bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues
Authors: Pearson Gemma L. , Walker Emily M. , Lawlor Nathan , Lietzke Anne , Sidarala Vaibhav , Zhu Jie , Stromer Tracy , Reck Emma C. , Stendahl Ava M. , Li Jin , Levi-D’Ancona Elena , Pasmooij Mabelle B. , Hubers Dre L. , Renberg Aaron , Mohamed Kawthar , Parekh Vishal S. , Zhang Irina X. , Thompson Benjamin , Zhang Deqiang , Ware Sarah A. , Haataja Leena , Parker Stephen C.J. , Arvan Peter , Yin Lei , Kaufman Brett A. , Satin Leslie S. , Sussel Lori , Stitzel Michael L. , Soleimanpour Scott A. 
Published: August 2022

ABSTRACTMitochondrial damage is a hallmark of metabolic diseases, including diabetes and metabolic dysfunction-associated steatotic liver disease, yet the consequences of impaired mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity across multiple metabolic tissues. Surprisingly, we demonstrate that defects in the mitochondrial quality control machinery, which we observe in pancreatic β cells of humans with type 2 diabetes, cause reductions of β cell mass due to dedifferentiation, rather than apoptosis. Utilizing transcriptomic profiling, lineage tracing, and assessments of chromatin accessibility, we find that targeted deficiency anywhere in the mitochondrial quality control pathway (e.g., genome integrity, dynamics, or turnover) activate the mitochondrial integrated stress response and promote cellular immaturity in β cells, hepatocytes, and brown adipocytes. Intriguingly, pharmacologic blockade of mitochondrial retrograde signalingin vivorestores β cell mass and identity to ameliorate hyperglycemia following mitochondrial damage. Thus, we observe that a shared mitochondrial retrograde response controls cellular identity across metabolic tissues and may be a promising target to treat or prevent metabolic disorders.
Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST
Authors: Long Yahui , Ang Kok Siong , Li Mengwei , Chong Kian Long Kelvin , Sethi Raman , Zhong Chengwei , Xu Hang , Ong Zhiwei , Sachaphibulkij Karishma , Chen Ao , Li Zeng , Fu Huazhu , Wu Min , Lim Hsiu Kim Lina , Liu Longqi , Chen Jinmiao 
Published: August 2022

AbstractAdvances in spatial transcriptomics technologies have enabled the gene expression profiling of tissues while retaining its spatial context. Effective exploitation of this data combination requires spatially informed analysis tools to perform three key tasks, spatial clustering, multi-sample integration, and cell type deconvolution. Here, we present GraphST, a novel graph self-supervised contrastive learning method that incorporates spatial location information and gene expression profiles to accomplish all three tasks in a streamlined process while outperforming existing methods in each task. GraphST combines graph neural networks with self-supervised contrastive learning to learn informative and discriminative spot representations by minimizing the embedding distance between spatially adjacent spots and vice versa. With GraphST, we achieved 10% higher clustering accuracy on multiple datasets than competing methods, and better delineated the fine-grained structures in tissues such as the brain and embryo. Moreover, GraphST is the only method that can jointly analyze multiple tissue slices in both vertical and horizontal integration while correcting for batch effects. Lastly, compared to other methods, GraphST’s cell type deconvolution achieved higher accuracy on simulated data and better captured spatial niches such as the germinal centers of the lymph node in experimentally acquired data. We further showed that GraphST can recover the immune cell distribution in different regions of breast tumor tissue and reveal spatial niches with exhausted tumor infiltrating T cells. Through our examples, we demonstrated that GraphST is widely applicable to a broad range of tissue types and technology platforms. In summary, GraphST is a streamlined, user friendly and computationally efficient tool for characterizing tissue complexity and gaining biological insights into the spatial organization within tissues.
UVC-based air disinfection system for rapid inactivation of SARS-CoV-2 present in the air
Authors: Garg Harry , Ringe Rajesh P. , Das Supankar , Parkash Suraj , Thakur Bhuwaneshwar , Delipan Rathina , Kumar Ajay , Kulkarni Kishor , Bansal Kanika , Patil Prabhu B. , Alam Tabish , Balam Nagesh Babu , Meena Chandan Swaroop , Thakur Krishan Gopal , Kumar Ashok , Kumar Ashwani 
Published: August 2022

AbstractThe novel coronavirus disease 2019 (COVID-19) infections have rapidly spread throughout the world, and the virus has acquired an ability to spread via aerosols even at long distances. Hand washing, face-masking, and social distancing are the primary preventive measures against infections. With mounting scientific evidence, World Health Organisation (WHO) declared COVID-19 an air-borne disease. This ensued the need to disinfect air to reduce the transmission. Ultraviolet C (UVC) comprising the light radiation of 200-280 nm range is a commonly used method for inactivation of pathogens. The heating, ventilation, and air conditioning (HVAC) systems are not beneficial in closed spaces due to poor or no ability to damage circulating viruses. Therefore, standard infection-prevention practices coupled with a strategy to reduce infectious viral load in air substantially might be helpful in reducing virus transmissibility. In this study, we implemented UV light-based strategies to combat COVID-19 and future pandemics. We tested various disinfection protocols by using UVC-based air purification systems and currently installed such a system in workspaces, rushed out places, hospitals and healthcare facilities for surface, air, and water disinfection. In this study, we designed a prototype device to test the dose of UVC required to inactivate SARS-CoV-2 in aerosols and demonstrate that the radiation rapidly destroys the virus in aerosols. The UVC treatment renders the virus non-infectious due to chemical modification of nucleic acid. We also demonstrate that UVC treatment alters the Spike protein conformation that may further affect the infectivity of the virus. We show by using a mathematical model based on the experimental data that UVC-based air disinfection strategy can substantially reduce the risk of virus transmission. The systematic treatment by UVC of air in the closed spaces via ventilation systems could be helpful in reducing the active viral load in the air.
Tudor domain containing protein 5-like(Tdrd5l) identifies a novel germline body and regulates maternal RNAs during oogenesis
Authors: Pozmanter Caitlin , Benner Leif , Kelly Sydney E , Curnutte Harrison , Van Doren Mark 
Published: August 2022

AbstractTudor domain-containing proteins are conserved across the animal kingdom for their function in germline development and fertility. Previously, we demonstrated thatTudor domain-containing protein 5-like (Tdrd5l)plays an important role in the germline where it promotes male identity. However, Tdrd5l is also expressed in both the ovary and testis during later stages of germline development, suggesting that it plays a role in germline differentiation in both sexes. We found that Tdrd5l localizes to a potentially novel germline body and plays a role in post-transcriptional gene regulation. RNA sequencing ofTdrd5l-mutant ovaries compared to wild-type showed that differentially expressed genes were enriched for maternally deposited RNAs. Additionally, embryos laid byTdrd5l-mutant females exhibited reduced viability and displayed dorsal appendage defects suggesting a failure of proper dorsal-ventral (D/V) patterning. As D/V patterning is dependent ongurken (grk), we examined Grk expression during oogenesis. We observed premature accumulation of Grk protein in nurse cells indicating that translation is no longer properly repressed during mRNA transport to the oocyte. We also observed increased nurse cell accumulation of the cytoplasmic polyadenylation element binding protein Oo18 RNA-Binding Protein (Orb or CPEB), a translational activator of Grk. Decreasingorbfunction was able to partially rescue theTdrd5l-mutant phenotype, and so defects in Orb are likely a primary cause of the defects inTdrd5lmutants. Our data indicate thatTdrd5lis important for translational repression of maternal mRNAs such asorb, and possibly others, following their synthesis in the nurse cells and during their transport to the oocyte.
Prediction of the 3D cancer genome from genomic rearrangements using InfoHiC
Authors: Lee Yeonghun , Park Sung-Hye , Lee Hyunju 
Published: August 2022

AbstractAlthough cancer genomes often contain complex genomic rearrangements, its impact on tumorigenesis is still unclear, especially when they are involved in non-coding regions. Understanding 3D genome architecture is crucial for uncovering the impacts of genomic rearrangements. Here, we present InfoHiC, a method for predicting 3D genome folding and cancer Hi-C from complex genomic rearrangements. InfoHiC provides distinct interaction views of multiple contigs from the cancer Hi-C matrix. We then validated cancer Hi-C prediction using breast cancer cell line data and found contig-specific interaction changes. Moreover, we applied InfoHiC to patients with breast cancer and identified neo topologically associating domains and super-enhancer hijacking events associated with oncogenic overexpression and poor survival outcomes. Finally, we applied InfoHiC to pediatric patients with medulloblastoma, and found genomic rearrangements in non-coding regions that caused super-enhancer hijacking events of medulloblastoma driver genes (GFI1, GFI1B, and PRDM6). In summary, InfoHiC can predict genome folding changes in cancer genomes and may reveal therapeutic targets by uncovering the functional impacts of non-coding genomic rearrangements.
A four-point molecular handover during Okazaki maturation
Authors: Botto Margherita M. , Borsellini Alessandro , Lamers Meindert H. 
Published: August 2022

ABSTRACTDNA replication introduces thousands of RNA primers into the lagging strand that need to be removed for replication to be completed. In Escherichia coli when the replicative DNA polymerase Pol IIIα terminates at a previously synthesized RNA primer, DNA Pol I takes over and continues DNA synthesis while displacing the downstream RNA primer. The displaced primer is subsequently excised by an endonuclease, followed by the sealing of the nick by a DNA ligase. Yet how the sequential actions of Pol IIIα, Pol I, endonuclease and ligase are coordinated is poorly defined. Here we show that each enzymatic activity prepares the DNA substrate for the next activity, creating an efficient four-point molecular handover. The cryo-EM structure of Pol I bound to a DNA substrate with both an upstream and downstream primer reveals how it displaces the primer in a manner analogous to the monomeric helicases. Moreover, we find that in addition to its flap-directed nuclease activity, the endonuclease domain of Pol I also specifically cuts at the RNA/DNA junction, thus marking the end of the RNA primer and creating an 5’ end that is a suitable substrate for the ligase activity of LigA once all RNA has been removed.
Pleiotropy promotes the evolution of inducible immune responses in a model of host-pathogen coevolution
Authors: Martin Reese A. , Tate Ann T. 
Published: August 2022

AbstractComponents of immune systems face significant selective pressure to efficiently use organismal resources, mitigate infection, and resist parasitic manipulation. A theoretically optimal immune defense balances investment in constitutive and inducible immune components depending on the kinds of parasites encountered, but genetic and dynamic constraints can force deviation away from theoretical optima. One such potential constraint is pleiotropy, the phenomenon where a single gene affects multiple phenotypes. Although pleiotropy can prevent or dramatically slow adaptive evolution, it is prevalent in the signaling networks that compose metazoan immune systems. We hypothesized that pleiotropy is maintained in immune signaling networks despite slowed adaptive evolution because it provides some other advantage, such as forcing network evolution to compensate in ways that increase host fitness during infection. To study the effects of pleiotropy on the evolution of immune signaling networks, we used an agent-based modeling approach to evolve a population of host immune systems infected by simultaneously co-evolving parasites. Four kinds of pleiotropic restrictions on evolvability were incorporated into the networks, and their evolutionary outcomes were compared to, and competed against, non-pleiotropic networks. As the networks evolved, we tracked several metrics of immune network complexity, relative investment in inducible and constitutive defenses, and features associated with the winners and losers of competitive simulations. Our results suggest non-pleiotropic networks evolve to deploy highly constitutive immune responses regardless of parasite prevalence, but some implementations of pleiotropy favor the evolution of highly inducible immunity. These inducible pleiotropic networks are no less fit than non-pleiotropic networks and can out-compete non-pleiotropic networks in competitive simulations. These provide a theoretical explanation for the prevalence of pleiotropic genes in immune systems and highlight a mechanism that could facilitate the evolution of inducible immune responses.Author SummaryGenes involved in immune defense are hotspots of adaptive evolution as they resist rapidly evolving parasites and pathogens. Pleiotropic genes, which affect multiple discrete traits, have been shown to evolve at a much slower rate than non-pleiotropic genes but are highly represented in the immune system. The evolutionary effects of pleiotropic signaling genes on immune evolution are poorly understood, so we developed a model of pleiotropic signaling network evolution to address this gap in knowledge. Our results show that pleiotropy may be an important genomic feature in the development of inducible immunity.
Coupling of protein condensates to ordered lipid domains determines functional membrane organization
Authors: Wang Hong-Yin , Chan Sze Ham , Dey Simli , Castello-Serrano Ivan , Ditlev Jonathon A. , Rosen Michael K. , Levental Kandice R , Levental Ilya 
Published: August 2022

ABSTRACTDuring T-cell activation, the transmembrane adaptor Linker of Activation of T-cells (LAT) forms biomolecular condensates with Grb2 and Sos1, facilitating signaling. LAT has also been associated with cholesterol-rich condensed lipid domains. However, the potential coupling between protein condensation and lipid phase separation and its role in organizing T-cell signaling were unknown. Here, we report that LAT/Grb2/Sos1 condensates reconstituted on model membranes can induce and template lipid domains, indicating strong coupling between lipid- and protein-based phase separation. Correspondingly, activation of T-cells induces protein condensates that associate with and stabilize raft-like membrane domains. Inversely, lipid domains nucleate and stabilize LAT protein condensates in both reconstituted and living systems. This coupling of lipid and protein assembly is functionally important, since uncoupling of lipid domains from cytoplasmic protein condensates abrogates T-cell activation. Thus, thermodynamic coupling between protein condensates and ordered lipid domains regulates the functional organization of living membranes.SUMMARYMembrane-associated protein condensates couple to ordered membrane domains to determine the functional organization of T-cell plasma membranes
How Subjective Idea Valuation Energizes and Guides Creative Idea Generation
Authors: Lopez-Persem Alizée , Rodriguez Sarah Moreno , Ovando-Tellez Marcela , Bieth Théophile , Guiet Stella , Brochard Jules , Volle Emmanuelle 
Published: August 2022

AbstractWhat drives us to search for creative ideas, and why does it feel good to find one? While previous studies demonstrated the positive influence of motivation on creative abilities, how reward and subjective values play a role in creativity remains unknown. This study proposes to characterize the role of individual preferences (how people value ideas) in creative ideation via behavioral experiments and computational modeling. Using the Free Generation of Associates Task coupled with rating tasks, we demonstrate the involvement of valuation processes during idea generation: preferred ideas are provided faster. We found that valuation depends on the adequacy and originality of ideas and guides response selection and creativity. Finally, our computational model correctly predicts the speed and quality of human creative responses, as well as interindividual differences in creative abilities. Altogether, this model introduces the mechanistic role of valuation in creativity. It paves the way for a neurocomputational account of creativity mechanisms.Public Significance StatementThis study addresses the role of individual preferences in creativity. It demonstrates that preferences for ideas energize creative idea production: the more participants like their ideas, the faster they provide them. Moreover, preferences rely on an equilibrium between the adequacy and originality of ideas and vary across individuals. This study introduces a computational model which incorporates individual preferences and that correctly predicts the speed and quality of responses in a creative idea generation task, as well as inter-individual differences in creative abilities. Comparison of several versions of this model demonstrated that preferences guide the selection of creative responses.
A high-speed, modular display system for diverse neuroscience applications
Authors: Isaacson Matthew , Ferguson Lisa , Loesche Frank , Ganguly Ishani , Chen Jim , Chiu Andy , Liu Jinyang , Dickson William , Reiser Michael 
Published: August 2022

AbstractVisual stimulation of animals in the laboratory is a powerful technique for studying sensory control of complex behaviors. Since commercial displays are optimized for human vision, we established a novel display system based on custom-built modular LED panels that provides millisecond refresh, precise synchronization, customizable color combinations, and varied display configurations. This system simplifies challenging experiments. With variants of this display, we probed the speed limits of motion vision and examined the role of color vision in behavioral experiments with tethered flying Drosophila. Using 2-photon calcium imaging, we comprehensively mapped the tuning of visual projection neurons across the fly’s field of view. Finally, using real-time behavior analysis, we developed low-latency interactive virtual environments and found that flying flies can independently control their navigation along two dimensions. This display system uniquely addresses most technical challenges of small animal vision experiments and is thoroughly documented for replicability.
Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
Authors: Casalino Lorenzo , Seitz Christian , Lederhofer Julia , Tsybovsky Yaroslav , Wilson Ian A. , Kanekiyo Masaru , Amaro Rommie E. 
Published: August 2022

AbstractInfluenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from human convalescent plasma, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza.One-Sentence SummaryIn situ dynamics of influenza glycoproteins expose antigenically relevant states and a new site of vulnerability in neuraminidase.
Multiple T6SSs, mobile auxiliary modules, and effectors revealed in a systematic analysis of theVibrio parahaemolyticuspan-genome
Authors: Jana Biswanath , Keppel Kinga , Fridman Chaya Mushka , Bosis Eran , Salomon Dor 
Published: August 2022

AbstractType VI secretion systems (T6SSs) play a major role in interbacterial competition and in bacterial interactions with eukaryotic cells. The distribution of T6SSs and the effectors they secrete vary between strains of the same bacterial species. Therefore, a pan-genome investigation is required to better understand the T6SS potential of a bacterial species of interest. Here, we performed a comprehensive, systematic analysis of T6SS gene clusters and auxiliary modules found in the pan-genome ofVibrio parahaemolyticus, an emerging pathogen widespread in marine environments. We identified four different T6SS gene clusters within genomes of this species; two systems appear to be ancient and widespread, whereas the other two systems are rare and appear to have been more recently acquired via horizontal gene transfer. In addition, we identified diverse T6SS auxiliary modules containing putative effectors with either known or predicted toxin domains. Many auxiliary modules are possibly horizontally shared betweenV. parahaemolyticusgenomes, since they are flanked by DNA mobility genes. We further investigated a DUF4225-containing protein encoded on an Hcp auxiliary module, and we showed that it is an antibacterial T6SS effector that exerts its toxicity in the bacterial periplasm, leading to cell lysis. Computational analyses of DUF4225 revealed a widespread toxin domain associated with various toxin delivery systems. Taken together, our findings reveal a diverse repertoire of T6SSs and auxiliary modules in theV. parahaemolyticuspan-genome, as well as novel T6SS effectors and toxin domains that can play a major role in the interactions of this species with other cells.ImportanceGram-negative bacteria employ toxin delivery systems to mediate their interactions with neighboring cells.Vibrio parahaemolyticus, an emerging pathogen of humans and marine animals, was shown to deploy antibacterial toxins into competing bacteria via the type VI secretion system (T6SS). Here, we analyzed 1,727V. parahaemolyticusgenomes and revealed the pan-genome T6SS repertoire of this species, including the T6SS gene clusters, horizontally shared auxiliary modules, and toxins. We also identified a role for a previously uncharacterized domain, DUF4225, as a widespread antibacterial toxin associated with diverse toxin delivery systems.