bluuebunny/crossref_metadata_2025_split huggingface dataset:
A D-2-Hydroxyglutarate dehydrogenase mutant reveals a critical role for ketone body metabolism in Caenorhabditis elegans development
Authors: Ponomarova Olga , Zhang Hefei , Li Xuhang , Nanda Shivani , Leland Thomas B. , Fox Bennett W. , Giese Gabrielle E. , Schroeder Frank C. , Yilmaz L. Safak , Walhout Albertha J.M. 
Published: May 2022

SUMMARYIn humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Deletion of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the upregulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG, or by supplementing either vitamin B12 or the ketone body 3-hydroxybutyrate (3HB). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low, and in which a loss of dhgd-1 causes lethality by limiting ketone body production.HIGHLIGHTS-D-2-hydroxyglutarate is produced by HPHD-1 in the propionate shunt pathway-DHGD-1 recycles 2-hydroxyglutarate to sustain flux through the propionate shunt-dhgd-1 loss perturbs ketone body metabolism and causes embryonic lethality-3-Hydroxybutyrate, vitamin B12 or hphd-1 RNAi rescue dhgd-1 mutant lethality
Genomic screening reveals UBA1 as a potent and druggable target in c-MYC-high TNBC models
Authors: Jacob Sheeba , Turner Tia H. , Cai Jinyang , Floros Konstantinos V. , Yu Ann K. , Coon Colin M. , Khatri Rishabh , Alzubi Mohammad A. , Jakubik Charles T. , Bouck Ynes M. , Puchalapalli Madhavi , Shende Mayuri , Dozmorov Mikhail G. , Boikos Sosipatros A. , Hu Bin , Harrell J. Chuck , Benes Cyril H. , Koblinski Jennifer E. , Costa Carlotta , Faber Anthony C. 
Published: May 2022

AbstractTriple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10%–15% of total breast cancer cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Targeting UBA1 with the first in-class UBA1 inhibitor TAK-243 induced unresolvable ER-stress and activating transcription factor 4 (ATF4)-mediated upregulation of pro-apoptotic NOXA, leading to cell death. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. In an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. Lastly, c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. We posit UBA1 is an important new target in TNBC expressing high levels of c-MYC.SignificanceGenomic screening of TNBC cell lines revealed broad sensitivity to depletion of the E1 ubiquitin enzyme, UBA1. Disrupting UBA1 with the first in-class inhibitor TAK-243 in TNBC models induces ER-stress through an ATF4-NOXA axis that is dependent on c-MYC, leading to apoptosis, in vitro and in vivo, primary tumor growth inhibition and metastatic inhibition.
Molecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2
Authors: Yuan Meng , Wang Yiquan , Lv Huibin , Wilson Ian A. , Wu Nicholas C. 
Published: May 2022

ABSTRACTAs SARS-CoV-2 variants of concerns (VOCs) continue to emerge, cross-neutralizing antibody responses become key towards next-generation design of a more universal COVID-19 vaccine. By analyzing published data from the literature, we report here that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes all VOCs to date, including Omicron and its sub-lineages. Detailed molecular analysis shows that the complementarity-determining region H3 sequences of IGHV2-5/IGLV2-14-encoded RBD antibodies have a preferred length of 11 amino acids and a conserved HxIxxI motif. In addition, these antibodies have a strong allelic preference due to an allelic polymorphism at amino-acid residue 54 of IGHV2-5, which locates at the paratope. These findings have important implications for understanding cross-neutralizing antibody responses to SARS-CoV-2 and its heterogenicity at the population level as well as the development of a universal COVID-19 vaccine.
stainlib: a python library for augmentation and normalization of histopathology H&E images
Authors: Otálora Sebastian , Marini Niccoló , Podareanu Damian , Hekster Ruben , Tellez David , Van Der Laak Jeroen , Müller Henning , Atzori Manfredo 
Published: May 2022

AbstractComputational pathology is a domain of increasing scientific and social interest. The automatic analysis of histopathology images stained with Hematoxylin and Eosin (H&E) can help clinicians diagnose and quantify diseases. Computer vision methods based on deep learning can perform on par or better than pathologists in specific tasks [1, 2, 15]. Nevertheless, the visual heterogeneity in histopathology images due to batch effects, differences in preparation in different pathology laboratories, and the scanner can produce tissue appearance changes in the digitized whole-slide images. Such changes impede the application of the trained models in clinical scenarios where there is high variability in the images. We introduce stainlib, an easy-to-use and expandable python3 library that collects and unifies state-of-the-art methods for color augmentation and normalization of histopathology H&E images. stainlib also contains recent deep learning-based approaches that perform a robust stain-invariant training of CNN models. stainlib can help researchers build models robust to color domain shift by augmenting and harmonizing the training data, allowing the deployment of better models in the digital pathology practice.
Cartilage-penetrating hyaluronic acid hydrogel preserves tissue content and reduces chondrocyte catabolism
Authors: Kowalski Michael A. , Fernandes Lorenzo M. , Hammond Kyle E. , Labib Sameh , Drissi Hicham , Patel Jay M. 
Published: May 2022

AbstractArticular cartilage injuries have a limited healing capacity and, due to inflammatory and catabolic activities, often experience progressive degeneration towards osteoarthritis. Current repair techniques generally provide short-term symptomatic relief; however, the regeneration of hyaline cartilage remains elusive, leaving both the repair tissue and surrounding healthy tissue susceptible to long-term wear. Therefore, methods to preserve cartilage following injury, especially from matrix loss and catabolism, are needed to delay, or even prevent, the deteriorative process. The goal of this study was to develop and evaluate a cartiage-penetrating hyaluronic-acid (HA) hydrogel to improve damaged cartilage biomechanics and prevent tissue degeneration. At time zero, the HA-based hydrogel provided a 46.5% increase in compressive modulus and a decrease in permeability after simulated degeneration of explants (collagenase application). Next, in a degenerative culture model (interleukin-1 β [IL-1β] for 2 weeks), hydrogel application prior to or midway through the culture mitigated detrimental changes to compressive modulus and permeability observed in non-treated explants. Furthermore, localized loss of proteoglycan was observed in degenerative culture conditions alone (non-treated), but hydrogel administration significantly improved the retention of matrix elements. Finally, NITEGE staining and gene expression analysis showed the ability of the HA gel to decrease chondrocyte catabolic activity. These results highlight the importance of reinforcing damaged cartilage with a biomaterial system to both preserve tissue content and reduce catabolism associated with injury and inflammation.
Benefits of global mutant huntingtin lowering diminish over time in a Huntington’s disease mouse model
Authors: Marchionini Deanna M. , Liu Jeh-Ping , Ambesi-Impiombato Alberto , Cox Kimberly , Cirillo Kim , Bansal Mukesh , Mushlin Rich , Brunner Daniela , Ramboz Sylvie , Kwan Mei , Kuhlbrodt Kirsten , Tillack Karsten , Peters Finn , Rauhala Leena , Obenauer John , Greene Jonathan R. , Hartl Christopher , Khetarpal Vinod , Lager Brenda , Rosinski Jim , Aaronson Jeff , Alam Morshed , Signer Ethan , Muñoz-Sanjuán Ignacio , Howland David , Zeitlin Scott O. 
Published: May 2022

AbstractWe have developed a novel inducible Huntington’s disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant Huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (∼50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow up revealed that the benefits, in all mHtt lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12- months of age and late mHtt lowering was unable to ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefit in humans.
Visual experience has opposing influences on the quality of stimulus representation in adult primary visual cortex
Authors: Jeon Brian B. , Fuchs Thomas , Chase Steven M. , Kuhlman Sandra J. 
Published: May 2022

AbstractTransient dark exposure, typically 7-10 days in duration, followed by light reintroduction is an emerging treatment for improving the restoration of vison in amblyopic subjects whose occlusion is removed in adulthood. Dark exposure initiates homeostatic mechanisms that together with light-induced changes in cellular signaling pathways result in the re-engagement of juvenile-like plasticity in the adult such that previously deprived inputs can gain cortical territory. It is possible that dark exposure itself degrades visual responses, and this could place constraints on the optimal duration of dark exposure treatment. To determine whether eight days of dark exposure has a lasting negative impact on responses to classic grating stimuli, neural activity was recorded before and after dark exposure in awake head-fixed mice using 2-photon calcium imaging. Neural discriminability, assessed using classifiers, was transiently reduced following dark exposure; a decrease in response reliability across a broad range of spatial frequencies accounted for the disruption. Both discriminability and reliability recovered. Fixed classifiers were used to demonstrated that stimulus representation rebounded to the original, pre-deprivation state, thus DE did not appear to have a lasting negative impact on visual processing. Unexpectedly, we found that dark exposure significantly stabilized orientation preference and signal correlation. Our results reveal that natural vision exerts a disrupting influence on the stability of stimulus preference for classic grating stimuli, and at the same time improves neural discriminability for both low and high spatial frequency stimuli.
Zygotic genome activation by the totipotency pioneer factor Nr5a2
Authors: Gassler Johanna , Kobayashi Wataru , Gáspár Imre , Ruangroengkulrith Siwat , Kümmecke Maximilian , Kravchenko Pavel , Zaczek Maciej , Vallot Antoine , Hernandez Laura Gomez , Rico Laura Cuenca , Ladstätter Sabrina , Tachibana Kikuë 
Published: May 2022

AbstractLife begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA) in totipotent embryos. Despite its importance, the essential regulators of ZGA remain largely unknown in mammals. Based on de novo motif searches, we identified the orphan nuclear receptor Nr5a2 as a key activator of major ZGA in mouse embryos. Nr5a2 binds to its motif within a subtype of SINE B1/Alu transposable elements found in cis-regulatory regions of ZGA genes. Chemical inhibition suggests that 72% of ZGA genes are regulated by Nr5a2 and potentially other orphan nuclear family receptors. Consistent with a role in ZGA, Nr5a2 is required for progression beyond the 2-cell stage. Nr5a2 promotes chromatin accessibility during ZGA and binds to entry/exit sites of nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that distinctly regulates totipotency and pluripotency during mammalian development.One-Sentence SummaryNr5a2 is an essential pioneer transcription factor that activates expression of zygotic genes in mouse embryos.
Limited Cross-Species Virus Transmission in a Spatially Restricted Coral Reef Fish Community
Authors: Costa Vincenzo A. , Bellwood David R. , Mifsud Jonathon C.O. , Geoghegan Jemma L. , Holmes Edward C. , Harvey Erin 
Published: May 2022

AbstractThe Great Barrier Reef (GBR) – the largest coral reef ecosystem in the world – supports over 1200 fish species with some of the highest population densities and diversities seen in vertebrates, offering a high potential for virus transmission among species. As such, the GBR represents an exceptional natural ecosystem to determine the impact of host community diversity on virus evolution and emergence. In recent decades the GBR has also experienced significant threats of extinction, making it one of the most vulnerable ecosystems on the planet. However, our understanding of virus diversity and connectivity in tropical reef fishes remains poor. Here, we employed metatranscriptomic sequencing to reveal the viromes of 61 reef fish species. This identified a total of 132 viruses, 38 of which were vertebrate-associated and therefore likely infecting the fish, including a novel isolate ofSantee-cooper ranavirus(Iridoviridae). Notably, we found little evidence for virus transmission between fish species living within a very restricted geographical space – a 100 m2coral reef ecosystem – suggesting that there might be important host genetic barriers to successful cross-species transmission despite regular exposure. We also identified differences in virome composition between reef fish families, such that cryptobenthic reef fishes – characterized by small body sizes and short life-spans – exhibited greater virome richness compared to large reef fishes. This study suggests that there are important barriers to cross-species transmission, and that successful emergence in a reef fish community likely requires active host adaptation, even among closely related host species.
Lipidomic profiling reveals concerted temporal patterns of functionally related lipids inAedes aegyptifemales following blood feeding
Authors: Lau Meng-Jia , Nie Shuai , Yang Qiong , Harshman Lawrence G. , Mao Cungui , Williamson Nicholas A. , Hoffmann Ary A. 
Published: May 2022

AbstractWe conducted a lipidomic analysis of the whole body of femaleAedes aegyptimosquitoes at different time points over the course of feeding and reproduction. There were temporal biphasic increases of more than 80% of lipids identified at the time of feeding and from 16 h to 30 h post blood meal. During these two increases, the abundance of many lipids dropped while body weight remained stable, probably reflecting blood lipid digestion and the synthesis of vitellogenin in this period. A concerted temporal pattern was particularly strong at the second peak for membrane and signalling lipids such as PE, PI, CL, HexCer and LPA. Lyso-glycerophospholipids showed three distinct change patterns which are functionally related: LPE and LPC, which are membrane lipids, showed little change; LPA, a signalling lipid, showed a dramatic increase from 16 to 30 h PBM; LPI, a bioactive lipid, and both LPG and LPS which are bacterial membrane lipids, showed one significant increase from the time of feeding to 16 hours post blood meal. The result of our study on the anautogenous insectAe. aegyptipoint to specific lipids likely to be important in the reproductive process with a role in the formation and growth of ovarian follicles.
Mating disrupts morning anticipation inDrosophila melanogasterfemales
Authors: Riva Sabrina , Ispizua Juan Ignacio , Breide María Trinidad , Polcowñuk Sofía , Lobera José Ricardo , Ceriani M. Fernanda , Risau Gusman Sebastian , Franco D. Lorena 
Published: May 2022

AbstractAfter mating, the physiology ofDrosophilafemales undergoes several important changes, some of which are reflected in their rest-activity cycles. To explore the hypothesis that mating modifies the temporal organization of locomotor activity patterns, we recorded the fly activity by a video tracking method. Monitoring rest-activity patterns under light/dark (LD) cycles indicated that mated females lose their ability to anticipate the night-day transition, in stark contrast to males and virgins; this postmating response is mediated by the sex peptide (SP) acting mainly onpickpocket(ppk) expressing neurons, since reducing expression of the SP receptor (SPR) in these neurons restores the ability to anticipate the LD transition in mated females. We further provide evidence of connectivity between PPK+ neurons and the pigment-dispersing factor (PDF)-positive ventral lateral neurons (sLNv), which play a central role in the temporal organization of daily activity. Since PDF has been associated to the generation of the morning activity peak, we hypothesized that the mating signal could modulate PDF levels. Indeed, mated females have reduced PDF levels at the dorsal protocerebrum; moreover, SPR downregulation in PPK+ neurons mimics PDF levels observed in males. In sum, our results are consistent with a model whereby mating-triggered signals reaches clock neurons in the fly central nervous system to modulate the temporal organization of circadian behavior according to the needs of the new status.Author SummaryAfter mating,Drosophilafemales undergoes striking behavioral changes, specially in their activity patterns. Despite some of the circuits that deliver mating signals to the female brain are known the connection with the circadian network has not been explored in detail. Here, we show that mating changes the onset of daily activity, masking a central function of the clock. This modulation is mediated by the sex peptide (transferred during courtship) acting on PPK+ neurons, which, in turn, directly contact PDF+ neurons, responsible for the increase of the activity that precedes dawn. Thus, our work identifies a postmating response directly related to the circadian clock, and begins to unravel the underlying neuronal circuit.
Collective directional migration drives the formation of heteroclonal cancer cell clusters
Authors: Palmiero Miriam , Di Blasio Laura , Monica Valentina , Peracino Barbara , Primo Luca , Puliafito Alberto 
Published: May 2022

ABSTRACTMetastasisation occurs through the acquisition of invasive and survival capabilities that allow tumour cells to colonise distant sites. While the role of multicellular aggregates in cancer dissemination is acknowledged, the mechanisms that drive the formation of multi-clonal cell aggregates are not fully elucidated. Here we show that cancer cells of different tissue of origins can perform collective directional migration and can actively form heteroclonal aggregates in 3D, through a proliferation-independent mechanism. Coalescence of distant cell clusters is mediated by subcellular actin-rich protrusions and multicellular outgrowths that extend towards neighbouring aggregates. Coherently, perturbation of cytoskeletal dynamics impairs collective migration while myosin II activation is necessary for multicellular movements. We put forward the hypothesis that cluster attraction is mediated by secreted soluble factors consistently with the abrogation of aggregation by inhibition of PI3K/AKT/mTOR and MEK/ERK, with evidence that conditioned culture media act as chemoattractant and corroborated by a wide screening on secreted proteins. Our results present a novel collective migration model and shed light on the mechanisms of formation of heteroclonal aggregates in cancer.
Analysis of proteome adaptation reveals a key role of the bacterial envelope in starvation survival
Authors: Schink Severin , Ammar Constantin , Chang Yu-Fang , Zimmer Ralf , Basan Markus 
Published: May 2022

AbstractBacteria reorganize their physiology upon entry to stationary phase. What part of this reorganization improves starvation survival is a difficult question, because the change in physiology includes a global reorganization of the proteome, envelope and metabolism of the cell. In this work, we used several trade-offs between fast growth and long survival to statistically score over 2000E. coliproteins for their global correlation with death rate. The combined ranking allowed us to narrow down the set of proteins that positively correlate with survival and validate the causal role of a subset of proteins. Remarkably, we found that important survival genes are related to the cell envelope, i.e., periplasm and outer membrane, because maintenance of envelope integrity ofE. coliplays a crucial role during starvation. Our results uncover a new protective feature of the outer membrane that adds to the growing evidence that the outer membrane is not only a barrier that prevents abiotic substances from reaching the cytoplasm, but essential for bacterial proliferation and survival.Standfirst textA trade-off between the two major modes of bacterial lifestyle, growth and starvation can be explained by bacteria investing resources into the cell envelope to make it impermeable to ions, which improves their lifespan but comes at the expense of slowing down growth.HighlightsA trade-off between growth rate and death rate confines fitness of bacteria across environments.Analysis of proteome signatures in 126 conditions across five independent perturbations reveals the cell envelope as a key determinant of death rate.The trade-off can be abolished by changing environment to a low-salt, but osmo-balanced medium where cell envelope integrity is not limiting.