bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cells in the Polyaneuploid Cancer Cell (PACC) state have increased metastatic potential
Authors: Mallin Mikaela M. , Kim Nicholas , Choudhury Mohammad Ikbal , Lee Se Jong , An Steven S. , Sun Sean X. , Konstantopoulos Konstantinos , Pienta Kenneth J. , Amend Sarah R. 
Published: September 2022

AbstractAlthough metastasis is the leading cause of cancer deaths, it is quite rare at the cellular level. Only a rare subset of cancer cells (∼1 in 1.5 billion) can complete the entire metastatic cascade: invasion, intravasation, survival in the circulation, extravasation, and colonization (i.e. are metastasis competent). We propose that cells engaging a Polyaneuploid Cancer Cell (PACC) phenotype are metastasis competent. PACCs are enlarged, non-dividing cells with increased genomic content that form in response to stress. Single-cell tracking using time-lapse microscopy reveals that PACCs are more motile than nonPACCs. Additionally, PACCs exhibit increased capacity for environment-sensing and directional migration in chemotactic environments, predicting successful invasion. Magnetic Twisting Cytometry and Atomic Force Microscopy reveal that cells in the PACC state display hyper-elastic properties like increased peripheral deformability and maintained peri-nuclear cortical integrity that predict successful intravasation and extravasation. Furthermore, four orthogonal methods reveal that PACCs have increased expression of Vimentin, a known hyper-elastic biomolecule. Lastly, anoikis-resistance assays and detection of PACCs in the blood of a patient with metastatic castrate-resistant prostate cancer using a selection- free circulating tumor cell detection platform reveal that PACCs are capable of surviving in the circulation. Taken together with the knowledge that PACCs are capable of eventual depolyploidization and progeny formation (as a potential route to colonization), these data support PACCs as candidate metastasis-competent cells worthy of further analysis.
A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer
Authors: Mayoh Chelsea , Gifford Andrew J , Terry Rachael , Lau Loretta MS , Wong Marie , Rao Padmashree , Shai-Hee Tyler , Saletta Federica , Khuong-Quang Dong-Anh , Qin Vicky , Mateos Marion , Meyran Deborah , Miller Katherine E , Yuksel Aysen , Mould Emily VA , Bowen-James Rachael , Govender Dinisha , Senapati Akanksha , Zhukova Nataliya , Omer Natacha , Dholaria Hetal , Alvaro Frank , Tapp Heather , Diamond Yonatan , Pozza Luciano Dalla , Moore Andrew S , Nicholls Wayne , Gottardo Nicholas G , McCowage Geoffrey , Hansford Jordan R , Khaw Seong-Lin , Wood Paul J , Catchpoole Daniel , Cottrell Catherine E , Mardis Elaine R , Marshall Glenn M , Tyrrell Vanessa , Haber Michelle , Ziegler David S , Vittorio Orazio , Trapani Joseph A , Cowley Mark J , Neeson Paul J , Ekert Paul G 
Published: September 2022

AbstractMolecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. We combined immunohistochemistry (IHC) and molecular profiling to develop an alternative, expression-based signature associated with CD8+T-cell infiltration of the TIME in high-risk paediatric tumours. Using this novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.
Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer
Authors: Plattner Christina , Lamberti Giorgia , Blattmann Peter , Kirchmair Alexander , Rieder Dietmar , Loncova Zuzana , Sturm Gregor , Scheidl Stefan , Ijsselsteijn Marieke , Fotakis Georgios , Noureen Asma , Lisandrelli Rebecca , Böck Nina , Nemati Niloofar , Krogsdam Anne , Daum Sophia , Finotello Francesca , Somarakis Antonios , Schäfer Alexander , Wilflingseder Doris , Acera Miguel Gonzalez , Öfner Dietmar , Huber Lukas A. , Clevers Hans , Becker Christoph , Farin Henner F. , Greten Florian R. , Abersold Ruedi , da Cunha Carvalho de Miranda Noel Filipe , Trajanoski Zlatko 
Published: September 2022

AbstractBackgroundDespite major advances in the development of targeted therapies, precision (immuno)oncology approaches for patients with colorectal cancer continue to lag behind other solid cancers. Functional precision oncology – a strategy that is based on perturbing primary tumor cells from cancer patients with drugs – could provide an alternate road forward to personalize treatment.MethodsWe extend here the functional precision oncology paradigm to measuring phosphoproteome landscapes using patient-derived organoids (PDOs). We first employed steady-state multi-omics (exome sequencing, RNA sequencing, and proteomics) and single-cell characterization of the PDOs. The PDOs were then perturbed with kinase inhibitors (MEKi, PI3Ki, mTORi, TBKi, BRAFi, and TAKi), and large-scale phosphoproteomics profiling using data-independent acquisition was carried out. Further, we used imaging mass-cytometry-based single-cell proteomic profiling of the primary tumors to characterize cellular composition of the tumor-microenvironment (TME) and to quantify heterocellular signaling crosstalk.ResultsWe show that kinase inhibitors induce profound off-target effects resulting in a crosstalk with oncogenic and immune-related pathways. Reconstruction of the topologies of the kinase networks revealed that the patient-specific rewiring of the central EGFR-RAS-MAPK network is unaffected by mutations. Moreover, we show non-genetic heterogeneity of the PDOs and patient- and inhibitor-specific upregulation of stemness and differentiation genes by kinase inhibitors. We complemented our functional profiling by spatial proteomics profiling of the primary tumors using imaging mass cytometry. We quantify spatial heterocellular crosstalk and tumor-immune cell interactions, showing an avoidance of PD1+ immune cells and PD-L1+ tumor cells.ConclusionsCollectively, we provide a multi-modal framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno)-oncology in colorectal cancer.
Microbiota-stimulated Interleukin-22 regulates brain neurons and protects against stress-induced anxiety
Authors: Ilanges Anoj , Xia Mengyu , Lu Junmei , Chen Lei , Shiao Rani , Wang Changchun , Jin Zheyu , Feng Ru , Qi Qingqing , Yi Han , Li Jixi , Schneeberger Marc , Lu Boxun , Friedman Jeffrey M. , Yu Xiaofei 
Published: September 2022

SummaryPsychological stress and its sequelae are a major public health problem. While the immune system has been implicated in the development of stress-related disorders, how the immune signals modulate neural responses to stress is poorly understood. Contrary to our expectations, we found that the immune cytokine Interleukin (IL)-22 is the key mediator of an immune-to-brain pathway that diminishes, rather than amplifies, stress-induced anxiety. We showed that stress induced TH17 differentiation and IL-22 production in the intestine following barrier dysfunction and microbiota stimulation. IL-22 then directly signaled to septal neurons in the brain to mitigate anxiety-like behavior. Accordingly, mice treated with exogenous IL-22 showed resilience to chronic stress-induced anxiety disorders. Our study thus reveals a previously-unappreciated immune-to-brain axis that defends against psychological stress, suggesting a potential intervention strategy for stress-related mental diseases.
Analysis of somatic mutations in senescent cells using single-cell whole-genome sequencing
Authors: Zhang Lei , De Cecco Marco , Lee Moonsook , Hao Xiaoxiao , Maslov Alexander Y. , Montagna Cristina , Campisi Judith , Dong Xiao , Sedivy John M. , Vijg Jan 
Published: September 2022

SummarySomatic mutations accumulate in multiple organs and tissues during aging and are a known cause of cancer. Here we tested whether mutations accumulate during replicative senescence. Cellular senescence is also a possible cause of functional decline in aging, yet also acts as an anti-cancer mechanism in vivo. Using single-cell whole-genome sequencing, we compared mutation burdens between early passage and deeply senescent human fibroblasts. The results showed that single-nucleotide variations and small insertions and deletions increased in senescent cells by about two-fold, but have the same spectrum as early passage cells, while it has been known that particular mutational signatures are found in tumor cells. In contrast, aneuploidies were observed in half the senescent cells, but largely absent in early passage cells. Thus, the patterns of mutations among senescent, normal-aged and tumor cells differ significantly.
DRDs and Brain Derived Neurotrophic Factor share a common therapeutic ground: A novel bioinformatic approach sheds new light towards pharmacological treatment of Cognitive and Behavioral Disorders
Authors: Papageorgiou Louis , Kalospyrou Efstathia , Papakonstantinou Eleni , Diakou Io , Pierouli Katerina , Dragoumani Konstantina , Bacopoulou Flora , Chrousos George P , Exarchos Themis P , Vlamos Panagiotis , Eliopoulos Elias , Vlachakis Dimitrios 
Published: September 2022

AbstractCognitive and behavioral disorders are subgroups of mental health disorders. Both cognitive and behavioral disorders can occur in people of different ages, genders, and social backgrounds and they can cause serious physical, mental or social problems. The risk factors for these diseases are numerous, with a range from genetic and epigenetic factors to physical factors. In most cases, the appearance of such a disorder in an individual is a combination of his genetic profile and environmental stimuli. To date, researchers have not been able to identify the specific causes of these disorders and as such, there is urgent need for innovative study approaches. The aim of the present study was to identify the genetic factors which seem to be more directly responsible for the occurrence of a cognitive and/or behavioral disorder. More specifically, through bioinformatics tools and software as well as analytical methods such as systemic data and text mining, semantic analysis, and scoring functions, we extracted the most relevant single nucleotide polymorphisms (SNPs) and genes connected to these disorders. All the extracted SNPs were filtered, annotated, classified, and evaluated in order to create the “genomic grammar” of these diseases. The identified SNPs guided the search for top suspected genetic factors, dopamine receptors D and Neurotrophic Factor BDNF, for which regulatory networks were built. The identification of the “genomic grammar” and underlying factors connected to cognitive and behavioral disorders can aid the successful disease profiling, the establishment of novel pharmacological targets and provide the basis for personalized medicine, which takes into account the patient’s genetic background as well as epigenetic factors.
The time to initiate retrieval of a memory depends on recency
Authors: Bright Ian M. , Singh Inder , DiDomenica Rebecca , Oliva Aude , Howard Marc W. 
Published: September 2022

AbstractContinuous recognition has long been used to study the recency effect in recognition memory. In continuous recognition, response time (RT) increases as a logarithmic function of the lag since a probe was last presented. Although this could simply be due to decaying trace strength, careful examination of response time (RT) distributions showed that the onset of RT distributions changed with the logarithm of the lag since a probe was originally presented. Each doubling of lag resulted in a shift of roughly 20 ms in the rise time of the RT distributions. To test the hypothesis that this increase was simply due to increased facility in processing the probe item, Experiment six repeated items six times. Repetition resulted in faster RTs, but did not change the effect of log lag on RT. In light of recent neurophysio-logical evidence, we consider the hypothesis that memory requires a recovery of temporal context, and the time to retrieve a prior temporal context goes up with the logarithm of the time since it was experienced.
Towards In-Silico CLIP-seq: Predicting Protein-RNA Interaction via Sequence-to-Signal Learning
Authors: Horlacher Marc , Wagner Nils , Moyon Lambert , Kuret Klara , Goedert Nicolas , Salvatore Marco , Ule Jernej , Gagneur Julien , Winther Ole , Marsico Annalisa 
Published: September 2022

AbstractUnraveling sequence determinants which drive protein-RNA interaction is crucial for studying binding mechanisms and the impact of genomic variants. While CLIP-seq allows for transcriptome-wide profiling ofin vivoprotein-RNA interactions, it is limited to expressed transcripts, requiring computational imputation of missing binding information. Existing classification-based methods predict binding with low resolution and depend on prior labeling of transcriptome regions for training. We present RBPNet, a novel deep learning method, which predicts CLIP crosslink count distribution from RNA sequence at single-nucleotide resolution. By training on up to a million regions, RBPNet achieves high generalization on eCLIP, iCLIP and miCLIP assays, outperforming state-of-the-art classifiers. CLIP-seq suffers from various technical biases, complicating downstream interpretation. RBPNet performs bias correction by modeling the raw signal as a mixture of the protein-specific and background signal. Through model interrogation via Integrated Gradients, RBPNet identifies predictive sub-sequences corresponding to known binding motifs and enables variant-impact scoring via in silico mutagenesis. Together, RBPNet improves inference of protein-RNA interaction, as well as mechanistic interpretation of predictions.
Physiological constraints on the rapid dopaminergic modulation of striatal reward activity
Authors: Long Charltien , Lee Kwang , Yang Long , Dafalias Theresia , Wu Alexander K. , Masmanidis Sotiris C. 
Published: September 2022

AbstractWhile the contribution of dopaminergic (DA) neurons to associative learning is firmly established, their importance for influencing imminent behavior on short (subsecond) timescales is less clear. Mechanistically, it is thought that DA neurons drive these behavioral changes because of their ability to rapidly alter striatal spiking activity. However, due to limitations of previous approaches, the straightforward prediction that striatal spiking is rapidly influenced by physiologically relevant DA signals has not been rigorously tested. Here, we monitored changes in spiking responses in the ventral striatum while transiently reducing or increasing DA levels. Contrary to the predicted effect, neither spontaneous nor reward-evoked striatal spiking activity was strongly influenced by optogenetic manipulations, except when DA exceeded reward-matched levels. These findings challenge the view that DA plays a major role in rapidly influencing striatal activity. Finally, they suggest a need to distinguish between the modulatory functions of DA under physiological and supra-physiological conditions.
Acute stress impairs target enhancement but not distractor suppression in attention selection: Evidence from the N2pc and Pd
Authors: Luo Yu , Nian Jingqing , Yang Run , Xie Jiao , Zhang Yu 
Published: September 2022

AbstractAcute stress has a profound impact on attention selection. However, the cognitive mechanism of acute stress on attention selection for neutral stimuli remains unclear. The current study aimed to investigate how acute stress affects target enhancement and distractor suppression in attention selection using a visual search task while EEG was recorded. The Maastricht Acute Stress Test was successfully induced a stress response in the stress group, as indexed by the higher salivary cortisol, state anxiety, and negative emotion. Crucially, the stress group showed significantly smaller N2pc than the control group in the lateral target/midline and contralateral distractor conditions when the distractor salience was high, whereas no significant differences in the Pd were observed in the lateral distractor/midline target condition. These results suggest that acute stress impairs target enhancement rather than distractor suppression in attention selection. This impairment may be due to the impaired function of the prefrontal cortex under acute stress. The present research provides the first insight into the cognitive mechanism of acute stress on attention selection.
Proteogenomic analysis reveals RNA as an important source for tumor-agnostic neoantigen identification correlating with T-cell infiltration
Authors: Tretter Celina , de Andrade Krätzig Niklas , Pecoraro Matteo , Lange Sebastian , Seifert Philipp , von Frankenberg Clara , Untch Johannes , Dreyer Florian S , Bräunlein Eva , Wilhelm Mathias , Zolg Daniel P , Engleitner Thomas , Uhrig Sebastian , Boxberg Melanie , Steiger Katja , Slotta-Huspenina Julia , Ochsenreither Sebastian , von Bubnoff Nikolas , Bauer Sebastian , Boerries Melanie , Jost Philipp J , Schenck Kristina , Dresing Iska , Bassermann Florian , Friess Helmut , Reim Daniel , Grützmann Konrad , Pfütze Katrin , Klink Barbara , Schrock Evelin , Haller Bernhard , Kuster Bernhard , Mann Matthias , Weichert Wilko , Fröhling Stefan , Rad Roland , Hiltensperger Michael , Krackhardt Angela M 
Published: September 2022

AbstractSystemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types by combining proteogenomics with phenotypic and functional analyses. By using an optimized computational approach, we discovered a large number of novel tumor-specific and tumor-associated antigens including shared common target candidates. To create a pipeline for the identification of neoantigens in our cohort, we combined deep DNA and RNA sequencing with MS- based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity. In fact, we could detect a broad variety of non-wild type HLA-binding peptides in the majority of patients and confirmed the immunogenicity of 24 neoantigens. Most interestingly, the majority of total and immunogenic neoantigens originated from variants identified in the RNA dataset, illustrating the importance of RNA as a still understudied source of cancer antigens. Moreover, the amount of these mainly RNA-based immunogenic neoantigens correlated positively with overall CD8+ tumor-infiltrating T cells. This study therefore underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.Statement of significanceThe significance of this study lies not only in the potential of our optimized proteogenomic workflow for the discovery of neoantigens (in particular RNA-derived neoantigens) for clinical application, but sheds light on the entity-agnostic prevalence of HLA class I peptide presentation of RNA processing events to be used for tumor targeting.
Cascades of neuronal plasticity in the macaque visual cortex
Authors: Koyano Kenji W. , Esch Elena M. , Hong Julie J. , Waidmann Elena N. , Leopold David A. 
Published: September 2022

AbstractPrimates readily learn new visual objects, with neurons in the inferior temporal cortex exhibiting diminished visual responses to familiar stimuli. The mechanisms of visual plasticity expressed within a neural population are largely unknown. Here we used chronic microwire electrodes in a face-selective cortical area in the macaque to longitudinally track cohorts of neurons across several weeks of exposure to novel faces. Neurons showed gradual adaptation in their late-phase visual responses, with cell-specific time constants ranging from two to twenty days. These time constants were governed by the number of testing days rather than by the cumulative number of stimulus exposures. This gradual buildup of altered visual responses may serve as an internal and graded mark of stimulus familiarity, a central component of visual recognition.
Rigidified Scaffolds for 3 Angstrom Resolution Cryo-EM of Small Therapeutic Protein Targets
Authors: Castells-Graells Roger , Meador Kyle , Arbing Mark A. , Sawaya Michael R. , Gee Morgan , Cascio Duilio , Gleave Emma , Debreczeni Judit É. , Breed Jason , Phillips Chris , Yeates Todd O. 
Published: September 2022

AbstractNumerous technical advances have made cryo-EM an attractive method for atomic structure determination. Cryo-EM is ideally suited for large macromolecular structures, while problems of low signal-to-noise prevent routine structure determination of proteins smaller than about 50 kDa. This size limitation excludes large numbers of important cellular proteins from structural characterization by this powerful technique, including many cell-signaling proteins of high therapeutic interest. In the present work, we use molecular engineering techniques to rigidify an imaging scaffold, based on a designed protein cage, to the point where 3 Å resolution can be achieved, even for very small proteins. After optimizing the design of the rigidified scaffold on test proteins, we apply this imaging system to the key oncogenic signaling protein KRAS, which represents an outstanding challenge in the area of structure-based drug design. Despite its 19 kDa size, we show that the structure of KRAS, in multiple mutant forms, and bound to its GDP ligand, can be readily interpreted at a resolution slightly better than 3.0 Å. This advance further expands the capability of cryo-EM to become an essentially universal method for protein structure determination, including for applications to small therapeutic protein targets.