Miracle-dz/UniFAR-FTUs huggingface dataset:
Cortico-motor control dynamics orchestrates visual sampling

Movements overtly sample sensory information, making sensory analysis an active-sensing process. In this study, we show that visual information sampling is not just locked to the (overt) movement dynamics, but it is structured by the internal (covert) dynamics of cortico-motor control. We asked human participants to perform an isometric motor task – based on proprioceptive feedback – while detecting unrelated near-threshold visual stimuli. The motor output (Force) shows zero-lag coherence with brain activity (recorded via electroencephalography) in the beta-band, as previously reported. In contrast, cortical rhythms in the alpha-band systematically forerun the motor output by 200ms. Importantly, visual detection is facilitated when cortico-motor alpha (not beta) synchronization is enhanced immediately before stimulus onset, namely at the optimal phase relationship for sensorimotor communication. These findings demonstrate an automatic gating of visual inputs by the ongoing motor control processes, providing evidence of an internal and alpha-cycling visuomotor loop.
Studies on the Association between Genetic Polymorphisms and Clozapine Drug Response in Treatment Resistant Schizophrenia.

Schizophrenia is a severe disabling neuropsychiatric disorder . It is almost equally prevalent in all societies around the world. The lifetime prevalence of schizophrenia is estimated around 1%. It affects men and women equally. It often starts in adolescence or in early adulthood and follows a chronic or episodic course. Both genetic and environmental factors contribute towards the complex etiopathogenesis of schizophrenia. Despite the absence of any laboratory tests, reliable clinical diagnoses of schizophrenia can be made by the standard international diagnostic criteria. Patients with schizophrenia suffer positive psychotic symptoms, such as delusions and hallucinations, negative symptoms, such as motivation and social deficits, as well as cognitive difficulties. They are usually treated with antipsychotic medications and with comprehensive psychosocial interventions. One third of patients with schizophrenia recover well with their treatment. Clinical variables are useful to predict response to clozapine and to model a dosing nomogram for serum clozapine levels. Smoking is a potentially modifiable risk factor for non-response to clozapine. Importance of caffeine consumption and Valproate co-medication should be considered during clozapine dose adjustments to enhance its therapeutic response and safety profile. As the four CYP1A2 gene single nucleotide polymorphisms do not help to predict the clinical response to clozapine, routine screening for them prior to starting clozapine is currently unwarranted. Combined clinical and pharmacogenetic models could predict responses to clozapine better than HTR3A pharmacogenetic associations alone. The results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions. This research indicates that future pharmacogenetic studies should evaluate associated clinical variables. It highlights the need for consensus criteria to define treatment outcomes in pharmacogenetic studies of schizophrenia.
Profiling microglia from AD donors and non-demented elderly in acute human post-mortem cortical tissue

Microglia are the tissue-resident macrophages of the central nervous system (CNS). Recent studies based on bulk and single-cell RNA sequencing in mice indicate high relevance of microglia with respect to risk genes and neuro-inflammation in Alzheimer’s disease. Here, we investigated microglia transcriptomes at bulk and single cell level in non-demented elderly and AD donors using acute human post-mortem cortical brain samples. We identified 9 human microglial subpopulations with heterogeneity in gene expression. Notably, gene expression profiles and subcluster composition of microglia did not differ between AD donors and non-demented elderly in bulk RNA sequencing nor in single-cell sequencing.
Activation of Macrophages by CpG DNA and LPS: an FTIR Spectroscopic Study

The innate immune response triggered by CpG DNA can improve host survival following pathogen challenge. Whether CpG ODN-mediated immune activation leads to global molecular changes in cells that are detectable by FTIR spectroscopy is currently unknown. Here, we used Attenuated Total Reflectance (ATR) Fourier Transform Infrared (FTIR) spectroscopy to monitor the molecular changes in murine macrophage RAW 264.7 cells upon activation with CpG DNA and lipopolysaccharide (LPS). By PCA analysis, we identified the sources of variation to follow with detailed spectral analysis. CpG DNA and LPS treatment increase the total nucleic acid concentration from the early periods post-activation, and DNA synthesis follows RNA synthesis. RNA-specific peak shows the activation state of macrophages in early periods post-treatment. CpG DNA and LPS result in an initial rapid increase in the total protein concentration, leveling off two hours post-activation. Both activated groups increase the concentration of fatty acids, triglycerides, and cholesterol, pointing out to a shared synthesis pathway and de novo lipogenesis. This study, for the first time, demonstrates the use of FTIR spectroscopy as an independent modality to monitor the activation dynamics of murine macrophages upon activation with CpG DNA and LPS.
Assessing the perceived reverberation in different rooms for a set of musical instrument sounds

Previous research has shown that the perceived reverberation in a room, or reverberance, depends on the sound source that is being listened to. In a study by Osses et al. [(2017) J. Acoust. Soc. Am. 141(4), EL381-EL387], reverberance estimates obtained from an auditory model for 23 musical instrument sounds in 8 rooms supported this sound-source dependency. As a follow-up to that study, a listening experiment with 24 participants was conducted using a subset of the original sounds with the purpose of mapping each test sound onto a reverberance scale. The experimentally-obtained reverberance estimates were significantly correlated with the simulated reverberance, providing further evidence that the sensation of reverberance is sound-source dependent.
Aerobiosis is not associated with GC content and G to T mutations are not the signature of oxidative stress in prokaryotic evolution

Aerobiosis is not associated with GC content and G to T 1 mutations are not the signature of oxidative stress in prokaryotic 2 evolution 3 4 Sidra Aslam†, Xin-Ran Lan†, Bo-Wen Zhang, Zheng-Lin Chen and Deng-Ke Niu* 5 MOE Key Laboratory for Biodiversity Science and Ecological Engineering and Beijing Key 6 Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing 7 Normal University, Beijing 100875, China 8
Synchronised oscillations in growing cell populations are explained by demographic noise

Understanding synchrony in growing populations is important for applications as diverse as epidemiology and cancer treatment. Recent experiments employing fluorescent reporters in melanoma cell lines have uncovered growing subpopulations exhibiting sustained oscillations, with nearby cells appearing to synchronise their cycles. In this study we demonstrate that the behaviour observed is consistent with long-lasting transient phenomenon initiated, and amplified by the finite-sample effects and demographic noise. We present a novel mathematical analysis of a multi-stage model of cell growth which accurately reproduces the synchronised oscillations. As part of the analysis, we elucidate the transient and asymptotic phases of the dynamics and derive an analytical formula to quantify the effect of demographic noise in the appearance of the oscillations. The implications of these findings are broad, such as providing insight into experimental protocols that are used to study the growth of asynchronous populations and, in particular, those investigations relating to anti-cancer drug discovery. Statement of Significance Recent experiments have reported strong evidence of periodic oscillations in the proportion of young and old melanoma cells. The biological mechanism generating this synchronisation and the potential impact that can have on commonly used experimental protocols is still unclear. Here we studied a population of melanoma cells for which we found oscillations in the proportions of cells in each phase of the cell cycle. We demonstrate that these observations may be triggered by intrinsic demographic noise alone, rather than any active synchronisation mechanism requiring cell-cell communication. Our findings may have implications for typical experimental protocols which aim to produce asynchronous cell populations.
Human-Genetic Ancestry Inference and False Positives in Forensic Familial Searching

In forensic familial search methods, a query DNA profile is tested against a database to determine if the query profile represents a close relative of a database entrant. One challenge for familial search is that the calculations may require specification of allele frequencies for the unknown population from which the query profile has originated. Allele-frequency misspecification can substantially inflate false-positive rates compared to use of allele frequencies drawn from the same population as the query profile. Here, we use ancestry inference on the query profile to circumvent the high false-positive rates that result from highly misspecified allele frequencies. In particular, we perform ancestry inference on the query profile and make use of allele frequencies based on its inferred genetic ancestry. In a test for sibling matches on profiles that represent unrelated individuals, we demonstrate that false-positive rates for familial search with use of ancestry inference to specify the allele frequencies are similar to those seen when allele frequencies align with the population of origin of a profile. Because ancestry inference is possible to perform on query profiles, the extreme allele-frequency misspecifications that produce the highest false-positive rates can be avoided. We discuss the implications of the results in the context of concerns about the forensic use of familial searching.
Evidence of population specific selection inferred from 289 genome sequences of Nilo-Saharan and Niger-Congo linguistic groups in Africa

Background There are over 2000 genetically diverse ethno-linguistic groups in Africa that could help decipher human evolutionary history and the genetic basis of phenotypic variation. We have sequenced 300 genomes from Niger-Congo populations from six sub-Saharan African countries (Uganda, Democratic Republic of Congo, Cameroon, Zambia, Ivory Coast, Guinea) and a Nilo-Saharan population from Uganda. Of these, we analysed 289 samples for population structure, genetic admixture, population history and signatures of selection. These samples were collected as part of the TrypanoGEN consortium project [1]. Results The population genetic structure of the 289 individuals revealed four clusters, which correlated with ethno-linguistic group and geographical latitude. These were the West African Niger-Congo A, Central African Niger-Congo B, East African Niger-Congo B and the Nilo-Saharan. We observed a spatial distribution of positive natural selection signatures in genes previously associated with AIDS, Tuberculosis, Malaria and Human African Trypanosomiasis among the TrypanoGEN samples. Having observed a marked difference between the Nilo-Saharan Lugbara and Niger-Congo populations, we identified four genes (APOBEC3G, TOP2B, CAPN9, LANCL2), which are highly differentiated between the two ethnic groups and under positive selection in the Lugbara population (_iHS -log p > 3.0, Rsb -log p > 3.0, Fst > 0.1 bonferroni p > 1.8x10e4). Conclusion The signatures that differentiate ethnically distinct populations could provide information on the specific ecological adaptations with respect to disease history and susceptibility/resistance. For instance in this study we identified APOBEC3G which is believed to be involved in the susceptibility of the Nilo-Saharan Lugbara population to Hepatitis B virus infection.
Attentional Bias Modification Alters fMRI Response towards Negative Stimuli in Residual Depression

Background Modification of attentional biases (ABM) in residual depression may lead to more adaptive emotion perception and emotion regulation reflected in changes in brain activity. There are growing efforts to characterize the neural underpinnings of ABM in depression, but task related emotion processing has so far not been investigated in a larger sample. Methods A total of 134 previously depressed individuals with residual symptoms were allocated to 14 days of ABM or placebo in a pre-registered RCT followed by an fMRI modified emotion perception task. Results ABM was associated with reduced amygdala and anterior cingulate cortex (ACC) activation compared to placebo during negative images. Response within the insular cortex was associated with the induction of positive affective bias following ABM and with improvement in symptoms. Conclusions ABM training has an early effect on brain function within circuitry associated with emotional appraisal and the generation of affective states.
Strategies for identifying dynamic regions in protein complexes: flexibility changes accompany methylation in chemotaxis receptor signaling states

Bacterial chemoreceptors are organized in arrays composed of helical receptors arranged as trimers of dimers, coupled to a histidine kinase CheA and a coupling protein CheW. Ligand binding to the external domain inhibits the kinase activity, leading to a change in the swimming behavior. Adaptation to an ongoing stimulus involves reversible methylation and demethylation of specific glutamate residues. However, the exact mechanism of signal propagation through the helical receptor to the histidine kinase remains elusive. Dynamics of the receptor cytoplasmic domain is thought to play an important role in the signal transduction, and current models propose inverse dynamic changes in different regions of the receptor. We hypothesize that the adaptational modification (methylation) controls the dynamics by stabilizing a partially ordered domain, which in turn modulates the binding of the kinase, CheA. We investigated the difference in dynamics between the methylated and unmethylated states of the chemoreceptor using solid-state NMR. The unmethylated receptor (CF4E) shows increased flexibility relative to the methylation mimic (CF4Q). Methylation helix 1 (MH1) has been shown to be flexible in the methylated receptor. Our analysis indicates that in addition to MH1, methylation helix 2 also becomes flexible in the unmethylated receptor. In addition, we have demonstrated that both states of the receptor have a rigid region and segments with intermediate dynamics. The strategies used in the study for identifying dynamic regions are applicable to a broad class of proteins and protein complexes with intrinsic disorder and dynamics spanning multiple timescales. Graphical Abstract Highlights Receptors exhibit greater ns timescale dynamics in unmethylated vs methylated state Methylation helix 2 likely involved in increased flexibility of unmethylated state Dynamics occur on multiple timescales in both states of the receptor
A codon model for associating phenotypic traits with altered selective patterns of sequence evolution

Changes in complex phenotypes, such as pathogenicity levels, trophic lifestyle, and habitat shifts are brought on by multiple genomic changes: sub- and neofunctionalization, loss of function, and levels of gene expression. Thus, detecting the signature of selection in coding sequences and associating it with shifts in phenotypic state can unveil the genes underlying complex traits. Phylogenetic branch-site codon models are routinely applied to detect changes in selective patterns along specific branches of the phylogeny. These methods rely on a pre-specified partition of the phylogeny to branch categories, thus treating the course of trait evolution as fully resolved and assuming that transitions in phenotypic states have occurred only at speciation events. Here we present TraitRELAX, a new phylogenetic model that alleviates these strong assumptions by explicitly accounting for the uncertainty in the evolution of both trait and coding sequences. This joint statistical framework enables the detection of changes in selection intensity upon repeated trait transitions. We evaluated the performance of TraitRELAX using simulations and then applied it to two case studies. Using TraitRELAX, we found an intensification of selection in the SEMG2 gene in polygynandrous species of primates compared to species of other mating forms, as well as changes in the intensity of purifying selection operating on sixteen bacterial genes upon transitioning from free-living to an endosymbiotic lifestyle.
Excess entropies reveal higher organization levels in developing neuron cultures

Multi-component systems often exhibit dynamics of a high degree of complexity, rendering it difficult to assess whether a proposed model’s description is adequate. For the multitude of systems that allow for a symbolic encoding, we provide a symbolic-dynamics based entropy measure that quantifies the degree of deviation obtained by a systems’s internal dynamics from random dynamics using identical average symbol probabilities. We apply this measure to several well-studied theoretical models and show its ability to characterize differences in internal dynamics, thus providing a means to accurately compare model and experiment. Data from neuronal cultures on a multi-electrode array chip validate the usefulness of our approach, revealing inadequacies of existing models and providing guidelines for their improvement. We propose our measure to be systematically used to develop future models and simulations.
The (dis)similarities between neural networks based upon functional connectivity, representational similarity, and univariate analyses

In fMRI research, univariate analysis (UNIVAR), representational similarity analysis (RSA, following multi-voxel pattern analysis (MVPA)), and functional connectivity analysis (FCA) are the most commonly used methods by cognitive neuroscientists investigating the functional organization of the human brain. Despite their popularity, few studies have examined the relationship between the network structures as identified through these different methods. Thus, the current study aims to evaluate the similarities between neural networks derived from UNIVAR, RSA, and FCA, and to clarify how these methods relate to each other. To achieve this goal, we analyzed the data of a previously published study with the three methods and compared the results by performing (partial) correlation and multiple regression analysis. Our findings reveal that neural networks resulting from UNIVAR, RSA, and FCA methods are highly similar to each other even after ruling out the effect of anatomical proximity between the network nodes. Nevertheless, the neural network from each method shows idiosyncratic structure that cannot be explained by any of the other methods. Thus, we conclude that the UNIVAR, RSA, and FCA methods provide similar but not identical information on how brain regions are organized in functional networks.
A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the ER. Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control at the ER.
Genetic and bioinformatic approaches to characterize ethanol teratogenesis

Fetal Alcohol Spectrum Disorders (FASD) describes the full range of defects that result from prenatal alcohol exposure. The clinical diagnosis of Fetal Alcohol Syndrome (FAS) is the most severe outcome, characterized by facial dysmorphism and neurological deficits. Gene-ethanol interactions underlie susceptibility to FASD but we lack a clear understanding of the genetic risk factors. Here, we leverage the genetic tractability of zebrafish to address this problem. We first show that vangl2, a member of the Wnt/planar cell polarity (Wnt/PCP) pathway that mediates convergent extension movements, strongly interacts with ethanol during late blastula and early gastrula stages. Embryos mutant or heterozygous for vangl2 are sensitized to ethanol-induced midfacial hypoplasia. However, we have no understanding of the potential mechanism of this sensitization. We performed single-embryo RNA-Seq during early embryonic stages, to assess individual variation to the transcriptional response to ethanol and determine the mechanism of the vangl2-ethanol interaction. Transcriptional changes due to ethanol are indicative of increased oxidative stress and ion transport as well as reduced DNA replication and cell division. To identify the pathway(s) that are disrupted by ethanol we used these global changes in gene expression to identify small molecules, often pathway inhibitors, that mimic the effects of ethanol via the Library of Integrated Network-based Cellular Signatures (LINCS L1000) dataset. This dataset predicted that the Sonic Hedgehog (Shh) pathway inhibitor, cyclopamine, would mimic the effects of ethanol, despite ethanol not altering the expression levels of direct targets of Shh signaling. Indeed, we found that ethanol and cyclopamine strongly interact to disrupt midfacial development. Collectively, these results suggest that the midfacial defects in ethanol-exposed vangl2 mutants are due to an indirect interaction between ethanol and the Shh pathway. Vangl2 functions as part of a signaling pathway that regulates coordinated cell movements during midfacial development. Consistent with an indirect model, a critical source of Shh signaling that separates the developing eye field into bilateral eyes, allowing the expansion of the midface, becomes mispositioned in ethanol-exposed vangl2 mutants.