bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incorporating efficacy data from initial trials into subsequent evaluations: Application to vaccines against respiratory syncytial virus
Authors: Warren Joshua L. , Sundaram Maria , Pitzer Virginia E. , Omer Saad B. , Weinberger Daniel M. 
Published: March 2023

ABSTRACTBackgroundWhen a randomized controlled trial fails to demonstrate statistically significant efficacy against the primary endpoint, a potentially costly new trial would need to be conducted to receive licensure. Incorporating data from previous trials might allow for the conduct of more efficient follow-up trials to demonstrate efficacy, speeding the availability of effective vaccines.MethodsBased on the outcomes from a failed trial of a maternal vaccine against respiratory syncytial virus (RSV), we simulated data for a new Bayesian group-sequential trial. The data were analyzed either ignoring data from the previous trial (i.e., weakly informative prior distributions) or using prior distributions that incorporate the historical data into the analysis. We evaluated scenarios where the efficacy in the new trial was the same, greater than, or less than the efficacy in the original trial. For each scenario, we evaluated the statistical power and type I error rate for estimating the vaccine effect following interim analyses.ResultsIf a stringent threshold is used to control the type I error rate, the analyses that incorporated historical data had a small advantage over trials that did not. If control of type I error is less important (e.g., in a post-licensure evaluation), the incorporation of historical data can provide a substantial boost in efficiency.ConclusionsDue to the need to control the type I error rate in trials used to license a vaccine, the incorporation of historical data provides little additional benefit in terms of stopping the trial early. However, these statistical approaches could be promising in evaluations that use real-world evidence following licensure.
Exposome approaches to assessing the association between urban land use environment and depressive symptoms in young adulthood: a FinnTwin12 cohort study
Authors: Wang Zhiyang , M.Whipp Alyce , Heinonen-Guzejev Marja , Júlvez Jordi , Kaprio Jaakko 
Published: March 2023

AbstractBackgroundDepressive symptoms lead to a serious public health burden and are considerably affected by the environment. Land use, describing the urban living environment, has an impact on mental health, but complex relationship assessment is rare.ObjectivesWe aimed to examine the complicated association between urban land use and depressive symptoms among young adults with differential land use environments, by applying multiple models, as an exposome study.MethodsWe included 1804 individual twins from the FinnTwin12 cohort, living in urban areas in 2012. There were 8 types of land use exposures in 3 buffer radii. The depressive symptoms were assessed through General Behavior Inventory (GBI) in young adulthood (mean age: 24.1). First, K- means clustering was performed to distinguish participants with differential land use environments. Then, linear elastic net penalized regression and eXtreme Gradient Boosting (XGBoost) were used to reduce dimensions or prioritize for importance and examine the linear and nonlinear relationships.ResultsTwo clusters were identified with notable differences in the percentage of high-density residential, low-density residential, and natural land use. One is more typical of city centers, and another of suburban areas. A heterogeneous pattern in results was detected from the linear elastic net penalized regression model among the overall sample and the two separated clusters. Agricultural residential land use in a 100 m buffer contributed to GBI most (coefficient: 0.097) in the “suburban” cluster among 11 selected exposures. In the “city center” cluster, none of the land use exposures was associated with GBI. From the XGBoost models, we observed that ranks of the importance of land use exposures on GBI and their nonlinear relationships are also heterogeneous in the two clusters.DiscussionAs a hypothesis-generating study, we found heterogeneous linear and nonlinear relationships between urban land use environment and depressive symptoms under different contexts in pluralistic exposome analyses.
Looking under the lamp-post: quantifying the performance of contact tracing in the United States during the SARS-CoV-2 pandemic
Authors: Bayly Henry , Stoddard Madison , Van Egeren Debra , Murray Eleanor J , Raifman Julia , Chakravarty Arijit , White Laura F 
Published: March 2023

AbstractContact tracing forms a crucial part of the public-health toolbox in mitigating and understanding emergent pathogens and nascent disease outbreaks. Contact tracing in the United States was conducted during the pre-Omicron phase of the ongoing COVID-19 pandemic. This tracing relied on voluntary reporting and responses, often using rapid antigen tests (with a high false negative rate) due to lack of accessibility to PCR tests. These limitations, combined with SARS-CoV-2’s propensity for asymptomatic transmission, raise the question “how reliable was contact tracing for COVID-19 in the United States”? We answered this question using a Markov model to examine the efficiency with which transmission could be detected based on the design and response rates of contact tracing studies in the United States. Our results suggest that contact tracing protocols in the U.S. are unlikely to have identified more than 1.65% (95% uncertainty interval: 1.62%-1.68%) of transmission events with PCR testing and 0.88% (95% uncertainty interval 0.86%-0.89%) with rapid antigen testing. When considering an optimal scenario, based on compliance rates in East Asia with PCR testing, this increases to 62.7% (95% uncertainty interval: 62.6%-62.8%). These findings highlight the limitations in interpretability for studies of SARS-CoV-2 disease spread based on U.S. contact tracing and underscore the vulnerability of the population to future disease outbreaks, for SARS-CoV-2 and other pathogens.
Population genetic structure and range limits ofProstanthera cineolifera(Lamiaceae), a vulnerable shrub with a patchy distribution
Authors: Palsson Ruth L. , Telford Ian R.H. , Bruhl Jeremy J. , Andrew Rose L. 
Published: March 2023

AbstractIntegrating molecular data is essential for clarifying the distributions and genetic structures of species that have histories of misidentification and misapplication of names. There has been confusion about the species limits of the VulnerableProstanthera cineoliferawith respect to morphologically similar specimens in the Hunter Valley, New South Wales Australia and morphologically dissimilar specimens in the Lower Hawkesbury Valley New South Wales and from northeastern New South Wales. To test the species limits ofP. cineoliferaand related taxa specimens were collected from across the range and augmented with herbarium specimens. We used morphometric analysis of 18 morphological characters across 51 operational taxonomic units. Using the DArTseq reduced representation sequencing platform, 9,559 single-nucleotide polymorphisms (SNPs) across 122 individuals were recovered for molecular analysis. Both morphological and molecular analyses produced three concordant clusters (1)P. cineolifera, (2) a group sharing similarities withP. sp. Hawkesbury (B.J.Conn 2591), and (3) a group allied withP. lanceolataandP. ovalifolia. These results indicate that the specimens form northeastern New South Wales are more likely to beP. lanceolata, notP. cineolifera, and that specimens from the Lower Hawkesbury are of an undescribed species with the phrase nameP. sp. Hawkesbury (B.J.Conn 2591). WithinP. cineoliferathere was pronounced genetic differentiation among populations. Little evidence of inbreeding was observed, but the newly recognised, more isolated populations had the lowest genetic diversity. This study provides new information about the range of the species and its genetic structure that informs the conservation priorities for this species.
Phospho-seq: Integrated, multi-modal profiling of intracellular protein dynamics in single cells
Authors: Blair John D. , Hartman Austin , Zenk Fides , Dalgarno Carol , Treutlein Barbara , Satija Rahul 
Published: March 2023

AbstractCell signaling plays a critical role in regulating cellular behavior and fate. While multimodal single-cell sequencing technologies are rapidly advancing, scalable and flexible profiling of cell signaling states alongside other molecular modalities remains challenging. Here we present Phospho-seq, an integrated approach that aims to quantify phosphorylated intracellular and intranuclear proteins, and to connect their activity with cis-regulatory elements and transcriptional targets. We utilize a simplified benchtop antibody conjugation method to create large custom antibody panels for simultaneous protein and scATAC-seq profiling on whole cells, and integrate this information with scRNA-seq datasets via bridge integration. We apply our workflow to cell lines, induced pluripotent stem cells, and 3-month-old brain organoids to demonstrate its broad applicability. We demonstrate that Phospho-seq can define cellular states and trajectories, reconstruct gene regulatory relationships, and characterize the causes and consequences of heterogeneous cell signaling in neurodevelopment.
A role for N6-methyldeoxyadenosine inC. elegansmitochondrial genome regulation
Authors: Grub Lantana K. , Held James P. , Hansen Tyler J. , Schaffner Samantha H. , Canter Marleigh R. , Malagise Evi M. , Patel Maulik R. 
Published: March 2023

AbstractEpigenetic modifications provide powerful means for transmitting information from parent to progeny. As a maternally inherited genome that encodes essential components of the electron transport chain, the mitochondrial genome (mtDNA) is ideally positioned to serve as a conduit for the transgenerational transmission of metabolic information. Here, we provide evidence that mtDNA ofC. eleganscontains the epigenetic mark N6-methyldeoxyadenosine (6mA). Bioinformatic analysis of SMRT sequencing data and methylated DNA IP sequencing data reveal thatC. elegansmtDNA is methylated at high levels in a site-specific manner. We further confirmed that mtDNA contains 6mA by leveraging highly specific anti-6mA antibodies. Additionally, we find that mtDNA methylation is dynamically regulated in response to antimycin, a mitochondrial stressor. Further, 6mA is increased innmad-1mutants and is accompanied by a significant decrease in mtDNA copy number. Our discovery paves the way for future studies to investigate the regulation and inheritance of mitochondrial epigenetics.
A naturally occurring variant ofMBD4causes maternal germline hypermutation in primates
Authors: Stendahl Alexandra M. , Sanghvi Rashesh , Peterson Samuel , Ray Karina , Lima Ana C. , Rahbari Raheleh , Conrad Donald F. 
Published: March 2023

AbstractAs part of an ongoing genome sequencing project at the Oregon National Primate Research Center, we identified a rhesus macaque with a rare homozygous frameshift mutation in the gene Methyl-CpG binding domain 4 (MBD4). MBD4 is responsible for the repair of C>T deamination mutations at CpG locations and has been linked to somatic hypermutation and cancer predisposition in humans. We show here that MBD4-associated hypermutation also affects the germline: the 6 offspring of theMBD4-null dam have a 4-6 fold increase inde novomutation burden. This excess burden was predominantly C>T mutations at CpG locations consistent withMBD4loss-of-function in the dam. There was also a significant excess of C>T at CpA sites, indicating an important, underappreciated role for MBD4 to repair deamination in CpA contexts. TheMBD4-null dam developed sustained eosinophilia later in life, but we saw no other signs of neoplastic processes associated withMBD4loss-of-function in humans, nor any obvious disease in the hypermutated offspring. This work provides what is likely the first evidence for a genetic factor causing hypermutation in the maternal germline of a mammal, and adds to the very small list of naturally occurring variants known to modulate germline mutation rates in mammals.
Mechanism of histone H2B monoubiquitination by Bre1
Authors: Zhao Fan , Hicks Chad W. , Wolberger Cynthia 
Published: March 2023

AbstractMonoubiquitination of histone H2BK120/123 plays multiple roles in regulating transcription, DNA replication and the DNA damage response. The structure of a nucleosome in complex with the dimeric RING E3 ligase, Bre1, reveals that one RING domain binds to the nucleosome acidic patch, where it can position the Rad6 E2, while the other RING domain contacts the DNA. Comparisons with H2A-specific E3 ligases suggests a general mechanism of tuning histone specificity via the non-E2-binding RING domain.
Neural timescales reflect behavioral demands in freely moving rhesus macaques
Authors: Manea Ana M.G. , Zilverstand Anna , Hayden Benjamin , Zimmermann Jan 
Published: March 2023

SummaryPrevious work has demonstrated remarkably reproducible and consistent hierarchies of neural timescales across cortical areas at rest. The question arises how such stable hierarchies give rise to adaptive behavior that requires flexible adjustment of temporal coding and integration demands. Potentially, this previously found lack of variability in the hierarchical organization of neural timescales could be a reflection of the structure of the laboratory contexts in which they were measured. Indeed, computational work demonstrates the existence of multiple temporal hierarchies within the same anatomical network when the input structure is altered. We posit that unconstrained behavioral environments where relatively little temporal demands are imposed from the experimenter are an ideal test bed to address the question of whether the hierarchical organization and the magnitude of neural timescales reflect ongoing behavioral demands. To tackle this question, we measured timescales of local field potential activity while rhesus macaques were foraging freely in a large open space. We find a hierarchy of neural timescales that is unique to this foraging environment. Importantly, although the magnitude of neural timescales generally expanded with task engagement, the brain areas’ relative position in the hierarchy was stable across the recording sessions. Notably, the magnitude of neural timescales monotonically expanded with task engagement across a relatively long temporal scale spanning the duration of the recording session. Over shorter temporal scales, the magnitude of neural timescales changed dynamically around foraging events. Moreover, the change in the magnitude of neural timescales contained functionally relevant information, differentiating between seemingly similar events in terms of motor demands and associated reward. That is, the patterns of change were associated with the cognitive and behavioral meaning of these events. Finally, we demonstrated that brain areas were differentially affected by these behavioral demands - i.e., the expansion of neural timescales was not the same across all areas. Together, these results demonstrate that the observed hierarchy of neural timescales is context-dependent and that changes in the magnitude of neural timescales are closely related to overall task engagement and behavioral demands.
Improved rescue of immature oocytes obtained from conventional gonadotropin stimulation cycles via human induced pluripotent stem cell-derived ovarian support cell co-culture
Authors: Giovannini Alexa , Piechota Sabrina , Marchante Maria , Potts Kathryn S , Rockwell Graham , Paulsen Bruna , Noblett Alexander D , Estevez Samantha L , Figueroa Alexandra B , Aschenberger Caroline , Kelk Dawn A , Forti Marcy , Marcinyshyn Shelby , Barrachina Ferran , Wiemer Klaus , Sanchez Marta , Belchin Pedro , Smela Merrick Pierson , Fortuna Patrick R.J. , Chatterjee Pranam , McCulloh David H , Copperman Alan , Ordonez-Perez Daniel , Klein Joshua U , Kramme Christian C 
Published: March 2023

Structured AbstractPurposeTo determine if rescuein vitromaturation (IVM) of human oocytes can be improved by co-culture with ovarian support cells (OSCs) derived from human induced pluripotent stem cells (hiPSCs).MethodsFertility patients undergoing conventional ovarian stimulation for oocyte cryopreservation or IVF donated denuded immature germinal vesicle (GV) and metaphase I (MI) oocytes for research, which were allocated between either the control or intervention cultures. Fertility patients aged 25 to 45 years old donated immature oocytes under informed consent, with no additional inclusion criteria. The 24-28 hour OSC-IVM culture condition was composed of 100,000 OSCs in suspension culture with human chorionic gonadotropin (hCG), recombinant follicle stimulating hormone (rFSH), androstenedione and doxycycline supplementation. The Media-IVM control lacked OSCs and contained the same supplementation. Primary endpoints consisted of MII formation rate and morphological quality assessment. Additionally, metaphase spindle assembly location and oocyte transcriptomic profiles were assessed compared toin vivomatured MII oocyte controls.ResultsWe observed significant improvement in maturation outcome rates (∼1.7X) for oocytes that underwent IVM with OSCs. Specifically, the OSC-IVM group yielded a maturation rate of 62% ± 5.57% SEM versus 37% ± 8.96% SEM in the Media-IVM (p=0.0138, unpairedt-test). Oocyte morphological quality between OSC-IVM and the Media-IVM control did not significantly differ. OSC-IVM resulted in MII oocytes with no instances of spindle absence and no significant difference in position compared toin vivomatured IVF-MII controls. OSC-IVM treated MII oocytes display a transcriptomic signature significantly more similar to IVF-MII controls than the Media-IVM control MII oocytes did.ConclusionThe novel OSC-IVM platform is an effective tool for rescue maturation of human oocytes obtained from conventional stimulation cycles, yielding oocytes with improved nuclear and cytoplasmic maturation. OSC-IVM shows broad utility for application in modern fertility treatment to improve the total number of available mature oocytes for fertility treatment.
Complex Formation of Immunoglobulin Superfamily Molecules Side-IV and Beat-IIb Regulates Synaptic Specificity in theDrosophilaVisual System
Authors: Osaka Jiro , Ishii Arisa , Wang Xu , Iwanaga Riku , Kawamura Hinata , Sugie Atsushi , Hakeda-Suzuki Satoko , Suzuki Takashi 
Published: March 2023

SUMMARYNeurons establish specific synapses based on the adhesive properties of cell-surface proteins, while also retaining the ability to form synapses in a relatively non-selective manner. However, the comprehensive understanding of the underlying mechanism reconciling these opposing characteristics remains incomplete. Here, we have identified Side-IV/Beat-IIb, members of theDrosophilaimmunoglobulin superfamily, as a novel combination of cell-surface recognition molecules inducing synapse formation. The Side-IV/Beat-IIb combination transduces bifurcated signaling with Side-IV’s co-receptor, Kirre, and a synaptic scaffold protein, Dsyd-1. Genetic experiments and subcellular protein localization analyses showed the newly characterized Side-IV/Beat-IIb/Kirre/Dsyd-1 complex to have two essential functions. First, it narrows neuronal binding specificity through Side-IV/Beat-IIb extracellular interactions. Second, it recruits synapse formation factors, Kirre and Dsyd-1, to restrict synaptic loci and inhibit miswiring. This dual function explains how the combinations of cell-surface molecules enable the ranking of preferred interactions among neuronal pairs to achieve synaptic specificity in complex circuitsin vivo.
Is exercising better for your Mental Health?
Authors: Desai Dev Himanshubhai , Shukla Aparajita , Desai Himanshu 
Published: March 2023

AbstractObjectiveTo correlate psychological changes with exercise.MethodologyThis cross sectional study was conducted on 102 participants in a known Gym with age group 17-75 (28.3 ± 10.4, 70.59% males). They were given“Rosenberg self-esteem Questionnaire”, “Satisfaction with life scale” & “Hamilton & Beck’s Depression Inventory” inpen-paper type and were asked to fill it twice; once at the present time and once in retrospection before they started doing exercise. Three different values of Self-esteem, Satisfaction and Depression were collected. Answers from these Depression, Self-esteem questionnaire and Satisfaction questionnaire were summed up to get the final individual score.ResultsOverall gain was 62.53% suggesting positive impact of exercise. Highest impact was seen in age group of 17-30 of 72.46%. Lower education groups showed significantly higher gain, compared to higher educational groups (191.80%vs42.64%,p<0.05), which may be because of already higher scores in pre-exercise stage among higher education group. Target-achievers showed significantly higher gain compared to non-target-achievers (84.84%vs33.18%,p<0.01)).ConclusionExercise has an overall positive impact on satisfaction, self-esteem and reduction in depression. People are influenced by different factors into getting fit and most of them agree that body image has a value in their perception of any individual.
Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease
Authors: Mehta Puja , Sanz-Magallón Duque de Estrada Blanca , Denneny Emma K , Foster Kane , Turner Carolin T , Mayer Andreas , Milighetti Martina , Platé Manuela , Worlock Kaylee B , Yoshida Masahiro , Brown Jeremy S , Nikolić Marko Z , Chain Benjamin M , Noursadeghi Mahdad , Chambers Rachel C , Porter Joanna C , Tomlinson Gillian S 
Published: March 2023

AbstractBackgroundPersistent radiological lung abnormalities are evident in many survivors of acute coronavirus disease 2019 (COVID-19). Consolidation and ground glass opacities are interpreted to indicate subacute inflammation whereas reticulation is thought to reflect fibrosis. We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis.MethodsWe compared single-cell transcriptomic profiles and T cell receptor (TCR) repertoires of bronchoalveolar cells obtained from convalescent individuals with each radiological pattern, targeting lung segments affected by the predominant abnormality.ResultsSingle-cell transcriptomes of inflammatory and fibrotic post-COVID lung disease closely resembled each other across all cell types. However, CD4 central memory T cells and CD8 effector memory T cells were significantly more abundant in those with inflammatory radiology. Clustering of similar TCRs from multiple donors was a striking feature of both phenotypes, consistent with tissue localised antigen-specific immune responses. There was no enrichment for known SARS-CoV-2-reactive TCRs, raising the possibility of T cell-mediated immunopathology driven by failure in immune self-tolerance.ConclusionsWe found no evidence that post-COVID radiographic inflammation and fibrosis are associated with differential immmunopathological pathways. Both show evidence of shared antigen-specific T cell responses, suggesting a role for therapies targeting T cells in limiting post-COVID lung damage.