Miracle-dz/UniFAR-FTUs huggingface dataset:
Concurrent Meta Reinforcement Learning

State-of-the-art meta reinforcement learning algorithms typically assume the setting of a single agent interacting with its environment in a sequential manner. A negative side-effect of this sequential execution paradigm is that, as the environment becomes more and more challenging, and thus requiring more interaction episodes for the meta-learner, it needs the agent to reason over longer and longer time-scales. To combat the difficulty of long time-scale credit assignment, we propose an alternative parallel framework, which we name "Concurrent Meta-Reinforcement Learning" (CMRL), that transforms the temporal credit assignment problem into a multi-agent reinforcement learning one. In this multi-agent setting, a set of parallel agents are executed in the same environment and each of these "rollout" agents are given the means to communicate with each other. The goal of the communication is to coordinate, in a collaborative manner, the most efficient exploration of the shared task the agents are currently assigned. This coordination therefore represents the meta-learning aspect of the framework, as each agent can be assigned or assign itself a particular section of the current task's state space. This framework is in contrast to standard RL methods that assume that each parallel rollout occurs independently, which can potentially waste computation if many of the rollouts end up sampling the same part of the state space. Furthermore, the parallel setting enables us to define several reward sharing functions and auxiliary losses that are non-trivial to apply in the sequential setting. We demonstrate the effectiveness of our proposed CMRL at improving over sequential methods in a variety of challenging tasks.
The heme-regulatory motif of nuclear receptor Rev-erbβ is a key mediator of heme and redox signaling in circadian rhythm maintenance and metabolism

Rev-erbβ is a heme-responsive transcription factor that regulates genes involved in circadian rhythm maintenance and metabolism, effectively bridging these critical cellular processes. Heme binding to Rev-erbβ indirectly facilitates its interaction with the nuclear receptor co-repressor (NCoR1), resulting in repression of Rev-erbβ target genes. Fe3+-heme binds in a 6-coordinate complex with axial His and Cys ligands, the latter provided by a heme-regulatory motif (HRM). Rev-erbβ was thought to be a heme sensor based on a weak Kd value for the Rev-erbβ·heme complex of 2 μm determined with isothermal titration calorimetry. However, our group demonstrated with UV-visible difference titrations that the Kd value is in the low nanomolar range, and the Fe3+-heme off-rate is on the order of 10−6 s−1 making Rev-erbβ ineffective as a sensor of Fe3+-heme. In this study, we dissected the kinetics of heme binding to Rev-erbβ and provided a Kd for Fe3+-heme of ∼0.1 nm. Loss of the HRM axial thiolate via redox processes, including oxidation to a disulfide with a neighboring cysteine or dissociation upon reduction of Fe3+- to Fe2+-heme, decreased binding affinity by >20-fold. Furthermore, as measured in a co-immunoprecipitation assay, substitution of the His or Cys heme ligands in Rev-erbβ was accompanied by a significant loss of NCoR1 binding. These results demonstrate the importance of the Rev-erbβ HRM in regulating interactions with heme and NCoR1 and advance our understanding of how signaling through HRMs affects the major cellular processes of circadian rhythm maintenance and metabolism.
Enhanced DNA binding capacity on up‐regulated epidermal wild‐type p53 in vitiligo by H2O2‐mediated oxidation: a possible repair mechanism for DNA damage

Vitiligo is characterized by a patchy loss of inherited skin color affecting ̃0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H2O2)‐induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun‐induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8‐oxoguanine in the skin and plasma in association with epidermal up‐regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76MDM2. Shortpatch base‐excision repair via hOggl, APE1, and polymeraseβ DNA repair is up‐regulated. Overexpression of Bcl‐2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO−) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO− (300×10−6 M) abrogates DNA binding, while H2O2‐oxidized p53 (10−3 M) enhances DNA binding capacity and prevents ONOO−induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we pro! pose up‐regulated wild‐type p53 together with p76MDM2 as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo. —Salem, M. M. A. E. L. , Shalbaf, M. , Gibbons, N. C. J., Chavan, B. , Thornton, J. M. , Schallreuter, K. U. Enhanced DNA binding capacity on up‐regulated epidermal wild‐type p53 in vitiligo by H! O! ‐mediated oxidation: a possible repair mechanism for DNA damage. FASEB J. 23, 3790–3807 (2009). www.fasebj. org
Isoform- and cell type-specific structure of apolipoprotein E lipoparticles as revealed by a novel Forster resonance energy transfer assay

Apolipoprotein E (apoE) has an important role in the pathogenesis of Alzheimer's disease with its three isoforms having distinct effects on disease risk. Here, we assessed the conformational differences between those isoforms using a novel flow cytometry-Forster resonance energy transfer (FRET) assay. We showed that the conformation of intracellular apoE within HEK cells and astrocytes adopts a directional pattern; in other words, E4 adopts the most closed conformation, E2 adopts the most open conformation, and E3 adopts an intermediate conformation. However, this pattern was not maintained upon secretion of apoE from astrocytes. Intermolecular interactions between apoE molecules were isoform-specific, indicating a great diversity in the structure of apoE lipoparticles. Finally, we showed that secreted E4 is the most lipidated isoform in astrocytes, suggesting that increased lipidation acts as a folding chaperone enabling E4 to adopt a closed conformation. In conclusion, this study gives insights into apoE biology and establishes a robust screening system to monitor apoE conformation.
How far is too close? restricted, sex‐biased dispersal in black‐capped vireos

Understanding the interplay of dispersal and how it translates into gene flow is key to understanding population processes, and especially so for endangered species occupying fragmented habitats. In migratory songbirds, there is evidence that long‐distance movement capabilities do not translate well into observed dispersal. Our objectives were to (i) define the fine‐scale spatial genetic structure in endangered black‐capped vireos to characterize dispersal patterns and (ii) to correlate dispersal dynamics to overall population genetic structure using a simulation approach. We sampled 160 individuals over 2 years to (i) describe the fine‐scale genetic structuring and (ii) used this information to model scenarios to compare with actual data on change in population structuring over a 100‐year interval. We found that black‐capped vireos exhibit male philopatry and restricted dispersal distances, relative to females. Our simulations also support a sex‐biased dispersal model. Additionally, we find that fragmentation related changes in rates of dispersal might be a likely cause for increasing levels of population structure over a 100‐year period. We show that restricted sex‐biased dispersal can explain population structuring in this species and that changes in dispersal rates due to fragmentation may be a continuing threat to genetic viability in this species.
Colouring Non-Even Digraphs

A colouring of a digraph as defined by Neumann-Lara in 1982 is a vertex-colouring such that no monochromatic directed cycles exist. The minimal number of colours required for such a colouring of a loopless digraph is defined to be its dichromatic number. This quantity has been widely studied in the last decades and can be considered as a natural directed analogue of the chromatic number of a graph. A digraph $D$ is called even if for every $0$-$1$-weighting of the edges it contains a directed cycle of even total weight. We show that every non-even digraph has dichromatic number at most $2$ and an optimal colouring can be found in polynomial time. We strengthen a previously known NP-hardness result by showing that deciding whether a directed graph is $2$-colourable remains NP-hard even if it contains a feedback vertex set of bounded size.
Graphical Contrastive Losses for Scene Graph Generation

Most scene graph generators use a two-stage pipeline to detect visual relationships: the first stage detects entities, and the second predicts the predicate for each entity pair using a softmax distribution. We find that such pipelines, trained with only a cross entropy loss over predicate classes, suffer from two common errors. The first, Entity Instance Confusion, occurs when the model confuses multiple instances of the same type of entity (e.g. multiple cups). The second, Proximal Relationship Ambiguity, arises when multiple subject-predicate-object triplets appear in close proximity with the same predicate, and the model struggles to infer the correct subject-object pairings (e.g. mis-pairing musicians and their instruments). We propose a set of contrastive loss formulations that specifically target these types of errors within the scene graph generation problem, collectively termed the Graphical Contrastive Losses. These losses explicitly force the model to disambiguate related and unrelated instances through margin constraints specific to each type of confusion. We further construct a relationship detector, called RelDN, using the aforementioned pipeline to demonstrate the efficacy of our proposed losses. Our model outperforms the winning method of the OpenImages Relationship Detection Challenge by 4.7\% (16.5\% relative) on the test set. We also show improved results over the best previous methods on the Visual Genome and Visual Relationship Detection datasets.
Elevated CO2 selectively inhibits interleukin‐6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage

Elevated blood and tissue CO2, or hypercapnia, is common in severe lung disease. Patients with hypercapnia often develop lung infections and have an increased risk of death following pneumonia. To explore whether hypercapnia interferes with host defense, we studied the effects of elevated PCO2 on macrophage innate immune responses. In differentiated human THP‐1 macrophages and human and mouse alveolar macrophages stimulated with lipopolysaccharide (LPS) and other Toll‐like receptor ligands, hypercapnia inhibited expression of tumor necrosis factor and interleukin (IL)‐6, nuclear factor (NF)‐KB‐dependent cytokines critical for antimicrobial host defense. Inhibition of IL‐6 expression by hypercapnia was concentration dependent, rapid, reversible, and independent of extracellular and intracellular acidosis. In contrast, hypercapnia did not down‐regulate IL‐10 or interferon‐ß, which do not require NF‐κB. Notably, hypercapnia did not affect LPS‐induced degradation of IκBα, nuclear translocation of RelA/p65, or activation of mitogen‐activated protein kinases, but it did block IL‐6 promoter‐driven luciferase activity in mouse RAW 264.7 macrophages. Elevated PCO2 also decreased phagocytosis of opsonized polystyrene beads and heat‐killed bacteria in THP‐1 and human alveolar macrophages. By interfering with essential innate immune functions in the macrophage, hypercapnia may cause a previously unrecognized defect in resistance to pulmonary infection in patients with advanced lung disease. —Wang, N. , Gates, K. L. , Trejo, H. , Favoreto, Jr., S. , Schleimer, R P., Sznajder, J. I. , Beitel, G. J., Sporn, P. H. S. Elevated CO2 selectively inhibits interleukin‐6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage. FASEB J. 24, 2178–2190 (2010). www.fasebj. org
The calmodulin‐sensitive adenylate cyclase of Bordetella pertussis: cloning and expression in Escherichia col

The adenylate cyclase toxin of the prokaryote Bordetella pertussis is stimulated by the eukaryotic regulatory protein, calmodulin. A general strategy, using the adenylate‐cyclase‐calmodulin interaction as a tool, has permitted cloning and expression of the toxin in Escherichia coli in the absence of any B. pertussis trans‐activating factor. We show that the protein is synthesized in a large precursor form composed of 1706 amino acids. The calmodulin‐stimulated catalytic activity resides in the amino‐terminal 450 amino acids of the adenylate cyclase. The enzyme expressed in E. coli is recognized in Western blots by antibodies directed against purified B. pertussis adenylate cyclase, and its activity is inhibited by these antibodies.
Dopamine transporter phosphorylation site threonine 53 is stimulated by amphetamines and regulates dopamine transport, efflux, and cocaine analog binding

The dopamine transporter (DAT) controls the spatial and temporal dynamics of dopamine neurotransmission through reuptake of extracellular transmitter and is a target for addictive compounds such as cocaine, amphetamine (AMPH), and methamphetamine (METH). Reuptake is regulated by kinase pathways and drug exposure, allowing for fine-tuning of clearance in response to specific conditions, and here we examine the impact of transporter ligands on DAT residue Thr-53, a proline-directed phosphorylation site previously implicated in AMPH-stimulated efflux mechanisms. Our findings show that Thr-53 phosphorylation is stimulated in a transporter-dependent manner by AMPH and METH in model cells and rat striatal synaptosomes, and in striatum of rats given subcutaneous injection of METH. Rotating disc electrode voltammetry revealed that initial rates of uptake and AMPH-induced efflux were elevated in phosphorylation-null T53A DAT relative to WT and charge-substituted T53D DATs, consistent with functions related to charge or polarity. These effects occurred without alterations of surface transporter levels, and mutants also showed reduced cocaine analog binding affinity that was not rescued by Zn2+. Together these findings support a role for Thr-53 phosphorylation in regulation of transporter kinetic properties that could impact DAT responses to amphetamines and cocaine.
Symmetrical Reality: Toward a Unified Framework for Physical and Virtual Reality

In this paper, we review the background of physical reality, virtual reality, and some traditional mixed forms of them. Based on the current knowledge, we propose a new unified concept called symmetrical reality to describe the physical and virtual world in a unified perspective. Under the framework of symmetrical reality, the traditional virtual reality, augmented reality, inverse virtual reality, and inverse augmented reality can be interpreted using a unified presentation. We analyze the characteristics of symmetrical reality from two different observation locations (i.e., from the physical world and from the virtual world), where all other forms of physical and virtual reality can be treated as special cases of symmetrical reality.
Characterization of Trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target; structural, kinetic and RNAi studies

Nucleotide biosynthesis pathways have been reported to be essential in some protozoan pathogens. Hence, we evaluated the essentiality of one enzyme in the pyrimidine biosynthetic pathway, dihydroorotate dehydrogenase (DHODH) from the eukaryotic parasite Trypanosoma brucei through gene knockdown studies. RNAi knockdown of DHODH expression in bloodstream form T. brucei did not inhibit growth in normal medium, but profoundly retarded growth in pyrimidine‐depleted media or in the presence of the known pyrimidine uptake antagonist 5‐fluorouracil (5‐FU). These results have significant implications for the development of therapeutics to combat T. brucei infection. Specifically, a combination therapy including a T. brucei‐specific DHODH inhibitor plus 5‐FU may prove to be an effective therapeutic strategy. We also show that this trypanosomal enzyme is inhibited by known inhibitors of bacterial Class 1A DHODH, in distinction to the sensitivity of DHODH from human and other higher eukaryotes. This selectivity is supported by the crystal structure of the T. brucei enzyme, which is reported here at a resolution of 1.95 Å. Additional research, guided by the crystal structure described herein, is needed to identify potent inhibitors of T. brucei DHODH.
Selection and versatile application of virus‐specific aptamers

Although the significance of molecular diagnostics in routine plant virus detection is rapidly growing, the preferred methods are still antibody‐based enzyme immunoassays. In the past decade, aptamers have been demonstrated to be viable alternatives of antibodies in many applications. We set out to select apple stem pitting virus (ASPV)‐specific aptamers and to apply them as antibody substitutes in various immu‐noassay methods. The applied systematic evolution of ligands by exponential enrichment (SELEX) procedure resulted in highly discriminative aptamers selectively binding to the target virus coat protein even in complex protein matrixes. We developed protocols for exploitation of aptamers in diverse plant virus diagnosis methods, such as dot and Western blot analyses and enzyme‐linked oligonucleotide assay (ELONA). Our selected aptamers proved to be superior to the available antibody in all aspects. In contrast to the antibody, the aptamers decorate both native and denaturated proteins, and ELONA produces higher signal intensity than traditional enzyme‐linked immunosorbent assay (ELISA) with virus‐infected plant extract. Summarily, our results present the selection and practical utilization of first plant virus‐specific aptamers. Most important, the first application of ELONA for virus detection is demonstrated, which proposes a novel, more flexible, and cost‐effective means of virus diagnostics. —Balogh, Z. , Lautner, G. , Bardoczy, V. , Komorowska, B. , Gyurcsanyi, R. E. , Meszaros, T. Selection and versatile application of virus‐specific aptamers. FASEB J. 24, 4187–4195 (2010). www.fasebj. org
Characterization of an acyl‐CoA: carboxylate CoA‐transferase from Aspergillus nidulans involved in propionyl‐CoA detoxification

Filamentous fungi metabolize toxic propionyl‐CoA via the methylcitrate cycle. Disruption of the methylcitrate synthase gene leads to an accumulation of propionyl‐CoA and attenuates virulence of Aspergillus fumigatus. However, addition of acetate, but not ethanol, to propionate‐containing medium strongly reduces the accumulation of propionyl‐CoA and restores growth of the methylcitrate synthase mutant. Therefore, the existence of a CoA‐transferase was postulated, which transfers the CoASH moiety from propionyl‐CoA to acetate and, thereby, detoxifying the cell. In this study, we purified the responsible protein from Aspergillus nidulans and characterized its biochemical properties. The enzyme used succinyl‐, propionyl‐ and acetyl‐CoA as CoASH donors and the corresponding acids as acceptor molecules. Although the protein displayed high sequence similarity to acetyl‐CoA hydrolases this activity was hardly detectable. We additionally identified and deleted the coding DNA sequence of the CoA‐transferase. The mutant displayed weak phenotypes in the presence of propionate and behaved like the wild type when no propionate was present. However, when a double‐deletion mutant defective in both methylcitrate synthase and CoA‐transferase was constructed, the resulting strain was unable to grow on media containing acetate and propionate as sole carbon sources, which confirmed the in vivo activity of the CoA‐transferase.
Loss of tafazzin in yeast leads to increased oxidative stress during respiratory growth

The tafazzin (TAZ) gene is highly conserved from yeast to humans, and the yeast taz1 null mutant shows alterations in cardiolipin (CL) metabolism, mitochondrial dysfunction and stabilization of supercomplexes similar to those found in Barth syndrome, a human disorder resulting from loss of tafazzin. We have previously shown that the yeast tafazzin mutant taz1Δ, which cannot remodel CL, is ethanol‐sensitive at elevated temperature. In the current report, we show that in response to ethanol, CL mutants taz1Δ as well as crd1Δ, which cannot synthesize CL, exhibited increased protein carbonylation, an indicator of reactive oxygen species (ROS). The increase in ROS is most likely not due to defective oxidant defence systems, as the CL mutants do not display sensitivity to paraquat, menadione or hydrogen peroxide (H2O2). Ethanol sensitivity and increased protein carbonylation in the taz1Δ mutant but not in crd1Δ can be rescued by supplementation with oleic acid, suggesting that oleoyl‐CL and/or oleoyl‐monolyso‐CL enables growth of taz1Δ in ethanol by decreasing oxidative stress. Our findings of increased oxidative stress in the taz1Δ mutant during respiratory growth may have important implications for understanding the pathogenesis of Barth syndrome.
kinC/D‐mediated heterogeneous expression of spo0A during logarithmical growth in Bacillus subtilis is responsible for partial suppression of φ29 development

The host of the lytic bacteriophage φ29 is the spore‐forming bacterium Bacillus subtilis. When infection occurs during early stages of sporulation, however, φ29 development is suppressed and the infecting phage genome becomes trapped into the developing spore. Recently, we have shown that Spo0A, the key transcriptional regulator for entry into sporulation, is directly responsible for suppression of the lytic φ29 cycle in cells having initiated sporulation. Surprisingly, we found that φ29 development is suppressed in a subpopulation of logarithmically growing culture and that spo0A is heterogeneously expressed during this growth stage. Furthermore, we showed that kinC and, to a minor extent, kinD, are responsible for heterogeneous expression levels of spo0A during logarithmical growth that are below the threshold to activate sporulation, but sufficient for suppression of the lytic cycle of φ29. Whereas spo0A was known to be heterogeneously expressed during the early stages of sporulation, our findings show that this also occurs during logarithmical growth. These insights are likely to have important consequences, not only for the life cycle of φ29, but also for B. subtilis developmental processes.