bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Quantitative Systems Pharmacology Model of the Pathophysiology and Treatment of COVID-19 Predicts Optimal Timing of Pharmacological Interventions
Authors: Rao Rohit , Musante Cynthia J. , Allen Richard 
Published: December 2021

AbstractA quantitative systems pharmacology (QSP) model of the pathogenesis and treatment of SARS-CoV-2 infection can streamline and accelerate the development of novel medicines to treat COVID-19. Simulation of clinical trials allows in silico exploration of the uncertainties of clinical trial design and can rapidly inform their protocols. We previously published a preliminary model of the immune response to SARS-CoV-2 infection. To further our understanding of COVID-19 and treatment we significantly updated the model by matching a curated dataset spanning viral load and immune responses in plasma and lung. We identified a population of parameter sets to generate heterogeneity in pathophysiology and treatment and tested this model against published reports from interventional SARS-CoV-2 targeting Ab and anti-viral trials. Upon generation and selection of a virtual population, we match both the placebo and treated responses in viral load in these trials. We extended the model to predict the rate of hospitalization or death within a population. Via comparison of the in silico predictions with clinical data, we hypothesize that the immune response to virus is log-linear over a wide range of viral load. To validate this approach, we show the model matches a published subgroup analysis, sorted by baseline viral load, of patients treated with neutralizing Abs. By simulating intervention at different timepoints post infection, the model predicts efficacy is not sensitive to interventions within five days of symptom onset, but efficacy is dramatically reduced if more than five days pass post-symptom onset prior to treatment.
Dimensionality and homogeneity of the Colombian version of the Cocaine Craving Questionnaire (CCQ-N-10)
Authors: Cassiani-Miranda Carlos Arturo , Scoppetta Orlando , Quintero-Gómez Tito Cesar , Arraut-Camargo Eduard , Castaño-Pérez Guillermo , Cabanzo-Arenas Diego Fernando , Campo-Arias Adalberto 
Published: December 2021

AbstractBackground and aimIt is essential to have a validated instrument to measure craving for cocaine use. However, in Colombia, there is no instrument to screen cocaine craving. The study aimed to determine the homogeneity and dimensionality of the CCQ-N-10 in patients with cocaine use disorder in Colombia.Materials and methodsAn adaptation and subsequent analysis of the psychometric properties of the CCQ-N-10 scale was carried out with 102 hospitalized or outpatient adults diagnosed with substance use disorders in addiction units in Bucaramanga, Colombia. Internal consistency and construct validity were estimated by confirmatory factor analysis and correlation analysis with scales with similar objectives.ResultsAn omega coefficient of 0.93 was obtained, and adjustment indicators of the confirmatory model were acceptable (RMSEA of 0.08, CFI and TLI of 0.99) when two of the original scale items were removed from the original scale analysis.ConclusionsThis study shows that the craving scale reduced to eight items can be helpful to assess the construct in the Colombian population; However, the small sample size makes it challenging to carry out other analyzes to corroborate its psychometric properties.
Clinical and genomic signatures of rising SARS-CoV-2 Delta breakthrough infections in New York
Authors: Duerr Ralf , Dimartino Dacia , Marier Christian , Zappile Paul , Levine Samuel , François Fritz , Iturrate Eduardo , Wang Guiqing , Dittmann Meike , Lighter Jennifer , Elbel Brian , Troxel Andrea B. , Goldfeld Keith S. , Heguy Adriana 
Published: December 2021

AbstractIn 2021, Delta has become the predominant SARS-CoV-2 variant worldwide. While vaccines effectively prevent COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occur. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contribute to increased rates of breakthrough infections compared to unvaccinated controls. Here, we show a steep and near complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25, its spike mutation S112L, and nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthroughs increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. Our data indicate a limited impact of vaccine escape in favor of Delta’s increased epidemic growth in times of waning vaccine protection.
Nonlinear dynamics in auditory cortical activity reveal the neural basis of perceptual warping in speech categorization
Authors: Carter Jared A. , Buder Eugene H. , Bidelman Gavin M. 
Published: December 2021

ABSTRACTSurrounding context influences speech listening, resulting in dynamic shifts to category percepts. To examine its neural basis, event-related potentials (ERPs) were recorded during vowel identification with continua presented in random, forward, and backward orders to induce perceptual nonlinearities. Behaviorally, sequential order shifted listeners’ categorical boundary vs. random delivery revealing perceptual warping (biasing) of the heard phonetic category dependent on recent stimulus history. ERPs revealed later (∼300 ms) activity localized to superior temporal and middle/inferior frontal gyri that predicted listeners’ hysteresis magnitudes. Findings demonstrate that top-down, stimulus history effects on speech categorization are governed by interactions between frontotemporal brain regions.
Trailing-edge zombie forests can increase population persistence in the face of climate change
Authors: Decker Robin R. , Baskett Marissa L. , Hastings Alan 
Published: December 2021

AbstractClimate-driven habitat shifts pose challenges for dispersal-limited, late-maturing taxa such as trees. Older trees are often the most reproductive individuals in the population, but as habitats shift, these individuals can be left behind in the trailing range edge, generating “zombie forests” that may persist long after the suitable habitat has shifted. Are these zombie forests vestiges of ecosystems past or do they play an ecological role? To understand how zombie forests affect population persistence, we developed a spatially explicit, stage-structured model of tree populations occupying a shifting habitat. Our model shows that seed dispersal from zombie forests to the range core can considerably increase the maximum rate of climate change that a population can withstand. Moreover, the entire core population can ultimately descend from recruitment-limited zombie forests, highlighting their demographic value. Our results suggest that preserving trailing-edge zombie forests can greatly increase population persistence in the face of climate change.
High genetic diversity of bivalve transmissible neoplasia in the blue mussel Mytilus trossulus Gould from the subarctic Sea of Okhotsk
Authors: Skazina M.A. , Odintsova N.A. , Maiorova M.A. , Frolova L.T. , Dolganova I.A. , Regel K.V. , Strelkov P.P. 
Published: December 2021

AbstractThere are increasing findings of the bivalve transmissible neoplasia derived from the Pacific mussel Mytilus trossulus (MtrBTN) in populations of different Mytilus species worldwide. The Subarctic is an area where this disease has not yet been sought despite the fact that Mytilus spp. are widespread there, and M. trossulus itself is a boreal species. We used cytological and histological techniques to diagnose disseminated neoplasia in a sample of M. trossulus from Magadan in the subarctic Sea of Okhotsk. Neoplasia was identified in 11 of 214 mussels studied. Using mtDNA COI sequencing, we revealed genotypes identical or nearly identical to known MtrBTN ones in the hemolymph of most of the diseased mussels. Both MtrBTN evolutionary lineages have been identified, the widespread MtrBTN2, and MtrBTN1, so far only known from M. trossulus in British Columbia on the other side of the Pacific from Magadan. In addition, MtrBTN2 was represented by two common diverged mtDNA haplolineages. These conclusions have been confirmed for selected cancerous mussels by molecular cloning of COI and additional nuclear and mtDNA genes. On the background of high genetic diversity, different cancers were similar in terms of ploidy (range 4.0 - 5.8n) and nuclear to cell ratio. Our study provides the first description of neoplasia and MtrBTN in mussels from the Sea of Okhotsk and from the Subarctic, of both MtrBTN1 and MtrBTN2 in the same mussel population, and the first direct comparison between these transmissible cancers.
Single cell quantification of ribosome occupancy in early mouse development
Authors: Tonn Tori , Ozadam Hakan , Han Crystal , Segura Alia , Tran Duc , Catoe David , Salit Marc , Cenik Can 
Published: December 2021

AbstractTechnological limitations precluded transcriptome-wide analyses of translation at single cell resolution. To solve this challenge, we developed a novel microfluidic isotachophoresis approach, named RIBOsome profiling via IsoTachoPhoresis (Ribo-ITP), and characterized translation in single oocytes and embryos during early mouse development. We identified differential translation efficiency as a key regulatory mechanism of genes involved in centrosome organization and N6-methyladenosine modification of RNAs. Our high coverage measurements enabled the first analysis of allele-specific ribosome engagement in early development and led to the discovery of stage-specific differential engagement of zygotic RNAs with ribosomes. Finally, by integrating our measurements with proteomics data, we discovered that ribosome occupancy in germinal vesicle stage oocytes is the predominant determinant of protein abundance in the zygote. Taken together, these findings resolve the long-standing paradox of low correlation between RNA expression and protein abundance in early embryonic development. The novel Ribo-ITP approach will enable numerous applications by providing high coverage and high resolution ribosome occupancy measurements from ultra-low input samples including single cells.
Computationally defined and in vitro validated putative genomic safe harbour loci for transgene expression in human cells
Authors: Autio Matias I. , Motakis Efthymios , Perrin Arnaud , Amin Talal Bin , Tiang Zenia , Do Dang Vinh , Wang Jiaxu , Tan Joanna , Tan Wei Xuan , Keong Teo Adrian Kee , Foo Roger S.-Y. 
Published: December 2021

SummarySelection of the target site is an inherent question for any project aiming for directed transgene integration. Genomic safe harbour (GSH) loci have been proposed as safe sites in the human genome for transgene integration. Although several sites have been characterised for transgene integration in the literature, most of these do not meet criteria set out for a GSH and the limited set that do have not been characterised extensively. Here, we conducted a computational analysis using publicly available data to identify 25 unique putative GSH loci that reside in active chromosomal compartments. We validated stable transgene expression and minimal disruption of the native transcriptome in three GSH sites in vitro using human embryonic stem cells (hESCs) and their differentiated progeny. Furthermore, for easy targeted transgene expression, we have engineered constitutive landing pad expression constructs into the three validated GSH in hESCs.
No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination
Authors: Lu-Culligan Alice , Tabachnikova Alexandra , Tokuyama Maria , Lee Hannah J. , Lucas Carolina , Monteiro Valter Silva , Muenker M. Catherine , Mohanty Subhasis , Huang Jiefang , Kang Insoo , Cruz Charles Dela , Farhadian Shelli , Campbell Melissa , Yildirim Inci , Shaw Albert C. , Ko Albert I. , Omer Saad B. , Iwasaki Akiko 
Published: December 2021

AbstractThe impact of coronavirus disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated two of the most widely propagated claims to determine 1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities, and 2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from vaccinated murine pregnancies exhibit high circulating levels of anti-Spike and anti-RBD antibodies to SARS-CoV-2 consistent with maternal antibody status, indicating transplacental transfer. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.
Lysophosphatidylcholine induces heat pain hypersensitivity in obese mice fed with a high-fat diet through activation of peripheral Acid-Sensing Ion Channel 3
Authors: Ahmed Negm , Katharina Stobbe , Lucile Fleuriot , Delphine Debayle , Emmanuel Deval , Eric Lingueglia , Carole Rovere , Jacques Noel 
Published: December 2021

AbstractDiet induced obesity is one of the major causes of obesity, which affects 13% of the world’s adult population. Obesity is correlated to chronic pain regardless of other components of the metabolic syndrome. Our study focuses on investigating the effect of high-fat diet induced obesity on peripheral sensory neurons activity and pain perception, followed by deciphering the underlying cellular and molecular mechanisms that involve Acid-Sensing Ion Channel 3 (ASIC3). We show here that heat sensitive C-fibers from mice made obese by consumption of a high-fat diet exhibited an increased activity during baseline and upon heating. Obese mice showed long-lasting heat pain hypersensitivity once obesity was well established, while mechanical sensitivity was not affected. We found that the serum of obese mice was enriched in lysophosphatidylcholine (LPC) species (LPC16:0, LPC18:0 and LPC18:1), which activate ASIC3 channels and increased peripheral neuron excitability. Genetic deletion and in vivo pharmacological inhibition of ASIC3 protected and rescued mice from obesity-induced thermal hypersensitivity. Our results identify ASIC3 channels in DRG neurons and circulating LPC species that activate them as a mechanism contributing to heat pain hypersensitivity associated with high-fat diet induced obesity.
Intermittent brain network reconfigurations and the resistance to social media influence
Authors: Pinto Italo’Ivo Lima Dias , Rungratsameetaweemana Nuttida , Flaherty Kristen , Periyannan Aditi , Meghdadi Amir , Richard Christian , Berka Chris , Bansal Kanika , Garcia Javier Omar 
Published: December 2021

AbstractSince their development, social media has grown as a source of information and has a significant impact on opinion formation. Individuals interact with others and content via social media platforms in a variety of ways but it remains unclear how decision making and associated neural processes are impacted by the online sharing of informational content, from factual to fabricated. Here, we use EEG to estimate dynamic reconfigurations of brain networks and probe the neural changes underlying opinion change (or formation) within individuals interacting with a simulated social media platform. Our findings indicate that the individuals who changed their opinions are characterized by less frequent network reconfigurations while those who did not change their opinions tend to have more flexible brain networks with frequent reconfigurations. The nature of these frequent network configurations suggests a fundamentally different thought process between intervals in which individuals are easily influenced by social media and those in which they are not. We also show that these reconfigurations are distinct to the brain dynamics during an in-person discussion with strangers on the same content. Together, these findings suggest that brain network reconfigurations may not only be diagnostic to the informational context but also the underlying opinion formation.Author SummaryDistinctive neural underpinnings of opinion formation and change during in-person and online social interactions are not well understood. Here, we analyze EEG recordings of the participants interacting with a simulated social media platform and during an in-person discussion using a network-based analysis approach. We show that the structure of network reconfigurations during these interactions is diagnostic of the opinion change and the context in which information was received.
Predicting the Toxicity of Druggable Proteins to Human Tissues
Authors: Hao Yun , Thangaraj Phyllis , Tatonetti Nicholas P. 
Published: December 2021

ABSTRACTAssessing in vivo tissue toxicity of therapeutic targets remains a major challenge in drug development and drug safety research. We developed TissueTox, an algorithm that learns from multi-omic features of a target protein and predicts toxicity in human body systems and tissues. Predicted TissueTox scores accurately differentiate drugs that failed clinical trials from those that succeeded, and, importantly, can be used to identify the tissues where toxic events occurred.
Molecular mechanism of claudin-15 strand flexibility
Authors: Fuladi Shadi , McGuinness Sarah , Shen Le , Weber Christopher R. , Khalili-Araghi Fatemeh 
Published: December 2021

AbstractClaudins are one of the major components of tight junctions that play a key role in formation and maintaining epithelial barrier function. Tight junction strands are dynamic and capable of adapting their structure in response to large-scale tissue rearrangement and cellular movement. Here, we present molecular dynamics simulations of claudin-15 strands of up to 225 nm in length in two parallel lipid membranes and characterize their mechanical properties. The persistence length of claudin-15 strands is comparable with experiments leading to a curvature of 0.12 nm−1 at room temperature. Our results indicate that lateral flexibility of claudin strands is due to an interplay of three sets of interfacial interaction networks between four linear claudin strands in the membranes. In this model, claudins are assembled into interlocking tetrameric ion channels along the strand that slide with respect to each other as the strands curve over sub-micrometer length scales. These results suggest a novel molecular mechanism underlying claudin-15 strand flexibility. It also sheds light on the inter-molecular interactions and their role in maintaining epithelial barrier function.
The eukaryotic translation initiation factor eIF4E reprogrammes the splicing machinery and drives alternative splicing
Authors: Ghram Mehdi , Morris Gavin , Culjkovic-Kraljacic Biljana , Mars Jean-Clement , Gendron Patrick , Skrabanek Lucy , Revuelta Maria Victoria , Cerchietti Leandro , Guzman Monica L , Borden Katherine LB 
Published: December 2021

AbstractAberrant RNA splicing contributes to the pathogenesis of many malignancies including Acute Myeloid Leukemia (AML). While mutation is the best described mechanism underpinning aberrant splicing, recent studies show that predictions based on mutations alone likely underestimate the extent of this dysregulation. Here, we show that elevation of the eukaryotic translation initiation factor eIF4E reprogrammes splicing of nearly a thousand RNAs in model cell lines. Further, in AML patient specimens which did not harbour known splice factor mutations, ∼4000 transcripts were differentially spliced based on eIF4E levels and this was associated with poor prognosis. Inhibition of eIF4E in cell lines reverted the eIF4E-dependent splice events examined. Splicing targets of eIF4E act in biological processes consistent with its role in malignancy. This altered splicing program likely arose from eIF4E-dependent increases in the production of spliceosome components including SF3B1 and U2AF1 which are frequently mutated in AML. Notably, eIF4E did not drive mutation of these factors, only their production. eIF4E also physically associated with many splice factors including SF3B1, U2AF1, and UsnRNAs. Interestingly, eIF4E interacted with both pre-mRNA splicing substrates as well as the resulting product RNAs suggesting that eIF4E could chaperone RNAs throughout splicing as well as other aspects of post-splicing transcript regulation. Importantly, many eIF4E-dependent splice events differed from those arising from splice factor mutation and were more extensive highlighting that these splicing profiles arise from distinct, but potentially overlapping, mechanisms. In all, our studies provide a paradigm for how dysregulation of a single factor, eIF4E, can reprogramme splicing.
mCherry contains a fluorescent protein isoform that interferes with its reporter function
Authors: Fages-Lartaud Maxime , Tietze Lisa , Elie Florence , Lale Rahmi , Hohmann-Marriott Martin Frank 
Published: December 2021

AbstractFluorescent proteins are essential reporters in cell biology and molecular biology. Here, we reveal that red-fluorescent proteins possess an alternative translation initiation site that produces a short functional protein isoform. The short isoform creates significant background fluorescence that biases the outcome of expression studies. Our investigation identifies the short protein isoform, traces its origin, and determines the extent of the issue within the family of red fluorescent protein. Our analysis shows that the short isoform defect of the red fluorescent protein family may affect the interpretation of many published studies. Finally, we provide a re-engineered mCherry variant that lacks background expression as an improved tool for imaging and protein expression studies.