bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer
Authors: Memon Danish , Rizvi Hira , Fromm George , Lihm Jayon , Schoenfeld Adam J. , Sauter Jennifer L. , Luo Jia , Chow Andrew , Bhanot Umesh K. , McCarthy Caroline , Ye Darwin , Vanderbilt Chad M. , Liu Cailian , Abu-Akeel Mohsen , Plodkowski Andrew J. , McGranahan Nicholas , Łuksza Marta , Greenbaum Benjamin D. , Merghoub Taha , Minn Andy J. , Beltrao Pedro , Schreiber Taylor H. , Miller Martin L. , Hellmann Matthew D. 
Published: July 2021

AbstractAlthough cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance generally had enriched signals of inflammation (including IFNγ signaling and inferred CD8+ T cells) and could be separated into IFNγ upregulated and stable subsets. IFNγ upregulated tumors had putative routes of resistance with signatures of dysfunctional interferon signaling and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from a murine model of acquired resistance to PD-(L)1 blockade also showed evidence of dysfunctional interferon signaling and acquired insensitivity to in vitro interferon gamma treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but dysfunctional IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.
skater: An R package for SNP-based Kinship Analysis, Testing, and Evaluation
Authors: Turner Stephen D. , Nagraj V. P. , Scholz Matthew , Jessa Shakeel , Acevedo Carlos , Ge Jianye , Woerner August E. , Budowle Bruce 
Published: July 2021

AbstractMotivationSNP-based kinship analysis with genome-wide relationship estimation and IBD segment analysis methods produces results that often require further downstream processing and manipulation. A dedicated software package that consistently and intuitively implements this analysis functionality is needed.ResultsHere we present the skater R package for SNP-based kinship analysis, testing, and evaluation with R. The skater package contains a suite of well-documented tools for importing, parsing, and analyzing pedigree data, performing relationship degree inference, benchmarking relationship degree classification, and summarizing IBD segment data.AvailabilityThe skater package is implemented as an R package and is released under the MIT license at https://github.com/signaturescience/skater. Documentation is available at https://signaturescience.github.io/skater.
Democratizing Data-Independent Acquisition Proteomics Analysis on Public Cloud Infrastructures Via The Galaxy Framework
Authors: Fahrner Matthias , Föll Melanie Christine , Grüning Björn , Bernt Matthias , Röst Hannes , Schilling Oliver 
Published: July 2021

AbstractData-independent acquisition (DIA) has become an important approach in global, mass spectrometric proteomic studies because it provides in-depth insights into the molecular variety of biological systems. However, DIA data analysis remains challenging due to the high complexity and large data and sample size, which require specialized software and large computing infrastructures. Most available open-source DIA software necessitate basic programming skills and cover only a fraction of the analysis steps, often yielding a complex of multiple software tools, severely limiting usability and reproducibility. To overcome this hurdle, we have integrated a suite of DIA tools in the Galaxy framework for reproducible and version-controlled data processing. The DIA suite includes OpenSwath, PyProphet, diapysef and swath2stats. We have compiled functional Galaxy pipelines for DIA processing, which provide a web-based graphical user interface to these pre-installed and pre-configured tools for their usage on freely accessible, powerful computational resources of the Galaxy framework. This approach also enables seamless sharing workflows with full configuration in addition to sharing raw data and results. We demonstrate usability of the all-in-one DIA pipeline in Galaxy by the analysis of a spike-in case study dataset. Additionally, extensive training material is provided, to further increase access for the proteomics community.
Structure insights, thermodynamic profiles, dsDNA melting activity, and liquid-liquid phase separation of the SARS-CoV-2 nucleocapsid N-terminal domain binding to DNA
Authors: Caruso Icaro Putinhon , dos Santos Almeida Vitor , Juliani do Amaral Mariana , de Andrade Guilherme Caldas , de Araújo Gabriela Rocha , de Araújo Talita Stelling , de Azevedo Jéssica Moreira , Barbosa Glauce Moreno , Bartkevihi Leonardo , Bezerra Peter Reis , dos Santos Cabral Katia Maria , Lourenço Isabella Otênio , Malizia-Motta Clara L. F. , de Luna Marques Aline , Mebus-Antunes Nathane Cunha , Neves-Martins Thais Cristtina , de Sá Jéssica Maróstica , Sanches Karoline , Santana-Silva Marcos Caique , Vasconcelos Ariana Azevedo , da Silva Almeida Marcius , de Amorim Gisele Cardoso , Anobom Cristiane Dinis , Da Poian Andrea T. , Gomes-Neto Francisco , Pinheiro Anderson S. , Almeida Fabio C. L. 
Published: July 2021

ABSTRACTThe SARS-CoV-2 nucleocapsid protein (N) is a multifunctional promiscuous nucleic acid-binding protein, which plays a major role in nucleocapsid assembly and discontinuous RNA transcription, facilitating the template switch of transcriptional regulatory sequences (TRS). Here, we dissect the structural features of the N protein N-terminal domain (N-NTD), either with or without the SR-rich motif (SR), upon binding to single and double-stranded TRS DNA, as well as their activities for dsTRS melting and TRS-induced liquid-liquid phase separation (LLPS). Our study gives insights on specificity for N-NTD/N-NTD-SR interaction with TRS, including an unfavorable energetic contribution to binding along with hydrogen bonds between the triple-thymidine (TTT) motif in the dsTRS and β-sheet II due to the defined position and orientation of the DNA duplex, a well-defined pattern (ΔH > 0 and ΔS > 0 for ssTRS, and ΔH < 0 and ΔS < 0 for dsTRS) for the thermodynamic profile of binding, and a preference for TRS in the formation of liquid condensates when compared to a non-specific sequence. Moreover, our results on DNA binding may serve as a starting point for the design of inhibitors, including aptamers, against N, a possible therapeutic target essential for the virus infectivity.
Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis
Authors: Priyadarshini Medha , Navarro Guadalupe , Reiman Derek J , Sharma Anukriti , Xu Kai , Lednovich Kristen , Manzella Christopher R , Khan Md Wasim , Wicksteed Barton , Chlipala George E , Sanzyal Barbara , Bernabe Beatriz Penalver , Maki Pauline M , Gill Ravinder K , Gilbert Jack , Dai Yang , Layden Brian T 
Published: July 2021

AbstractBackground and aimsNormal gestation involves reprogramming of maternal gut microbiome (GM) that may contribute to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM – maternal metabolism interaction.MethodsThe GM and plasma metabolome of CD1, NIH-Swiss and C57BL/6J mice were analyzed using 16S rRNA sequencing and untargeted LC-MS throughout gestation and postpartum. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM in the process was studied using fecal microbial transplants (FMT).ResultsSignificant variation in gut microbial alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time-point specific, with species enriched at gestation day 15/19 (G15/19), a point of heightened IR, distinct from those enriched pre- or post- pregnancy. Untargeted and targeted metabolomics revealed elevated plasma kynurenine at G15/19 in all three mouse strains. IDO1, the rate limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine levels effects on IR derive from the GM in both mouse and human pregnancy.ConclusionsGM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1.
Transfer of learned cognitive flexibility to novel stimuli and task sets
Authors: Wen Tanya , Geddert Raphael M. , Madlon-Kay Seth , Egner Tobias 
Published: July 2021

AbstractAdaptive behavior requires learning about the structure of one’s environment to derive optimal action policies, and previous studies have documented transfer of such structural knowledge to bias choices in new environments. Here, we asked whether people could also acquire and transfer more abstract knowledge across different task environments, specifically expectations about cognitive control demands. Over three experiments, participants performed a probabilistic card-sorting task in environments of either a low or high volatility of task rule changes (requiring low or high cognitive flexibility respectively) before transitioning to a medium-volatility environment. Using reinforcement learning modeling, we consistently found that previous exposure to high task rule volatilities led to faster adaptation to rule changes in the subsequent transfer phase. These transfers of expectations about cognitive flexibility demands were both task- (Experiment 2) and stimulus- (Experiment 3) independent, thus demonstrating the formation and generalization of environmental structure knowledge to guide cognitive control.Statement of RelevanceWe investigated whether structural knowledge of one task environment can be transferred to guide cognitive control strategies in new environments. Past research has found that while learning generally improves subsequent performance, it does so only for the learned task (“near transfer”) and has little or no generalizability to novel task rules and stimuli (“far transfer”). However, recent studies suggest that learning more abstract, structural task features (e.g., cognitive maps) allows for that knowledge to be applied to new environments. Here, we took a critical additional step and showed that people can acquire and transfer expectations about cognitive control demands (specifically cognitive flexibility) across different task environments. To our knowledge, this is the first demonstration of people’s ability to extract and re-use cognitive control learning parameters that transcend specific stimuli and tasks. This transfer of learned cognitive flexibility is particularly noteworthy because such flexibility is impaired in several common psychiatric conditions.
Retrosplenial cortex is necessary for spatial and non-spatial latent learning in mice
Authors: Bottura de Barros Ana Carolina , Baruchin Liad J. , Panayi Marios C. , Nyberg Nils , Samborska Veronika , Mealing Mitchell T. , Akam Thomas , Kwag Jeehyun , Bannerman David M. , Kohl Michael M. 
Published: July 2021

AbstractLatent learning occurs when associations are formed between stimuli in the absence of explicit reinforcement. Traditionally, latent learning in rodents has been associated with the creation internal models of space. However, increasing evidence points to roles of internal models also in non-spatial decision making. Whether the same brain structures and processes support the creation of spatially-anchored or non-spatial internal models via latent learning, is an open question. To address this question, we developed a novel operant box task that allows to test spatial and non-spatial versions of a flavour-based sensory preconditioning paradigm. We probed the role of the retrosplenial cortex, a brain area associated with spatial cognition and subjective value representation, in this task using precise, closed-loop optogenetic silencing during different task phases. We show that the retrosplenial cortex is necessary for both spatial and non-spatial latent learning in mice. We further demonstrate that the requirement of retrosplenial cortex is limited to the preconditioning phase of the task. Our results provide insight into the specific role of the retrosplenial cortex in latent learning, demonstrate that latent learning plays a general part in the creation of internal models, independent of spatial anchors, and provide a novel avenue for studying model-based decision making.
Csp1, A Cold-Shock Protein Homolog in Xylella fastidiosa Influences Pili Formation, Stress Response, and Gene Expression
Authors: Wei Wei , Sawyer Teresa , Burbank Lindsey P. 
Published: July 2021

AbstractBacterial cold shock-domain proteins (CSPs) are conserved nucleic acid binding chaperones that play important roles in stress adaptation and pathogenesis. Csp1 is a temperature-independent cold shock protein homolog in Xylella fastidiosa, a bacterial plant pathogen of grapevine and other economically important crops. Csp1 contributes to stress tolerance and virulence in X. fastidiosa. However, besides general single stranded nucleic acid binding activity, little is known about the specific function(s) of this protein. To further investigate the role(s) of Csp1, we compared phenotypic differences between wild type and a csp1 deletion mutant (Δcsp1). We observed decreases in cellular aggregation and surface attachment with the Δcsp1 strain compared to the wild type. Transmission electron microscopy imaging revealed that Δcsp1 had reduced pili compared to the wild type and complemented strains. The Δcsp1 strain also showed reduced survival after long term growth, in vitro. Since Csp1 binds DNA and RNA, its influence on gene expression was also investigated. Long-read Nanopore RNA-Seq analysis of wild type and Δcsp1 revealed changes in expression of several genes important for attachment and biofilm formation in Δcsp1. One gene of intertest, pilA1, encodes a type IV pili subunit protein and was up regulated in Δcsp1. Deleting pilA1 increased surface attachment in vitro and reduced virulence in grapevines. X. fastidiosa virulence depends on bacterial attachment to host tissue and movement within and between xylem vessels. Our results show Csp1 may play a role in both virulence and stress tolerance by influencing expression of genes important for biofilm formation.ImportanceXylella fastidiosa is a major threat to the worldwide agriculture industry (1, 2). Despite its global importance, many aspects of X. fastidiosa biology and pathogenicity are poorly understood. There are currently few effective solutions to suppress X. fastidiosa disease development or eliminate bacteria from infected plants(3). Recently, disease epidemics due to X. fastidiosa have greatly expanded(2, 4, 5), exacerbating the need for better disease prevention and control strategies. Our studies show that Csp1 is involved in X. fastidiosa virulence and stress tolerance. Understanding how Csp1 influences pathogenesis and bacteria survival can aide in developing novel pathogen and disease control strategies. We also streamlined a bioinformatics protocol to process and analyze long read Nanopore bacterial RNA-Seq data, which has previously not been reported for X. fastidiosa.
Pich, an ATP-dependent chromatin remodeling protein, transcriptionally co-regulates oxidative stress response
Authors: Dutta Anindita , Das Apurba , Bisht Deepa , Arya Vijendra , Muthuswami Rohini 
Published: July 2021

ABSTRACTCells respond to oxidative stress by elevating the levels of antioxidants, signaling, and transcriptional regulation often implemented by chromatin remodeling proteins. The study presented in this paper shows that the expression of PICH, an ATP-dependent chromatin remodeler, is upregulated during oxidative stress in HeLa cells. We also show that PICH regulates the expression of Nrf2, a transcription factor regulating antioxidant response, both in the absence and presence of oxidative stress. In turn, Nrf2 regulates the expression of PICH in the presence of oxidative stress. Both PICH and Nrf2 together regulate the expression of antioxidant genes and this transcriptional regulation is dependent on the ATPase activity of PICH. In addition, H3K27ac modification also plays a role in activating transcription in the presence of oxidative stress. Co-immunoprecipitation experiments show that PICH and Nrf2 interact with H3K27ac in the presence of oxidative stress. Mechanistically, PICH recognizes ARE sequences present on its target genes and introduces a conformational change to the DNA sequences leading us to hypothesize that PICH regulates transcription by remodeling DNA. PICH ablation leads to reduced expression of Nrf2 and impaired antioxidant response leading to increased ROS content, thus, showing PICH is essential for the cell to respond to oxidative stress.
CD8+ T cell signature in acute SARS-CoV-2 infection identifies memory precursors
Authors: Adamo Sarah , Michler Jan , Zurbuchen Yves , Cervia Carlo , Taeschler Patrick , Raeber Miro E. , Sain Simona Baghai , Nilsson Jakob , Moor Andreas E. , Boyman Onur 
Published: July 2021

AbstractImmunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen1,2. Since the outbreak of the ongoing coronavirus disease 19 (COVID-19) pandemic, a key question has focused on whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells stimulated during acute infection give rise to long-lived memory T cells3. Using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor (TCR) sequencing we longitudinally characterize individual SARS-CoV-2-specific CD8+ T cells of COVID-19 patients from acute infection to one year into recovery and find a distinct signature identifying long-lived memory CD8+ T cells. SARS-CoV-2-specific memory CD8+ T cells persisting one year after acute infection re-express CD45RA and interleukin-7 receptor α (CD127), upregulate T cell factor-1 (TCF1), and maintain low CCR7, thus resembling CD45RA+ effector-memory T (TEMRA) cells. Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, we reveal that an interferon signature marks clones giving rise to long-lived cells, whereas prolonged proliferation and mammalian target of rapamycin (mTOR) signaling are associated with clone contraction and disappearance. Collectively, we identify a transcriptional signature differentiating short-from long-lived memory CD8+ T cells following an acute virus infection in humans.
E-cadherin regulates the stability and transcriptional activity of β-catenin in embryonic stem cells
Authors: Bhattacharyya Sinjini , Mote Ridim D. , Freimer Jacob W. , Singh Surya Bansi , Arumugam Sandhya , Narayana Yadavalli V. , Rajan Raghav , Subramanyam Deepa 
Published: July 2021

AbstractE-CADHERIN is abundantly expressed in embryonic stem cells (ESCs) and plays an important role in the maintenance of cell-cell adhesions. However, the exact function of this molecule beyond cell adhesion, in the context of cell fate decisions is largely unknown. Using mouse ESCs (mESCs), we demonstrate that E-CADHERIN and β- CATENIN interact at the membrane and continue to do so upon internalization within the cell. Knockout of the gene encoding E-CADHERIN, Cdh1, in mESCs resulted in a failure to form tight colonies, accompanied by altered expression of differentiation markers, and retention of pluripotency factor expression during differentiation. Interestingly, Cdh1-/- mESCs showed a dramatic reduction in β-CATENIN levels. Transcriptional profiling of Cdh1-/- mESCs displayed a significant alteration in the expression of a subset of β-CATENIN targets, in a cell-state dependent manner. While treatment with a pharmacological inhibitor against GSK3β could rescue levels of β-CATENIN in Cdh1-/- mESCs, expression of downstream targets were altered in a context-dependent manner, indicating an additional layer of regulation within this subset. Together, our results reveal the existence of a cell-state-dependent regulation of β-CATENIN and its transcriptional targets in an E-CADHERIN dependent manner. Our findings hint at hitherto unknown roles played by E- CADHERIN in regulating the activity of β-CATENIN in ESCs.Significance StatementAre cell adhesions only responsible for maintaining tissue architecture, or do they also regulate cell fate decisions during early embryonic stages by modulating the output of specific signalling pathways? In this study, we study the role of E- CADHERIN, a crucial component of cell-cell adhesions in the context of mouse embryonic stem cells (mESCs). We find that E-CADHERIN regulates the stability and activity of β-CATENIN in mESCs through physical interactions. However, the loss of E-CADHERIN affected the expression of only a subset of downstream targets of β-CATENIN in a cell-state dependent manner. This study highlights a critical cross-talk between molecules involved in cell-cell adhesion and the underlying signalling network critical for establishing cell fate during early mammalian development.
Cryo-EM structure of the NLRP3 decamer bound to the cytokine release inhibitory drug CRID3
Authors: Hochheiser Inga V. , Pilsl Michael , Hagelueken Gregor , Moecking Jonas , Marleaux Michael , Brinkschulte Rebecca , Latz Eicke , Engel Christoph , Geyer Matthias 
Published: July 2021

AbstractNLRP3 is an intracellular sensor protein whose activation by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis. The mechanisms leading to NLRP3 activation and the way how antagonistic small molecules function remain poorly understood. Here we report the cryo-electron microscopy structures of full-length NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950). Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined LRR domains that assemble back-to-back as pentamers with the NACHT domain located at the apical axis of this spherical structure. Molecular contacts between the concave sites of two opposing LRRs are mediated by an acidic loop extending from an LRR transition segment. Binding of CRID3 significantly stabilizes the NACHT and LRR domains relative to each other, allowing structural resolution of 3.9-4.2 Å. CRID3 binds into a cleft, connecting four subdomains of the NACHT with the transition LRR. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain and is sandwiched between two arginines from opposing sites, explaining the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this lead therapeutic, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization are within reach.