bluuebunny/crossref_metadata_2025_split huggingface dataset:
MULTISCALE ANALYSIS AND VALIDATION OF EFFECTIVE DRUG COMBINATIONS TARGETING DRIVER KRAS MUTATIONS IN NON-SMALL CELL LUNG CANCER
Authors: Bruggemann Liana , Falls Zackary , Mangione William , Schwartz Stanley A , Battaglia Sebastiano , Aalinkeel Ravikumar , Mahajan Supriya D. , Samudrala Ram 
Published: September 2022

1.AbstractPharmacogenomics is a rapidly growing field with the goal of providing personalized care to every patient. Previously, we developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to screen optimal compounds for any indication/disease by performing analytics on their interactions with large protein libraries. We implemented a comprehensive precision medicine drug discovery pipeline within the CANDO platform to determine which drugs are most likely to be effective against mutant phenotypes of non-small cell lung cancer (NSCLC) based on the supposition that drugs with similar interaction profiles (or signatures) will have similar behavior and therefore show synergistic effects. CANDO predicted that osimertinib, an EGFR inhibitor, is most likely to synergize with four KRAS inhibitors.Validation studies with cellular toxicity assays confirmed that osimertinib in combination with ARS-1620, a KRAS G12C inhibitor, and BAY-293, a pan-KRAS inhibitor, showed a synergistic effect on decreasing cellular proliferation by acting on mutant KRAS. Gene expression studies revealed that MAPK suppression is a key correlate of decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. Our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales.
Glucose PTS Modulates Pyruvate Metabolism, Bacterial Fitness, and Microbial Ecology in Oral Streptococci
Authors: Zeng Lin , Walker Alejandro R. , Burne Robert A. , Taylor Zachary A. 
Published: September 2022

AbstractSpontaneous mutants with defects in the primary glucose phosphotransferase (PTS) permease (manLMNO) of Streptococcus sanguinis SK36 showed enhanced fitness at low pH. Transcriptomics and metabolomics with a manL deletion mutant (SK36/manL) revealed redirection of pyruvate to production of acetate and formate, rather than lactate. The observations were consistent with measurements of decreased lactic acid accumulation and increased excretion of pyruvate and H2O2. Genes showing increased expression in SK36/manL included those encoding carbohydrate transporters, extracellular glycosidases, intracellular polysaccharide (IPS) metabolism, arginine deiminase, and pathways for metabolism of acetoin, ethanolamine, ascorbate and formate; along with genes required for membrane biosynthesis and adhesion. Streptococcus mutans UA159 persisted much better in biofilm co-cultures with SK36/manL than with SK36, an effect that was further enhanced by culturing the biofilms anaerobically but dampened by adding arginine to the medium. We posited that the enhanced persistence of S. mutans with SK36/manL was in part due to excess excretion of pyruvate by the latter, as addition of pyruvate to S. mutans-S. sanguinis co-cultures increased the proportions of UA159 in the biofilms. Reduction of the buffer capacity or increasing the concentration of glucose benefited UA159 when co-cultured with SK36, but not with SK36/manL; likely due to the altered metabolism and enhanced acid tolerance of the mutant. When manL was deleted in S. mutans or Streptococcus gordonii, the mutants presented altered fitness characteristics. Our study demonstrated that PTS-dependent modulation of central metabolism can profoundly affect streptococcal fitness and metabolic interactions, revealing another dimension in commensal-pathogen relationships influencing dental caries development.ImportanceDental caries is underpinned by a dysbiotic microbiome and increased acid production. As beneficial bacteria that can antagonize oral pathobionts, oral streptococci such as S. sanguinis and S. gordonii can ferment many carbohydrates, despite their relative sensitivity to low pH. We characterized the molecular basis for why mutants of glucose transporter ManLMNO of S. sanguinis showed enhanced production of hydrogen peroxide and ammonia, and improved persistence under acidic conditions. Significant metabolic shift involving more than 300 genes required for carbohydrate transport, energy production, and envelope biogenesis was observed. Significantly, manL mutants engineered in three different oral streptococci displayed altered capacities for acid production and interspecies antagonism, highlighting the potential for targeting the glucose-PTS to modulate the pathogenicity of oral biofilms.
Rare Maternally Inherited Coding Variants on Chromosome X Carry Predominantly Male Risk in Autism, Tourette Syndrome, and Attention-deficit/Hyperactivity Disorder
Authors: Wang Sheng , Wang Belinda , Drury Vanessa , Drake Sam , Sun Nawei , Alkhairo Hasan , Arbelaez Juan , Duhn Clif ,   Tourette International Collaborative Genetics (TIC Genetics), Bal Vanessa H. , Langley Kate , Martin Joanna , Xing Jinchuan , Heiman Gary A. , Tischfield Jay A. , Fernandez Thomas V. , Owen Michael J. , O’Donovan Michael C. , Thapar Anita , State Matthew W. , Willsey A. Jeremy 
Published: September 2022

ABSTRACTAutism spectrum disorders (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of “male vulnerability”, rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of “idiopathic” ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in TS and ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.
Integrating comparative modeling and accelerated simulations reveals conformational and energetic basis of actomyosin force generation
Authors: Ma Wen , You Shengjun , Regnier Michael , McCammon J. Andrew 
Published: September 2022

Muscle contraction is performed by arrays of contractile proteins in the sarcomere. Serious heart diseases, such as cardiomyopathy, can often be results of mutations in myosin and actin. Direct characterization of how small changes in the myosin-actin complex impact its force production remains challenging. Molecular dynamics (MD) simulations, although capable of studying protein structurefunction relationships, are limited owing to the slow timescale of the myosin cycle as well as a lack of various intermediate structures for the actomyosin complex. Here, employing comparative modeling and enhanced sampling MD simulations, we show how the human cardiac myosin generates force during the mechanochemical cycle. Initial conformational ensembles for different myosin-actin states are learned from multiple structural templates with Rosetta. This enables us to efficiently sample the energy landscape of the system using Gaussian accelerated MD. Key myosin loop residues, whose substitutions are related to cardiomyopathy, are identified to form stable or metastable interactions with the actin surface. We find that the actin-binding cleft closure is allosterically coupled to the myosin core transitions and ATP-hydrolysis product release from the active site. Furthermore, a gate between switch I and switch II is suggested to control phosphate release at the pre-powerstroke state. Our approach demonstrates the ability to link sequence and structural information to motor functions.Significance StatementInteractions between myosin and actin are essential in producing various cellular forces. Targeting cardiac myosin, several small molecules have been developed to treat cardiomyopathy. A clear mechanistic picture for the allosteric control in the actomyosin complex can potentially facilitate drug design by uncovering functionally important intermediate states. Here, integrating Rosetta comparative modeling and accelerated molecular dynamics, we reveal how ATP-hydrolysis product release correlates with powerstroke and myosin tight binding to actin. The predicted metastable states and corresponding energetics complement available experimental data and provide insights into the timing of elementary mechanochemical events. Our method establishes a framework to characterize at an atomistic level how a molecular motor translocates along a filament.
Genome evolution and transcriptome plasticity associated with adaptation to monocot and eudicot plants inColletotrichumfungi
Authors: Baroncelli Riccardo , Cobo-Díaz José F. , Benocci Tiziano , Peng Mao , Battaglia Evy , Haridas Sajeet , Andreopoulos William , LaButti Kurt , Pangilinan Jasmyn , Lipzen Anna , Koriabine Maxim , Bauer Diane , Floch Gaetan Le , Mäkelä Miia R. , Drula Elodie , Henrissat Bernard , Grigoriev Igor V. , Crouch Jo Anne , de Vries Ronald P. , Sukno Serenella A. , Thon Michael R. 
Published: September 2022

ABSTRACTColletotrichumfungi infect a wide diversity of monocot and eudicot hosts, causing plant diseases on almost all economically important crops worldwide. In addition to its economic impact,Colletotrichumis a suitable model for the study of gene family evolution on a fine scale to uncover events in the genome that are associated with the evolution of biological characters important for host interactions. Here we present the genome sequences of 30Colletotrichumspecies, 18 of them newly sequenced, covering the taxonomic diversity within the genus. A time-calibrated tree revealed that theColletotrichumancestor diverged in the late Cretaceous around 70 million years ago (mya) in parallel with the diversification of flowering plants. We provide evidence of independent host jumps from eudicots to monocots during the evolution of this pathogen, coinciding with a progressive shrinking of the degradative arsenal and expansions in lineage specific genes. Comparative transcriptomics of four reference species with different evolutionary histories and adapted to different hosts revealed similarity in gene content but differences in the modulation of their transcription profiles. Only a few orthologs show similar expression profiles on different plant cell walls. Combining genome sequences and expression profiles we identified a set of core genes, such as specific transcription factors, involved in plant cell wall degradation inColletotrichum.Together, these results indicate that the ancestralColletotrichumwere associated with eudicot plants and certain branches progressively adapted to different monocot hosts, reshaping part of the degradative and transcriptional arsenal.
Data driven model discovery and interpretation for CAR T-cell killing using sparse identification and latent variables
Authors: Brummer Alexander B. , Xella Agata , Woodall Ryan , Adhikarla Vikram , Cho Heyrim , Gutova Margarita , Brown Christine E. , Rockne Russell C. 
Published: September 2022

ABSTRACTIn the development of cell-based cancer therapies, quantitative mathematical models of cellular interactions are instrumental in understanding treatment efficacy. Efforts to validate and interpret mathematical models of cancer cell growth and death hinge first on proposing a precise mathematical model, then analyzing experimental data in the context of the chosen model. In this work, we present the first application of the sparse identification of non-linear dynamics (SINDy) algorithm to a real biological system in order discover cell-cell interaction dynamics inin vitroexperimental data, using chimeric antigen receptor (CAR) T-cells and patient-derived glioblastoma cells. By combining the techniques of latent variable analysis and SINDy, we infer key aspects of the interaction dynamics of CAR T-cell populations and cancer. Importantly, we show how the model terms can be interpreted biologically in relation to different CAR T-cell functional responses, single or double CAR T-cell-cancer cell binding models, and density-dependent growth dynamics in either of the CAR T-cell or cancer cell populations. We show how this data-driven model-discovery based approach provides unique insight into CAR T-cell dynamics when compared to an established model-first approach. These results demonstrate the potential for SINDy to improve the implementation and efficacy of CAR T-cell therapy in the clinic through an improved understanding of CAR T-cell dynamics.
When Mechanical Stress Matters: Generation of Polyploid Giant Cancer Cells in Tumor-like Microcapsules
Authors: Bühler Adrian , Krüger René , Monavari Mahshid , Fuentes-Chandía Miguel , Palmisano Ralf , Schödel Johannes , Boccaccini Aldo R. , Boßerhoff Anja K. , Kappelmann-Fenzl Melanie , Letort Gaelle , Leal-Egaña Aldo 
Published: September 2022

AbstractIn this work, we studied the generation and rising of polyploid cancer cells as a product of mechanical stress. To this purpose, MCF7 breast cancer cells were cultured on 2D (i.e. flasks, or flat hydrogels), and in 3D milieus (i.e. Spheroids, or immobilized within alginate-gelatin microbeads, named in this work as tumor-like microcapsules), and further analyzed by biophysical and genetic methods (i.e. single-cell Traction Force Microscopy and RNA-seq respectively).Our results show that MCF7 cells preconditioned onto 2D surfaces exhibit a low number of polynucleated cells, while their culture in 3D environments triggered their progressive generation with time. Genetic studies enabled us to determine that polyploid cells found in tumor-like microcapsules are likely originated by cell-cell fusion and disrupted cytokinesis, showing most of the genetic markers for Polyploid Giant Cancer Cell, while cells cultured as spheroids seem to be likely generated by other mechanisms, such as cell cannibalisms, entosis, or emperipolesis.Our outcomes strongly suggest that both mechanical stress and confinement are required to stimulate cell polyploidy, which can be easily addressed by the immobilization of breast cancer cells in tumor-like microcapsules.
One Health Approach for the sampling of different bat species living in a sympatric colony
Authors: Perera Thejanee , Siriwardana Sahan , Muzeniek Therese , Becker-Ziaja Beate , Bas Dilara , Bayram Fatimanur , Öruc Mizgin , Perera Inoka , Weerasena Jagathpriya , Handunnetti Shiroma , Schwarz Franziska , Premawansa Gayani , Premawansa Sunil , Yapa Wipula , Nitsche Andreas , Kohl Claudia 
Published: September 2022

AbstractBats are important contributors to the global ecosystems; at the same time, they are known to be a natural reservoir host for a number of human pathogenic viruses. These and many other unique features make them an interdisciplinary research object in the context of One Health, comprising zoology, ecology, virology, microbiology, molecular biology, immunology and public health issues. Performing field studies for bat research often aims to cover several of these topics and requires the combination of specific expertise in different fields. We carried out three individual field studies in Wavul Galge cave (Koslanda, Sri Lanka), where several bat species roost sympatrically. The main goals were to study the bat colony for ecological aspects and to sample bats for virological and molecular biological analyses. In the course of the field studies, we optimized the sampling procedure regarding safety aspects, a preferably low impact on the captured bats and an improved output of high-quality samples for further analysis. Different sampling methods and procedures were compared in order to establish a suitable strategy for frequent sampling and monitoring of these bats. In the present case study, we report on this process of optimizing our field work and provide suggestions for bat sampling methods that cause comparably less stress for the captured animals. We also report on constraints and obstacles encountered during the practical implementation and possible measures to overcome these.With these practical experiences, we hope to give support to other interdisciplinary research teams preparing for bat field work. Furthermore, we emphasize the need for the respectful treatment of the animals and minimized disturbance of their natural habitat when carrying out sustainable bat research.
Pathogenic mis-splicing of CPEB4 in schizophrenia
Authors: Ollà Ivana , Pardiñas Antonio F. , Parras Alberto , Hernández Ivó H. , Santos-Galindo María , Picó Sara , Callado Luis F. , Elorza Ainara , Fernández-Miranda Gonzalo , Belloc Eulàlia , Walters James T.R. , O’Donovan Michael C. , Toma Claudio , Méndez Raúl , Meana J. Javier , Owen Michael J. , Lucas José J. 
Published: September 2022

ABSTRACTSchizophrenia (SCZ) is caused by a complex interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ risk genes. The RNA binding protein family CPEB (CPEB1, CPEB2, CPEB3, CPEB4) regulates the translation of target RNAs bearing CPE sequences in their 3’UTR (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), proving that its neuronal-specific microexon (exon 4) is mis-spliced in brains of ASD probands, leading to concerted underexpression of a plethora of high confidence ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD make it plausible that mis-splicing of CPEB4 might occur also in SCZ patients, leading to downstream altered brain expression of multiple SCZ-related genes. In this study, we first analyzed Psychiatric Genomics Consortium GWAS data and found significant enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased inclusion of CPEB4 microexon in postmortem prefrontal cortex of SCZ probands. This mis-splicing is associated with decreased protein levels of SCZ-associated genes that are targets of CPEB4. Interestingly, this happens specifically in individuals with low exposure to antipsychotic medication. Finally, we show that mild overexpression of a CPEB4 transcript lacking exon 4 (CPEB4Δ4) in mice suffices to induce decreased protein levels of SCZ genes targeted by CPEB4; these mice are also characterized by SCZ-linked behaviors. In summary, this study identifies aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.
Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain
Authors: Cermak Samantha , Centeno Maria Virginia , Jabakhanji Rami , Vigotsky Andrew , Cox Julia , Brink Andrew , Apkarian Apkar Vania 
Published: September 2022

AbstractWe studied the behavioral consequences of fentanyl vapor self-administration (SA) in mice with and without chronic neuropathic pain (one month after spared-nerve injury(SNI) model or sham injury). We assessed fentanyl consumption, motivation, and seeking during as well as anxiety, hyperactivity, immobility, and pain for two regimens of fentanyl SA: 1) Dose escalation, where over a 3-week period mice are exposed (daily 2-hour sessions) to escalating numbers of fentanyl puffs per active nosepoke (from 1 puff/active nosepoke for first 3 days, up to 6 puffs/active nosepoke in days 16-18). 2) Effort escalation, where over a 3-week period (daily 2-hour sessions) mice need to increase effort to acquire the same amount of fentanyl (fixed ratio 1 (FR) = 1 active nosepoke results in 1 fentanyl puff, while second and third week we use FR5 and FR10). We observe sex-, injury- and regimen-dependent differences in outcomes. Importantly the dose escalation regimen resulted in higher seeking behavior (post forced abstinence, context and cue driven nosepoking in the absence of fentanyl delivery), long lasting increased anxiety, immobility, and hyperactivity, as well as transient but full pain relief in SNI mice. Therefore, this regimen seems a better rodent model for translating outcomes to human chronic pain patients managed with opioids.
Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism
Authors: Mhlekude Baxolele , Postmus Dylan , Weiner January , Stenzel Saskia , Zapatero-Belinchón Francisco J. , Olmer Ruth , Jansen Jenny , Richter Anja , Heinze Julian , Heinemann Nicolas , Mühlemann Barbara , Schroeder Simon , Jones Terry C. , Müller Marcel Alexander , Drosten Christian , Pich Andreas , Thiel Volker , Martin Ulrich , Niemeyer Daniela , Gerold Gisa , Beule Dieter , Goffinet Christine 
Published: September 2022

ABSTRACTInhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of ACE2 expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions on their clinical suitability in the context of COVID-19.