bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of the macrolide resistance ABC-F translation factor MsrD
Authors: Fostier Corentin R. , Ousalem Farès , Leroy Elodie C. , Ngo Saravuth , Soufari Heddy , Innis C. Axel , Hashem Yaser , Boёl Grégory 
Published: November 2021

SUMMARYAntibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors currently proliferating among human pathogens that provide resistance against clinically important ribosome-targeting antibiotics. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure and also demonstrate that MsrD twin-ATPase sites work asymmetrically to mediate the dynamic of MsrD interaction with the ribosome. We show that cladinose-containing macrolides lead to insertion of MsrDL leader peptide into an undocumented conserved crevice of the ribosomal exit tunnel concomitantly with 23S rRNA rearrangements that prevent peptide bond formation and preclude accommodation of release factors. The stalled ribosome obstructs formation of a Rho-independent terminator which prevents msrD transcriptional attenuation. This stalled ribosome is rescued by MsrD, but not by MsrD mutants which do not provide antibiotic resistance, showing evidence of equivalence between MsrD function in antibiotic resistance and its action on this complex.
Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes
Authors: Bedi Suhana , Richardson Tiffany M. , Jia Baofeng , Saab Hadeel , Brinkman Fiona S.L. , Westley Monica 
Published: November 2021

AbstractA variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase domain of human GAD65 which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T-cell receptor epitopes which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities, we found between humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D.
Salmonella Typhimurium infection drives NK cell loss and conversion to ILC1-like cells, and CIS inhibition enhances antibacterial immunity
Authors: McCulloch Timothy R. , Rossi Gustavo R. , Wells Timothy J. , Souza-Fonseca-Guimaraes Fernando 
Published: November 2021

AbstractImmunotherapy has revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes. More recently, immunotherapy has emerged to restore immunity against infectious agents, including bacterial infections. Immunotherapy primarily targets inhibitory pathways in tumor-resident T cells, however interest in other effector populations, such as natural killer (NK) cells, is growing. We have previously discovered that NK cell metabolism, proliferation, and activation can be neutralized through the TGF-β immunosuppressive pathway by inducing plasticity of NK cells and differentiation into ILC1-like subsets. NK cells are also regulated through cytokine-inducible SH2-containing protein (CIS), which is induced by IL-15 and is a potent intracellular checkpoint suppressing NK cell survival and function. Targeting these two distinct pathways to restore NK cell function has shown promise is cancer models, but their application in bacterial infection remains unknown. Here, we investigate whether enhancement of NK cell function can improve anti-bacterial immunity, using Salmonella Typhimurium as a model. We identified conversion of NK cells to ILC1-like for the first time in the context of bacterial infection, however TGF-β signaling was curiously redundant in this plasticity. Future work should focus on identifying drivers of ILC1 plasticity and its functional implication in bacterial infection models. We further describe that CIS-deficient mice displayed enhanced pro-inflammatory function and dramatically enhanced anti-infection immunity. Inhibition of CIS may present as a viable therapeutic option to enhance immunity towards bacterial infection.
Structure of Dunaliella Photosystem II reveals conformational flexibility of stacked and unstacked supercomplexes
Authors: Caspy Ido , Fadeeva Maria , Mazor Yuval , Nelson Nathan 
Published: November 2021

AbstractPhotosystem II (PSII) generates an oxidant whose redox potential is high enough to enable water oxidation1,2, a substrate so abundant that it assures a practically unlimited electron source for life on earth3. Our knowledge on the mechanism of water photooxidation was greatly advanced by high-resolution structures of prokaryotic PSII4–6. Here we show high-resolution structures of eukaryotic PSII from the green algae Dunaliella salina at two distinct conformations. The conformers are also present in stacked PSII, exhibiting flexibility that is relevant to the grana formation in chloroplasts of the green lineage. CP29, one of PSII associated light harvesting antennae, plays a major role in distinguishing the two conformations of the supercomplex. We also show that the stacked PSII dimer, a form suggested to support the organization of thylakoid membranes7,8, can appear in many different orientations providing a flexible stacking mechanism for the arrangement of grana stacks in thylakoids. Our findings provide a structural basis for the heterogenous nature of the eukaryotic PSII on multiple levels.
Nrf1 is not a direct target gene of SREBP1, albeit both are integrated into the rapamycin-responsive regulatory network in human hepatoma cells
Authors: Liu Keli , Hu Shaofan , Qiu Lu , Wang Meng , Zhang Zhengwen , Sun Guiyin , Zhang Yiguo 
Published: November 2021

AbstractIt is questionable why no further experimental evidence confirming those findings, since being reported by Manning’s group in 2014’s Nature (doi: 10.1038/nature13492), has been provided in the hitherto known literature. They found that ‘Growth factors stimulate an increase in Nrf1 through mTORC1, which induces NRF1 transcription in an SREBP1-dependent manner’ and asserted that Nrf1 is directly regulated by SREBP1. Thereby, a key issue arising from their work is of particular concern about whether the mTORC1 signaling to upregulation of Nrf1-targeted proteasomal expression profiles occurs directly by SREBP1. In this study, our experiment evidence revealed that Nrf1 is not a direct target of SREBP1, although both are involved in the rapamycin-responsive regulatory networks. Closely scrutinizing two distinct transcriptomic datasets unraveled no significant changes in transcriptional expression of Nrf1 and almost all proteasomal subunits in either siSREBP2-silencing cells or SREBP1–/– MEFs, when compared to equivalent controls. However, distinct upstream signaling to Nrf1 dislocation by p97 and its processing by DDI1/2, along with downstream proteasomal expression, may be monitored by mTOR signaling, to various certain extents, depending on distinct experimental settings in different types of cells. Our further evidence has been obtained from DDI1–/–(DDI2insC) cells, demonstrating that putative effects of mTOR on the rapamycin-responsive signaling to Nrf1 and proteasomes may also be executed partially through a DDI1/2-independent mechanism, albeit the detailed regulatory events remain to be determined.
Cross-modal Semantic Relationships Guide Spontaneous Orienting in Real-life Scenes
Authors: Kvasova Daria , Stewart Travis , Soto-Faraco Salvador 
Published: November 2021

AbstractIn real-world scenes, the different objects and events available to our senses are interconnected within a rich web of semantic associations. These semantic links help parse information and make sense of the environment. For example, during goal-directed attention, characteristic everyday life object sounds help speed up visual search for these objects in natural and dynamic environments. However, it is not known whether semantic correspondences also play a role under spontaneous observation. Here, we investigated this question addressing whether crossmodal semantic congruence can drive spontaneous, overt visual attention in free-viewing conditions. We used eye-tracking whilst participants (N=45) viewed video clips of realistic complex scenes presented alongside sounds of varying semantic congruency with objects within the videos. We found that characteristic sounds increased the probability of looking, the number of fixations, and the total dwell time on the semantically corresponding visual objects, in comparison to when the same scenes were presented with semantically neutral sounds or just with background noise only. Our results suggest that crossmodal semantic congruence has an impact on spontaneous gaze and eye movements, and therefore on how attention samples information in a free viewing paradigm. Our findings extend beyond known effects of object-based crossmodal interactions with simple stimuli and shed new light upon how audio-visual semantically congruent relationships play out in everyday life scenarios.
Translational suppression via IFG-1/eIF4G confers resistance to stress-induced RNA alternative splicing in Caenorhabditis elegans
Authors: Chomyshen Samantha C. , Wu Cheng-Wei 
Published: November 2021

SUMMARYSplicing of pre-mRNA is an essential process for dividing cells and splicing defects have been linked to aging and various chronic diseases. Environmental stress has recently been shown to alter splicing fidelity and molecular mechanisms that protect against splicing disruption remains unclear. Using an in vivo RNA splicing reporter, we performed a genome-wide RNAi screen in Caenorhabditis elegans and found that protein translation suppression via silencing of the conserved initiation factor 4G (IFG-1/eIF4G) protects against cadmium-induced splicing disruption. Transcriptome analysis of an ifg-1 deficient mutant revealed an overall increase in splicing fidelity and resistance towards cadmium-induced alternative splicing compared to the wild-type. We found that the ifg-1 mutant up-regulates >80 RNA splicing regulatory genes that are controlled by the TGF-β transcription factor SMA-2. The extended lifespan of the ifg-1 mutant is partially reduced upon sma-2 depletion and completely nullified when core spliceosome genes including snr-1, snr-2, and uaf-2 are knocked down. Together, these data describe a molecular mechanism that provides resistance towards stress-induced alternative splicing and demonstrate an essential role for RNA homeostasis in promoting longevity in a translation-compromised mutant.
KymoMerge: a new tool for analysis of multichannel kymographs
Authors: McMahon Lloyd P. , Digilio Laura , Duston Alois , Yap Chan Choo , Winckler Bettina 
Published: November 2021

AbstractKymograph analysis is commonly used by researchers to study dynamic processes in cells. Current tools widely available only allow for analysis of one channel kymographs. Here we provide a python-coded, open source program to use as a plug-in for ImageJ which creates one kymograph from the kymographs of two separate channels of one time-lapse movie. This add-in, which we call KymoMerge, therefore allows for analysis of only the co-located tracks in multi-channel movies.
Systems genetics uncovers microbe-lipid-host connections in the murine gut
Authors: Zhang Q , Linke V , Overmyer KA , Traeger LL , Kasahara K , Miller IJ , Manson DE , Polaske TJ , Kerby RL , Kemis JH , Trujillo EA , Reddy TR , Russell JD , Schueler KL , Stapleton DS , Rabaglia ME , Seldin M , Gatti DM , Keele GR , Pham DT , Gerdt JP , Vivas EI , Lusis AJ , Keller MP , Churchill GA , Blackwell HE , Broman KW , Attie AD , Coon JJ , Rey FE 
Published: November 2021

AbstractThe molecular bases of how host genetic variation impact gut microbiome remain largely unknown. Here, we used a genetically diverse mouse population and systems genetics strategies to identify interactions between molecular phenotypes, including microbial functions, intestinal transcripts and cecal lipids that influence microbe-host dynamics. Quantitative trait loci (QTL) analysis identified genomic regions associated with variations in bacterial taxa, bacterial functions, including motility, sporulation and lipopolysaccharide production, and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and cecal levels of ornithine lipids (OL). Follow-up studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that OL have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits. Collectively, these results suggest that OL are key players in A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.
Carbon Dot-based Fluorescent Antibody Nanoprobes as Brain Tumour Glioblastoma Diagnostics
Authors: Ghirardello Mattia , Shyam Radhe , Liu Xia , Garcia-Millan Teodoro , Sittel Imke , Ramos-Soriano F. Javier , Kurian Kathreena , Galan M. Carmen 
Published: November 2021

AbstractThe development of efficient and sensitive tools for the detection of brain cancer in patients is of the utmost importance particularly because many of these tumours go undiagnosed until the disease has advanced and when treatment is less effective. Current strategies employ antibodies (Abs) to detect Glial Fibrillary Acid Protein (GFAP) in tissue samples, since GFAP is unique to the brain and not present in normal peripheral blood, and it relies on fluorescent reporters.Herein we describe a low cost, practical and general method for the labelling of proteins and antibodies with fluorescent carbon dots (CD) to generate diagnostic probes that are robust, photostable and applicable to the clinical setting. The two-step protocol relies on the conjugation of a dibenzocyclooctyne (DBCO)-functionalised CD with azide functionalised proteins by combining amide conjugation and strain promoted alkyne-azide cycloaddition (SPAAC) ligation chemistry. The new class of Ab-CD conjugates developed using this strategy was successfully used for the immunohistochemical staining of human brain tissues of patients with glioblastoma (GBM) validating the approach. Overall, these novel fluorescent probes offer a promising and versatile strategy in terms of costs, photostability and applicability which can be extended to other Abs and protein systems.
Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine
Authors: Singh Kanchan , Faraoni Erika Y. , Dai Yulin , Chandra Vidhi , Vucic Emily , Mills Tingting , Pruski Melissa , Clark Trent , Van Buren George , Thosani Nirav C. , Bynon John S. , Wray Curtis J. , Bar-Sagi Dafna , Poulsen Kyle L. , Vornik Lana A. , Savage Michelle I. , Sei Shizuko , Mohammed Altaf , Zhao Zhongming , Eltzschig Holger K. , Brown Powel H. , McAllister Florencia , Bailey-Lundberg Jennifer 
Published: November 2021

ABSTRACTThe microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention.Abstract Figure
Positive feedback promotes terrestrial emergence behaviour in an amphibious fish
Authors: Tigert Liam , Turko Andy J. , Wright Patricia A. 
Published: November 2021

AbstractMajor ecological transitions such as the invasion of land by aquatic vertebrates have been hypothesised to be facilitated by positive feedback between habitat choice and phenotypic plasticity. We tested whether aquatic hypoxia, emergence behaviour, and plastic changes in gill surface area could create such a positive feedback loop and drive an amphibious fish to spend increasing amounts of time out of water. We found that terrestrially acclimated amphibious mangrove rivulus Kryptolebias marmoratus were more sensitive to, and less tolerant of, aquatic hypoxia relative to water-acclimated fish, which are necessary trade-offs for positive feedback to occur. Next, we acclimated fish to normoxic or hypoxic water with the opportunity to emerge for 7d to test the predictions that fish in hypoxic conditions should regularly leave water, reduce gill surface area, and become less hypoxia tolerant. Consistent with these predictions, fish in severe hypoxia spent almost 50% of the time out of water and coverage of the gill lamellae by an inter-lamellar cell mass almost doubled. Hypoxia acclimated fish were also more sensitive to acute aquatic hypoxia (emergence at higher oxygen levels), and lost equilibrium faster in hypoxic water compared to control fish. Thus, we show that a positive feedback loop develops in amphibious fish where emergence behaviour begets further emergence behaviour, driven by gill remodelling which reduces aquatic respiratory function. Such a scenario may explain how amphibious behaviour has repeatedly evolved in fishes that occupy hypoxic aquatic habitats despite the associated challenges of life on land.
OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases
Authors: Sturm Gabriel , Karan Kalpita R , Monzel Anna , Santhanam Balaji S , Taivassalo Tanja , Bris Céline , Ware Sarah A , Cross Marissa , Towheed Atif , Higgins-Chen Albert , McManus Meagan J , Cardenas Andres , Lin Jue , Epel Elissa S , Rahman Shamima , Vissing John , Grassi Bruno , Levine Morgan , Horvath Steve , Haller Ronald G , Lenaers Guy , Wallace Douglas C , St-Onge Marie-Pierre , Tavazoie Saeed , Procaccio Vincent , Kaufman Brett A , Seifert Erin L , Hirano Michio , Picard Martin 
Published: November 2021

AbstractPatients with primary mitochondrial diseases present with fatigue and multi-system disease, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. Integrating data from 17 cohorts of patients with mitochondrial diseases (n=690), we find that clinical mitochondrial disorders increase resting energy expenditure, a state termed hypermetabolism. In a longitudinal cellular model of primary patient-derived fibroblasts from multiple donors, we show that genetic and pharmacological disruptions of oxidative phosphorylation (OxPhos) similarly trigger increased energy consumption in a cell-autonomous manner, despite near-normal OxPhos coupling efficiency. Hypermetabolism is associated with mtDNA instability, activation of the integrated stress response, increased extracellular secretion of age-related cytokines and metabokines including GDF15, as well as an accelerated rate of telomere erosion and epigenetic aging, and a reduced Hayflick limit. Together with these dynamic measures, we have generated a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations in response to OxPhos dysfunction. The increased energetic cost of living, or hypermetabolism, in cells and organisms with OxPhos defects has important biological and clinical implications.
Olfactory sensory preconditioning in Drosophila: role of memory forgetting in gating S1/S2 associations
Authors: Phan Anna , Martinez-Cervantes Juan , Cervantes-Sandoval Isaac 
Published: November 2021

AbstractLearning and memory storage is a complex process that has proven challenging to tackle. It is likely that, in real nature, the instructive value of reinforcing experiences is acquired rather than innate. The association between seemingly neutral stimuli increases the gamut of possibilities to create meaningful associations and increases the predictive power of moment-by-moment experiences. Here we report physiological and behavioral evidence of olfactory unimodal sensory preconditioning in fruit flies. We show that the presentation of a pair of odors (S1 and S2) before one of them (S1) is associated with electric shocks elicits a conditional response not only to the trained odor (S1) but to the odor previously paired with it (S2). This occurs even if the S2 odor was never presented in contiguity with the aversive stimulus. In addition, we show that inhibition of the small G protein and known forgetting regulator Rac1 facilitates the association between S1/S2 odors. These results indicate that flies can infer value to non-paired odor based on the previous associative structure between odors, and inhibition of Rac1 lengthens the time of olfactory “sensory buffer,” allowing linking of neutral odors presented in sequence.