Miracle-dz/UniFAR-FTUs huggingface dataset:
MCHelper automatically curates transposable element libraries across species

The number of species with high quality genome sequences continues to increase, in part due to scaling up of multiple large scale biodiversity sequencing projects. While the need to annotate genic sequences in these genomes is widely acknowledged, the parallel need to annotate transposable element sequences that have been shown to alter genome architecture, rewire gene regulatory networks, and contribute to the evolution of host traits is becoming ever more evident. However, accurate genome-wide annotation of transposable element sequences is still technically challenging. Several de novo transposable element identification tools are now available, but manual curation of the libraries produced by these tools is needed to generate high quality genome annotations. Manual curation is time-consuming, and thus impractical for large-scale genomic studies, and lacks reproducibility. In this work, we present the Manual Curator Helper tool MCHelper, which automates the TE library curation process. By leveraging MCHelper’s fully automated mode with the outputs from two de novo transposable element identification tools, RepeatModeler2 and REPET, in fruit fly, rice, and zebrafish, we show a substantial improvement in the quality of the transposable element libraries and genome annotations. MCHelper libraries are less redundant, with up to 54% reduction in the number of consensus sequences, have up to 11.4% fewer false positive sequences, and also have up to ∼45% fewer “unclassified/unknown” transposable element consensus sequences. Genome-wide transposable element annotations were also improved, including larger unfragmented insertions. MCHelper is a fast, easy to install, and easy to use tool and is available at https://github.com/GonzalezLab/MCHelper. Significant statement The number and quality of genome sequences available is rapidly increasing across the tree of life. Transposable elements, DNA fragments with the ability to move within the genome often generating copies of themselves in the process, constitute significant proportions of the total genome content across species. Although transposable elements are a major source of genome variation, they are often ignored as it is still challenging to accurately annotate them. We have developed MCHelper, an automatic tool to curate transposable element libraries that allows for high quality, fast, and replicable transposable elements annotations.
CENsible: Interpretable Insights into Small-Molecule Binding with Context Explanation Networks

We present a novel and interpretable approach for predicting small-molecule binding affinities using context explanation networks (CENs). Given the specific structure of a protein/ligand complex, our CENsible scoring function uses a deep convolutional neural network to predict the contributions of pre-calculated terms to the overall binding affinity. We show that CENsible can effectively distinguish active vs. inactive compounds for many systems. Its primary benefit over related machine-learning scoring functions, however, is that it retains interpretability, allowing researchers to identify the contribution of each pre-calculated term to the final affinity prediction, with implications for subsequent lead optimization.
Drug-Mediated Control of Receptor Valency Enhances Immune Cell Potency

Designer T cells offer a novel paradigm for treating diseases like cancer, yet they are often hindered by target recognition evasion and limited in vivo control. To overcome these challenges, we develop valency-controlled receptors (VCRs), a novel class of synthetic receptors engineered to enable precise modulation of immune cell activity. VCRs use custom-designed valency-control ligands (VCLs) to modulate T cell signaling via spatial molecular clustering. Using multivalent DNA origami as VCL, we first establish that valency is important for tuning the activity of CD3-mediated immune activation. We then generate multivalent formats of clinically relevant drugs as VCL and incorporate VCR into the architecture of chimeric antigen receptors (CARs). Our data demonstrate that VCL-mediated VCRs can significantly amplify CAR activities and improve suboptimal CARs. Finally, through medicinal chemistry, we synthesize programmable, bioavailable VCL drugs that potentiate targeted immune response against low-antigen tumors both in vitro and in vivo. Our findings establish receptor valency as a core mechanism for enhancing CAR functionality and offer a synthetic chemical biology platform for strengthening customizable, potent, and safer cell therapies.
Characterization of the cryptic interspecific hybrid Lemna × mediterranea by an integrated approach provides new insights into duckweed diversity

Lemnaceae taxonomy is challenged by the particular morphology of these tiny free-floating angiosperms, reduced to a single leaf-like structure called frond, without or with one to few roots. Although molecular taxonomy has helped clarify the phylogenetic history of this family, inconsistency between morphological data and nuclear and plastid markers still poses challenging questions in some cases, leading to frequent misclassifications in the genus Lemna. Recently, the finding that Lemna japonica is an interspecific hybrid between Lemna minor and Lemna turionifera, provided a clear explanation to one of such taxonomic questions. Here we demonstrated that L. minor is also capable to hybridize with Lemna gibba, generating a cryptic, previously unrecognized, but widespread taxon in the Mediterranean area. The nothotaxon Lemna × mediterranea is described through the detailed investigation of seven hybrid clones from a living germplasm collection and compared with clones of the putative parental species L. minor and L. gibba. Genetic analysis revealed that two different cytotypes, diploid and triploid, originated by at least two independent hybridization events. Despite high overall similarity, morphometrical, physiological and biochemical analyses showed an intermediate position of L. × mediterranea between its parental species in most qualitative and quantitative characters, and also separation of the two hybrid cytotypes by some criteria. These data provide evidence that hybridization and polyploidization, driving forces of terrestrial plant evolution, contribute to the duckweed genetic diversity and may have also shaped the phylogenetic history of these mainly asexual, aquatic plants. Further elucidation of hybridization mechanisms and flowering regulation will provide perspectives for future breeding strategies.
RNA Polymerase II-mediated transcription is required for repair of ribosomal DNA breaks in nucleolar caps, guarding against genomic instability

Oversized nucleoli and enhanced ribosome biogenesis are hallmarks of cancer, reflecting tumor cells’ aberrantly high demand for protein synthesis during tumorigenesis. The high-copy ribosomal DNA (rDNA) genes are highly transcribed by RNA Polimerase I (RNAPI) and inherently unstable, often subject to DNA double-strand breaks (DSBs) caused by transcription-replication conflicts. When DSBs happen, RNAPI becomes silenced by ATM signaling and rDNA DSBs are translocated to nucleolar periphery for repair mainly by homologous recombination in newly formed nucleolar caps. The molecular mechanisms underlying these processes are incompletely understood. Herein, we report that rDNA DSB translocation and nucleolar cap formation require the presence and activity of RNAPII. Nascent RNA deficiency upon RNAPII inhibition in rDNA damaged cells provoke rDNA instability and cell death. Finally, the enhanced cytotoxic effect of combined RNA transcription inhibition and rDNA damage, reported here, is consistent with addiction of cancer to nucleolar function, indicating an emerging targetable vulnerability of cancer cells that may inspire innovative treatment strategies in oncology. Teaser Nascent RNA synthesis by RNA PolymeraseII safeguards ribosomal DNA integrity to avoid genomic instability in human cells. Graphical Abstract
Metabolic changes that allow Plasmodium falciparum artemisinin-resistant parasites to tolerate the oxidative stress

1.1 Background Artemisinin-based treatments (ACTs) are the first therapy currently used to treat malaria produced by Plasmodium falciparum. However, in recent years increasing evidence shows that some strains of P. falciparum are less susceptible to ACT in the Southeast Asian region. 1.2 Materials & Methods A data reanalysis of several omics approaches currently available about parasites of P. falciparum that have some degree of resistance to ACT was carried out. The data used was from transcriptomics and metabolomics studies. One mitochondrial carrier of the parasite possibly involved in the mechanisms of tolerance to oxidative stress was modelled and subjected to molecular dockings with citrate and oxoglutarate. 1.3 Results An increase in glutathione production was detected, changing the direction of the flux of metabolites in the tricarboxylic acid cycle, and boosting glucose consumed. The models of the mitochondrial carrier, called PfCOCP, show that it may be important in transporting citrate and oxoglutarate from the mitochondrial matrix to cytosol. If so, it may allow the parasite to tolerate the oxidative stress produced by artemisinin. 1.4 Conclusions This in-silico analysis shows that P. falciparum may tolerate the artemisinin’s oxidative stress through metabolic changes not reported before, showing the need for further research on the many metabolic aspects linked to this phenotype.
Unique Binding and Stabilization Mechanisms Employed By and Engineered Into Nanobodies

Nanobodies are single domain antibody variants that bind an antigen with the precision and affinity of a conventional antibody at only a fraction of their size. In solving the crystal structures of our nanobody-GFP complexes and compared with other available structures, we uncover mechanism that enable nanobodies to function so efficiently and effectively as single-domain antibodies. We show that unlike conventional antibodies, a nanobody repertoire maximizes sampling of their antigen surface by binding a single antigen in at least three different orientations which can be predicted by their paratope composition. We also structurally reengineering these nanobodies to improve their antigen affinity, their stability, or both – results which also revealed the strong connection between nanobody stability and affinity. We achieved this by either directly modifying the paratope, or by altering a particular region within their third framework, which is a highly conserved area that we determined plays a role in controlling nanobody stability. Our study suggests that these unique characteristics of nanobodies allow them to interact with antigens as effectively as conventional antibodies, despite their smaller size. This understanding provides methods to facilitate optimizing, humanizing and functionalizing nanobodies, thus paving the way for their utilization in diverse areas such as research, diagnostics, and therapeutic development. Significance Statement Nanobodies are a unique type of antibody fragment found in select animals, containing all its antigen binding ability reduced to a single ∼15 kDa protein. There is increasing development of nanobodies for research, diagnostics, and therapeutics, yet how nanobodies function so effectively as single domain antigen binders with the precision and affinity of conventional antibodies is unclear. In this study, we present key observations to help answer this question, where one key finding is the strong relationship between nanobody stability and antigen affinity aided by the identification of a highly conserved region in nanobodies essential for maintaining nanobody stability. This region may have been retained in nanobodies in lieu of stabilizing mechanisms induced by dimerization as seen in conventional antibodies.
Building RNA Backbone in Constant Time by Numerical Approximation

We present a numerical approximation method designed to swiftly create RNA ribose conformations in constant time. The method’s parameterization relies on the atomic coordinates of a given base along with its two neighboring phosphate groups. Such a parameterization suits three dimensional modeling engines that determine the RNA conformational search space using base operations instead of backbone sampling. These engines consider phosphate groups as part of the base rigid bodies. Reconstructing ribose conformations result in less than 1 Å of RMSD (root-mean-square deviation) compared to original conformations derived from high-resolution X-ray crystallographic structures. By incorporating this ribose construction method into MC-Sym, a well-established RNA three dimensional modeling software, we streamline the modeling process into two phases. This enhances the search algorithm’s speed and improves model consistency and precision. Additionally, we employed the method to pinpoint 27 irregular ribose stereoisomers in high-resolution RNA X-ray crystal structures.
Identification and full-genome assembly of novel Colorado potato beetle iflavirus and solinvi-like virus with SISPA Sequencing

The Colorado potato beetle is one of the most devastating potato pests widespread in the world. However, its viral pathogens remain highly unexplored. Here using SISPA high-throughput sequencing of Colorado potato beetle (CPB) samples derived from prepupal larvae that died from an unknown infection, we have identified two previously unknown viruses and assembled their full-length genomic sequences. The subsequent genetic and phylogenetic analysis of the obtained sequences demonstrated that the isolated viruses, named Leptinotarsa iflavirus 1 and Leptinotarsa solinvi-like virus 1, are the novel representatives of Iflaviridae and Solinviviridae viral families, respectively. To the best of our knowledge, these are the first sequencing-confirmed insect viruses derived directly from CPB samples. And we also propose that Leptinotarsa iflavirus 1 may be associated with lethal disease in CPB.
Systemic Risk Spillovers in the European Banking and Sovereign Network *

We propose a framework for estimating time-varying systemic risk contributions that is applicable to a high-dimensional and interconnected financial system. Tail risk dependencies and contributions are estimated based on a penalized two-stage fixed-effects quantile approach, which explicitly links time-varying interconnectedness tofonds (WWTF). M.Schienle thanks Deutsche Forschungsgemeinschaft for financial support. The views presented in the paper are those of the authors only and do not necessarily represent the views of the Euro-pean Systemic Risk Board, European Central Bank, the Eurosystem or the European Investment Bank. 1 systemic risk contributions. For the purposes of surveillance and regulation of financial systems, network dependencies in extreme risks are much more relevant than simple (mean) correlations. Thus, the framework provides a tool for supervisors, reflecting market's view of tail dependences and systemic risk contributions. The framework is applied to a system of 51 large European banks and 17 sovereigns in 2006-13, utilizing both equity and CDS prices. We provide new evidence on how banking sector fragmentation and sovereign-bank linkages evolved over the Euro-pean sovereign debt crisis, and how it is reflected in estimated network statistics and systemic risk measures. Finally, our evidence provides an indication that the fragmentation of the European financial system has peaked.
Capturing variability in business process models: the Provop approach

Usually, for a particular business process different variants exist. Each of them constitutes an adjustment of a reference process model to specific requirements building the process context. Contemporary process management tools do not adequately support the modeling of such process variants. Either the variants have to be specified as separate process models or they are expressed in terms of conditional branches within the same process model. Both methods often lead to redundancies making model adaptations a time consuming and error-prone task. In this paper we discuss selected concepts of the Provop approach for modeling and managing process variants. A particular process variant can be configured at a high level of abstraction by applying a set of well-defined change operations to a reference process model. In particular, this paper discusses advanced concepts for the design and modeling of such a reference process model as well as for the adjustments required to configure the different process variants. Altogether, Provop provides a flexible and powerful solution for process variant management.
Embedded landmark acquisition system for visual slam using star identification based stereo correspondence descriptor

The use of cameras as the main sensors in Simultane ous Localization and Mapping, what is called Visual SLAM, has risen recently due to the fall in camera prices. While images bring richer information than other typical SLAM se nsors, such as lasers and sonars, there is significant extra processing cost when they are use d. The extra depth information available from stereo camera setups makes them preferable for SLAM applications. In this particular approach, great part of the added processing cost c omes from extracting unique points or image patches in both stereo images and solving the corr spondence problem between them. With this information, the horizontal disparity bet ween the pair can be used to retrieve depth information. This work explores the use of an embedded system-on -a-chip (SoC) platform that integrates a multicore ARM processor with FPGA fabr ic as a stereo vision processing module. The Harris and Stephens corner detector (Ha rris & Stephens, 1988) is used to find Point of Interests (POIs) in stereo images in a har dw e soft co-processor synthesized in the FPGA to speed up feature extraction and relieve thi s highly parallelizable process from the main embedded processor. Remaining tasks such as im ge correction from camera calibration, finding unique descriptor for the dete cted features and the correspondence between POIs in the stereo pair are solved in softw are running on the main processor. The proposed architecture for the co-processor enabled the corner extraction task to be performed in about half the time taken by the main processor without aid. After finding the POIs, for each point a unique des criptor is needed for finding the correspondent POI in the other image. This work als o proposes an innovative descriptor that considers a global two-dimensional spatial relation ship between the detected points to describe them individually. In each image, every po int in the cloud of points detected by the Harris and Stephens algorithm is described by consi dering only the relative position between it and its neighbors. When position alone is consid ere , a starry night pattern is formed by the POIs. With the POI pattern being considered as star s, he descriptors already used in star identification problems can be reapplied to uniquel y identify POIs. A prototype of the descriptor based on the Padgett and KreutzDelgado's grid algorithm (Padgett & KreutzDelgado, 1997) is written and the results com pared with common descriptors used for this purpose, showing that two-dimensional spatial information alone can be used to solve the correspondence problem. The number of useful matche s was comparable to what was obtained with SIFT, the best performing descriptor in this matter, while the speed was superior to BRIEF, the fastest descriptor used in t he comparison, on the ARM platform, with a speedup of 1.64 and 1.40 on the tested datasets.
Hold Your Horses: a Dynamic Computational Role for the Subthalamic Nucleus in Decision Making

The basal ganglia (BG) coordinate decision making processes by facilitating adaptive frontal motor commands while suppressing others. In previous work, neural network simulations accounted for response selection deficits associated with BG dopamine depletion in Parkinson's disease. Novel predictions from this model have been subsequently confirmed in Parkinson patients and in healthy participants under pharmacological challenge. Nevertheless, one clear limitation of that model is in its omission of the subthalamic nucleus (STN), a key BG structure that participates in both motor and cognitive processes. The present model incorporates the STN and shows that by modulating when a response is executed, the STN reduces premature responding and therefore has substantial effects on which response is ultimately selected, particularly when there are multiple competing responses. Increased cortical response conflict leads to dynamic adjustments in response thresholds via cortico-subthalamic-pallidal pathways. The model accurately captures the dynamics of activity in various BG areas during response selection. Simulated dopamine depletion results in emergent oscillatory activity in BG structures, which has been linked with Parkinson's tremor. Finally, the model accounts for the beneficial effects of STN lesions on these oscillations, but suggests that this benefit may come at the expense of impaired decision making.
Exacerbated Zika virus–induced neuropathology and microcephaly in fetuses of dengue-immune nonhuman primates

Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is not fully understood why some fetuses experience severe complications after in utero exposure to ZIKV, whereas others do not. Given the antigenic similarity between ZIKV and the closely related virus dengue (DENV) and the potential of DENV-specific antibodies to enhance ZIKV disease severity in mice, we questioned whether maternal DENV immunity could influence fetal outcomes in a nonhuman primate model of ZIKV vertical transmission. We found significantly increased severity of congenital Zika syndrome (CZS) in fetuses of DENV-immune cynomolgus macaques infected with ZIKV in early pregnancy compared with naïve controls, which occurred despite no effect on maternal ZIKV infection or antibody responses. Ultrasound measurements of head circumference and biparietal diameter measurements taken sequentially throughout pregnancy demonstrated CZS in fetuses of DENV-immune pregnant macaques. Furthermore, severe CZS enhanced by DENV immunity was typified by reduced cortical thickness and increased frequency of neuronal death, hemorrhaging, cellular infiltrations, calcifications, and lissencephaly in fetal brains. This study shows that maternal immunity to DENV can worsen ZIKV neurological outcomes in fetal primates, and it provides an animal model of vertical transmission closely approximating human developmental timelines that could be used to investigate severe ZIKV disease outcomes and interventions in fetuses. Description Fetal neurological complications after ZIKV exposure in utero can be worsened by maternal dengue immunity in cynomolgus macaques. Editor’s summary Pregnant women infected with Zika virus (ZIKV) can vertically transmit virus to fetuses, which has been linked to congenital ZIKV syndrome. Understanding how ZIKV infection affects prenatal and neonatal development is critical for human health. Here, Saron et al. and Moadab et al. used cynomolgus and rhesus macaque models, respectively, to understand how maternal ZIKV infection influences fetal development. Saron et al. found that preexisting immunity to dengue virus, a related flavivirus, worsened severity of CZS. Moadab et al. found that maternal ZIKV infection alone was sufficient to reduce infant size and affect social behaviors. Together, these papers shed light on the impacts of ZIKV infection on fetal and early life development. —Christiana Fogg and Courtney Malo