Miracle-dz/UniFAR-FTUs huggingface dataset:
Atrial t-tubules adopt a specialist developmental state while alterations to Ca2+ buffering maintain systolic Ca2+ during postnatal development

Transverse (t)-tubules ensure a uniform rise in calcium (Ca2+) and thus contraction in cardiac cells. Though more extensively studied in the ventricle, t-tubules also play a key role in the atria of large mammals, such as human, and their loss in heart failure is associated with impaired Ca2+ release and thus contractility. T-tubule restoration is therefore an ideal therapeutic target but the process of t-tubule formation is not understood. The aim of this study was to determine how t-tubules develop in the healthy atria and the impact this has on Ca2+ handling. Postnatal development was assessed in sheep from newborn through to adulthood. Atrial t-tubules were present at birth in the sheep atria and increased in density up until 3 months of age. In the latter part of development (3 months to adult) a lack of t-tubule growth but increase in cell width results in t-tubule density decreasing. In the newborn, despite reduced t-tubule density, we found the amplitude of the Ca2+ transient was maintained and this was associated with increases in the L-type Ca2+ current (ICa-L) and the Ca2+ content of the sarcoplasmic reticulum (SR). We suggest these changes are sufficient to overcome the elevated cytosolic Ca2+ buffering in the newborn and the decreased t-tubule density. We have shown the neonate atria is highly specialised to negate reduced central Ca2+ release through enhanced surface ICa-L and SR load. This maintains atrial function despite immature t-tubules highlighting important differences in Ca2+ handling in the newborn and heart failure atria where t-tubules are sparse.
RECLUSIVE CHANDELIERS: FUNCTIONAL ISOLATION OF DENTATE AXO-AXONIC CELLS AFTER EXPERIMENTAL STATUS EPILEPTICUS

Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells without altering reliability, short-term plasticity, or AIS GABA reversal potential. These changes compromised AAC-dependent shunting of granule cell firing in a multicompartmental model. These early post-SE changes in AAC physiology would limit their ability to receive and respond to input, undermining a critical brake on the dentate throughput during epileptogenesis.
DNA i-motif levels are overwhelmingly depleted in living human cells: insights from in-cell NMR

I-Motifs (iM) are non-canonical DNA structures potentially forming in accessible, single-stranded, cytosine-rich genomic regions, with regulatory roles. Chromatin, protein interactions, and intracellular properties seem to govern iM formation at sites with i-motif formation propensity (iMFPS) in human cells, yet their specific contributions remain unclear. Using in-cell NMR with oligonucleotide iMFPS models, we monitored iM-associated structural equilibria in asynchronous and cell cycle-synchronized HeLa cells at 37°C. Our findings show that iMFPS displaying pHT<7 under reference in vitro conditions occur predominantly in unfolded states in cells, while those with pHT >7 occur as a mix of folded and unfolded states depending on the cell cycle phase. Comparing these results with previous data obtained using an iM-specific antibody (iMab) revealed that cell cycle-dependent iM formation has a dual origin and iM formation concerns only a small fraction (possibly 1%) of genomic sites with iM formation propensity. We propose a comprehensive model aligning observations from iMab and in-cell NMR and enabling the identification of iMFPS capable of adopting iM structures under physiological conditions in living human cells. Our results suggest that many iMFPS may have biological roles linked to their unfolded states.
Changes in high-frequency aperiodic 1/f slope and periodic activity reflect post-stimulus functional inhibition in the visual cortex

It has been shown that cessation of intensive sensory stimulation is associated with a transient increase in functional inhibition in the sensory cortical areas. However, the electrophysiological correlates of this post-stimulus inhibition in the human brain have not been properly investigated. To investigate post-stimulus inhibition, we recorded magnetoencephalogram (MEG) at rest and after cessation of visual stimulation of varying intensity (high-contrast gratings drifting at a slow, medium, or high rate) in 25 healthy women aged 18-40 years. We analyzed condition- and intensity-related changes in MEG parameters sensitive to functional inhibition: periodic alpha-beta power, peak alpha frequency (PAF), and 1/f aperiodic slope. We also investigated the association of these parameters with sensory sensitivity and avoidance assessed by a questionnaire. To evaluate the influence of hormonal status on the studied parameters, participants were examined twice, during the follicular and luteal phases of the menstrual cycle (MC). Regardless of MC phase, increasing intensity of the preceding visual stimulation resulted in increased posterior post-stimulus alpha-beta power, PAF, and a more negative/steeper aperiodic (1/f) slope of the power spectrum in the 35-45 Hz range. Compared to rest, the post-stimulus period was characterized by higher PAF, a steeper 35-45 Hz 1/f slope in posterior cortical areas, and a widespread increase in beta power. While condition- and intensity-dependent changes in alpha-beta power and 1/f slope were correlated, changes in PAF did not correlate with either of them. Greater intensity-dependent increase in visual alpha-beta power predicted higher subjective sensory sensitivity/avoidance, suggesting stronger regulatory top-down modulation of visual cortex in individuals with heightened sensitivity. Our results show that several MEG parameters concordantly indicate a post-stimulus enhancement of inhibition that is proportional to the intensity of the preceding visual stimulation. While post-stimulus changes in alpha-beta power and 1/f slope may share some common mechanisms, changes in PAF reflect a distinct aspect of inhibitory regulation. Our results inform potential inhibition-based biomarkers for clinical and translational research. Key points: The cessation of visual stimulation leads to a transient increase in functional inhibition. Changes in MEG parameters reflect post-stimulus enhancement of inhibition. These changes scale with the intensity of the preceding stimulation.
Identification of a convergent spinal neuron population that encodes itch

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca2+ imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca2+ oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch. In brief Through population imaging, Sheahan et al. identify a network of neurons in the dorsal horn that is activated by pruritogens and find that kappa opioid receptor signaling inhibits itch through the selective inhibition of GRPR spinoparabrachial neurons. Highlights Itch-inducing agents drive activity in a common population of GRPR-expressing spinal interneurons GRPR spinal projection neurons transmit itch from the spinal cord to the brain Kappa opioids reduce itch through the inhibition of GRPR spinoparabrachial neurons GRPR activation elicits persistent, intrinsic Ca2+ oscillations
Context dependent multisensory integration: Mechanosensation depends on luminance for robust performance

Multisensory, goal-directed behaviors are ubiquitous and essential in animals across taxa. Individual sensory modalities may be significantly tuned by environmental context, and yet they must continue to combine and produce multisensory behaviors. This necessitates either behavioral robustness or goal-relevant adaptation in sensorimotor systems. In the case of hover-feeding hawkmoths of the species Manduca sexta, proboscis mechanosensation and vision are known to combine linearly in tracking of moving flowers. This tracking behavior is affected by light-levels, and visual compensation is necessary for robust flower-tracking. Whether the mechanosensory response also adjusts to light-level, in order to produce linear combination across luminance contexts, is not known. We applied control theoretic analyses to study integration of mechanosensory and visual information in flower tracking hawkmoths in the context of high luminance. This was performed using a two-part robotic flower system. Under the conditions of high luminance, we verified the linear combination of mechanosensory and visual systems, and the complementary modulation of these systems. We show that both systems tune their frequency response with changing environmental light level, while keeping their combined error low at relevant frequencies. Thus, the animal adapts to changing conditions, across modalities, even when only one of the modalities (vision) is directly affected. This cross-talk between sensorimotor systems is constrained, and possibly driven, by performance requirements.
Cochlear tuning characteristics arise from temporal prediction of natural sounds

The cochlea decomposes incoming sound waveforms into different frequency components along the length of its basilar membrane. The receptor hair cells at the apical end of this resonant membrane are tuned to the lowest sound frequencies, with the preferred sound frequency of hair cell tuning increasing near-exponentially along the length of the membrane towards its basal end. This frequency composition of the sound is then transmitted to the brain by the auditory nerve fibers that innervate the inner hair cells. Hair cells respond to a sound impulse with a temporally asymmetric envelope and the sharpness of their tuning changes as the frequency to which they are most sensitive varies with their position along the basilar membrane. We ask if there is a normative explanation for why the cochlea decomposes sounds in this manner. Inspired by findings in the retina, we propose that cochlear tuning properties may be optimized for temporal prediction. This principle states that the sensory features represented by neurons are optimized to predict immediate future input from recent past input. We show that an artificial neural network optimized for temporal prediction of the immediate future of raw waveforms of natural sounds from their recent past produces tuning properties that resemble those observed in the auditory nerve. Specifically, the model captures the temporally asymmetric impulse responses, the tonotopic distribution and variation in tuning sharpness along the cochlea, and the frequency glide polarity of the impulse responses. These characteristics are not captured by a similar model optimized for compression of the sound waveform, rather than prediction. Given its success in accounting for the tuning properties at various processing levels in the auditory and visual systems, this finding for the cochlea provides further evidence that temporal prediction may be a general principle of sensory processing.
Evolution of olfactory sensitivity, preferences and behavioral responses in Mexican cavefish: fish personality matters

Animals are adapted to their natural habitats and lifestyles. Their brains perceive the external world via their sensory systems, compute information and generate appropriate behavioral outputs. However, how do these processes evolve across evolution? Here, focusing on the sense of olfaction, we have studied the evolution in olfactory sensitivity, preferences and behavioral responses to six different amino acid odors in the two morphs of the fish Astyanax mexicanus. To this end, we have developed a high-throughput behavioral setup and pipeline of quantitative and qualitative behavior analysis, and we have tested 425 six-week-old Astyanax larvae. The blind, dark-adapted morphs of the species showed markedly distinct basal swimming patterns and behavioral responses to odors, higher olfactory sensitivity and a strong preference for alanine, as compared to their river-dwelling eyed conspecifics. In addition, we discovered that fish have an individual “swimming personality”, and that this personality influences their capability to respond efficiently to odors and find the source. Importantly, the personality traits that favored significant responses to odors were different in surface fish and cavefish. Moreover, the responses displayed by second-generation cave x surface F2 hybrids suggested that olfactory-driven behavior is a quantitative genetic trait. Our findings show that olfactory processing has rapidly evolved in cavefish at several levels: detection threshold, odor preference, and foraging behavior strategy. Cavefish is therefore an outstanding model to understand the genetic, molecular and neurophysiological basis of sensory specialization in response to environmental change.
Comparing Approaches to Specimen Identification using Neotropical Freshwater Fishes in the Barra del Colorado Wildlife Refuge, Costa Rica

As global biodiversity declines continue, conservation efforts are increasingly important in megadiverse areas such as the Neotropics where biodiversity is especially imperiled. The accurate identification of specimens is critical to successful conservation plans. However, in groups such as freshwater fishes, different identification methodologies have documented challenges. Using a biodiversity survey of fishes from the Barra del Colorado Wildlife Refuge in northeastern Costa Rica, we compared: (1) morphological identifications in the field, (2) morphological identifications in the lab by experts, (3) DNA barcode-based identifications, and (4) identifications based on an integrative approach. Our results suggest that both barcode-based identifications and field morphological identifications provided fewer correct species identifications than lab identifications performed by experts using morphology. We attribute shortfalls of DNA barcoding in this case to the misidentification of reference material, the use of outdated taxonomy for references sequences, and the non-uniform representation of groups in public databases across taxa. We suggest the use of an integrative approach to identify freshwater fishes in Costa Rica and other megadiverse areas of the Neotropics where similar issues with public barcode reference libraries exist. We also recommend the creation of regional curated barcode reference libraries to aid in the identification of traditionally difficult to identify species/specimens. We also provide the most up to date species list for the ichthyofauna of the Barra del Colorado Wildlife Refuge identifying 51 species from 42 genera, 21 families, and 17 orders. Generating accurate species lists for protected areas and areas of importance will provide conservation practitioners with effective tools for tracking diversity changes over time.
Molecular dynamics simulations of HIV-1 matrix-membrane interactions at different stages of viral maturation

Although the structural rearrangement of the membrane-bound matrix (MA) protein trimers upon HIV-1 maturation has been reported, the consequences of MA maturation on the MA-lipid interactions are not well understood. Long-timescale molecular dynamics (MD) simulations of the MA multimeric assemblies of immature and mature virus particles with our realistic asymmetric membrane model have explored MA-lipid interactions and lateral organization of lipids around MA complexes. The number of stable MA-PS and MA-PIP2 interactions at the trimeric interface of the mature MA complex is observed to be greater compared to that of the immature MA complex. Our simulations identified an alternative PIP2 binding site in the immature MA complex where the multivalent headgroup of a PIP2 lipid with a greater negative charge binds to multiple basic amino acid residues such as, ARG3 residues of both the MA monomers at the trimeric interface, and HBR residues (LYS29, LYS31) of one of the MA monomers. Our enhanced sampling simulations have explored the conformational space of phospholipids at different binding sites of the trimeric interface of MA complexes. Unlike the immature MA complex, the 2’ acyl tail of two PIP2 lipids at the trimeric interface of the mature MA complex is observed to sample stable binding pockets of MA consisting of helix4 residues. Together, our results provide molecular-level insights into the interactions of MA trimeric complexes with membrane and different lipid conformations at the specific binding sites of MA protein before and after viral maturation. Significance HIV-1 maturation facilitates the conversion of a newly formed immature virus particle to a mature infectious virion and initiates a new round of infection. The contributions of specific protein-lipid interactions in the HIV-1 assembly process are well recognized, however, the interactions of matrix protein lattice with the membrane before and after HIV-1 maturation are yet to be fully understood. Based on our simulated data, supported by prior experimental observations, the present study provides a molecular-level understanding of possible altered binding mode of PIP2 lipids after viral maturation. Identification of protein-lipid specific interactions, and lipid sorting data obtained from our long-time and large-scale atomistic MD simulations advance the understanding of the HIV-1 matrix and membrane maturation.
The Olmec Legacy: Cultural Continuity and Change in Mexico's Southern Gulf Coast Lowlands

Abstract Archaeological research in the southern Gulf lowlands of Mexico has focused on the notable accomplishments of the Formative Period Olmec. Yet, with few exceptions, the spectacular early cultural developments in the region have not been well articulated with local patterns of cultural continuity and change during subsequent Classic and Postclassic times. Research in the Hueyapan region of Veracruz in Mexico's southern Gulf lowlands provides new data for examining the Olmec legacy in this important region and a clearer picture of issues concerning chronology, settlement patterns, economy, and political organization that must be examined in the future. The research described here builds a foundation for comparing the political and economic development of this part of the prehispanic lowlands to other regions of ancient Mesoamerica.
Subcritical Junction Flow

The main flow features of subcritical junction flows are explored, based on an extended hydraulic model study. The flow conditions chosen resulted in flows that are governed by the Froude similarity law. So-called simple junctions with junction angles of 30°, 60°, and 90° were tested. The main emphasis was made in determining the characteristics of the lateral flow and the flow contraction in the tailwater branch. Further, expressions for the momentum correction coefficients, the lateral wall pressure force, and the ratio of flow depths in the lateral and upstream branches were provided. A rational approach for the momentum contribution of the lateral branch is presented and applied for the prediction of the backwater effect across a simple junction. The complex flow pattern is further documented with selected photographs such that a rather complete description of junction flow is now available.
Spatial and temporal biodiversity variations in a high mountain environment: the case of the proglacial margin of the Evettes, Natura 2000 area (Savoie, French Alps)

The aim of this paper is to contribute to the understanding of the changes in plant cover after the recent glacier retreat,in an alpine environment. The selected study site in Savoie in the French Alps (2502-2509m asl), belonging to the European network Natura 2000, provides favourable conditions for the study due to the flat glacier foreland, where the glacier did not advance since the Little Ice Age. Data collected from 110 botanical plots were correlated with dated glacial and proglacial landforms. Species diversity has been analysed using the Shannon-Weaver index, the Grime classification, and the uncommon species described in the European list of Natura 2000 European Network. Classical and multivariate analyses have been made to determine the impact of the glacial retreat on the biodiversity variation. We show that the changes in species richness and vegetation cover were related to the distance from the glacier front. The biodiversity index was less than 2.5 near the glacier but above 4 at the furthest point. The highest plant diversity, however, was observed at an intermediate position, where competitive and pioneer plants were equally represented in the field. This location, concurrently, showed the highest heterogeneity in the activity of periglacial processes. It seems that the most heterogeneous and disturbed soils, due to inherited deposits and currently active periglacial processes, are responsible for an increase in biodiversity.
The lunar regolith: comparative studies of the Apollo and Luna sites. Chemistry of soils from Apollo 17, Luna 16, 20, and 24.

A progress report is presented concerning an investigation involving a comprehensive chemical and petrologic study of surface soils from all nine lunar sampling sites. The soils selected for this study are part of the lunar highlands soils suite and represent the soils at each site that contain abundant highland-derived material. The current report takes into consideration, in addition to the eight soils discussed by Labotka et al. (1980) and by Laul and Papike (1980), three Apollo 17 soils (72501, 76501, and 78221), and three Luna soils (21000, L-16; 22001, L-20; and 24999, L-24). Attention is given to the modal petrology of the 1000-90 micrometer fraction of all 14 soils, and the modes and mineral and glass chemistries of the 90-20 and 20-10 micrometer fractions of the Apollo 17 and Luna soils. In an evaluation of the obtained results, it is found that except for rare, large-scale impacts, lateral mixing is an inefficient process. Comminution and vertical mixing appear to be the dominant process.