Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficient parameter calibration and real-time simulation of large-scale spiking neural networks with GeNN and NEST

Spiking neural networks (SNN) represent the state-of-the-art approach to the biologically realistic modeling of nervous system function. The systematic calibration for multiple free model parameters is necessary to achieve robust network function and demands high computing power and large memory resources. Special requirements arise from closed-loop model simulation in virtual environments, and from real-time simulation in robotic application. Here, we compare two complementary approaches to efficient large scale and realtime SNN simulation. The widely used NEural Simulation Tool (NEST) parallelizes simulation across multiple CPU cores. The GPU-enhanced Neural Network (GeNN) simulator uses the highly parallel GPU-based architecture to gain simulation speed. We quantify fixed and variable simulation costs on single machines with different hardware configurations. As benchmark model we use a spiking cortical attractor network with a topology of densely connected excitatory and inhibitory neuron clusters with homogeneous or distributed synaptic time constants and in comparison to the random balanced network. We show that simulation time scales linearly with the simulated biological model time and, for large networks, approximately linearly with the model size as dominated by the number of synaptic connections. Additional fixed costs with GeNN are almost independent of model size, while fixed costs with NEST increase linearly with model size. We demonstrate how GeNN can be used for simulating networks with up to 3.5 · 106 neurons (> 3 · 1012 synapses) on a high-end GPU, and up to 250, 000 neurons (25 ·109 synapses) on a low-cost GPU. Real-time simulation was achieved for networks with 100, 000 neurons. Network calibration and parameter grid search can be efficiently achieved using batch processing. We discuss the advantages and disadvantages of both approaches for different use cases.
Pytri: A multi-weight detection system for biological entities

The enumeration of biological entities is a critical part of experimental assays and usually requires large lengths of time. The standard method is to count the entities by hand or with OpenCV-based software, which can lead to inaccurate results. Here, we propose an online platform for biologists consisting of a system with multiple trained machine learning weights to detect various biological entities such as yeast colonies, bacterial colonies, and melanoma clusters. The Pytri model achieved a median relative error rate of 7.56% for bacterial and yeast colonies on Petri dishes, 6.58% for colonies on 96-well plates and 10.28% for melanoma cluster microscopy images. We showcase the application of state-of-the-art deep learning tools in bacterial entity detection, achieving significantly higher accuracy than traditional methods when compared to our base standard manual count.
Contrasting reproductive strategies despite convergent traits for two dryland river-floodplain species

Aquatic plants share a range of convergent reproductive strategies, such as the ability to reproduce both sexually and asexually through vegetative growth. In dryland river systems, floodplain inundation is infrequent and irregular, and wetlands consist of discrete and unstable habitat patches. In these systems life-history strategies such as long-distance dispersal, seed longevity, self-fertilisation, and reproduction from vegetative propagules are important strategies which allow plants to persist. Using two aquatic plants Marsilea drummondii and Eleocharis acuta, we investigated the proportions of sexual and asexual reproduction and self-fertilisation employing next generation sequencing approaches and used this information to understand population genetic structure in a large inland floodplain, in western New South Wales (NSW) Australia. Asexual vegetative reproduction and self-fertilisation was more common in M. drummondii, but both species used sexual reproduction as the main mode of reproduction. This resulted in highly differentiated genetic structure between wetlands and similar genetic structure within wetlands. The similarity in genetic structure was influenced by the wetland in the two species highlighting the influence of the floodplain landscape and hydrology in structuring population genetic structure. The high levels of genetic variation among wetlands and low variation within wetlands suggests that dispersal and pollination occur within close proximity and that gene flow is restricted. This suggests a reliance on locally sourced (persistent) seed, rather than asexual (clonal) reproduction or recolonisation via dispersal, for population maintenance in plants in dryland rivers. This highlights the importance of floodplain inundation to promote seed germination, establishment and reproduction in dryland regions.
Ena/VASP clustering at microspike tips involves lamellipodin but not I-BAR proteins, and absolutely requires unconventional myosin-X

Sheet-like membrane protrusions at the leading edge, termed lamellipodia, drive 2D-cell migration using active actin polymerization. Microspikes comprise actin-filament bundles embedded within lamellipodia, but the molecular mechanisms driving their formation and their potential functional relevance have remained elusive. Microspike formation requires the specific activity of clustered Ena/VASP proteins at their tips to enable processive actin assembly in the presence of capping protein, but the factors and mechanisms mediating Ena/VASP clustering are poorly understood. Systematic analyses of B16-F1 melanoma mutants lacking potential candidate proteins revealed that neither inverse BAR-domain proteins, nor lamellipodin or Abi are essential for clustering, although they differentially contribute to lamellipodial VASP accumulation. In contrast, unconventional myosin-X (MyoX) identified here as proximal to VASP was obligatory for Ena/VASP clustering and microspike formation. Interestingly, and despite the invariable distribution of other relevant marker proteins, the width of lamellipodia in MyoX-KO mutants was significantly reduced as compared to B16-F1 control, suggesting that microspikes contribute to lamellipodium stability. Consistently, MyoX removal caused marked defects in protrusion and random 2D-cell migration. Strikingly, Ena/VASP-deficiency also uncoupled MyoX cluster dynamics from actin assembly in lamellipodia, establishing their tight functional association in microspike formation. Significance Statement Unlike filopodia that protrude well beyond the cell periphery and are implicated in sensing, morphogenesis and cell-to-cell communication, the function of microspikes consisting of actin-filament bundles fully embedded within lamellipodia is less clear. Microspike formation involves specific clustering of Ena/VASP family members at filament-barbed ends to enable processive actin polymerization in the presence of capping protein, but the factors and mechanisms mediating Ena/VASP clustering have remained unknown. Here, we systematically analyzed these processes in genetic knockout mutants derived from B16-F1 cells and show that Ena/VASP clustering at microspike tips involves Lamellipodin, but not inverse BAR-domain proteins, and strictly requires unconventional Myosin-X. Complete loss of microspikes was confirmed with CRISPR/Cas9-mediated MyoX knockout in Rat2 fibroblasts, excluding cell type-specific effects.
The homodimeric structure of the LARGE1 dual glycosyltransferase

LARGE1 is a bifunctional glycosyltransferase responsible for generating a long linear polysaccharide termed matriglycan that links the cytoskeleton and the extracellular matrix and is required for proper muscle function. This matriglycan polymer is made with an alternating pattern of xylose and glucuronic acid monomers. Mutations in the LARGE1 gene have been shown to cause life-threatening dystroglycanopathies through the inhibition of matriglycan synthesis. Despite its major role in muscle maintenance, the structure of the LARGE1 enzyme and how it assembles in the Golgi are unknown. Here we present the structure of LARGE1, obtained by a combination of X-ray crystallography and single-particle cryo-EM. We found that LARGE1 homo-dimerizes in a configuration that is dictated by its coiled-coil stem domain. The structure shows that this enzyme has two canonical GT-A folds with each of its catalytic domains. In the context of its dimeric structure, the two types of catalytic domains are brought into close proximity from opposing monomers to allow efficient shuttling of the substrate between the two domains. Together with putative retention of matriglycan by electrostatic interactions, this dimeric organization offers a possible mechanism for the high processivity of LARGE1. The structural information further reveals the mechanisms in which disease-causing mutations disrupt the activity of LARGE1. Collectively, these data shed light on how matriglycan is synthesized alongside the functional significance of glycosyltransferase oligomerization.
Biophysical and functional characterization of K+-Cl- co-transporters from Drosophila melanogaster and Hydra vulgaris

The cation-chloride co-transporter (CCC) superfamily includes ion symporters, which co-transport monovalent cations and Cl-. CCCs have crucial roles in shaping signalling and neuronal connectivity in the vertebrate brain. K+-Cl- co-transporters (KCCs) are a subfamily of CCCs and carry out the symport of K+ and Cl− ions across the plasma membrane. The KCC proteins are involved in various physiological processes, such as cell volume regulation, transepithelial ion transport, synapse formation and signal transmission, and blood pressure regulation. Among KCCs, KCC2 has gained attention because of its unique and crucial functions in the central nervous system neuronal network. Loss of activity of this transporter has been associated with several neurological disorders including schizophrenia, epilepsy, and chronic pain. On the other hand, only a limited number of studies of KCCs have been published for invertebrates. Among invertebrate proteins, the Drosophila melanogaster KCC (DmKCC) has been studied most and suggested critical for neuronal transmission. Also Cnidarian Hydra vulgaris has been shown to have a functional KCC (HvKCC). Comparative analyses of these transporters with vertebrate ones and understanding functional and biophysical aspects of them as a model system can help understand the KCC mechanism of ion transport and its regulation and evolution broadly. In this study, we chose DmKCC and HvKCC as model systems and purified DmKCC and HvKCC from Sf9 insect cells and characterized their biophysical properties with differential scanning fluorimetry and light scattering techniques. We tested their functionality using a fluorescence assay and developed a method to measure recombinant KCC ion transport activity with flame photometry.
Predictive Models of Genome-wide Aryl Hydrocarbon Receptor DNA Binding Reveal Tissue Specific Binding Determinants

Background The Aryl Hydrocarbon Receptor (AhR) is an inducible transcription factor (TF) whose ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-mediated toxicity occurs through activation of AhR and its subsequent binding to the Dioxin Response Element (DRE), comprising the DNA motif 5’-GCGTG-3’. However, AhR binding in human tissues is highly dynamic and tissue specific. Approximately 50% of all experimentally verified AhR binding sites do not contain a DRE. Additionally, most accessible DREs are not bound by AhR. Identification of tissue specific AhR binding determinants is crucial for understanding downstream gene regulation and potential adverse outcomes of AhR activation. Results We applied XGBoost, a supervised machine learning architecture, to predict the genome wide AhR binding status of DREs in open chromatin as a function of DNA sequence flanking the DRE, chromatin accessibility, histone modifications (HM), TF binding, and proximity of the DRE to gene promoters. We trained and validated our models using 5-fold cross validation to predict the binding status of DREs in AhR-activated MCF-7 breast cancer cells, primary human hepatocytes, and lymphoblastoid GM17212 cells, as well as AhR non-activated HepG2 hepatocellular carcinoma cells. Our results demonstrate highly accurate and robust models of AhR binding; and identify patterns of transcription factor binding and histone modifications predictive of AhR binding. These patterns are consistent within tissues but highly variable across tissues, which is suggestive of tissue-specific mechanisms of AhR binding. Conclusions AhR binding is driven by a complex interplay of tissue-agnostic DNA sequence flanking its binding motif and tissue-specific local chromatin context.
Strategic exploration in the macaque’s prefrontal cortex

Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scare resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether that information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback, about the option not chosen. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.
Tracking single cell evolution via clock-like 1 chromatin accessibility

Single cell chromatin accessibility sequencing (scATAC) reconstructs developmental 23 trajectory by phenotypic similarity. However, inferring the exact developmental trajectory is challenging. Here we show a simple, accurate and phenotypic-neutral 25 measure of cell developmental hierarchy – the fraction of accessible clock-like 26 differential methylation loci (ClockDML). As cell undergone mitosis, heterogeneity 27 of chromatin accessibility on ClockDML reduced, providing a measure of mitotic age. 28 We developed a method, EpiTrace , that counts the fraction of opened ClockDML 29 from scATAC data to determine cell age and perform lineage tracing. EpiTrace 30 derived cell age shows concordance to known developmental hierarchies, correlates 31 well with DNA methylation-based clocks, and is complementary with mutation-based 32 lineage tracing, RNA velocity, and stemness predictions. Applying EpiTrace to 33 human scATAC data revealed a multitude of novel biological insights with clinically 34 relevant implications, ranging from hematopoiesis, organ development, tumor biology 35 and immunity to cortical gyrification. Our work discovered a universal epigenomic 36 hallmark during cellular development, which facilitates the study of cellular 37 hierarchies and organismal aging. To develop a mitotic age estimator for scATAC data, we determined ClockDML across human genome and characterized the chromatin accessibility changes on these loci associated with cell mitotic age. The heterogeneity of chromatin accessibility on these loci reduced across cell division. We leveraged this phenomenon to develop a computational framework, EpiTrace, which infers cell mitotic age from scATAC data by counting the opened fraction of ClockDML in single cells. cells their evolution (TRCC) specifically activated in progenitor cell and shows age-dependent decrease of activity. In contrast, all hereditary renal dysgenesis (CAKUT) genes FGF8, FGFR2, SLIT3, GDNF and NHS are associated with differentiated cell-specific, age-dependent increased peaks. These results suggest that CAKUT is linked to genes functioning in terminal proximal tubule cell fate determination and function, whilst TRCC oncogenesis is linked to the mis-expression of progenitor-specific transcription factor, possibly forcing de-differentiation of terminally differentiated proximal tubule cells into a stem-like state.
Increased structural connectivity in high schizotypy

The link between brain structural connectivity and schizotypy was explored in two healthy-participant cohorts, collected at two different neuroimaging centres, comprising 140 and 115 participants respectively. The participants completed the Schizotypal Personality Questionnaire (SPQ), through which their schizotypy scores were calculated. Diffusion-MRI data were used to perform tractography and to generate the structural brain networks of the participants. The edges of the networks were weighted with the inverse radial diffusivity. Graph theoretical metrics of the default-mode, sensorimotor, visual and auditory subnetworks were derived and their correlation coefficients with the schizotypy scores were calculated. To the best of our knowledge, this is the first time that graph theoretical measures of structural brain networks are investigated in relation to schizotypy. A positive correlation was found between the schizotypy score and the mean node degree and mean clustering coefficient of the sensorimotor and the default-mode subnetworks. The nodes driving these correlations were the right postcentral gyrus, the left paracentral lobule, the right superior frontal gyrus, the left parahippocampal gyrus and the bilateral precuneus, i.e., nodes that exhibit compromised functional connectivity in schizophrenia.
Agency as a Bridge to Form Associative Memories

The perception of agency occurs when individuals feel their decisions exert control over their environment. While agency can increase memory for items, most real-life situations are more complex. The decisions we make not only affect the item we act upon, but all the other items in direct proximity of our decisions. Here, we examined how an individual’s agency to influence a situation affects their ability to learn associations between items that occur prior to and after making a decision. In our paradigm, participants were told they were playing a game show where they had to help a trial unique ‘contestant’ choose between three doors. On ‘agency’ trials, participants were allowed to pick any door they wanted. On ‘forced-choice’ trials, participants were instructed to select a door that was highlighted. They then saw the outcome, a ‘prize’ that was behind the selected door. Across two studies, participants show enhanced memory for contestants they saw in agency vs forced-choice trials. Memory benefits also extended to contestant - door and door - prize associations in both studies. Study 2 found this effect in the contestant - prize association. Notably, we found that agency also shaped the representation of memories such that they were stored as integrated sequences rather than individual relational pairs. Together, these data suggest agency over a situation leads to enhanced memory for all items in that situation. This enhanced binding for items may be occurring by the formation of causal links when an individual has agency over their learning environment.
The 5-LOX/COX-2 cross-over metabolite, hemiketal E2, enhances VEGFR2 activation and promotes angiogenesis

Consecutive oxygenation of arachidonic acid by 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) yields the hemiketal (HK) eicosanoids, HKE2 and HKD2. HKs stimulate angiogenesis by inducing endothelial cell tubulogenesis in culture; however, how this process is regulated has not been determined. Here, we identify vascular endothelial growth factor receptor 2 (VEGFR2) as a mediator of HKE2-induced angiogenesis in vitro and in vivo. HKE2 treatment of human umbilical vein endothelial cells dose-dependently increased phosphorylation of VEGFR2 and the downstream kinases ERK and Akt that mediated endothelial cell tubulogenesis. In vivo, HKE2 induced the growth of blood vessels into polyacetal sponges implanted in mice. HKE2-mediated effects in vitro and in vivo were blocked by the VEGFR2 inhibitor vatalanib, indicating that the pro-angiogenic effect of HKE2 was mediated by VEGFR2. We found that HKE2 covalently bound and inhibited PTP1B, a protein tyrosine phosphatase that dephosphorylates VEGFR2, thereby providing a possible molecular mechanism for how HKE2 induced pro-angiogenic signaling. Our studies indicate that biosynthetic cross-over of the 5-LOX and COX-2 pathways gives rise to a potent lipid autacoid that regulates endothelial cell function in vitro and in vivo. Significance Angiogenesis, the growth of new blood vessels from existing vessels, contributes to both physiological and pathological conditions, including tissue repair after injury and tumorigenesis. Novel approaches to control pathologic angiogenesis are urgently needed since current therapy targeting the pro-angiogenic receptor VEGFR2 has significant side effects. We show that a metabolite of arachidonic acid, formed in a biosynthetic cross-over of the enzymes that generate the pro-inflammatory leukotriene and prostaglandin mediators, respectively, promotes VEGFR2 activation to induce angiogenesis. This finding suggests that common drugs targeting the arachidonic acid pathway may be viewed as valid anti-angiogenic candidates.
Transcriptome analysis in the silkworm Bombyx mori overexpressing piRNA-resistant Masculinizer gene

Dosage compensation is a process that produces a similar expression of sex-linked and autosomal genes. In the silkworm Bombyx mori with a WZ sex-determination system, the expression from the single Z in WZ females matches that of ZZ males due to the suppression of Z-linked genes in males. A primary maleness determinant gene, Masculinizer (Masc), is also required for dosage compensation. In females, P-element induced wimpy testis (PIWI) is complexed with the W chromosome-derived female-specific Feminizer (Fem) PIWI-interacting RNA (piRNA) and cleaves Masc mRNA. When Fem piRNA-resistant Masc cDNA (Masc-R) is overexpressed in both sexes, only female larvae are dead during the larval stage. In this study, transcriptome analysis was performed in neonate larvae to examine the effects of Masc-R overexpression on a global gene expression profile. Z-linked genes were globally repressed in Masc-R-overexpressing females due to force-driven dosage compensation. In contrast, Masc-R overexpression had little effect on the expression of Z-linked genes and the male-specific isoform of B. mori insulin-like growth factor II mRNA-binding protein in males, indicating that excessive Masc expression strengthens neither dosage compensation nor maleness in males. Fourteen genes were differentially expressed between Masc-R-overexpressing and control neonate larvae in both sexes, suggesting Masc functions other than dosage compensation and masculinization. Highlights Transcriptome analysis was performed in Masc-R-overexpressing neonate Bombyx mori larvae. Z-linked genes were globally suppressed in Masc-R-overexpressing females. Masc-R overexpression had little effect on BmImpM expression in males. Several genes may be controlled by Masc-R regardless of sex.