bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cognitive map for value-guided choice in ventromedial prefrontal cortex
Authors: Veselic Sebastijan , Muller Timothy H. , Gutierrez Elena , Behrens Timothy E. J. , Hunt Laurence T. , Butler James L. , Kennerley Steven W. 
Published: December 2023

AbstractThe prefrontal cortex is crucial for economic decision-making and representing the value of options. However, how such representations facilitate flexible decisions remains unknown. We reframe economic decision-making in prefrontal cortex in line with representations of structure within the medial temporal lobe because such cognitive map representations are known to facilitate flexible behaviour. Specifically, we framed choice between different options as a navigation process in value space. Here we show that choices in a 2D value space defined by reward magnitude and probability were represented with a grid-like code, analogous to that found in spatial navigation. The grid-like code was present in ventromedial prefrontal cortex (vmPFC) local field potential theta frequency and the result replicated in an independent dataset. Neurons in vmPFC similarly contained a grid-like code, in addition to encoding the linear value of the chosen option. Importantly, both signals were modulated by theta frequency – occurring at theta troughs but on separate theta cycles. Furthermore, we found sharp-wave ripples – a key neural signature of planning and flexible behaviour – in vmPFC, which were modulated by accuracy and reward. These results demonstrate that multiple cognitive map-like computations are deployed in vmPFC during economic decision-making, suggesting a new framework for the implementation of choice in prefrontal cortex.
H7 influenza A viruses bind sialyl-LewisX, a potential intermediate receptor between species
Authors: Spruit Cindy M. , Palme Diana I. , Li Tiehai , Ríos Carrasco María , García Alba Gabarroca , Sweet Igor R. , Kuryshko Maryna , Maliepaard Joshua C. L. , Reiding Karli R. , Scheibner David , Boons Geert-Jan , Abdelwhab Elsayed M. , de Vries Robert P. 
Published: December 2023

AbstractInfluenza A viruses (IAVs) can overcome species barriers by adaptation of the receptor binding site of the hemagglutinin (HA). To initiate infection, HAs bind to glycan receptors with terminal sialic acids, which are eitherN-acetylneuraminic acid (NeuAc) orN-glycolylneuraminic acid (NeuGc), the latter is mainly found in horses and pigs but not in birds and humans. We investigated the influence of previously identified equine NeuGc-adapting mutations (S128T, I130V, A135E, T189A, and K193R) in avian H7 IAVsin vitroandin vivo.We observed that these mutations negatively affected viral replication in chicken cells, but not in duck cells, and positively affected replication in horse cells.In vivo, the mutations reduced virus virulence and mortality in chickens. Ducks excreted high viral loads for a longer time than chickens, although they appeared clinically healthy. To elucidate why chickens and ducks were infected by these viruses despite the absence of NeuGc, we re-evaluated the receptor binding of H7 HAs using glycan microarray and flow cytometry studies. This revealed that mutated avian H7 HAs also bound to α2,3-linked NeuAc and sialyl-LewisX, which have an additional fucose moiety in their terminal epitope, explaining why infection of ducks and chickens was possible. Interestingly, the α2,3-linked NeuAc and sialyl-LewisX epitopes were only bound when presented on tri-antennaryN-glycans, emphasizing the importance of investigating the fine receptor specificities of IAVs. In conclusion, the binding of NeuGc-adapted H7 IAV to sialyl-LewisX enables viral replication and shedding by chickens and ducks, potentially facilitating interspecies transmission of equine-adapted H7 IAVs. (249 words)ImportanceInfluenza A viruses cause millions of deaths and illness in birds and mammals each year. The viral surface protein hemagglutinin initiates infection by binding to host cell terminal sialic acids. Hemagglutinin adaptations affect the binding affinity to these sialic acids and therefore the potential host species targeted. While avian and human IAVs tend to bindN-acetylneuraminic acid (a form of sialic acid), equine H7 viruses prefer binding toN-glycolylneuraminic acid (NeuGc). To better understand the function of NeuGc-specific adaptations in hemagglutinin and to elucidate interspecies transmission potential NeuGc-adapted viruses, we evaluated the effects of NeuGc-specific mutations in avian H7 viruses in chickens and ducks, important economic hosts and reservoir birds, respectively. We also examined the impact on viral replication and found a binding affinity to sialyl-LewisX, another terminal epitope. These findings are important as they contribute to the understanding of the role of sialyl-LewisX in avian influenza infection. (148 words)
Acidity-induced dysfunction of CD8+T cells is characterized by impaired IL-2 responsiveness and perturbations to mTORC1 signaling and c-Myc levels
Authors: Vuillefroy de Silly Romain , Pericou Laetitia , Seijo Bili , Crespo Isaac , Coukos George , Irving Melita 
Published: December 2023

AbstractCD8+T cells play a critical role in cancer control but a range of barriers in the tumor microenvironment, including low pH, can impair their function. Here, we demonstrate that acidity dampens T-cell expansion mainly due to impaired IL-2 responsiveness, blunts cytokine secretion upon re-activation, and lowers the cytolytic capacity of CD8+T cells expressing weak affinity TCR. We further reveal and dissect defects in both mTORC1 activity and c-Myc accumulation at low pH, the latter of which is largely due to proteasome-mediated degradation. In addition, lower intracellular levels of glutamine, glutamate and aspartate as well as elevated proline were noted, with no apparent impact on mTORC1 or c-Myc. Overall, low pH disrupts diverse intracellular signaling pathways as well as nutrient uptake/processing by T cells and we conclude that unless intracellular pH can be restored, multiple interventions will be required to overcome acidity-induced dysfunction.
Genome organization in double-stranded DNA viruses observed by cryoET
Authors: Chen Muyuan , Sahoo Bibekananda , Mou Zongjun , Song Xiyong , Tsai Tiffany , Dai Xinghong 
Published: December 2023

AbstractDouble-stranded DNA (dsDNA) viruses package their genetic material into protein cages with diameters usually a few hundred times smaller than the length of their genome. Compressing the relatively stiff and highly negatively charged dsDNA into a small volume is energetically costly and mechanistically enigmatic. Multiple models of dsDNA packaging have been proposed based on various experimental evidence and simulation methods, but direct observation of any viral genome organization is lacking. Here, using cryoET and an improved data processing scheme that utilizes information from the encaging protein shell, we present 3D views of dsDNA genome inside individual viral particles at resolution that densities of neighboring DNA duplexes are readily separable. These cryoET observations reveal a “rod-and-coil” fold of the dsDNA that is conserved among herpes simplex virus type 1 (HSV-1) with a spherical capsid, bacteriophage T4 with a prolate capsid, and bacteriophage T7 with a proteinaceous core inside the capsid. Finally, inspired by the genome arrangement in partially packaged T4 particles, we propose a mechanism for the genome packaging process in dsDNA viruses.
High-energy demand and nutrient exhaustion in MTCH2 knockout cells
Authors: Chourasia Sabita , Petucci Christopher , Wang Hu , Han Xianlin , Sivan Ehud , Brandis Alexander , Mehlman Tevie , Malitsky Sergey , Itkin Maxim , Rotkopf Ron , Regev Limor , Zaltsman Yehudit , Gross Atan 
Published: December 2023

AbstractMitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection from diet-induced obesity. We now show using temporal metabolomics that MTCH2 deletion results in a high ATP demand, an oxidized environment, a high lipid/amino acid/carbohydrate metabolism, and in the decrease of many metabolites. Lipidomics analyses show a strategic adaptive decrease in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, all the metabolic changes in the MTCH2 knockout cells were rescued by MTCH2 re-expression. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion inhibits adipocyte differentiation, an energy consuming reductive biosynthetic process. In summary, loss of MTCH2 results in an increase in energy demand that triggers a catabolic and oxidizing environment, which fails to fuel the anabolic processes during adipocyte differentiation.
Osteopontin in colitis-associated carcinoma
Authors: Manna Subhakankha , Sehn Maximilian , Cardoso da Silva Danielle , Wiese Jakob J. , Heldt Claudia , Plumbom Izabela , Conrad Thomas , Husemann Cora C. , Kleo Karsten , Derêzanin Lorena , Dony Violaine , Farahani Saeed K. , Weiss Franziska , Branchi Federica , Kühl Anja A. , Schallenberg Simon , Weiner January , Elezkurtaj Sefer , Weixler Benjamin , Gröne Jörn , Siegmund Britta , Hummel Michael , Schumann Michael 
Published: December 2023

AbstractPatients with ulcerative colitis (UC) and Crohn’s disease (CD) face a lifelong risk of developing colitis-associated carcinoma (CAC). Current insights into CAC development originate from murine CAC models, while human CAC studies primarily focus on mutational analysis of patient samples. Although the mutational landscape reveals distinct patterns and frequencies compared to colorectal cancer, it falls short in elucidating the inflammatory mechanisms of CAC development. Consequently, we adopted a multi-omics approach to unravel CAC carcinogenesis from an immunological perspective. Our data revealed a robust upregulation ofSPP1gene in CAC at both RNA and protein levels, expressed byCD68+macrophages. In vitro OPN stimulation demonstrated no direct effect on intestinal epithelial organoids. However, the mutually exclusive spatial location ofSPP1/OPN+macrophages andCD8+T cells suggests a crucial indirect role ofSPP1/OPNin mediating an immunosuppressive tumour microenvironment.
Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis
Authors: Vannan Annika , Lyu Ruqian , Williams Arianna L. , Negretti Nicholas M. , Mee Evan D. , Hirsh Joseph , Hirsh Samuel , Nichols David S. , Calvi Carla L. , Taylor Chase J. , Polosukhin Vasiliy. V. , Serezani Ana PM , McCall A. Scott , Gokey Jason J. , Shim Heejung , Ware Lorraine B. , Bacchetta Matthew J. , Shaver Ciara M. , Blackwell Timothy S. , Walia Rajat , Sucre Jennifer MS , Kropski Jonathan A. , McCarthy Davis J , Banovich Nicholas E. 
Published: December 2023

AbstractThe human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell-types, established the cellular and molecular basis of classical PF histopathologic disease features, and identified a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Using machine-learning and trajectory analysis methods to segment and rank airspaces on a gradient from normal to most severely remodeled, we identified a sequence of compositional and molecular changes that associate with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially-resolved characterization of the cellular and molecular programs of PF and control lungs, provide new insights into the heterogeneous pathobiology of PF, and establish analytical approaches which should be broadly applicable to other imaging-based spatial transcriptomic studies.
Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction
Authors: Moon Brianna F. , Zhou Iris Y. , Ning Yingying , Chen Yin-Ching I. , Fur Mariane Le , Shuvaev Sergey , Akam Eman A. , Ma Hua , Solsona Cesar Molinos , Weigand-Whittier Jonah , Rotile Nicholas , Hariri Lida P. , Drummond Matthew , Boice Avery T. , Zygmont Samantha E. , Sharma Yamini , Warburton Rod R. , Martin Gregory L. , Blanton Robert M. , Fanburg Barry L. , Hill Nicholas S. , Caravan Peter , Penumatsa Krishna C. 
Published: December 2023

AbstractBackgroundAging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in an LV dysfunction model.MethodsLV dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone (SAMP8) mice, a subset of mice received sham surgery. Three weeks post-surgery, mice underwent simultaneous PET-MR imaging at 4.7 T. Collagen–targeted PET and fibrogenesis MR probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent signal increase (%SI) and ΔLMR were computed from the pre-/post-injection MR images. Tissue specimens were analyzed for hydroxyproline (Hyp) and allysine content. Ventricular structure and function were measured by echocardiography and hemodynamic pressure-volume (PV) loop analysis.ResultsAllysine in the heart (22±5 (TAC), 13±5 (sham) nmol/g,P=0.02) and lungs (7.5±4 (TAC), 5.8±2 (sham) nmol/lung,P=0.17) of TAC mice corresponded to an increase in myocardial MRI %SI (29±15 (TAC), 6.1±4 (sham),P<0.0001) and ΔLMR (0.3±0.1 (TAC), 0.08±0.1 (sham),P<0.0001). Hyp in the heart (555±90 (TAC), 400±80 (sham) µg/g,P<0.0001) and lungs (189±63 (TAC), 143±31 (sham) µg/lung,P<0.01) were elevated in TAC mice, which corresponded to an increase in PET signal (MMR: 1.8±0.1 (TAC), 1.6±0.2 (sham),P=0.02; LMR: 1.5±0.1 (TAC), 1.2±0.1 (sham),P<0.001). PV loop and echocardiography demonstrated adverse LV remodeling, function, and increased right ventricular systolic pressure in TAC mice.ConclusionsAdministration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-MRI signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-MR imaging protocol.
Formation of the pyruvoyl-dependent proline reductase Prd fromClostridioides difficilerequires the maturation enzyme PrdH
Authors: Behlendorf Christian , Diwo Maurice , Neumann-Schaal Meina , Fuchs Manuela , Faber Franziska , Blankenfeldt Wulf 
Published: December 2023

AbstractStickland fermentation, the coupled oxidation and reduction of amino acid pairs, is a major pathway for obtaining energy in the nosocomial bacteriumClostridioides difficile. D-proline is the preferred substrate for the reductive path, making it not only a key component of the general metabolism but also impacting on the expression of the clostridial toxins TcdA and TcdB. D-proline reduction is catalyzed by the proline reductase Prd, which belongs to the pyruvoyl-dependent enzymes. These enzymes are translated as inactive proenzymes and require subsequent processing to install the covalently bound pyruvate. Whereas pyruvoyl formation by intramolecular serinolysis has been studied in unrelated enzymes, details about pyruvoyl generation by cysteinolysis such as in Prd are lacking. Here we show that Prd maturation requires a small dimeric protein that we have named PrdH. PrdH is co-encoded with the PrdA and PrdB subunits of Prd and also found in species producing similar reductases. By producing stable variants of PrdA and PrdB, we demonstrate that PrdH-mediated cleavage and pyruvoyl formation in the PrdA subunit require PrdB, which can be harnessed to produce active recombinant Prd for subsequent analyses. We further created PrdA- and PrdH-mutants to get insight into the interaction of the components and into the processing reaction itself. Finally, we show that deletion ofprdHinC. difficilerenders the corresponding mutant blind to proline, suggesting that this processing factor is essential for proline utilization. Due to the link between Stickland fermentation and pathogenesis, we suggest PrdH may be an attractive target for drug development.Significance StatementEnergy conservation via Stickland fermentation was first described in the 1930s, yet information about the key enzyme of this process, Prd, is scarce, despite the fact that its central role in both metabolism and toxin production make it a promising potential drug target. Here we show how a small, previously overlooked protein that we named PrdH mediates the formation of the catalytically essential pyruvoyl-group in the active center of Prd.In vivostudies inC. difficileemphasize its critical importance in the utilization of proline. The known interplay between proline reduction and toxin production leads us to suggest PrdH as a potential drug target. Moreover, our findings open the door for further structural and functional studies with recombinantly produced active Prd.
Informing the need for a SARS-CoV-2 booster based upon the immune response among young, healthy adults to variants circulating during late 2023
Authors: Nguyen Huy C. , Lal Kerri G. , Balinsky Corey A. , Smith Lauren , Pan Li , Cheng Ying , Fox Isabella , Hontz Robert D. , Lizewski Stephen E. , Foo Hayley S. , Krebs Shelly J. , Sun Peifang , Letizia Andrew G. 
Published: December 2023

ABSTRACTCOVID-19 remains a global public health challenge due to ongoing emergence of new immune-evasive SARS-CoV-2 variants, heterogeneous immunity, poor education campaigns, and suboptimal surveillance. In this cross-sectional study, we evaluated the adaptive immune responses in US active-duty service members who completed a COVID-19 primary vaccine series to 3 previously dominant variants (Ancestral, Delta, BA.5) and compared them to 3 variants currently circulating (XBB.1.5, EG.5, and BA.2.86). Analyses were performed based upon time (within or beyond 12 months) and type (vaccine or infection) of most recent exposure. Significant reduction was observed in binding antibodies, neutralization antibodies, memory B cells, and CD8+T cells against current circulating variants compared to previous dominant variants. The reduction in antibody response was more pronounced in those whose most recent exposure, regardless if vaccination or infection, was greater than 12 months from study enrollment. In contrast, the CD4+T cell response was largely consistent across all tested variants. Our study did not show that the type exposure in the last 12 months was a significant factor in determining the magnitude of immune responses. However, the antibody responses to circulating variants were decreased among participants who received the bivalent booster compared to those with an infection in the past 12 months, potentially due to immunological imprinting of the Ancestral strain. Administration of the new XBB.1.5-based booster is likely to enhance cross-reactive humoral immune responses against current SARS-CoV-2 circulating strains.
Towards cascading genetic risk in Alzheimer’s disease
Authors: Altmann Andre , Aksman Leon M , Oxtoby Neil P , Young Alexandra ,   ADNI, Alexander Daniel C , Barkhof Frederik , Shoai Maryam , Hardy John , Schott Jonathan M 
Published: December 2023

AbstractAlzheimer’s disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: Amyloid (A), Tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, where each of the biomarkers can be either positive (+) or negative (-). Over the past decades genome wide association studies have implicated about 90 different loci involved with the development of late onset Alzheimer’s disease. Here we investigate whether genetic risk for Alzheimer’s disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect.Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer’s Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we employed Cox proportional hazards models to estimate the contribution ofAPOEand polygenic risk scores (beyondAPOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex, and years of education.For progression from A-T- to A+T-, APOE-e4 burden showed significant effect (HR=2.88; 95% CI: 1.70-4.89; P<0.001), while polygenic risk did not (HR=1.09; 95% CI: 0.84-1.42; P=0.53). Conversely, for the transition from A+T- to A+T+, the APOE-e4 burden contribution was reduced (HR=1.62 95% CI: 1.05-2.51; P=0.031), while the polygenic risk showed an increased contribution (HR=1.73; 95% CI:1.27-2.36; P<0.001). The marginalAPOEeffect was driven by e4 homozygotes (HR=2.58; 95% CI: 1.05-6.35; P=0.039) as opposed to e4 heterozygotes (HR=1.74; 95% CI: 0.87-3.49; P=0.12).The genetic risk for late-onset Alzheimer’s disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of transition between ATN stages, a better understanding of the molecular processes leading to Alzheimer’s disease as well as opening therapeutic windows for targeted interventions.