Miracle-dz/UniFAR-FTUs huggingface dataset:
Asparagine hydroxylation is likely to be a reversible post-translational modification

Amino acid hydroxylation is a common post-translational modification, which generally regulates protein interactions or adds a functional group that can be further modified. Such hydroxylation is currently considered irreversible, necessitating the degradation and re-synthesis of the entire protein to reset the modification. Here we present evidence that the cellular machinery can reverse FIH-mediated asparagine hydroxylation on intact proteins. These data suggest that asparagine hydroxylation is a flexible and dynamic post-translational modification akin to modifications involved in regulating signalling networks, such as phosphorylation, methylation and ubiquitylation.
Wildlife health surveillance in Australia

It is now recognised that those countries which conduct disease surveillance of their wild animal populations are more likely to detect the presence of infectious and zoonotic diseases and to swiftly adopt counter measures. The surveillance and monitoring of disease outbreaks in wildlife populations is particularly relevant in these days of rapid human and animal translocation, when the contact between wild and domestic animals is close and the threat of bioterrorist attack is very real. A major advantage of an efficient disease monitoring program for wildlife is the early detection of new and emerging diseases, some of which may have serious zoonotic and economic implications. A clear understanding of disease agents present in wildlife, and their effects on wildlife, domestic animals and humans is thus of paramount importance for management.
TaqMan quantitative real-time PCR for detecting Avipoxvirus DNA in various sample types from hummingbirds

Background Avian pox is a viral disease documented in a wide range of bird species. Disease related detrimental effects can cause dyspnea and dysphagia, therefore birds with high metabolic requirements, such as hummingbirds, are especially vulnerable. Hummingbirds have a strong presence in California, especially in urban environments; however, little is understood regarding the impact of pox virus on hummingbird populations. Diagnosing pox infections relies on obtaining a tissue biopsy that poses significant bird risks and field challenges. Understanding the ecology of hummingbird pox viral infections could be advanced by a minimally invasive ante-mortem diagnostic method. This study’s goal was to address this gap in understanding if pox infections can be diagnosed using integumentary system samples besides tissue biopsies. To meet this goal, we tested multiple integumentary sample types and tested them using a quantitative real-time PCR assay. A secondary study goal was to determine which sample types (ranging from minimally to highly invasive sampling) were optimal for identifying infected birds. Methodology/Principal Findings Lesion tissue, pectoral muscle, feathers, toenail, blood, and swabs (both lesion tissue and non-lesion tissues) were taken from live birds and carcasses of two species of hummingbirds found in California. To maximize successful diagnosis, especially for samples with low viral load, a real-time quantitative PCR assay was developed for detecting the hummingbird-specific Avipoxvirus 4b core protein gene. Avipoxvirus DNA was successfully amplified from all sample types across 27 individuals. Our results were then compared to those of conventional PCR. Comparisons were also made between sample types utilizing lesion tissue samples as the gold standard. Conclusions/Significance Hummingbird avian pox can be diagnosed without relying on tissue biopsies. Feather samples can be used for diagnosing infected birds and reduces sampling risk. A real-time PCR assay detected viral DNA in various integumentary system sample types and could be used for studying hummingbird disease ecology in the future.
Cytotoxic Activity of CD4 T Cells During the Early Stage of Autoimmune Neuroinflammation

Pathogenic CD4+ T cells are capable of initiating neuroinflammation in experimental autoimmune encephalomyelitis (EAE). However, the precise effector mechanism of these autoaggressive CD4+ T cells is not entirely elucidated. Here, we demonstrated that pathogenic CD4+ T cells, upon autoantigen stimulation, developed a cytotoxic phenotype at the onset of EAE. The cytotoxic activity of pathogenic CD4+ T cells was sufficient to explain the initial myelin lesion. Consistently, CD4+ T cells of peripheral blood (PBMCs) and cerebrospinal fluid (CSF) from relapse-remitting multiple sclerosis (RRMS) patients present an enhancement of the cytotoxic profile in comparison with healthy control (HC). Moreover, cytotoxic CD4+ T cells (CD4-CTLs) are restrained in the PBMCs of Natalizumab-treated RRMS patients. Mechanistically, autoaggressive CD4-CTLs matched the majority of the molecular pathways of effector CD8+ T cells. Altogether, our findings point to potential new targets for monitoring MS diagnosis, treatment, and the development of novel therapeutic avenues.
Near-Infrared Light Increases Functional Connectivity with a Non-thermal Mechanism

Abstract Although techniques for noninvasive brain stimulation are under intense investigation, an approach that has received limited attention is transcranial photobiomodulation (tPBM), the delivery of near-infrared light to the brain with a laser or light-emitting diode directed at the scalp. Here we employed functional magnetic resonance imaging to measure the blood-oxygenation-level–dependent signal in n = 20 healthy human participants while concurrently stimulating their right frontal pole with a near-infrared laser. Functional connectivity with the illuminated region increased by up to 15% during stimulation, with a quarter of all connections experiencing a significant increase. The time course of connectivity exhibited a sharp rise approximately 1 min after illumination onset. Brain-wide connectivity increases were also observed, with connections involving the stimulated hemisphere showing a significantly larger increase than those in the contralateral hemisphere. We subsequently employed magnetic resonance thermometry to measure brain temperature during tPBM (separate cohort, n = 20) and found no significant temperature differences between active and sham stimulation. Our findings suggest that near-infrared light synchronizes brain activity with a nonthermal mechanism, underscoring the promise of tPBM as a new technique for stimulating brain function.
Stiffness of Nanoparticulate Mineralized Collagen Scaffolds Triggers Osteogenesis via Mechanotransduction and Canonical Wnt Signaling

The ability of the extracellular matrix (ECM) to instruct progenitor cell differentiation has generated excitement for the development of materials-based regenerative solutions. We previously described a nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) material capable of inducing in vivo skull regeneration approaching 60% of the biomechanical properties of native calvarium without exogenous growth factors or ex vivo progenitor cell-priming, suggesting promise as a first-generation material for skull regeneration. Here, we evaluated the contribution of titrating stiffness to osteogenicity by comparing non-crosslinked (NX-MC) and crosslinked (MC) forms of MC-GAG. While both materials were osteogenic, MC demonstrated an increased expression of osteogenic markers and mineralization compared to NX-MC. Both materials were capable of autogenously activating the canonical bone morphogenetic protein receptor (BMPR) signaling pathway with phosphorylation of Smad1/5 (small mothers against decapentaplegic-1/5). However, unlike NX-MC, hMSCs cultured on MC demonstrated significant elevations in the major mechanotransduction mediators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) expression coincident with β-catenin activation in the canonical Wnt signaling pathway. Inhibition of YAP/TAZ activation reduced osteogenic marker expression, mineralization, and β-catenin activation in MC with a much lesser of an effect on NX-MC. YAP/TAZ inhibition also resulted in a reciprocal increase in Smad1/5 phosphorylation as well as BMP2 expression. Our results indicate that increasing MC-GAG stiffness induces osteogenic differentiation via the mechanotransduction mediators YAP/TAZ and the canonical Wnt signaling pathway, whereas the canonical BMPR signaling pathway is activated in a manner independent of mechanical cues.
Rapid heuristic inference of antibiotic resistance and susceptibility by genomic neighbor typing

Surveillance of drug-resistant bacteria is essential for healthcare providers to deliver effective empiric antibiotic therapy. However, traditional molecular epidemiology does not typically occur on a timescale that could impact patient treatment and outcomes. Here we present a method called ‘genomic neighbor typing’ for inferring the phenotype of a bacterial sample by identifying its closest relatives in a database of genomes with metadata. We show that this technique can infer antibiotic susceptibility and resistance for both S. pneumoniae and N. gonorrhoeae. We implemented this with rapid k-mer matching, which, when used on Oxford Nanopore MinION data, can run in real time. This resulted in determination of resistance within ten minutes (sens/spec 91%/100% for S. pneumoniae and 81%/100% N. gonorrhoeae from isolates with a representative database) of sequencing starting, and for clinical metagenomic sputum samples (75%/100% for S. pneumoniae), within four hours of sample collection. This flexible approach has wide application to pathogen surveillance and may be used to greatly accelerate appropriate empirical antibiotic treatment.
Kinetochore protein Spindly controls microtubule polarity in Drosophila axons

Significance Neurons send and receive electrical signals through long microtubule-filled neurites called axons and dendrites. One of the main structural differences between axons and dendrites is how their microtubules are organized. Axons contain microtubules with their plus-ends out while microtubules in dendrites are organized with mixed or plus-end-in orientation. Dynein, the main minus-end microtubule motor anchored to cortical actin filaments in the axons, is responsible for uniform microtubule polarity in axons. However, it is unknown how dynein is recruited to the actin cortex in axons. The major finding of this work is that Spindly, a protein involved in anchoring dynein to kinetochores during cell division, has a second important function in interphase cells: recruiting dynein to the actin cortex in axons. Microtubule polarity in axons and dendrites defines the direction of intracellular transport in neurons. Axons contain arrays of uniformly polarized microtubules with plus-ends facing the tips of the processes (plus-end-out), while dendrites contain microtubules with a minus-end-out orientation. It has been shown that cytoplasmic dynein, targeted to cortical actin, removes minus-end-out microtubules from axons. Here we have identified Spindly, a protein known for recruitment of dynein to kinetochores in mitosis, as a key factor required for dynein-dependent microtubule sorting in axons of Drosophila neurons. Depletion of Spindly affects polarity of axonal microtubules in vivo and in primary neuronal cultures. In addition to these defects, depletion of Spindly in neurons causes major collapse of axonal patterning in the third-instar larval brain as well as severe coordination impairment in adult flies. These defects can be fully rescued by full-length Spindly, but not by variants with mutations in its dynein-binding site. Biochemical analysis demonstrated that Spindly binds F-actin, suggesting that Spindly serves as a link between dynein and cortical actin in axons. Therefore, Spindly plays a critical role during neurodevelopment by mediating dynein-driven sorting of axonal microtubules.
Coexpression uncovers a unified single-cell transcriptomic landscape

Researchers stand to gain insight into complex biological systems by assembling multiple single-cell RNA-sequencing (scRNA-seq) studies to reveal a panoramic view of overarching biological structure. Unfortunately, many existing scRNA-seq analyses are limited by sensitivity to study-specific noise patterns, by lack of scalability to large datasets, or by integrative transformations that obscure biological relevance. We therefore introduce a novel algorithmic framework that analyzes groups of cells in coexpression space across multiple resolutions, rather than individual cells in gene expression space, to enable multi-study analysis with enhanced biological interpretation. We show that our approach reveals the biological structure spanning multiple, large-scale studies even in the presence of batch effects while facilitating biological interpretation via network and latent factor analysis. Our coexpression-based analysis enables an unprecedented view into two complex and dynamic processes—neuronal development and hematopoiesis—by leveraging a total of seven studies containing 1,460,527 cells from laboratories spanning three continents, yielding systems-level insight unattainable by any individual experiment. Our work demonstrates a path toward probing highly complex biological systems from emerging consortium-scale single-cell transcriptomics.
Aerobic scope does matter in temperature-size rule, but only under optimal conditions

We united the theoretical predictions on the factors responsible for the occurrence and evolutionary significance of the temperature-size rule. We tested the causal connection among them assuming that (i) the temperature-size rule is the response to temperature-dependent oxygenic conditions, (ii) body size decrease is a consequence of cell shrinkage in response to exposure to hypoxia, (iii) this response enables to keep the wide scope for aerobic performance, and (iv) it prevents the decrease in fitness. We conducted our tests on three clones of the rotifer Lecane inermis with different thermal preferences. These clones were exposed to three experimental regimes: mild hypoxia, severe hypoxia driven by a too high temperature, and severe hypoxia driven by an inadequate oxygen concentration. The results showed that our causative reasoning was generally correct, but only under mildly hypoxic conditions. In more stressful environments, rotifers had clone- and condition-specific responses, which in fact were equally successful in terms of the levels of fitness. Our results join for the first time all factors connecting the cause and effect in the temperature-size rule. They indicate the importance of the conditions under which it should be tested. The most important messages from this study were that (i) a decrease in the body size was one of but not the only option for preventing fitness reduction under hypoxia, and (ii) such a response to higher temperature enabled the maintenance of wide aerobic scope in clone-specific, thermally optimal conditions.
Convergent evolution of the Hedgehog/Intein fold in protein splicing

The widely used molecular evolutionary clock assumes the divergent evolution of proteins. Convergent evolution has been proposed only for small protein elements but not for an entire protein fold. We investigated the structural basis of the protein splicing mechanism by class 3 inteins, which is distinct from class 1 and 2 inteins. We gathered structural and mechanistic evidence supporting the notion that the Hedgehog/INTein (HINT) superfamily fold, commonly found in protein splicing and related phenomena, could be an example of convergent evolution of an entire protein fold. We propose that the HINT fold is a structural and biochemical solution for trans-peptidyl and trans-esterification reactions.
Queen pheromone modulates the expression of epigenetic modifier genes in the brain of honeybee workers

Pheromones are used by many insects to mediate social interactions. In the highly eusocial honeybee (Apis mellifera) queen mandibular pheromone (QMP) is involved in the regulation of reproduction and behaviour of workers. The molecular mechanisms by which QMP acts are largely unknown. Here we investigate how genes responsible for epigenetic modifications to DNA, RNA and histones respond to the presence of QMP. We show that several of these genes are upregulated in the honeybee brain when workers are exposed to QMP. This provides a plausible mechanism by which pheromone signalling may influence gene expression in the brain of honeybee workers. We propose that pheromonal communication systems, such as those used by social insects, evolved to respond to environmental signals by making use of existing epigenomic machineries.
A high-resolution map of bacteriophage øX174 transcription

Bacteriophage øX174 is a model virus for studies across the fields of structural biology, genetics, gut microbiome, and synthetic biology, but did not have a high-resolution transcriptome until this work. In this study we used next-generation sequencing to measure the RNA produced from øX174 while infecting its host E. coli C. We broadly confirm the past transcriptome model while revealing several interesting deviations from previous knowledge. Additionally, we measure the strength of canonical øX174 promoters and terminators and discover both a putative new promoter that may be activated by heat shock sigma factors, as well as rediscover a controversial Rho-dependent terminator. We also provide evidence for the first antisense transcription observed in the Microviridae family, identify two promoters that may be involved in generating this transcriptional activity, and discuss possible reasons why this RNA may be produced.
Statistical properties of the optimal sensitivity matrix for compressed sensing with nonlinear sensors

There are numerous different odorant molecules in nature. Typical odors are sparse mixtures of a few types of odorant molecules each with a wide range of concentrations. However, there are only a relatively small number of olfactory receptor neurons (ORNs), which respond to odorant concentration nonlinearly (sigmoidal) with a finite sensitivity range. Thus, how to encode a large number of sparse odor mixtures with a relatively small number of nonlinear ORNs – the nonlinear compressed sensing problem – remains a puzzle. Here, by using an information theory approach, we study the optimal coding strategies that enable nonlinear ORNs to best represent olfactory information (both the odorants’ identities and their concentrations) in sparse odor mixtures. Our extensive numerical simulations and analytical analysis show that the optimal odor-receptor sensitivity matrix is sparse and the nonzero sensitivities follow roughly a log-normal distribution(matching the statistics of the odorants), both of which are consistent with existing experiments. For ORNs with a finite basal activity, our study shows that co-existence of both odor-evoked excitation and inhibition increases coding capacity, which provides a plausible explanation for such co-existence observed in the fly olfactory system. Furthermore, we show that coding the inputs with the optimal sensitivity matrix can enhance accuracy of the downstream decoding and learning tasks. These general statistical properties of the optimal sensitivity matrix for nonlinear compressed sensing may shed light on understanding the peripheral olfactory sensory system and improving performance of artificial neural networks.
Problem drinking among young people in Ireland

Alcohol is widely consumed in many societies. It is estimated to be responsible for 4% of the global disease burden, and is third only to tobacco and hypertension as a leading cause of death in high-income countries. Ireland has one of the highest levels of alcohol use per capita in the world. According to Barnardos (a children’s charity) there was a 48% increase in alcohol consumption per capita in Ireland between 1986 and 2006 (Barnardos, 2008). The Irish government endorsed the European Charter on Alcohol in 1995 but, in spite of this, the negative health consequences of alcohol consumption have increased (Mongan et al, 2002). About 28% of all injuries presenting to emergency departments in Ireland are alcohol related (Hope, 2008) and the number of hospital discharges related to alcohol increased by 92% between 1995 and 2002 (Mongan et al, 2002). Hope (2008) found that alcohol was implicated in 36.5% of road traffic fatalities in 2003 in Ireland, and was also a contributory factor in several cases of house fires and domestic abuse.
Neurons remap to represent memories in the human entorhinal cortex

The entorhinal cortex (EC) is known to play a key role in both memory and spatial navigation. Despite this overlap in spatial and mnemonic circuits, it is unknown how spatially responsive neurons contribute to our ability to represent and distinguish past experiences. Recording from medial temporal lobe (MTL) neurons in subjects performing cued recall of object–location memories in a virtual-reality environment, we identified “trace cells” in the EC that remap their spatial fields to locations subjects were cued to recall on each trial. In addition to shifting its firing field according to the memory cue, this neuronal activity exhibited a firing rate predictive of the cued memory’s content. Critically, this memory-specific neuronal activity re-emerged when subjects were cued for recall without entering the environment, indicating that trace-cell memory representations generalized beyond navigation. These findings suggest a general mechanism for memory retrieval via trace-cell activity and remapping in the EC.
Interspecific hybrids show a reduced adaptive potential under DNA damaging conditions

Hybridization may increase the probability of adaptation to extreme stresses. This advantage could be caused by an increased genome plasticity in hybrids, which could accelerate the search for adaptive mutations. High ultraviolet (UV) radiation is a particular challenge in terms of adaptation because it affects the viability of organisms by directly damaging DNA, while also challenging future generations by increasing mutation rate. Here we test if hybridization accelerates adaptive evolution in response to DNA damage, using yeast as a model. We exposed 180 populations of hybrids between species (Saccharomyces cerevisiae and Saccharomyces paradoxus) and their parental strains to UV mimetic and control conditions for approximately 100 generations. Although we found that adaptation occurs in both hybrids and parents, hybrids achieved a lower rate of adaptation, contrary to our expectations. Adaptation to DNA damage conditions comes with a large and similar cost for parents and hybrids, suggesting that this cost is not responsible for the lower adaptability of hybrids. We suggest that the lower adaptive potential of hybrids in this condition may result from the interaction between DNA damage and the inherent genetic instability of hybrids.