Miracle-dz/UniFAR-FTUs huggingface dataset:
Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion

Loss-of-function mutations in the deubiquitinase OTULIN result in an inflammatory pathology termed “OTULIN-related autoinflammatory syndrome” (ORAS). Genetic mouse models revealed essential roles for OTULIN in inflammatory and cell death signaling, but the mechanisms by which OTULIN deficiency connects cell death to inflammation remain unclear. Here, we identify OTULIN deficiency as a cellular condition that licenses RIPK3-mediated cell death in murine macrophages, leading to Nlrp3 inflammasome activation and subsequent IL-1β secretion. OTULIN deficiency uncoupled Nlrp3 inflammasome activation from gasdermin D–mediated pyroptosis, instead allowing RIPK3-dependent cell death to act as an Nlrp3 inflammasome activator and mechanism for IL-1β release. Accordingly, elevated serum IL-1β levels in myeloid-specific OTULIN-deficient mice were diminished by deleting either Ripk3 or Nlrp3. These findings identify OTULIN as an inhibitor of RIPK3-mediated IL-1β release in mice. Description OTULIN deficiency licenses RIPK3-dependent IL-1β secretion from macrophages. Editor’s summary Severe autoinflammation occurs in individuals bearing loss-of-function mutations in the deubiquitinase OTULIN, but how cell death and inflammatory pathways contribute to the pathology of OTULIN deficiency remains unclear. Doglio et al. found that mice lacking OTULIN in myeloid cells develop neutrophil-dominant autoinflammation that was dependent on Nlrp3. Macrophages from OTULIN-deficient mice displayed Nlrp3 inflammasome activation and IL-1β secretion in response to LPS treatment alone, which occurred independently of the pyroptosis effector gasdermin D. Instead, RIPK3-dependent cell death served as a trigger of Nlrp3 inflammasome activation and enabled IL-1β release. These findings demonstrate that specific cell death and inflammatory pathways become coupled and drive pathology during OTULIN deficiency. —Claire Olingy
ERK Activation by BRAFV600E suppresses mesenchymal migration and tumorigenesis by inhibiting RAC1

BRAFV600E mutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harbor BRAFV600E mutations. We show here that BRAFV600E inhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition leads to RAC1 activation and restores migration and invasion. In cells with BRAFV600E, activating RAC1 mutation, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% of BRAFV600E melanomas. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of cell migration. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.
A “suicide” BCG strain provides enhanced immunogenicity and robust protection against Mycobacterium tuberculosis in macaques

Intravenous (IV) BCG delivery provides robust protection against Mycobacterium tuberculosis (Mtb) in macaques but poses safety challenges. Here, we constructed two BCG strains (BCG-TetON-DL and BCG-TetOFF-DL) in which tetracyclines regulate two phage lysin operons. Once the lysins are expressed, these strains are cleared in immunocompetent and immunocompromised mice, yet induced similar immune responses and provided similar protection against Mtb challenge as wild type BCG. Lysin induction resulted in release of intracellular BCG antigens and enhanced cytokine production by macrophages. In macaques, cessation of doxycycline administration resulted in rapid elimination of BCG-TetOFF-DL. However, IV BCG-TetOFF-DL induced increased pulmonary CD4 T cell responses compared to WT BCG and provided robust protection against Mtb challenge, with sterilizing immunity in 6 of 8 macaques, compared to 2 of 8 macaques immunized with WT BCG. Thus, a “suicide” BCG strain provides an additional measure of safety when delivered intravenously and robust protection against Mtb infection.
Glutathione overproduction mediates lymphoma initiating cells survival and has a sex-dependent effect on lymphomagenesis

Lymphoid tumor patients often exhibit resistance to standard therapies or experience rapid relapse post-remission. Tumor-initiating cells (TICs), a small fraction of the tumor cell population known for their self-renewal capacity and resistance to cancer therapies, likely drive tumor relapse. Tumorigenicity strongly correlates with growth in soft gels and TICs are the only cancer cells capable of growing in soft gels. Targeting pathways critical for TIC survival or growth holds promise for improving cancer treatment outcomes but TIC biology remains poorly understood. Here, we show that culturing lymphoid cells in soft hydrogels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and even promotes the growth of primary non-tumor lymphoid cells in soft gels. Some lymphoma cells escape ROS-induced lethality by boosting antioxidant glutathione production, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell viability and proliferation in soft gels and tumor growth in immunodeficient mice. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.
Identifying cooperative genes causing cancer progression with dynamic causal inference

It is well known that some gene aberrations can cause cancer by disrupting the delicate balance of critical biological processes at the cellular level. Such aberrations are rare and are not limited to gene mutations alone and hence are difficult to be identified from data. Moreover, focusing exclusively on gene aberrations neglects other significant aspects of cancer development such as the fact that cancer occurs due to gene interactions evolving as a dynamical system. Therefore, expanding our knowledge about the dynamics of genetic mechanisms that cause cancer is crucial for a comprehensive understanding of cancer development. In this paper, a novel causal method for identifying collaborative networks of cancer drivers based on dynamic system analysis is introduced. The method integrates the temporal dimension of the data throughout cancer progression and provides a way of testing for the causality of candidate genes in cancer. We have applied our method to single-cell and bulk sequencing datasets of breast cancer. The evaluation results show that our method systematically identifies bona fide driver genes and detects sets of genes strongly linked to cancer progression. The results suggest that our method can discover mutated and non mutated drivers of cancer to provide a comprehensive view of cancer development. R package implementing our approach as well as scripts for the experiments and datasets used can be found at https://github.com/AndresMCB/DynamicCancerDriverKM.
The recombination initiation functions DprA and RecFOR suppress microindel mutations in Acinetobacter baylyi ADP1

Short-Patch Double Illegitimate Recombination (SPDIR) has been recently identified as a rare mutation mechanism. During SPDIR, ectopic DNA single-strands anneal with genomic DNA at microhomologies and get integrated in the course of DNA replication, presumably acting as Okazaki fragments. The resulting microindel mutations are highly variable in size and sequence. In the soil bacterium Acinetobacter baylyi, SPDIR mutations are tightly controlled by genome maintenance functions including RecA. In this study, we investigate the roles of DprA, RecFOR and RecBCD, which are cytoplasmic functions that load DNA single-strands with RecA. All three functions suppress SPDIR mutations in wildtype to levels below the detection limit. While SPDIR mutations are slightly elevated in the absence of DprA alone, they are strongly increased in the absence of both DprA and RecA. This SPDIR-avoiding function of DprA is not related to its role in natural transformation. These results suggest an antimutational function for DprA and offer an explanation for the ubiquity of dprA in the genomes of non-transformable bacteria.
The physiological costs of spatial positioning and leadership in collective movements

Forming collectives can generate substantial benefits, but much less is known about the costs that individuals incur in doing so. We simultaneously captured individual movement, within-group position, leadership, and heart rate for each member in a group of wild vulturine guineafowl. Individuals had significantly increased heart rates when moving collectively, occupying more central positions within the group, or attempting to initiate directional movement when consensus among group members was low. Such cardiac system activation can be indicative of physiological stress, entailing increased energy expenditure and long-term physiological damage. Thus, individuals paid the highest physiological costs in situations where theory predicts the benefits of collective behaviours should be greatest, revealing a hidden trade-off of social living.
Prokrustean graph: An efficient data structure used to extract sequence information for arbitrary k-mer size ranges

Despite the widespread adoption of k-mer-based methods in bioinformatics, a fundamental question persists: How to elucidate the structural transition of a k-mer set when the order switches to k′? Lacking a generalized answer, the problem has been considered application-specific, necessitating the effect of k to be studied empirically in each k-mer-based method, e.g. in areas of genome complexity, assembly, alignment, error corrections, etc. The challenge lies in the dynamic information space of k-mers, which transforms entirely with varying values of k. We unravel the problem with a principle: substring co-occurrence provides a localized scope grouping k-mers of different lengths that behave similarly. This principle is embodied in a model, the Prokrustean graph, which serves as a theoretical framework for analyzing the role of k in altering the distributions and properties of k-mers. Furthermore, the model can extract both overlap graphs and de Bruijn graphs of any order, indicating the potential emergence of a hybrid assembly graph. Practically, a Prokrustean graph is a space-efficient data structure capable of efficiently querying k-mer-related information across various k-mer sizes, with time complexity that is independent of the size range. We present a series of examples demonstrating its competitive performance in both time and space, comparable to purpose-built tools designed for single k values, such as KMC and GGCAT. A notable application involves counting maximal unitigs in de Bruijn graphs over the range of k = 30 … 50000 using a large long read dataset, accomplishing this task in approximately 30 seconds. This is a task that poses significant challenges for current state-of-the-art tools. Our construction algorithm of the Prokrustean graph utilizes an (extended) Burrows-Wheeler transform as input, is easily parallelizable, and operates in O(N) time where N is the cumulative input sequence length. We provide theoretical justification that the size of a Prokrustean graph is O(N), and in practice, is significantly smaller than N . All code and algorithms are publicly accessible at: https://github.com/KoslickiLab/prokrustean.
Multi-Scale Geometric Network Analysis Identifies Melanoma Immunotherapy Response Gene Modules

Melanoma response to immune-modulating therapy remains incompletely characterized at the molecular level. In this study, we assess melanoma immunotherapy response using a multi-scale network approach to identify gene modules with coordinated gene expression in response to treatment. Using gene expression data of melanoma before and after treatment with nivolumab, we modeled gene expression changes in a correlation network and measured a key network geometric property, dynamic Ollivier-Ricci curvature, to distinguish critical edges within the network and reveal multi-scale treatment-response gene communities. Analysis identified six distinct gene modules corresponding to sets of genes interacting in response to immunotherapy. One module alone, overlapping with the nuclear factor kappa-B pathway (NFKB), was associated with improved patient survival and a positive clinical response to immunotherapy. This analysis demonstrates the usefulness of dynamic Ollivier-Ricci curvature as a general method for identifying information-sharing gene modules in cancer.
Comparative single-cell transcriptomic atlases reveal conserved and divergent features of drosophilid central brains

To explore how brains change upon species evolution, we generated single-cell transcriptomic atlases of the central brains of three closely-related but ecologically-distinct drosophilids: the generalists Drosophila melanogaster and Drosophila simulans, and the noni fruit specialist Drosophila sechellia. The global cellular composition of these species’ central brains is well-conserved, but we predicted a few cell types (perineurial glia, sNPF and Dh44 peptidergic neurons) with divergent frequencies. Gene expression analysis revealed that distinct cell types within the central brain evolve at different rates and patterns; notably, glial cell types exhibit the greatest divergence between species. Compared to D. melanogaster, the cellular composition and gene expression patterns of the central brain in D. sechellia display greater deviation than those of D. simulans - despite their similar phylogenetic distance from D. melanogaster - that the distinctive ecological specialization of D. sechellia is reflected in the structure and function of its brain. Expression changes in D. sechellia encompass metabolic and ecdysone signaling genes, suggestive of adaptations to its novel ecological demands. Additional single-cell transcriptomic analysis on D. sechellia revealed genes and cell types responsive to dietary supplement with noni, pointing to glia as sites for both physiological and genetic adaptation to novel conditions. Our atlases represent the first comparative analyses of “whole” central brains, and provide a comprehensive foundation for studying the evolvability of nervous systems in a well-defined phylogenetic and ecological framework.
Haile mitigation 2 CO material for new modes of energy conversion and A thermochemical study of ceria : exploiting an old

(22 articles) energy (149 articles) materials science collections Articles on similar topics can be found in the following Email alerting service here in the box at the top right-hand corner of the article or click Receive free email alerts when new articles cite this article-sign up We present a comprehensive thermodynamic and kinetic analysis of the suitability of cerium oxide (ceria) for thermochemical fuel production. Both portions of the two-step cycle, (i) oxygen release from the oxide at 1773 and 1873 K under inert atmosphere, and (ii) hydrogen release upon hydrolysis at 1073 K, are examined theoretically as well as experimentally. We observe gravimetric fuel productivity that is in quantitative agreement with equilibrium, thermogravimetric studies of ceria. Despite the non-stoichiometric nature of the redox cycle, in which only a portion of the cerium atoms change their oxidation state, the fuel productivity of 8.5–11.8 ml of H 2 per gram of ceria is competitive with that of other solid-state thermochemical cycles currently under investigation. The fuel production rate, which is also highly attractive, at a rate of 4.6–6.2 ml of H 2 per minute per gram of ceria, is found to be limited by a surface-reaction step rather than by ambipolar bulk diffusion of oxygen through the solid ceria. An evaluation of the thermodynamic efficiency of the ceria-based thermochemical cycle suggests that, even in the absence of heat recovery, solar-to-fuel conversion efficiencies of 16 to 19 per cent can be achieved, assuming a suitable method for obtaining an inert atmosphere for the oxygen release step.
Session-based Recommendation Algorithm Based on Heterogeneous Graph Transformer

—Session-based recommendation is a technique that leverages the user's interaction sequence within a brief period to generate personalized recommendations. Currently, traditional transformer-based methods lack the capability to mitigate noise node interference in session sequences, while approaches based on heterogeneous graphs face challenges in capturing long-term sequential dependencies effectively. To tackle these challenges, a heterogeneous graph-enhanced Transformer session-based recommendation method is proposed in this paper. The proposed method constructs a heterogeneous session graph and utilizes a self-attention layer enhanced by the shortest path matrix. This enables the capturing of item embeddings that contains crucial graph structure information. Moreover, the method incorporates adversarial training to prevent excessive reliance on local graph information and achieve a more balanced integration of local and global information. After evaluating experiments on three public datasets, the results clearly demonstrate a remarkable enhancement compared to other robust baseline models, thus providing strong evidence of the method's effectiveness.
A System for Classification of Business Models and Strategies

Over the years, many assumptions and business practices that were once taken for granted began to break down, giving way to new concepts. The business strategy is a consequence of the business model, as the model represents the assumption of the strategy, being an initial factor for it. The objective of this research is to develop indicators to classify the relationship between business models and business strategies in different production systems and apply them in companies in Brazil and Poland to understand if the indicators remain the same. For the methodology, a qualitative approach was used, of the descriptive exploratory type; for the construction of the indicators, a study of multiple cases was applied to identify the similarities and differences between business models and strategies. Among the results, it can be highlighted that the unifications of the individual strategies of each pillar of the business model, when grouped, represent the relationships between business models and strategies of different production systems.
Occurrence and Severity of Ganoderma lucidum (Fr.) P. Karst. on Azadirachta indica Trees in University of Port Harcourt, Nigeria: Implications for Sustainable Harvesting and Replacement

More than 40% mortality of the 35 years old Neem trees (Azardirachta indica) used as avenue tree in University of Port Harcourt (UNIPORT) has been observed. This phenomenon is strongly believed to have been caused by Ganoderma lucidum - a fungus which causes root rots, cracking of the root and stem barks, heartwood rots, die-back of the branches, deformation of crown and eventually death. Therefore, occurrence and severity of Ganoderma lucidum on the Neem trees from Delta axis road to Ofrima/Senate roundabout were examined for 3 years. Epidemiological observations showed that two genera of Ganoderma appeared early in the years when there was rain and gradually reduce with decreasing rainfall intensity. High occurrences of G.lucidum were observed between April and July for the 3 years of study. Over the years, there were progressive increase in the damaging impact of G.lucidum in all trees and the total mortality associated with its occurrence was greater than 40% at the end of 2013. Occurrence-severity indicated that A. indica trees were affected mostly by decays of roots and stem butts that were associated with tree age (old), soil contact and moisture. Occurrence of Ganoderma lucidum in living trees is recognized as a distinct disease and is strongly associated with declining of A. indica among ornamental trees in University of Port Harcourt, Nigeria. A disk obtained from one of the dying tree was still hard enough without any visible xylem decay, stain, tunnel and discolouration to produce furniture and other indoor wood products for the University community. This study suggests that the trees could be selectively harvested for furniture while replacement with non-vulnerable and fast growing tree like Gmelina arborea is advised before complete harvesting is carried out. (Adedeji, G. A., A. A. Aiyeloja and G. E. Omokhua. Occurrence and Severity of Ganoderma lucidum (Fr.) P. Karst. on Azadirachta indica Tree in University of Port Harcourt, Nigeria: Implications for Sustainable Harvesting and Replacement. Nat Sci 2014;12(8):123-128). (ISSN: 1545-0740). http://www.sciencepub. net/nature. 17
Ridesharing in North America: Past, Present, and Future

Since the late 1990s, numerous ridematching programmes have integrated the Internet, mobile phones, and social networking into their services. Online ridematching systems are employing a range of new strategies to create “critical mass”: (1) regional and large employer partnerships, (2) financial incentives, (3) social networking to younger populations, and (4) real-time ridematching services that employ “smartphones” and automated ridematching software. Enhanced casual carpooling approaches, which focus on “meeting places”, are also being explored. Today, ridesharing represents approximately 8–11% of the transportation modal share in Canada and the USA, respectively. There are approximately 638 ridematching programmes in North America. Ridesharing's evolution can be categorized into five phases: (1) World War II car-sharing (or carpooling) clubs; (2) major responses to the 1970s energy crises; (3) early organized ridesharing schemes; (4) reliable ridesharing systems; and (5) technology-enabled ridematching. While ridesharing's future growth and direction are uncertain, the next decade is likely to include greater interoperability among services, technology integration, and stronger policy support. In light of growing concerns about climate change, congestion, and oil dependency, more research is needed to better understand ridesharing's impacts on infrastructure, congestion, and energy/emissions.
Paleomagnetic evidence for ∼4000 km of crustal shortening across the 1 Ga Grenville orogen of North America

Paleomagnetic data from the Grenville Province of North America suggest that Laurentia underwent ∼4000 ± 1000 km of crustal shortening from ca. 1040–1020 Ma to 980 Ma as a result of the Grenville orogeny, in which Laurentia was in collision with Amazonia. A corollary is that the size and scale of shortening affect the assembly of continental fragments that include Laurentia, which before 1 Ga may have been significantly larger in area than now by thousands of square kilometers, caused by crustal shortening in a broadly northwest-southeast direction by the Grenville orogeny.