bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nuclear dualism without extensive DNA elimination in the ciliateLoxodes magnus
Authors: Seah Brandon K. B. , Singh Aditi , Vetter David E. , Emmerich Christiane , Peters Moritz , Soltys Volker , Huettel Bruno , Swart Estienne 
Published: November 2023

AbstractCiliates are unicellular eukaryotes with two distinct kinds of nuclei in each cell: transcriptionally active somatic macronuclei (MAC) and silent germline micronuclei (MIC). In the best-studied model species, both nuclei can divide asexually, but only germline MICs participate in meiosis, karyogamy, and development into new MACs. During MIC-to-MAC development, thousands of mobile element relics in the germline, called internally eliminated sequences (IESs), are excised. This genome editing enables IESs to persist by shielding them from somatic natural selection. Editing itself is a costly, time-consuming process, hypothetically maintained by evolutionary addiction.Loxodes magnusand its relatives (class Karyorelictea) are cytologically unusual because their MACs do not divide asexually, but must develop anew from mitotically generated MIC copies every cell division. Here, we report thatLoxodesgenome development is also unconventional. We found no canonical germline-limited IESs inLoxodesdespite careful purification and long-read sequencing of MICs and MACs. The k-mer content of these nuclei overlapped, and indels found by read mapping were consistent with allele variants rather than IESs. Two other hallmarks of genome editing—domesticated DDE-family transposases and editing-associated small RNAs—were also absent. Nonetheless, histone marks, nucleosome and DNA N6-methyladenosine distributions in vegetativeLoxodescells are consistent with actively transcribed MACs and inactive MICs, like other ciliates. Both genomes, not only the MIC, were large and replete with retrotransposon sequences. Given the costs associated with genome editing, we hypothesize that karyorelicteans likeLoxodeshave lost or streamlined editing during MIC-to-MAC development, and have found a way out of the addictive cycle.
Identification of Cellular Interactions in the Tumor Immune Microenvironment Underlying CD8 T Cell Exhaustion
Authors: Klocke Christopher , Moran Amy , Adey Andrew , McWeeney Shannon , Wu Guanming 
Published: November 2023

AbstractWhile immune checkpoint inhibitors show success in treating a subset of patients with certain late-stage cancers, these treatments fail in many other patients as a result of mechanisms that have yet to be fully characterized. The process of CD8 T cell exhaustion, by which T cells become dysfunctional in response to prolonged antigen exposure, has been implicated in immunotherapy resistance. Single-cell RNA sequencing (scRNA-seq) produces an abundance of data to analyze this process; however, due to the complexity of the process, contributions of other cell types to a process within a single cell type cannot be simply inferred. We constructed an analysis framework to first rank human skin tumor samples by degree of exhaustion in tumor-infiltrating CD8 T cells and then identify immune cell type-specific gene-regulatory network patterns significantly associated with T cell exhaustion. Using this framework, we further analyzed scRNA-seq data from human tumor and chronic viral infection samples to compare the T cell exhaustion process between these two contexts. In doing so, we identified transcription factor activity in the macrophages of both tissue types associated with this process. Our framework can be applied beyond the tumor immune microenvironment to any system involving cell-cell communication, facilitating insights into key biological processes that underpin the effective treatment of cancer and other complicated diseases.
Oral delivery of the amylin receptor agonist pramlintide
Authors: Sinézia Celimar , Sisnande Tháyna , Icart Luis Peña , Lima Luís Maurício T. R. 
Published: November 2023

AbstractAimThe aims of this study were to design and characterize polymeric microparticles for oral delivery of pramlintide, a triple proline human amylin analogue clinically proved efficient in diabetes therapy.MethodsThe microparticles were prepared with gastric-resistant polymer Eudragit S100 by double-emulsion and solvent evaporation technique. The study responses were repeatability, encapsulation efficiency, yield, morphology, particle size, response to acidic and alkaline milieu and pharmacokinetics.ResultsWe obtained spherical microcapsules, with particle size of 66 μm ± 11, with 83.2 % ± 2.7 efficiency for pramlintide entrapment and 67.6 % ± 2.1 yield. Intra-venous pramlintide free in solution showed a plasmatic half-life of 6.8 min in mice. In contrast, oral delivery of acid-resistant pramlintide-loaded microparticles in mice showed a protracted release for 120 min compared to 30 min obtained for pramlintide in solution.ConclusionsOral route is an alternative for therapeutic development of pramlintide formulations.Graphical abstract
A Multi-task Platform for Profiling Cognitive and Motivational Constructs in Humans and Nonhuman Primates
Authors: Watson Marcus R. , Traczewski Nathan , Dunghana Seema , Boroujeni Kianoush Banaie , Neumann Adam , Wen Xuan , Womelsdorf Thilo 
Published: November 2023

AbstractBackgroundUnderstanding the neurobiological substrates of psychiatric disorders requires comprehensive evaluations of cognitive and motivational functions in preclinical research settings. The translational validity of such evaluations will be supported by (1) tasks with high construct validity that are engaging and easy to teach to human and nonhuman participants, (2) software that enables efficient switching between multiple tasks in single sessions, (3) software that supports tasks across a broad range of physical experimental setups, and (4) by platform architectures that are easily extendable and customizable to encourage future optimization and development.New MethodWe describe theMulti-task Universal Suite for Experiments(M-USE), a software platform designed to meet these requirements. It leverages the Unity video game engine and C# programming language to (1) support immersive and engaging tasks for humans and nonhuman primates, (2) allow experimenters or participants to switch between multiple tasks within-session, (3) generate builds that function across computers, tablets, and websites, and (4) is freely available online with documentation and tutorials for users and developers. M-USE includes a task library with seven pre-existing tasks assessing cognitive and motivational constructs of perception, attention, working memory, cognitive flexibility, motivational and affective self-control, relational long-term memory, and visuo-spatial problem solving.ResultsM-USE was used to test NHPs on up to six tasks per session, all available as part of the Task Library, and to extract performance metrics for all major cognitive and motivational constructs spanning the Research Domain Criteria (RDoC) of the National Institutes of Mental Health.Comparison with Existing MethodsOther experiment design and control systems exist, but do not provide the full range of features available in M-USE, including a pre-existing task library for cross-species assessments; the ability to switch seamlessly between tasks in individual sessions; cross-platform build capabilities; license-free availability; and its leveraging of video-engine capabilities used to gamify tasks.ConclusionsThe new multi-task platform facilitates cross-species translational research for understanding the neurobiological substrates of higher cognitive and motivational functions.
A neuromechanical model accounting for movement history dependency identifies subject-specific neural and non-neural origins of joint hyper-resistance: A simulation study
Authors: Willaert Jente , Desloovere Kaat , Van Campenhout Anja , Ting Lena H. , De Groote Friedl 
Published: November 2023

AbstractJoint hyper-resistance is a common symptom in neurological disorders. It has both neural and nonneural origins, but it has been challenging to distinguish different origins based on clinical tests alone. Combining instrumented tests with parameter identification based on a neuromechanical model may allow us to dissociate the different origins of joint hyper-resistance in individual patients. However, this requires that the model captures the underlying mechanisms. Here, we propose a neuromechanical model that, in contrast to previously proposed models, accounts for muscle shortrange stiffness and its interaction with muscle tone and reflex activity.We collected knee angle trajectories during the pendulum test in 15 children with cerebral palsy (CP) and 5 typically developing children. We did the test in two conditions – hold and pre-movement – that have been shown to alter knee movement. We modeled the lower leg as an inverted pendulum actuated by two antagonistic Hill-type muscles extended with SRS. Reflex activity was modeled as delayed, linear feedback from muscle force. We estimated neural and non-neural parameters by optimizing the fit between simulated and measured knee angle trajectories during the hold condition.The model could fit a wide range of knee angle trajectories in the hold condition. The model with personalized parameters predicted the effect of pre-movement demonstrating that the model captured the underlying mechanism and subject-specific deficits.Our model thus allows us to determine subject-specific origins of joint hyper-resistance and thereby opens perspectives for improved diagnosis and consequently treatment selection in children with spastic CP.
Chronic pain mediated changes in the appetitive value of affective gentle touch in mice
Authors: Zain Maham , Bennett Laura , Zhang Hantao , Pauli Quinn , Arsenault Juliet , Premachandran Shajenth , Cheung Jenny , Pham Christine , Wowk Lexi , Kaba Sékou-Oumar , Fung Samuel , Lecker Irene , Salter Eric , Wang Feng , Sharif-Naeini Reza , De Koninck Yves , Bonin Robert P. 
Published: November 2023

AbstractThe existence of skin-to-brain circuits for rewarding gentle touch highlight its critical nature across species. However, this gentle affective touch is not always appetitive and can produce aversion or negative affect in disorders such as chronic pain. Sensory neurons expressing the protein MrgprB4 detect gentle stroking in mice and their activation of these neurons known to be positively reinforcing. Here we assess whether activation of channelrhodopsin (ChR2) expressing MrgprB4 afferents signal positively valenced tactile information and whether this is altered in models of chronic pain. We further interrogate how this this sensory information is reflected in the downstream circuits recruited. Optogenetic activation of MrgprB4 lineage afferents was found to be appetitive in control and capsaicin sensitized mice but not nerve injured mice, indicating that the appetitive value is diminished in neuropathic pain. Remarkably, this appetitive value was partially recovered in male nerve injured mice by treatment with the analgesic gabapentin. These behavioral changes were also accompanied by different patterns of neuronal activity throughout the brain, including altered activation of sites that receive direct projections from the spinal cord between sham and nerve injured mice. Together, these findings highlight the plastic nature of these affective tactile circuits under pathological conditions.
HYPOTHESIS GENERATION FOR RARE AND UNDIAGNOSED DISEASES THROUGH CLUSTERING AND CLASSIFYING TIME-VERSIONED BIOLOGICAL ONTOLOGIES
Authors: Bradshaw Michael S. , Gibbs Connor P. , Martin Skylar , Firman Taylor , Gaskell Alisa , Fosdick Bailey K. , Layer Ryan M. 
Published: November 2023

AbstractRare diseases affect 1-in-10 people in the United States and despite increased genetic testing, up to half never receive a diagnosis. Even when using advanced genome sequencing platforms to discover variants, if there is no connection between the variants found in the patient’s genome and their phe-notypes in the literature, then the patient will remain undiagnosed. When a direct variant-phenotype connection is not known, putting a patient’s information in the larger context of phenotype relation-ships and protein-protein-interactions may provide an opportunity to find an indirect explanation. Databases such as STRING contain millions of protein-protein-interactions and HPO contains the relations of thousands of phenotypes. By integrating these networks and clustering the entities within we can potentially discover latent gene-to-phenotype connections. The historical records for STRING and HPO provide a unique opportunity to create a network time series for evaluating the cluster sig-nificance. Most excitingly, working with Children’s Hospital Colorado we provide promising hy-potheses about latent gene-to-phenotype connections for 38 patients with undiagnosed diseases. We also provide potential answers for 14 patients listed on MyGene2. Clusters our tool finds significant harbor 2.35 to 8.72 times as many gene-to-phenotypes edges inferred from known drug interactions than clusters find to be insignificant. Our tool, BOCC, is available as a web app and command line tool.
UDP-glucosyltransferase 71C4 regulates seed development by redistributing phenylpropanoid metabolism in cotton
Authors: Cao Yiwen , Han Zegang , He Lu , Huang Chujun , Chen Jinwen , Dai Fan , Xuan Lisha , Yan Sunyi , Si Zhanfeng , Hu Yan , Zhang Tianzhen 
Published: November 2023

ABSTRACTSeeds are important for plant reproduction, and hence it is important to identify genes regulating seed development. Here, we focused on a member of the glycosyltransferase (GT) family, UDP-glucosyltransferase 71C4 (UGT71C4), which influences the seed width, seed length, and yield traits (lint percentage and seed index) by regulating the lignin and flavonoid pathways of phenylpropane metabolism, affects the oil and protein contents of mature seeds, and controls the seed size by regulating cell proliferation. Overexpression ofUGT71C4leads to seed enlargement by activating expression of peroxiredoxins and the flavonoid metabolism pathway; induces accumulation of ROS, which promotes cell proliferation; and significantly improves yield traits, with the seed index increasing from 10.66 to 11.91 and protein increasing by 5.34%, but oil content decreasing 8.98%. Conversely, knockout ofUGT71C4causes seeds to become smaller; the lignin metabolism pathway to be activated, especially enzymes relating to lignin synthesis leading to increased ectopic deposition of lignin in the ovule and constrained ovule growth and development; and significant improvement of yield traits, with lint percentage increasing from 39.62% to 41.94%, seed index decreasing from 10.66 to 8.60, protein content decreasing 4.28%, and no significant change in oil content. Our research provides new insights into seed size regulation through UDP-glucosyltransferase, providing potential methods for improving plant yield.
The BET inhibitors JQ1, AZD5153, and I-BET151 co-opt ubiquitin proteasome system components for altering expression of the BRD4 interactome in a human B cell line
Authors: Nallur Girish 
Published: November 2023

ABSTRACTChemoproteomic analysis of the BET inhibitors, JQ1, AZD5153, and I-BET151, identified an extremely large signature of ubiquitin modified proteins associatingin vitrowith a recombinant BRD4 N-terminal protein fragment. The identified proteins included those with known functions in BRD4 complexes for transcriptional and epigenetic control (acetylated histones, the MED complex, BAF complex, RNA pol II transcription complexes, and chromatin-associated complexes). The BRD4 interactome in response to BET inhibitors is suggested to be orchestrated by compound-specific differential actions of up to 16 E3 ligases, 4 deubiquitinase enzymes, and 51 accessory proteins of the ubiquitin proteasome system (UPS). The UPS response of BET inhibition also involves proteins necessary for Myc enhancer binding and Myc response gene expression. A large cohort of UPS substrates commonly responsive to JQ1 and AZD5153 treatments suggests the existence of distinct mechanisms, one involving compound-activated UPS proteins, and another via their direct actions on BRD4. The findings raise the intriguing possibility that UPS triggers promoting proteostasis changes to the BRD4 interactome may be mechanistically coupled with BRD4 function in a proximity-dependent, chromatin-associated manner. Consequently, BET inhibitors and their downstream effects present highly complex environments which may lead to polypharmacology, the phenotypic outcomes or overall clinical benefits of which are hard to assess. However, many new targets and small molecule combinations suggested in this study may afford a path forward for narrowly and more selectively targeting Myc in the clinic with potentially cleaner profiles compared with BET inhibitors or BRD4 as target.
Phenotypic and genomic analysis of a large-scaleCorynebacterium diphtheriaeoutbreak among migrant populations in Europe
Authors: Hoefer Andreas , Seth-Smith Helena , Palma Federica , Schindler Stefanie , Freschi Luca , Dangel Alexandra , Berger Anja , D’Aeth Joshua , Indra Alexander , Fry Norman K. , Palm Daniel , Sing Andreas , Brisse Sylvain , Egli Adrian ,   the 2022 European diphtheria Consortium
Published: November 2023

AbstractBackgroundIncreased numbers of cases ofCorynebacterium diphtheriaeinfections were diagnosed in migrant-related facilities of Europe since summer 2022. Most cases involved cutaneous diphtheria, although some respiratory cases and fatalities were reported. A pan-European consortium was created to assess the clinical, epidemiological and microbiological features of this outbreak.MethodsAll 363 toxigenicC. diphtheriaeinfection cases from ten European countries were included. Data from case interviews regarding countries of origin and transit routes of migrants were collected. Bacterial isolates underwent whole genome sequencing and antibiotic susceptibility testing. Phylogenetic relationships of outbreak isolates and their antimicrobial resistance genes were studied.ResultsFour major genomic clusters were identified, revealing the multiclonal nature of the outbreak. Genes ermX, coding for erythromycin resistance, and genes pbp2m and blaOXA-2 for beta-lactam resistance, were detected in a subset of isolates. Isolates harboring ermX were resistant to erythromycin, and isolates carrying pbp2m were resistant to penicillin, but susceptible to amoxicillin, whereas those carrying blaOXA-2 remained susceptible to beta-lactams. Genomic variation within the four genomic clusters led to estimate their most recent common ancestors between 2017 and 2020.ConclusionsThe multi-country distribution of each cluster demonstrated repeated cross-border spread. The increased number ofC. diphtheriaecases among migrants is a cause for concern, particularly considering antimicrobial resistance phenotypes that threaten the efficacy of first-line treatments. This work provides important knowledge on modernC. diphtheriaeinfections, useful for addressing the reemergence of diphtheria in vulnerable populations and to guide clinical management and measures to control further dissemination.
Mutation in CDC42 gene set as a response biomarker for immune checkpoint inhibitor therapy
Authors: Wang Kun , Zhang Yingying , Su Zhaoming , Wang Bei , Zhou Yuanyang , Tong Xiaochu , Xie Chengying , Luo Xiaomin , Zhang Sulin , Zheng Mingyue 
Published: November 2023

AbstractBackgroundImmunotherapy has proven notably effective in treating tumors across diverse patient populations. However, some patients do not respond to immune checkpoint inhibitors (ICIs). Thus, there is a need for reliable biomarkers that can predict clinical responses to ICI treatment accurately.MethodsOur focus is on CDC42, a protein that stimulates multiple signaling pathways, promoting tumor growth. We hypothesize that its defective function may indicate a patient’s response to ICI therapy. We consider CDC42, along with its downstream binding and effector proteins, as a gene set. This is because their mutation could result in defective CDC42 function. We investigated the mutations in the CDC42 gene set as a potential biomarker for clinical benefits from ICI treatment. We also examined whether the combined use of a CDC42 inhibitor and ICI could enhance the efficacy of ICI.ResultsThe presence of mutations in the CDC42 gene set correlated with improved overall survival (OS: p = 2.9E-4) and progression-free survival (PFS: p = 2.92E-6). Furthermore, our analysis of immune response landscapes among different CDC42 gene set statuses supports its potential as a biomarker for ICI therapy. Animal experiments also revealed that combining the CDC42 inhibitor (ML141) with anti-PD-1 blockade can synergistically reduce tumor growth.ConclusionsOur study suggests that the CDC42 gene set could serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insight into the potential of combining ICI and CDC42 inhibitor use.
Network Enrichment Significance Testing in Brain-Phenotype Association Studies
Authors: Weinstein Sarah M. , Vandekar Simon N. , Alexander-Bloch Aaron F. , Raznahan Armin , Li Mingyao , Gur Raquel E. , Gur Ruben C. , Roalf David R. , Park Min Tae M. , Chakravarty Mallar , Baller Erica B. , Linn Kristin A. , Satterthwaite Theodore D. , Shinohara Russell T. 
Published: November 2023

AbstractFunctional networks often guide our interpretation of spatial maps of brain-phenotype associations. However, methods for assessing enrichment of associations within networks of interest have varied in terms of both scientific rigor and underlying assumptions. While some approaches have relied on subjective interpretations, others have made unrealistic assumptions about the spatial structure of imaging data, leading to inflated false positive rates. We seek to address this gap in existing methodology by borrowing insight from a method widely used in genomics research for testing enrichment of associations between a set of genes and a phenotype of interest. We propose Network Enrichment Significance Testing (NEST), a flexible framework for testing the specificity of brain-phenotype associations to functional networks or other sub-regions of the brain. We apply NEST to study phenotype associations with structural and functional brain imaging data from a large-scale neurodevelopmental cohort study.
OOCYTE AND EMBRYO CULTURE UNDER OIL PROFOUNDLY ALTERS EFFECTIVE CONCENTRATIONS OF SMALL MOLECULE INHIBITORS
Authors: Labrosse Gaudeline Rémillard , Cohen Sydney , Boucher Éliane , Gagnon Kéryanne , Vasilev Filip , Mihajlović Aleksandar I , FitzHarris Greg 
Published: November 2023

ABSTRACTCulture of oocytes and embryos in media under oil is a cornerstone of fertility treatment, and extensively employed in experimental investigation of early mammalian development. It has been noted anecdotally by some that certain small molecule inhibitors might lose activity in oil-covered culture systems, presumably by drug partitioning into the oil. Here we took a pseudo-pharmacological approach to appraise this formally. Using different culture dish designs with defined media:oil volume ratios, we show that the EC50of the widely employed microtubule poison nocodazole shifts as a function of the media:oil ratio, such that nocodazole concentrations that prevent cell division in oil-free culture fail to in oil-covered media drops. Relatively subtle changes in culture dish design lead to measurable changes in EC50. This effect is not specific to one type of culture oil, and can be readily observed both in oocyte and embryo culture experiments. We subsequently applied a similar approach to a small panel of widely employed cell cycle-related inhibitors, finding that most lose activity in standard oil-covered oocyte/embryo culture systems. Our data suggest that loss of small molecule activity in oil-covered oocyte and embryo culture is a widespread phenomenon with potentially far-reaching implications for data reproducibility, and we recommend avoiding oil-covered culture for experiments employing inhibitors/drugs wherever possible.