Miracle-dz/UniFAR-FTUs huggingface dataset:
K+ efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake

Glutamatergic transmission in the hippocampus prompts K+ efflux through postsynaptic N-methyl-D-aspartate receptors (NMDARs). This K+ efflux depolarizes local presynaptic terminals, boosting glutamate release, but whether it also depolarizes local astrocytic processes, thus affecting glutamate uptake, remains unknown. Here, we find that the pharmacological blockade, or conditional knockout, of NMDARs suppresses the progressive use-dependent increase in the amplitude and decay time of the astrocytic glutamate transporter current (IGluT), whereas blocking the astrocytic inward-rectifying K+ channels prevents the decay time increase only. Glutamate spot-uncaging reveals that local astrocyte depolarization, rather than extracellular K+ rises on their own, reduces the amplitude and prolong the decay of IGluT. Biophysical simulations of a realistic 3D astrocyte confirm that local transient elevations of extracellular K+ can inhibit local glutamate uptake in fine astrocytic processes. We conclude that K+ efflux through postsynaptic NMDARs can transiently depolarize local cell membranes, which facilitates presynaptic release while reducing local glutamate uptake. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K+ efflux to enhanced extrasynaptic glutamate signaling. Thus, the frequency of synaptic discharges can control the way the network handles its synaptic signal exchange. Significance statement A long-standing controversy in cellular neuroscience is the question of what controls well-documented extrasynaptic actions of glutamate, given that in baseline conditions, the high-affinity astrocytic transporters form a non-saturable protection shield around the synaptic cleft. The use-dependent mechanism that enables glutamate to pass this transporter shield during sustained activity remains unknown. Earlier, we suggested that activity-dependent K+ efflux through postsynaptic NMDA receptors was partially responsible for activity-dependent facilitation of glutamate release. Here, we provide evidence that this K+ efflux also depolarizes perisynaptic astrocytic leaflets, which reduces local glutamate uptake, thus enabling extrasynaptic glutamate spillover. Our mechanistic insights into the use-dependent suppression of glutamate transport are relevant to various pathologies involving disruption of extracellular K+ homeostasis, such as epilepsy or migraine.
Evaluation of the Abbott ARCHITECT HIV Ag/Ab combo assay for determining recent HIV-1 infection

Background Given the challenges and costs associated with implementing HIV-1 incidence assay testing, there is great interest in evaluating the use of commercial HIV diagnostic tests for determining recent HIV infection. A diagnostic test with the capability of providing reliable data for the determination of recent HIV infection without substantial modifications to the test protocol would have a significant impact on HIV surveillance. The Abbott ARCHITECT HIV Ag/Ab Combo Assay is an antigen/antibody immunoassay, which meets the criteria as the first screening test in the recommended HIV laboratory diagnostic algorithm for the United States. Methods In this study, we evaluated the performance characteristics of the ARCHITECT HIV Ag/Ab Combo signal-to-cutoff ratio (S/Co) for determining recent infection, including estimation of the mean duration of recent infection (MDRI) and false recent rate (FRR), and selection of recency cutoffs. Results The MDRI estimates for the S/Co recency cutoff of 400 is within the 4 to 12 months range recommended for HIV incidence assays, and the FRR rate for this cutoff was 1.5%. Additionally, ARCHITECT Combo S/Co values were compared relative to diagnostic test results from two prior prospective HIV-1 diagnostic studies in order to validate the use of the S/Co for both diagnostic and recency determination. Conclusion Dual-use of the ARCHITECT Combo assay data for diagnostic and incidence purposes would reduce the need for separate HIV incidence testing and allow for monitoring of recent infection for incidence estimation and other public health applications.
Expansion of Human Papillomavirus-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) β deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. Interferon-γ enzyme-linked immunospot assay identified significantly increased HPV-specific T cell response in the HPV 16 E6 91-115 region after 4 vaccinations (p=0.023). T cells with specificity to this region were sorted and analyzed using single-cell RNA-seq and TCR sequencing, HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR β bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells in the periphery and cervix.
WNT responsive SUMOylation of ZIC5 exerts multiple effects on transcription to promote murine neural crest cell development

Zinc finger of the cerebellum (Zic) proteins act as classical transcription factors to promote transcription of the Foxd3 gene during neural crest cell specification. Additionally, they can act as co-factors that bind TCF molecules to repress WNT/β-catenin dependent transcription without contacting DNA. Here, we show ZIC activity at the neural plate border is influenced by WNT-dependent SUMOylation. In a high WNT environment, a lysine within the highly conserved ZF-NC domain of ZIC5 is SUMOylated, which decreases formation of the TCF/ZIC co-repressor complex and shifts the balance towards transcription factor function. The modification is critical in vivo, as a ZIC5 SUMO-incompetent mouse strain exhibits neural crest specification defects. This work reveals the function of the ZIC ZF-NC domain, provides in vivo validation of target protein SUMOylation, and demonstrates that WNT/β-catenin signalling directs transcription at non-TCF DNA binding sites. Furthermore, it can explain how WNT signals convert a broad domain of Zic ectodermal expression into a restricted domain of neural crest cell specification.
Rude mechanicals in brain haemodynamics: non-neural actors that influence blood flow

Fluctuations in blood oxygenation and flow are widely used to infer brain activity during resting-state functional magnetic resonance imaging (fMRI). However, there are strong systemic and vascular contributions to resting-state signals that are unrelated to ongoing neural activity. Importantly, these non-neural contributions to haemodynamic signals (or ‘rude mechanicals’) can be as large as or larger than the neurally evoked components. Here, we review the two broad classes of drivers of these signals. One is systemic and is tied to fluctuations in external drivers such as heart rate and breathing, and the robust autoregulatory mechanisms that try to maintain a constant milieu in the brain. The other class comprises local, active fluctuations that appear to be intrinsic to vascular tissue and are likely similar to active local fluctuations seen in vasculature all over the body. In this review, we describe these non-neural fluctuations and some of the tools developed to correct for them when interpreting fMRI recordings. However, we also emphasize the links between these vascular fluctuations and brain physiology and point to ways in which fMRI measurements can be used to exploit such links to gain valuable information about neurovascular health and about internal brain states. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.
Non-invasive Ventilation in Children With Neuromuscular Disease

The respiratory muscles are rarely spared in children with neuromuscular diseases (NMD) which puts them at risk of alveolar hypoventilation. The role of non-invasive ventilation (NIV) is then to assist or “replace” the weakened respiratory muscles in order to correct alveolar hypoventilation by maintaining a sufficient tidal volume and minute ventilation. As breathing is physiologically less efficient during sleep, NIV will be initially used at night but, with the progression of respiratory muscle weakness, NIV can be extended during daytime, preferentially by means of a mouthpiece in order to allow speech and eating. Although children with NMD represent the largest group of children requiring long term NIV, there is a lack of validated criteria to start NIV. There is an agreement to start long term NIV in case of isolated nocturnal hypoventilation, before the appearance of daytime hypercapnia, and/or in case of acute respiratory failure requiring any type of ventilatory support. NIV is associated with a correction in night- and daytime gas exchange, an increase in sleep efficiency and an increase in survival. NIV and/or intermittent positive pressure breathing (IPPB) have been shown to prevent thoracic deformities and consequent thoracic and lung hypoplasia in young children with NMD. NIV should be performed with a life support ventilator appropriate for the child's weight, with adequate alarms, and an integrated (±additional) battery. Humidification is recommended to improve respiratory comfort and prevent drying of bronchial secretions. A nasal interface (or nasal canula) is the preferred interface, a nasobuccal interface can be used with caution in case of mouth breathing. The efficacy of NIV should be assessed on the correction of alveolar ventilation. Patient ventilator synchrony and the absence of leaks can be assessed on a sleep study with NIV or on the analysis of the ventilator's in-built software. The ventilator settings and the interface should be adapted to the child's growth and progression of respiratory muscle weakness. NIV should be associated with an efficient clearance of bronchial secretions by a specific program on the ventilator, IPPB, or mechanical insufflation-exsufflation. Finally, these children should be managed by an expert pediatric multi-disciplinary team.
Distinguishing Patients With Distant Metastatic Differentiated Thyroid Cancer Who Biochemically Benefit From Next Radioiodine Treatment

Background Repeated radioiodine (131I) treatment (RT) are commonly performed in patients with 131I-avid distant metastatic differentiated thyroid cancer (DM-DTC), but more precise indications remain indeterminate. This prospective study was conducted to explore predictors for biochemical response (BR) to next RT. Methods Totally thyroidectomized patients with 131I-avid DM-DTC demonstrated by initial post-therapeutic whole body scan (Rx-WBS) were consecutively recruited. Repeated RTs were performed at a fixed dose and a fixed interval, which was terminated once a decline in thyroid stimulating hormone-suppressed thyroglobulin (Tgon) could not be achieved or Rx-WBS was negative. BR was evaluated by change rate of Tgon level (ΔTgon%). Results After exclusion of 27 ineligible courses, a total of 166 neighboring course pairs from 77 patients were established and utilized. Univariate and multivariate analyses showed that the maximum target/background ratio (T/Bmax) on the whole body scan and ΔTgon% derived from the former RT were independently associated to the latter one. In predicting biochemical remission, the positive predictive value (PPV) and negative predictive value (NPV) of T/Bmax at the cut-off value of 8.1 were 79.1% and 84.0%, respectively; whereas the PPV and NPV of ΔTgon% at the cut-off value of 25.3% were 70.8% and 77.1%, respectively. Notably, the PPV of combined T/Bmax ≥ 8.1 and ΔTgon% ≥ 25.3% increased to 87.7%; while the NPV of T/Bmax ≥ 8.1 or ΔTgon% ≥ 25.3% reached as high as 97.7%. Conclusions This study revealed that combined use of the latest RT-derived T/Bmax and ΔTgon% may efficiently identify biochemical responders/non-responders to next RT, warranting management optimization of patients with 131I-avid DM-DTC.
A comparative advantage analysis of fishing sector and its impact on Iran’s economic development

The purpose of this study is to evaluate the value added of comparative advantage for fishing sector and its impact on economic development of the provinces in Iran in the period 2000-2014. At first the comparative advantage of any province of country was calculated. Then, the effects of fishing comparative advantage on economic development were studied using the generalized Solow model. The model study is based on empirical analysis such as panel unit root tests, panel co-integration test panel and it’s estimation of long-term relationships to help least-squares estimators modified (FMOLS). The results showed provinces of Hormozgan, Sistan and Baluchestan, Tehran, Guilan, Golestan and Mazandaran always had the comparative advantage during the study period. Also there was a cointegration long run relationship between variables that showed the value added of comparative advantage for fishing had a significant negative effect on economic development. So that for every unit increases in comparative advantage of this sector the economic development decreased 0.033 %. This could be due to more important role other economic sectors than fishing sector on the economic development of the provinces and the lack of expertise of comparative advantage in fishing sector. Finally suggestions were presented such as investment priority in the provinces where they have comparative advantage in the fishing sector and investigate the problems in the provinces that comparative advantage of them has decreased over time.
Hodgkin and Huxley Opsin Model for Computationally Efficient Optogenetic Neurostimulation in Cells and Networks

Optogenetics has a lot of potential to become an effective neuromodulative therapy for clinical application. Selecting the correct opsin is crucial to have an optimal optogenetic tool. With computational modeling, the neuronal response to the current dynamics of an opsin can be extensively and systematically tested. Unlike electrical stimulation where the effect is directly defined by the applied field, the stimulation in optogenetics is indirect, depending on the selected opsin’s non-linear kinetics. With the continuous expansion of opsin possibilities, computational studies are difficult due to the need for an accurate model of the selected opsin first. To this end, we propose a Hodgkin-and-Huxley based model (22HH) as alternative to the conventional three and four state Markov models used for opsin modeling. Furthermore, we provide a fitting procedure, which allows for nearly automatic model fitting starting from a vast parameter space. With this procedure, we successfully fitted two distinctive opsins ChR2(H134R) and MerMAID. Both models are able to represent the experimental data with great accuracy and were obtained within an acceptable time frame. This is due to the absence of differential equations in the fitting procedure, with an enormous reduction in computational cost as result. The performance of the proposed model with a fit to ChR2(H134R) was tested, by comparing the neural response in a regular spiking neuron to the response obtained with the non-instantaneous, four state Markov model (4SB), derived by Williams et al. (2013) [1]. Finally, a computational speed gain was observed with the 22HH model in a regular spiking and sparse Pyramidal-Interneuron-Network-Gamma (sPING) network simulation with respect to the 4SB-model, due to the former having two differential equations less. Consequently, the proposed model allows for computationally efficient optogenetic neurostimulation and with the proposed fitting procedure will be valuable for further research in the field of optogenetics.
RVAgene: generative modeling of gene expression time series data

Methods to model dynamic changes in gene expression at a genome-wide level are not currently sufficient for large (temporally rich or single-cell) datasets. Variational autoencoders offer means to characterize large datasets and have been used effectively to characterize features of single-cell datasets. Here we extend these methods for use with gene expression time series data. We present RVAgene: a recurrent variational autoencoder to model gene expression dynamics. RVAgene learns to accurately and efficiently reconstruct temporal gene profiles. It also learns a low dimensional representation of the data via a recurrent encoder network that can be used for biological feature discovery, and can generate new gene expression data by sampling from the latent space. We test RVAgene on simulated and real biological datasets, including embryonic stem cell differentiation and kidney injury response dynamics. In all cases, RVAgene accurately reconstructed complex gene expression temporal profiles. Via cross validation, we show that a low-error latent space representation can be learnt using only a fraction of the data. Through clustering and gene ontology term enrichment analysis on the latent space, we demonstrate the potential of RVAgene for unsupervised discovery. In particular, RVAgene identifies new programs of shared gene regulation of Lox family genes in response to kidney injury.
Allosteric Hotspots in the Main Protease of SARS-CoV-2

Inhibiting the main protease of SARS-CoV-2 is of great interest in tackling the COVID-19 pandemic caused by the virus. Most efforts have been centred on inhibiting the binding site of the enzyme. However, considering allosteric sites, distant from the active or orthosteric site, broadens the search space for drug candidates and confers the advantages of allosteric drug targeting. Here, we report the allosteric communication pathways in the main protease dimer by using two novel fully atomistic graph theoretical methods: Bond-to-bond propensity analysis, which has been previously successful in identifying allosteric sites without a priori knowledge in benchmark data sets, and, Markov transient analysis, which has previously aided in finding novel drug targets in catalytic protein families. We further score the highest ranking sites against random sites in similar distances through statistical bootstrapping and identify four statistically significant putative allosteric sites as good candidates for alternative drug targeting.
Maize centromeric chromatin scales with changes in genome size

Centromeres are defined by the location of Centromeric Histone H3 (CENP-A/CENH3) which interacts with DNA to define the locations and sizes of functional centromeres. An analysis of 26 maize genomes including 110 fully assembled centromeric regions revealed positive relationships between centromere size and genome size. These effects are independent of variation in the amounts of the major centromeric satellite sequence CentC. We also backcrossed known centromeres into two different lines with larger genomes and observed consistent increases in functional centromere sizes for multiple centromeres. Although changes in centromere size involve changes in bound CENH3, we could not mimic the effect by overexpressing CENH3 by threefold. Literature from other fields demonstrate that changes in genome size affect protein levels, organelle size and cell size. Our data demonstrate that centromere size is among these scalable features, and that multiple limiting factors together contribute to a stable centromere size equilibrium.
Resuscitation of soil microbiota after > 70-years of desiccation

The abundance and diversity of bacteria in 24 historical soil samples under air-dried storage conditions for more than 70 years were assessed by quantification and high-throughput sequencing analysis of 16S rRNA genes. All soils contained a measurable abundance of bacteria varying from 103 to 108 per gram of soil and contrasting community compositions were observed in different background soils, suggesting that the bacteria detected were indigenous to the soil. Following a 4-week soil rewetting event, the bacterial abundance significantly increased in soils, indicating strong adaptation of soil bacteria to extreme osmotic change and high resuscitation potential of some bacteria over long periods of desiccation. Paenibacillus, Cohnella and two unclassified Bacillales genera within the phylum Firmicutes represented the most ubiquitously active taxa, which showed growth in the highest number of soils (≥12 soils), while genera Tumebacillus, Alicyclobacillus and Brevibacillus in the phylum Firmicutes displayed the highest growth rates in soils (with >1000-fold average increase) following rewetting. Additionally, some Actinobacteria and Proteobacteria genera showed relatively high activity following rewetting, suggesting that the resilience to long-term desiccation and rewetting is a common trait across phylogenetically divergent microbes. The present study thus demonstrated that diversified groups of microbes are present and potentially active in historically desiccated soils, which might be of importance in the context of microbial ecology.
Quantifying the contribution of dominance effects to complex trait variation in biobank-scale data

The proportion of variation in complex traits that can be attributed to non-additive genetic effects has been a topic of intense debate. The availability of Biobank-scale datasets of genotype and trait data from unrelated individuals opens up the possibility of obtaining precise estimates of the contribution of non-additive genetic effects. We present an efficient method that can partition the variation in complex traits into variance that can be attributed to additive (additive heritability) and dominance (dominance heritability) effects across all genotyped SNPs in a large collection of unrelated individuals. Over a wide range of genetic architectures, our method yields unbiased estimates of heritability. We applied our method, in turn, to array genotypes as well as imputed genotypes (at common SNPs with minor allele frequency, MAF > 1%) and 50 quantitative traits measured in 291, 273 unrelated white British individuals in the UK Biobank. Averaged across these 50 traits, we find that additive heritability on array SNPs is 21.86% while dominance heritability is 0.13% (about 0.48% of the additive heritability) with qualitatively similar results for imputed genotypes. We find no evidence for dominance heritability ( accounting for the number of traits tested) and estimate that dominance heritability is unlikely to exceed 1% for the traits analyzed. Our analyses indicate a limited contribution of dominance heritability to complex trait variation.