Miracle-dz/UniFAR-FTUs huggingface dataset:
EEG resting state alpha dynamics predict individual proneness to auditory hallucinations

Introduction Auditory verbal hallucinations (AVH) are a transdiagnostic phenomenon but also occur in the general population. The disposition to experience AVH is considered a continuous expression from non-clinical to clinical hallucination proneness (HP). Currently, little is known about the neurophysiology of the non-clinical HP part of the continuum. AVH might result from a heightened sensitivity to sensory inputs and a decreased ability to differentiate between externally and internally generated input. Resting state (RS) alpha band activity is associated with perceptual sensitivity, attentional shifts, and cognitive control. Accordingly, spontaneous alpha fluctuations might present as a HP correlate. To investigate the time-varying dynamics of alpha band activity, we deployed a novel method for brain state allocation. Methods We recorded RS electroencephalography (EEG) data from 33 individuals with varying levels of HP but without clinically relevant hallucinations and used a Hidden Semi-Markov Model (HsMM) to identify five recurrent alpha states with unique temporal dynamics and topographies. The states’ mean duration and occupancy were analyzed as a function of HP. The sources of each state were reconstructed to identify the most active brain areas and their correspondence with known resting state networks. Results Occupancy and mean duration of a state corresponding to sensorimotor, auditory, and default-mode network (DMN) areas significantly predicted auditory and auditory-verbal HP, but not general HP. The temporal dynamics of all other states did not relate to HP. Conclusion Alpha brain state sources align with prior results on the role of the alpha in the DMN. The temporal dynamics of alpha might reflect individual differences for attentional biases to internally generated sensory events and altered auditory perceptual sensitivity. Thus, changes in the temporal brain state dynamics of RS alpha oscillations could present as a neural marker of increased vulnerability to auditory hallucinatory experiences.
Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low‐dose kainic acid systemic injection paradigm in mice

Sex differences in epilepsy appear driven in part due to effects of gonadal steroids, with varying results in experimental models based on species, strain, and method of seizure induction. Furthermore, removing the main source of these steroids via gonadectomy may impact seizure characteristics differently in males and females. Repeated low‐dose kainic acid (RLDKA) systemic injection paradigms were recently shown to reliably induce status epilepticus (SE) and hippocampal histopathology in C57BL/6J mice. Here, we investigated whether seizure susceptibility in a RLDKA injection protocol exhibits a sex difference and whether gonadectomy differentially influences response to this seizure induction paradigm in males and females.
Has recombination changed during the recent evolution of the guppy Y chromosome?

Genome sequencing and genetic mapping of molecular markers has demonstrated Y-linkage across most of the guppy (Poecilia reticulata) XY chromosome pair. However, they also revealed exchanges with the X, consistent with classical genetic observations of occasional exchanges of factors controlling visible male-specific phenotypic traits. It remains unclear whether this fish species has an extensive sex-determining region without crossing over (whose suppressed recombination could have evolved under selection created by sexually antagonistic effects of male coloration factors), or whether the fully Y-linked region is very small, perhaps within a single gene. Population genomic data support cytogenetic results indicating that it is within the terminal 5 Mb of the 26.5 Mb chromosome 12, just proximal to a highly recombining pseudo-autosomal region, PAR1. Using molecular markers, we studied recombination, focusing on this region of the XY pair. Despite assembly errors in the small terminal PAR1, our mapping identifies very similar genetic PAR boundaries in sires from four populations, suggesting that their crossover patterns have not changed. Our results also confirmed occasional crossovers proximal to the male-determining region, defining a second pseudo-autosomal region, PAR2, recombining much more rarely than PAR1. The crossover positions suggest that the male-determining factor is within a repetitive region near 21 Mb in the female assembly. A sex-reversed XX male had few crossovers in PAR2, suggesting that this region’s low crossover rate depends on the phenotypic, not the genetic, sex. Thus rare sex changes, and/or occasional crossovers in males can explain the failure to detect fully Y-linked variants.
Molecular dynamics of the interaction between the ALS/FTD-associated (GGGGCC)n RNA G-quadruplex structure and the three RRM domains of hnRNP H

Hexanucleotide repeat expansions (HRE), located in the first intron of chromosome 9 open reading frame 72 (C9orf72) are the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Presence of the HRE may cause various effects to neuronal cells, leading to pathogenicity. One of these is the sequestration of RNA-binding proteins by three-quartet parallel RNA G-quadruplexes (RG4s) formed from repeated (GGGGCC)n sequences on the sense transcripts of the HRE. Multiple studies imply a major role of the sequestration of heterogeneous nuclear ribonucleoprotein H (hnRNP H) in the pathology of ALS/FTD. In this study, molecular docking and molecular dynamics (MD) were used to simulate the interaction of the three RNA recognition motifs (RRMs) of hnRNP H with the RG4. Molecular Mechanics with Generalised Born and Surface Area Solvation (MM-GBSA) and hydrogen bonding analyses of MD simulations were performed. The MM-GBSA analyses revealed that Arg29, Arg150, and Arg299 are important contributors to the binding, consistent with previous observations of arginine-mediated binding of protein to RNA. In addition, our results point to a previously unknown role of the stretch of residues from Lys72 to Tyr82 on hnRNP H for binding the (GGGGCC)n RG4, forming a hydrogen bonding hotspot. Interestingly, the identified residues are not located in the beta sheet, as would be expected of RRMs in general, suggesting that the binding of hnRNP H to this pathological RG4 may be specifically targeted. This has implications for future in vitro studies including but not limited to mutational analysis of these mentioned residues as well as drug development to prevent the sequestration of hnRNP H in ALS/FTD.
Evidence for the cardiodepressive effects of the plasticizer di-2-ethylhexylphthalate (DEHP)

Di-2-ethylhexylphthalate (DEHP) is commonly used in the manufacturing of plastic materials, including intravenous bags, blood storage bags, and medical-grade tubing. DEHP can leach from plastic medical products, which can result in inadvertent patient exposure. DEHP concentrations were measured in red blood cell (RBC) units stored between 7-42 days (23-119 μg/mL). Using these concentrations as a guide, Langendorff-perfused rat heart preparations were acutely exposed to DEHP. Sinus activity remained stable with lower doses of DEHP (25-50 μg/mL), but sinus rate declined by 43% and sinus node recovery time prolonged by 56.5% following 30-minute exposure to 100 μg/ml DEHP. DEHP exposure also exerted a negative dromotropic response, as indicated by a 69.4% longer PR interval, 108.5% longer Wenckebach cycle length, and increased incidence of atrioventricular uncoupling. Pretreatment with doxycycline partially rescued the effects of DEHP on sinus activity, but did not ameliorate the effects on atrioventricular conduction. DEHP exposure also prolonged the ventricular action potential and effective refractory period, but had no measurable effect on intracellular calcium transient duration. Follow-up studies using hiPSC-CM confirmed that DEHP slows electrical conduction in a time (15 min – 3 hours) and dose-dependent manner (10-100 μg/mL). Previous studies have suggested that phthalate toxicity is specifically attributed to metabolites of DEHP, including mono-2-ethylhexyl phthalate (MEHP). This study demonstrates that DEHP exposure also contributes to cardiac dysfunction in a dose- and time-dependent manner. Future work is warranted to investigate the impact of DEHP (and its metabolites) on human health, with special consideration for clinical procedures that employ plastic materials.
Mifepristone decreases nicotine intake in dependent and non-dependent adult rats

Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders. The aim of these studies was to investigate if glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine. The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent (3 days per week) or daily access (7 days per week) for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine if the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded. The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access, but only the rats with daily access to nicotine showed signs of dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the total distance traveled and rearing in the open field test and operant responding for food pellets. These findings indicate that mifepristone decreases the reinforcing effects of nicotine and food, but it might also be somewhat sedative.
Coevolution increases robustness to extinctions in mutualistic but not antagonistic communities

Co-extinctions may exacerbate the current biodiversity crisis. Yet, we do not understand all the factors that shape the robustness of communities to the loss of species. Here we analyse how coevolution influences the robustness of mutualistic and antagonistic communities. We find that coevolution increases robustness in mutualism but reduces it in antagonism. These differences are due to coevolution altering the density of interactions in communities. The largest changes to robustness occur when coevolutionary selection is strong. Yet, the effect size of coevolution on robustness depends on the size of the community. Our results may broaden the suite of mechanisms affecting the resilience of ecological communities. These insights may inform efforts to reduce the risk of species loss in the face of global change.
Variation in Dental Tissues: Using Bayesian Multilevel Modelling to Explore Intra- and Inter-Individual Dental Variation

Objectives Dental variation within populations and, even more so, within individuals is far less well understood than variation between populations. This is problematic as a single tooth type is often used as a representative of the whole dentition, despite a lack of understanding of intra-tooth type relationships. This research investigates the variation of dental tissues and proportions within and between individuals. Materials and Methods Upper and lower first incisor to second premolar tooth rows were obtained from 30 individuals (n=300), from 3 archaeological samples. The teeth were micro-CT scanned and surface area and volumetric measurements were obtained from the surface meshes extracted. Dental variation of these measurements on a tooth and individual level was studied using Bayesian Multilevel Modelling. Results The individual and tooth level variation differed by dental measurement, ranging between 9.5%-47.5% and 52.6-90.5% respectively. Enamel volume had the highest degree of individual-level variation in contrast to coronal dentine volume that had the lowest of individual-level variation. Tooth type, isomere, and position in field all showed a significant effect on the dental measurements examined in this study. Discussion Tooth selection and sampling strategies should consider individual and tooth-level variation, with at least one tooth from each type and isomere included in analyses. This will ensure that any population-level differences are not masked by variability between teeth. The low level of coronal dentine volume individual variation indicates that it is particularly useful in studies with small sample sizes.
Climatic niche differentiation between native and non-native ranges is widespread in Ponto-Caspian amphipods

Niche conservatism posits that a species’ non-native populations establish in areas that match the native environmental conditions. Although the Ponto-Caspian region is a major source of inland aquatic alien species, the extent to which their climatic niches diverged between the invasive and native ranges remains poorly understood. Using an n-dimensional hypervolume approach, we quantified climatic niche overlap and inferred patterns of niche differentiation (shift, contraction, or expansion) among native and invaded ranges for 12 widespread Ponto-Caspian amphipod species (six genera in three families). Our results show that all investigated species experience substantially different climatic conditions in the invaded range. The invasive niche either contracted (five species), shifted (four species), expanded and shifted (two species), or shifted and contracted (one species) relative to the native niche. We conclude that although the focal taxa share a common geographic origin and evolutionary history, they exhibit disparate patterns of climatic niche change outside the native range. The niche conservatism hypothesis receives mixed support given that half of the studied species underwent niche shifts/expansion. Furthermore, congeners exhibited both identical and contrasting patterns of niche differentiation, suggesting a limited phylogenetic effect. The uncovered diversity of niche dynamics among closely related species indicates that each has a unique potential for invasiveness and long-term persistence. This has important implications for predicting invasion risk and refining management strategies.
Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. Animal experiments also demonstrate that epigenetic transfer of maladaptive information of advanced age fathers is associated with reduced offspring health including reduced life span. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. Experiments with transgenic mice demonstrate that the shift of the balance in favor of mTOR complex two rejuvenates sperm DNA-methylome while the shift in favor of mTOR complex one accelerates aging of the sperm DNA-methylome and results in a reproductive phenotype concordant with older age. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.
A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

Interleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7. In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr, and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm), which may be important for anti-tumor activities reported with IL-7 treatment. Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide lacks sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur.
RNA structures and dynamics with Å resolution revealed by x-ray free electron lasers

RNA macromolecules, like proteins, fold to assume shapes that are intimately connected to their broadly recognized biological functions; however, because of their high charge and dynamic nature, RNA structures are far more challenging to determine. We introduce an approach that exploits the high brilliance of x-ray free electron laser sources to reveal the formation and ready identification of Å scale features in structured and unstructured RNAs. New structural signatures of RNA secondary and tertiary structures are identified through wide angle solution scattering experiments. With millisecond time resolution, we observe an RNA fold from a dynamically varying single strand through a base paired intermediate to assume a triple helix conformation. While the backbone orchestrates the folding, the final structure is locked in by base stacking. In addition to understanding how RNA triplexes form and thereby function as dynamic signaling elements, this new method can vastly increase the rate of structure determination for these biologically essential, but mostly uncharacterized macromolecules.
Extinct and extant termites reveal the fidelity of behavior fossilization in amber

Fossils encompassing multiple individuals provide rare direct evidence of behavioral interactions among extinct organisms. However, the fossilization process can alter the spatial relationship between individuals and hinder behavioral reconstruction. Here, we report a Baltic amber inclusion preserving a female-male pair of the extinct termite species Electrotermes affinis. The head-to-abdomen contact in the fossilized pair resembles the tandem courtship behavior of extant termites, although their parallel body alignment differs from the linear alignment typical of tandem runs. To solve this inconsistency, we simulated the first stage of amber formation, the immobilization of captured organisms, by exposing living termite tandems to sticky surfaces. We found that the posture of the fossilized pair matches trapped tandems and differs from untrapped tandems. Thus, the fossilized pair likely is a tandem running pair, representing the first direct evidence of the mating behavior of extinct termites. Furthermore, by comparing the positions of partners on a sticky surface and in the amber inclusion, we estimated to 67% the probability that the leader role in the fossilized tandem was performed by a male. Our results demonstrate that past behavioral interactions can be reconstructed despite the spatial distortion of body poses during fossilization. Our taphonomic approach clarifies how certain behaviors can be inferred from fossil occurrences.
Bias in the arrival of variation can dominate over natural selection in Richard Dawkins’s biomorphs

Biomorphs, Richard Dawkins’ iconic model of morphological evolution, are traditionally used to demonstrate the power of natural selection to generate biological order from random mutations. Here we show that biomorphs can also be used to illustrate how developmental bias shapes adaptive evolutionary outcomes. In particular, we find that biomorphs exhibit phenotype bias, a type of developmental bias where certain phenotypes can be many orders of magnitude more likely than others to appear through random mutations. Moreover, this bias exhibits a strong Occam’s-razor-like preference for simpler phenotypes with low descriptional complexity. Such bias towards simplicity is formalised by an information-theoretic principle that can be intuitively understood from a picture of evolution randomly searching in the space of algorithms. By using population genetics simulations, we demonstrate how moderately adaptive phenotypic variation that appears more frequently upon random mutations will fix at the expense of more highly adaptive biomorph phenotypes that are less frequent. This result, as well as many other patterns found in the structure of variation for the biomorphs, such as high mutational robustness and a positive correlation between phenotype evolvability and robustness, closely resemble findings in molecular genotype-phenotype maps. Many of these patterns can be explained with an analytic model based on constrained and unconstrained sections of the genome. We postulate that the phenotype bias towards simplicity and other patterns biomorphs share with molecular genotype-phenotype maps may hold more widely for developmental systems, which would have implications for longstanding debates about internal versus external causes in evolution.