bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting Huntington’s disease state with ensemble learning & sMRI: more than just the striatum
Authors: Kohli Maitrei , Pustina Dorian , Warner John H. , Alexander Daniel C. , Scahill Rachael I. , Sampaio Cristina , Tabrizi Sarah J. , Wijeratne Peter A. 
Published: July 2023

AbstractDeveloping effective treatments for Huntington’s disease (HD) requires reliable markers of disease progression. Striatal atrophy has been the hallmark of HD progression, but volumetric anomalies are also found in other brain regions. Little is known about the potential increase in predictive biomarking accuracy when volumetric scores from multiple brain regions are combined to predict the HD status of individual participants. We used cross-sectional structural MRI data from 184 HD gene-positive participants to a) test a novel ensemble machine learning model in classifying participants in one of four HD progression states (PreHD A; PreHD B; HD1; HD2), and (b) identify the brain regions that carry HD biomarking signal from 15 regions. We used 5-fold cross validation and backward feature elimination to find the optimal predictors and investigated the stability of the findings through repeated analyses. The ensemble predictive model systematically matched or outperformed the accuracy of nine standard machine learning models, reaching 55.3%±6.1 balanced accuracy in 4-group classification. The accuracy was higher for binary classifications (PreHD vs HD: 83.3%±6.3; PreHD A vs PreHD B: 76.7%±8.0; PreHD B vs HD1: 75.9%±8.5; HD1 vs HD2: 70.9%±9.4). Striatal structures (caudate and putamen) were systematically found to be top predictors. However, the accuracy increased substantially when we included other regions in the model (e.g., occipital cortex, lateral ventricles, cingulate, temporal lobe). Optimal models frequently included 2-7 brain regions from different areas. Overall, the accuracy of classifications remained stable across repetitions but the list of selected brain regions could vary, likely due to collinearities in volumetric scores. This is the first study to demonstrate the improvement of classification accuracy when predicting HD progression with a stacked ensemble model. Our findings indicate that HD progression is marked not only by striatal atrophy but also by volumetric changes outside the striatum, without which biomarking models cannot achieve optimal results. The robust methods applied here exposed instability in the selection of brain regions despite the sizeable sample size (n=184); such instabilities could lead to different conclusions in different studies when single analyses are applied on smaller sample sizes. From a translational perspective, our study informs on the selection of candidate endpoints or target regions for therapeutic intervention in future clinical trials.
WEIRD or not: A Cross-Cultural Behavioral Economic Assessment of Demand for HIV and COVID-19 Vaccines
Authors: Tewogbola Promise , Jacobs Eric A. , McDaniel Justin T. 
Published: July 2023

AbstractBackgroundDespite empirical evidence supporting vaccine effectiveness, vaccine hesitancy continues to thrive. Demand as a behavioral economic process provides useful indices for evaluating vaccine acceptance likelihood in individuals and groups. Using this framework, our study investigates the dynamics governing vaccine acceptance in two culturally dissimilar countries.MethodsHypothetical purchase tasks (HPTs) assessed how Nigerian and US participants varied vaccine acceptance as a function of hospitalization risks due to vaccination (N= 109). Aggregate and individual demand indices (Q0andPmax) were computed with nonlinear regressions. Secondary analyses were conducted using repeated measures ANOVAs with vaccine type (COVID-19 and HIV) as the within-subject factor; country, age, and socioeconomic status as between-subjects factors; demand indices served as dependent variables.ResultsDemand indices varied significantly as a function of vaccine type (F(1, 57) = 17.609,p <.001,). Demand for HIV vaccines was higher relative to COVID19 vaccines. Interactions between vaccine type and country of origin (F(1, 56) = 4.001,p= .05,) were also significant with demand for HIV vaccines among Nigerian respondents higher than that of COVID-19 vaccines. This was reversed for US participants. Interactions between vaccine type, country of origin and age were also significant (F(2, 51) = 3.506,p <.05,).ConclusionsThese findings provide evidence that vaccine type can influence demand. The relationship between demand and vaccine type also varies as a function of country of origin and age. Significance, limitations, and future directions are also discussed.
Discovery of fibrotic intervertebral disc in mice
Authors: He Jian , Huang Sha , Yan Pulin , Li Yangyang , Jin Huaijian , Hu Ou , Zhu Jun , Lin Peng , Wang Yingbo , Zhang Liang , Guo Yu , Wang Liting , Zhao Jianhua , Xie Yangli , Chen Lin , Lan Yu , Liu Bing , Liu Peng , Gan Yibo 
Published: July 2023

AbstractMechanical overload on the spine is a critical factor in the onset of intervertebral disc (IVD) degeneration. However, the lack of a precise and reliable animal model impedes a comprehensive understanding of the pathogenesis associated with IVD degeneration. In this study, we identified the high prevalence of spontaneous fibrotic alterations in IVDs predominantly located in the tail base, spanning from Co3/4 to Co5/6 levels, as early as 28 days in mice. These fibrotic IVDs manifested characteristics including extracellular matrix fibrosis and a decline in cell density. We leveraged a finite element model of computational biomechanics to generate fully predictive, three-dimensional simulations of flexion motion in the mouse tail. Our simulations revealed that the caudal discs in the mouse tail base underwent various mechanical overloads. Hence, we propose that the caudal IVDs in mice can serve as a novel mechanical model for investigating the mechanisms underlying the pathogenesis of IVD degeneration.
Single-cell precision nanotechnologyin vivo
Authors: Molbay Muge , Kick Benjamin , Zhao Shan , Todorov Mihail Ivilinov , Ohn Tzu-Lun , Roth Stefan , Simats Alba , Singh Vikramjeet , Khalin Igor , Pan Chenchen , Bhatia Harsharan Singh , Hellal Farida , Zeidler Reinhard , Liesz Arthur , Plesnila Nikolaus , Dietz Hendrik , Erturk Ali 
Published: July 2023

ABSTRACTTargeting nanoparticle therapeutics with cellular accuracy in whole organisms could open breakthrough opportunities in precision medicine. However, evaluating and fine-tuning the biodistribution of such systems in the whole organism at the cellular level remains a major obstacle. Here, we constructed targetable DNA origami, and analyzed biodistribution in transparent mice, in addition to studying tolerability, clearance kinetics, and immune response parameters. Untargeted DNA origami primarily accumulated in the spleen and the liver, while an immune cell-targeting variant successfully attached to immune cells throughout the body. A cancer cell-targeting mimetic co-localized on solid-tumor metastasis in the liver and the lung. These findings indicate that DNA origami can be directed in vivo, providing an important proof-of-concept and highlights the potential of high-resolution tissue-clearing imaging technologies in their development.Graphical AbstractHighlightsThis study demonstrates the potential of DNA origami-based drug delivery systems as versatile tool for for targeted delivery, which could be used to treat a range of diseases with applications.The immune compatibility, half-life, targeting efficiency, and the biodistribution evaluation of DNA origami indicate its potential for systemic drug delivery.Our approach enables the assessment of biodistribution of nanoparticles in the intact body with a sensitivity to the single-cell level, highlighting the high-resolution tissue clearing technoloies in revealing DNA origami’s feasibility for drug targeting.
Characterization of trade-offs between immunity and reproduction inAstrangia poculata
Authors: Villafranca Natalie , Changsut Isabella , Diaz de Villegas Sofia C. , Womack Haley R. , Fuess Lauren E. 
Published: July 2023

AbstractBackgroundLiving organisms face ubiquitous pathogenic threats and have consequently evolved immune systems to protect against potential invaders. However, many components of the immune system are physiologically costly to maintain and engage, often drawing resources away from other organismal processes such as growth and reproduction. Evidence from a diversity of systems has demonstrated that organisms use complex resource allocation mechanisms to manage competing needs and optimize fitness. However, understanding of resource allocation patterns is limited across taxa. Cnidarians, which include ecologically important organisms like hard corals, have been historically understudied in the context of resource allocations. Improving understanding of resource allocation-associated tradeoffs in cnidarians is critical for understanding future ecological dynamics in the face of rapid environmental change.MethodsHere, we characterize trade-offs between constitutive immunity and reproduction in the facultatively symbiotic coral Astrangia poculata. Male colonies underwent ex situ spawning and sperm output was quantified. We then examined the effects of variable symbiont density and energetic budget on physiological traits, including immune activity and reproductive investment. Furthermore, we tested for potential trade-offs between immune activity and reproductive investment.ResultsWe found limited effects of energetic budget on immune metrics; melanin production was significantly positively associated with energetic budget. However, we failed to document any associations between immunity and reproductive output which would be indicative of trade-offs, possibly due to experimental limitations. Our results provide a preliminary framework for future studies investigating immune trade-offs in cnidarians.
Interactions between climate change, urban infrastructure and mobility are driving dengue emergence in Vietnam
Authors: Gibb Rory , Colón-González Felipe J. , Lan Phan Trong , Huong Phan Thi , Nam Vu Sinh , Duoc Vu Trong , Hung Do Thai , Dong Nguyễn Thanh , Chien Vien Chinh , Trang Ly Thi Thuy , Quoc Do Kien , Hoa Tran Minh , Tai Nguyen Hữu , Hang Tran Thi , Tsarouchi Gina , Ainscoe Eleanor , Harpham Quillon , Hofmann Barbara , Lumbroso Darren , Brady Oliver J. , Lowe Rachel 
Published: July 2023

AbstractDengue is expanding globally, but how dengue emergence is shaped locally by interactions between climatic and socio-environmental factors is not well understood. Here, we investigate the drivers of dengue incidence and emergence in Vietnam, through analyzing 23-years of monthly district-level case data spanning a period of significant socioeconomic change (1998-2020). We show that urban infrastructure factors (sanitation, water supply and long-term urban growth) predict local spatial patterns of dengue incidence, while human mobility is a more influential driver in subtropical northern regions than the endemic south. Temperature is the dominant factor shaping dengue’s geographical distribution and dynamics, and using long-term reanalysis temperature data we show that recent warming (since 1950) has generally expanded transmission risk throughout Vietnam, and most strongly in current dengue emergence hotspots (e.g. southern central regions and Ha Noi). In contrast, effects of hydrometeorology are complex, multi-scalar and dependent on local context: risk increases under both short-term precipitation excess and long-term drought, but improvements in water supply largely mitigate drought-associated risks except under extreme conditions. Our findings challenge the assumption that dengue is an urban disease, instead suggesting that incidence peaks in transitional landscapes with intermediate infrastructure provision, and provide evidence that interactions between recent climate change and mobility have contributed to dengue’s ongoing expansion throughout Vietnam.
Multiclass risk models for ovarian malignancy: an illustration of prediction uncertainty due to the choice of algorithm
Authors: Ashleigh Ledger , Jolien Ceusters , Lil Valentin , Antonia Testa , VAN Holsbeke Caroline , Dorella Franchi , Tom Bourne , Wouter Froyman , Dirk Timmerman , VAN Calster Ben 
Published: July 2023

ABSTRACTOBJECTIVETo compare performance and probability estimates of six algorithms to estimate the probabilities that an ovarian tumor is benign, borderline malignant, stage I primary invasive, stage II-IV primary invasive, or secondary metastatic.MATERIALS AND METHODSModels were developed on 5909 patients (recruited 1999-2012) and validated on 3199 patients (2012-2015). Nine clinical and ultrasound predictors were used. Outcome was based on histology following surgery within 120 days after the ultrasound examination. We developed models using multinomial logistic regression (MLR), Ridge MLR, random forest (RF), XGBoost, neural networks (NN), and support vector machines (SVM).RESULTSBenign tumors were most common (62%), secondary metastatic tumors least common (5%). XGBoost, RF, NN and MLR had similar performance: c-statistics for benign versus any type of malignant tumors were 0.92, multiclass c-statistics 0.54-0.55, average Estimated Calibration Indexes 0.03-0.07, and Net Benefits at the 10% malignancy risk threshold 0.33-0.34. Despite poorer discrimination and calibration performance for Ridge MLR and in particular SVM, Net Benefits were similar for all models. The estimated probabilities often differed strongly between models. For example, the probability of a benign tumor differed by more than 20 percentage points in 29% of the patients, and by more than 30 percentage points in 16% of the patients.DISCUSSIONSeveral regression and machine learning models had very good and similar performance in terms of discrimination, calibration and clinical utility. Nevertheless, individual probabilities often varied substantially.CONCLUSIONMachine learning did not outperform MLR. The choice of algorithm can strongly affect probabilities given to a patient.
Aub, Vasa and Armi localization to phase separated nuage is dispensable for piRNA biogenesis and transposon silencing inDrosophila
Authors: Ho Samantha , Rice Nicholas P , Yu Tianxiong , Weng Zhiping , Theurkauf William E 
Published: July 2023

AbstractFrom nematodes to placental mammals, key components of the germline transposon silencing piRNAs pathway localize to phase separated perinuclear granules. InDrosophila,the PIWI protein Aub, DEAD box protein Vasa and helicase Armi localize to nuage granules and are required for ping-pong piRNA amplification and phased piRNA processing.DrosophilapiRNA mutants lead to genome instability and Chk2 kinase DNA damage signaling. By systematically analyzing piRNA pathway organization, small RNA production, and long RNA expression in single piRNA mutants and correspondingchk2/mnkdouble mutants, we show that Chk2 activation disrupts nuage localization of Aub and Vasa, and that the HP1 homolog Rhino, which drives piRNA precursor transcription, is required for Aub, Vasa, and Armi localization to nuage. However, these studies also show that ping-pong amplification and phased piRNA biogenesis are independent of nuage localization of Vasa, Aub and Armi. Dispersed cytoplasmic proteins thus appear to mediate these essential piRNA pathway functions.
Identification of Late Pleistocene and Holocene fossil lizards from Hall’s Cave and a primer on morphological variation in North American lizard skulls
Authors: Ledesma David T. , Scarpetta Simon G. , Jacisin John J. , Meza Antonio , Kemp Melissa E. 
Published: July 2023

AbstractFossil identification practices have a profound effect on our interpretation of the past because these identifications form the basis for downstream analyses. Therefore, well-supported fossil identifications are paramount for examining the impact of past environmental changes on populations and communities. Here we apply an apomorphic identification framework in a case study identifying fossil lizard remains from Hall’s Cave, a late Quaternary fossil site located in Central Texas, USA. We present images and descriptions of a broad comparative sample of North American lizard cranial elements and compile new and previously reported apomorphic characters for identifying fossil lizards. Our fossil identifications from Hall’s Cave resulted in a minimum of 11 lizard taxa, including five lizard taxa previously unknown from the site. Most of the identified fossil lizard taxa inhabit the area around Hall’s Cave today, but we reinforce the presence of an extirpated species complex of horned lizard. A main goal of this work is to establish a procedure for making well-supported fossil lizard identifications across North America. The data from this study will assist researchers endeavoring to identify fossil lizards, increasing the potential for novel discoveries related to North American lizards and facilitating more holistic views of ancient faunal assemblages.
Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants
Authors: McDonnell Alexander F , Plech Marcin , Livesey Benjamin J , Gerasimavicius Lukas , Owen Liusaidh J , Hall Hildegard Nikki , FitzPatrick David R , Marsh Joseph A , Kudla Grzegorz 
Published: July 2023

ABSTRACTNonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To understand how changes of PAX6:DNA binding cause these phenotypes, we combined saturation mutagenesis of the paired domain of PAX6 with a yeast one-hybrid (Y1H) assay in which expression of a PAX6-GAL4 fusion gene drives antibiotic resistance. We quantified binding of more than 2,700 single amino-acid variants to two DNA sequence elements. Mutations in DNA-facing residues of the N-terminal subdomain and linker region were particularly detrimental, as were mutations to prolines and to negatively charged residues. Many variants caused molecular gain-of-function effects, including variants in position Ile71 that increased binding to the LE9 enhancer but decreased binding to a SELEX-derived binding site. Benchmarking against known patient variants and applying ACMG/AMP guidelines to variant classification, we obtained supporting to moderate evidence to suggest that 1,306 variants are likely benign, and 977, likely pathogenic. Our analysis shows that most pathogenic mutations in the paired domain of PAX6 can be explained simply by the effects of these mutations on PAX6:DNA association, and establishes Y1H as a generalisable assay for the interpretation of variant effects in transcription factors.
Genome-scale chromatin interaction dynamic measurements for key components of the RNA Pol II general transcription machinery
Authors: Kupkova Kristyna , Shetty Savera J. , Hoffman Elizabeth A. , Bekiranov Stefan , Auble David T. 
Published: July 2023

AbstractBackgroundA great deal of work has revealed in structural detail the components of the machinery responsible for mRNA gene transcription initiation. These include the general transcription factors (GTFs), which assemble at promoters along with RNA Polymerase II (Pol II) to form a preinitiation complex (PIC) aided by the activities of cofactors and site-specific transcription factors (TFs). However, less well understood are thein vivoPIC assembly pathways and their kinetics, an understanding of which is vital for determining on a mechanistic level how rates ofin vivoRNA synthesis are established and how cofactors and TFs impact them.ResultsWe used competition ChIP to obtain genome-scale estimates of the residence times for five GTFs: TBP, TFIIA, TFIIB, TFIIE and TFIIF in budding yeast. While many GTF-chromatin interactions were short-lived (< 1 min), there were numerous interactions with residence times in the several minutes range. Sets of genes with a shared function also shared similar patterns of GTF kinetic behavior. TFIIE, a GTF that enters the PIC late in the assembly process, had residence times correlated with RNA synthesis rates.ConclusionsThe datasets and results reported here provide kinetic information for most of the Pol II-driven genes in this organism and therefore offer a rich resource for exploring the mechanistic relationships between PIC assembly, gene regulation, and transcription. The relationships between gene function and GTF dynamics suggest that shared sets of TFs tune PIC assembly kinetics to ensure appropriate levels of expression.
Developmental regulation of zinc homeostasis in differentiating oligodendrocytes
Authors: Elitt Christopher M. , Ross Madeline M. , Wang Jianlin , Fahrni Christoph J. , Rosenberg Paul A. 
Published: July 2023

AbstractOligodendrocytes develop through well characterized stages and understanding pathways regulating their differentiation remains an active area of investigation. Zinc is required for the function of many enzymes, proteins and transcription factors, including those important in myelination and mitosis. Our previous studies using the ratiometric zinc sensor chromis-1 demonstrated a reduction in intracellular free zinc concentrations in mature oligodendrocytes compared with earlier stages (Bourassa et al., 2018). We performed a more detailed developmental study to better understand the temporal course of zinc homeostasis across the oligodendrocyte lineage. Using chromis-1, we found a transient increase in free zinc after developing oligodendrocytes were switched into differentiation medium. To gather other evidence for dynamic regulation of free zinc during oligodendrocyte development, qPCR was used to evaluate mRNA expression of the major zinc storage proteins metallothioneins (MTs), and metal regulatory transcription factor 1 (MTF-1) which controls expression of MTs. MT-1, MT-2 and MTF1 mRNAs were all increased several fold in mature oligodendrocytes compared to developing oligodendrocytes. To assess the depth of the zinc buffer, we assayed zinc release from intracellular stores using the oxidizing thiol reagent 2,2’-dithiodipyridine (DTDP). Exposure to DTDP resulted in a ∼100% increase in free zinc in developing oligodendrocytes but, paradoxically more modest ∼60% increase in mature oligodendrocytes despite the increased expression of MTs. These results suggest that zinc homeostasis is regulated during oligodendrocyte development, that oligodendrocytes are a useful model for studying zinc homeostasis in the central nervous system, and that regulation of zinc homeostasis may be important in oligodendrocyte differentiation.
BacScan: An Unbiased and Genome-Wide Approach to Identify Bacterial Highly Immunogenic Proteins
Authors: Dong Junhua , Zhang Qian , Yang Jinyue , Zhao Yacan , Miao Zhuangxia , Pei Siyang , Qin Huan , Wen Guoyuan , Zhang Anding , Tao Pan 
Published: July 2023

AbstractBacterial pathogens are the second leading cause of death worldwide. However, the development of bacterial vaccines has been challenged by the presence of multiple serotypes and the lack of cross-protection between serotypes. Therefore, there is an urgent need to identify protective antigens conserved across serotypes in order to develop a broadly protective vaccine. Here, we have developed an unbiased and genome-wide technique, BacScan, which uses bacterial-specific serum to rapidly identify highly conserved immunogenic proteins by combining phage display, immunoprecipitation, and next-generation sequencing. As a proof of concept, we identified 19 highly immunogenic proteins fromStreptococcus suiscore proteins. Immunoreactivity analysis of mouse, pig, and human sera indicated that 2 proteins could be the potential targets for the development of serological diagnostics. Eight proteins provided 20%-100% protection againstS. suischallenge in immunized animals, indicating the potential vaccine targets. BacScan can be applied to any bacterial pathogen and has the potential to accelerate the development of a broadly protective bacterial vaccine.TeaserA novel method to identify the highly conserved immunogenic bacterial proteins as targets for the development a broadly protective bacterial vaccine.