bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Leukocyte Antigen Homozygosity Contributes to Sensitization in Kidney Transplant Candidates
Authors: Rushakoff Joshua A. , Gragert Loren , Pando Marcelo J , Stewart Darren , Huang Edmund , Kim Irene , Jordan Stanley , Lindblad Kelsi , Zhang Xiaohai , Lalli Peter , Patel Jignesh K. , Kobashigawa Jon A. , Kransdorf Evan P. 
Published: January 2022

ABSTRACTBackgroundHomozygosity for human leukocyte antigens (HLA) has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization.MethodsWe measured sensitization using the calculated panel reactive antibody (CPRA) value for a large cohort of 147,461 patients added to the US OPTN/UNOS kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62,510 sensitized patients to 84,955 unsensitized controls.ResultsWe found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within highly- or extremely-sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared to men, with attenuation of this effect in Black candidates. In multinomial logistic modeling, the number of homozygous HLA loci was an independent predictor of sensitization and interacted with female sex but not with other factors associated with sensitization.ConclusionsThis study shows that HLA homozygosity is an innate genetic factor that contributes to HLA sensitization, and enhances the effect of pregnancy-related sensitization.
The interactome of Cryptococcus neoformans Rmt5 reveals multiple regulatory points in fungal cell biology and pathogenesis
Authors: Kalem Murat C. , Subbiah Harini , Shen Shichen , Chen Runpu , Terry Luke , Sun Yijun , Qu Jun , Panepinto John C. 
Published: January 2022

AbstractProtein arginine methylation is a key post-translational modification in eukaryotes that modulates core cellular processes, including translation, morphology, transcription, and RNA fate. However, this has not been explored in Cryptococcus neoformans, a human-pathogenic basidiomycetous encapsulated fungus. We characterized the five protein arginine methyltransferases in C. neoformans and highlight Rmt5 as critical regulator of cryptococcal morphology and virulence. An rmt5Δ mutant was defective in thermotolerance, had a remodeled cell wall, and exhibited enhanced growth in an elevated carbon dioxide atmosphere and in chemically induced hypoxia. We revealed that Rmt5 interacts with post-transcriptional gene regulators, such as RNA-binding proteins and translation factors. Further investigation of the rmt5Δ mutant showed that Rmt5 is critical for the homeostasis of eIF2α and its phosphorylation state following 3-amino-1,2,4-triazole-induced ribosome stalling. RNA sequencing of one rmt5Δ clone revealed stable chromosome 9 aneuploidy that was ameliorated by complementation but did not impact the rmt5Δ phenotype. As a result of these diverse interactions and functions, loss of RMT5 enhanced phagocytosis by murine macrophages and attenuated disease progression in mice. Taken together, our findings link arginine methylation to critical cryptococcal cellular processes that impact pathogenesis, including post-transcriptional gene regulation by RNA-binding proteins.SignificanceThe fungal pathogen Cryptococcus neoformans is a huge threat for people living with immune deficits, especially HIV/AIDS. Its virulence potential is dependent on virulence factors, stress adaptation, and thermotolerance. Post-transcriptional gene regulation is important for these pathogenic processes, but the mechanisms that govern post-transcriptional regulator function are unexplored. Protein arginine methylation is a major modification of post-transcriptional regulators that has not been investigated in pathogenic fungi. Here we investigated the role of arginine methylation by arginine methyltransferases on the biology and virulence of C. neoformans. Phenotypic characterization of deletion mutants revealed pleiotropic functions for RMTs in this pathogen. Further investigation of the Rmt5 interactome using proximity-dependent biotinylation revealed interactions with RNA binding proteins and translation factors, thereby impacting virulence-associated processes.
Increased insula activity precedes the formation of subjective Gestalt
Authors: Wilding Marilena , Körner Christof , Ischebeck Anja , Zaretskaya Natalia 
Published: January 2022

AbstractThe constructive nature of human perception sometimes leads us to perceiving rather complex impressions from simple sensory input. Bistable stimuli give us a rare opportunity to study the neural mechanisms behind this process. Such stimuli can be visually interpreted as simple or as more complex on the basis of the same sensory input. Previous studies demonstrated increased activity in the superior parietal cortex when participants perceived an illusory Gestalt impression compared to a simpler interpretation of individual elements. Here we tested whether activity related to the illusory Gestalt can be detected not only during, but also prior to it, by examining the slow fluctuations of resting-state-fMRI activity before the stimulus onset. We presented 31 participants with a bistable motion stimulus, which can be perceived either as four moving dot pairs (local) or two moving illusory squares (global). This allowed us to isolate the specific neural mechanisms that accompany the experience of an illusion under matched sensory input. fMRI was used to measure brain activity in a sparse event-related design. We observed stronger IPS and putamen responses to the stimulus when participants perceived the global interpretation compared to local, confirming the previously reported role of these areas in perceptual grouping. Most importantly, we also observed that the global stimulus interpretation was preceded by an increased activity of the bilateral dorsal insula, which is known to process saliency and gate information for conscious access. Our data suggest an important role of the dorsal insula in shaping an internally generated illusory Gestalt percept.
Enhancement of RecET-mediated in vivo linear DNA assembly by a xonA mutation
Authors: Sawitzke James A. , Costantino Nina , Hutchinson Ellen , Thomason Lynn C. , Court Donald L. 
Published: January 2022

AbstractAssembly of intact, replicating plasmids from linear DNA fragments introduced into bacterial cells, i.e. in vivo cloning, is a facile genetic engineering technology that avoids many of the problems associated with standard in vitro cloning. Here we report characterization of various parameters of in vivo linear DNA assembly mediated by either the RecET recombination system or the bacteriophage λ Red recombination system. As previously observed, RecET is superior to Red for this reaction when the terminal homology is 50 bases. Deletion of the E. coli xonA gene, encoding Exonuclease I, a 3’→5’ single-strand DNA exonuclease, substantially improves the efficiency of in vivo linear DNA assembly for both systems. Deletion of ExoI function allowed robust RecET assembly of six DNA segments to create a functional plasmid. The linear DNAs are joined accurately with very few errors. This discovery provides a significant improvement to previously reported in vivo linear DNA assembly technologies.
Expressing the pro-apoptotic Reaper protein via insertion into the structural open reading frame of Sindbis virus reduces the ability to infect Aedes aegypti mosquitoes
Authors: Carpenter Alexis , Clem Rollie J. 
Published: January 2022

ABSTRACTArboviruses continue to threaten a significant portion of the human population, and a better understanding is needed of the determinants of successful arbovirus infection of arthropod vectors. Avoiding apoptosis has been shown to be one such determinant. Previous work showed that a Sindbis virus (SINV) construct called MRE/rpr that expresses the pro-apoptotic protein Reaper via a duplicated subgenomic promoter had a reduced ability to orally infect Aedes aegypti mosquitoes at 3 days post-blood meal (PBM), but this difference diminished over time as virus variants containing deletions in the inserted reaper gene rapidly predominated. The goal of this study was to generate a SINV construct that more stably expressed Reaper, in order to further clarify the effect of midgut apoptosis on disseminated infection in Ae. aegypti. We did this by inserting reaper as an in-frame fusion into the structural open reading frame (ORF) of SINV. This construct, MRE/rprORF, successfully expressed Reaper, replicated similarly to MRE/rpr in cell lines, and induced apoptosis in cultured cells and in mosquito midgut tissue. Mosquitoes that fed on blood containing MRE/rprORF developed less midgut and disseminated infection when compared to MRE/rpr or a control virus up to at least 7 days PBM, when less than 50% of mosquitoes that ingested MRE/rprORF had detectable disseminated infection, compared with around 80% or more of mosquitoes fed with MRE/rpr or control virus. However, virus titer in mosquitoes infected with MRE/rprORF was not significantly different from control virus, suggesting that induction of apoptosis by expression of Reaper by this method can reduce infection prevalence, but if infection is established then apoptosis induced by this method has limited ability to continue to suppress replication.
National-scale surveillance of emerging SARS-CoV-2 variants in wastewater
Authors: Amman Fabian , Markt Rudolf , Endler Lukas , Hupfauf Sebastian , Agerer Benedikt , Schedl Anna , Richter Lukas , Zechmeister Melanie , Bicher Martin , Heiler Georg , Triska Petr , Thornton Matthew , Penz Thomas , Senekowitsch Martin , Laine Jan , Keszei Zsofia , Daleiden Beatrice , Steinlechner Martin , Niederstätter Harald , Scheffknecht Christoph , Vogl Gunther , Weichlinger Günther , Wagner Andreas , Slipko Katarzyna , Masseron Amandine , Radu Elena , Allerberger Franz , Popper Niki , Bock Christoph , Schmid Daniela , Oberacher Herbert , Kreuzinger Norbert , Insam Heribert , Bergthaler Andreas 
Published: January 2022

AbstractSARS-CoV-2 surveillance is crucial to identify variants with altered epidemiological properties. Wastewater-based epidemiology (WBE) provides an unbiased and complementary approach to sequencing individual cases. Yet, national WBE surveillance programs have not been widely implemented and data analyses remain challenging.We deep-sequenced 2,093 wastewater samples representing 95 municipal catchments, covering >57% of Austria’s population, from December 2020 to September 2021. Our Variant Quantification in Sewage pipeline designed for Robustness (VaQuERo) enabled us to deduce variant abundance from complex wastewater samples and delineate the spatiotemporal dynamics of the dominant Alpha and Delta variants as well as regional clusters of other variants of concern. These results were cross validated by epidemiological records of >130,000 individual cases. Finally, we provide a framework to predict emerging variants de novo and infer variant-specific reproduction numbers from wastewater.This study demonstrates the power of national-scale WBE to support public health and promises particular value for countries without dense individual monitoring.Graphical Abstract
Novel Application of a Force Sensor during Sit-to-Stands to Measure Dynamic Cerebral Autoregulation Onset
Authors: Whitaker Alicen A. , Vidoni Eric D. , Aaron Stacey E. , Rouse Adam G. , Billinger Sandra A. 
Published: January 2022

AbstractPurposeCurrent sit-to-stand methods measuring dynamic cerebral autoregulation (dCA) do not capture the precise onset of the time delay (TD) response. Reduced sit-to-stand reactions in older adults and individuals post-stroke could inadvertently introduce variability, error, and imprecise timing. We applied a force sensor during a sit-to-stand task to more accurately determine how TD before dCA onset may be altered.MethodsMiddle cerebral artery blood velocity (MCAv) and mean arterial pressure (MAP) were measured during two sit-to-stands separated by 15 minutes. Recordings started with participants sitting on a force-sensitive resistor for 60 seconds, then asked to stand for two minutes. Upon standing, the force sensor voltage immediately dropped and marked the exact moment of arise- and-off (AO). Time from AO until an increase in cerebrovascular conductance (CVC = MCAv/MAP) was calculated as TD.ResultsWe tested the sensor in 4 healthy young adults, 2 older adults, and 2 individuals post-stroke. Healthy young adults stood quickly and the force sensor detected a small change in TD compared to classically estimated AO, from verbal command to stand. When compared to the estimated AO, older adults had a delayed measured AO and TD decreased up to ~53% while individuals post-stroke had an early AO and TD increased up to ~14%.ConclusionThe transition reaction speed during the sit to stand has the potential to influence dCA metrics. As observed in the older adults and participants with stroke, this response may drastically vary and influence TD.New & NoteworthyWe developed a force sensor and are the first to apply it during sit-to-stands measuring the dynamic cerebral autoregulation (dCA) response. Current methodologies estimate the transition reaction speed of the sit-to-stand, which influences the dCA metrics. Compared to estimating the kinetic moment of arise-and-off (AO), our force sensor can detect early or delayed AO in individuals who may present with lower extremity weakness such as older adults and clinical populations such as stroke.
A Mixed-Methods Feasibility Study of a Novel AI-Enabled, Web-Based, Clinical Decision Support System for the Treatment of Major Depression in Adults
Authors: Qassim Sabrina , Golden Grace , Slowey Dominique , Sarfas Mary , Whitmore Kate , Perez Tamara , Strong Elizabeth , Lundrigan Eryn , Fradette Marie-Jeanne , Baxter Jacob , Desormeau Bennet , Tanguay-Sela Myriam , Popescu Christina , Israel Sonia , Perlman Kelly , Armstrong Caitrin , Fratila Robert , Mehltretter Joseph , Looper Karl , Steiner Warren , Rej Soham , Karp Jordan F. , Heller Katherine , Parikh Sagar V. , McGuire-Snieckus Rebecca , Ferrari Manuela , Margolese Howard , Benrimoh David 
Published: January 2022

AbstractThe objective of this paper is to discuss perceived clinical utility and impact on physician-patient relationship of a novel, artificial-intelligence (AI) enabled clinical decision support system (CDSS) for use in the treatment of adults with major depression. Patients had a baseline appointment, followed by a minimum of two appointments with the CDSS. For both physicians and patients, study exit questionnaires and interviews were conducted to assess perceived clinical utility, impact on patient-physician relationship, and understanding and trust in the CDSS. 17 patients consented to participate in the study, of which 14 completed. 86% of physicians (6/7) felt the information provided by the CDSS provided a more comprehensive understanding of patient situations and 71% (5/7) felt the information was helpful. 86% of physicians (6/7) reported the AI/predictive model was useful when making treatment decisions. 62% of patients (8/13) reported improvement in their care as a result of the tool. 46% of patients (6/13) felt the app significantly or somewhat improved their relationship with their physicians; 54% felt it did not change. 71% of physicians (5/7) and 62% of patients (8/13) rated they trusted the tool. Qualitative results are analyzed and presented. Findings suggest physicians perceived the tool as useful in conducting appointments and used it while making treatment decisions. Physicians and patients generally found the tool trustworthy, and it may have positive effects on physician-patient relationships.
Pramipexole Enhances Reward Learning by Preserving Value Estimates
Authors: Halahakoon Don Chamith , Kaltenboeck Alexander , Martens Marieke , Geddes John G. , Harmer Catherine J. , Cowen Philip , Browning Michael 
Published: January 2022

AbstractBackgroundDopamine D2-like receptor agonists show promise as treatments for depression. They are thought to act by altering how individuals learn from rewarding experiences. However, the nature of these reward learning alterations, and the mechanisms by which they are produced is not clear. Reinforcement learning accounts describe three distinct processes that may produce similar changes in reward learning behaviour; increased reward sensitivity, increased inverse decision temperature and decreased value decay. As these processes produce equivalent effects on behaviour, arbitrating between them requires measurement of how expectations and prediction errors are altered. In the present study, we characterised the behavioural effects of a sustained 2-week course of the D2/3/4 receptor agonist pramipexole on reward learning and used fMRI measures of expectation and prediction error to assess which of these three mechanistic processes were responsible for the behavioural effects.Methods40 healthy volunteers (Age: 18-43, 50% female) were randomly allocated to receive either two weeks of pramipexole (titrated to 1mg/day) or placebo in a double-blind, between subject design. Participants completed a probabilistic instrumental learning task, in which stimuli were associated with either rewards or losses, before the pharmacological intervention and twice between days 12-15 of the intervention (once with and once without fMRI). Both asymptotic choice accuracy, and a reinforcement learning model, were used to assess reward learning.ResultsBehaviourally, pramipexole specifically increased choice accuracy in the reward condition, with no effect in the loss condition. Pramipexole increased the BOLD response in the orbital frontal cortex during the expectation of win trials but decreased the BOLD response to reward prediction errors in the ventromedial prefrontal cortex. This pattern of results indicates that pramipexole enhances choice accuracy by reducing the decay of estimated values during reward learning.ConclusionsThe D2-like receptor agonist pramipexole enhances reward learning by preserving learned values. This is a plausible candidate mechanism for pramipexole’s observed anti-depressant effect.
Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant
Authors: Ebell Mark H. , Hamadani Roya , Kieber-Emmons Autumn 
Published: January 2022

AbstractImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, specifically whether to hospitalize a patient or if managed as an outpatient, how closely to follow them.ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging, including during the current Omicron wave.DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.SettingPrimary and urgent care clinics in a Pennsylvania health system.ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).ResultsOverall, 4.0% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21), 4.2% in the late validation cohort (3806 patients presenting 3/1/21 to 9/30/21), and 1.9% in an Omicron cohort were ultimately hospitalized. We developed and temporally validated four simple risk scores. The base score included age, dyspnea, and the presence of a comorbidity, with the other scores adding fever, respiratory rate and/or oxygen saturation. All had very good overall accuracy (AUC 0.85-0.87) and classified at least half of patients into a low risk with a < 1% likelihood of hospitalization. Hospitalization rates in the Omicron cohort were 0.22%, 1.3% and 8.7% for the base score. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization than our novel risk scores.Conclusions and relevanceA simple risk score applicable to outpatient and telehealth settings can classify over half of COVID-19 outpatients into a very low risk group with a 0.22% hospitalization risk in the Omicron cohort. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/.Key pointsQuestionIs it possible to predict the eventual likelihood of hospitalization for outpatients with COVID-19 using simple non-laboratory based risk scores?FindingsWe created and temporally validated in the same population 4 risk scores with 3 to 5 predictors that do not require laboratory testing. Groups with low (0.34% to 0.89%), moderate (4.0% to 6.2%), and high-risk (19.2% to 25.2%) of hospitalization were identified. The risk scores were also accurate in an Omicron dominant cohort with hospitalization rates of 0.22% to 0.43% in the low-risk groups, 1.3% to 1.7% in the moderate risk groups, and 8.7% to 15.3% in the high risk groups.MeaningSimple risk scores can help support decisions about hospitalization in the outpatient setting.
Empirical Approach to Developing an Optimal Socioeconomic Status Index for Health Surveillance
Authors: LaFantasie Jordge , Boscoe Francis 
Published: January 2022

AbstractThe association between multi-dimensional deprivation and public health is well established, and many area-based indices have been developed to measure or account for socioeconomic status in health surveillance. The Yost Index, developed in 2001, has been adopted in the US for cancer surveillance and is based on the combination of two heavily weighted (household income, poverty) and five lightly weighted (rent, home value, employment, education and working class) indicator variables. Our objectives were to 1) update indicators and find a more parsimonious version of the Yost Index by examining potential models that included indicators with more balanced weights/influence and reduced redundancy and 2) test the statistical consistency of the factor upon which the Yost Index is based. Despite the usefulness of the Yost Index, a one-factor structure including all seven Yost indicator variables is not statistically reliable and should be replaced with a three-factor model to include the true variability of all seven indicator variables. To find a one-dimensional alternative, we conducted maximum likelihood exploratory factor analysis on a subset of all possible combinations of fourteen indicator variables to find well-fitted one-dimensional factor models and completed confirmatory factor analysis on the resulting models. One indicator combination (poverty, education, employment, public assistance) emerged as the most stable unidimensional model. This model is more robust to extremes in local cost of living conditions, is comprised of ACS variables that rarely require imputation by the end-user and is a more parsimonious solution than the Yost index with a true one-factor structure.