R interface, including native R visualization capabilities. The package is comprehensively tested and documented at fastdfe.readthedocs.io.