bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-related changes in thromboelastography profiles in injured children
Authors: Morgan Katrina M. , Abou-Khalil Elissa , Strotmeyer Stephen , Richardson Ward M. , Gaines Barbara A. , Leeper Christine M. 
Published: June 2023

BACKGROUND
The role of age in mediating coagulation characteristics in injured children is not well defined. We hypothesize thromboelastography (TEG) profiles are unique across pediatric age groups.

METHODS
Consecutive trauma patients younger than 18 years from a Level I pediatric trauma center database from 2016 to 2020 with TEG obtained on arrival to the trauma bay were identified. Children were categorized by age according to the National Institute of Child Health and Human Development categories (infant, ≤1 year; toddler, 1–2 years; early childhood, 3–5 years; older childhood, 6–11 years; adolescent, 12–17 years). Thromboelastography values were compared across age groups using Kruskal-Wallis and Dunn's tests. Analysis of covariance was performed controlling for sex, Injury Severity Score (ISS), arrival Glasgow Coma Scale (GCS) score, shock, and mechanism of injury.

RESULTS
In total, 726 subjects were identified; 69% male, median (interquartile range [IQR]) ISS = 12 (5–25), and 83% had a blunt mechanism. On univariate analysis, there were significant differences in TEG α-angle (p < 0.001), MA (p = 0.004), and fibrinolysis 30 minutes after MA (LY30) (p = 0.01) between groups. In post hoc tests, the infant group had significantly greater α-angle (median, 77; IQR, 71–79) and MA (median, 64; IQR, 59–70) compared with other groups, while the adolescent group had significantly lower α-angle (median, 71; IQR, 67–74), MA (median, 60; IQR, 56–64), and LY30 (median, 0.8; IQR, 0.2–1.9) compared with other groups. There were no significant differences between toddler, early childhood, and middle childhood groups. On multivariate analysis, the relationship between age group and TEG values (α-angle, MA, and LY30) persisted after controlling for sex, ISS, GCS, shock, and mechanism of injury.

CONCLUSION
Age-associated differences in TEG profiles across pediatric age groups exist. Further pediatric-specific research is required to assess whether the unique profiles at extremes of childhood translate to differential clinical outcomes or responses to therapies in injured children.

LEVEL OF EVIDENCE
Prognostic and Epidemiological; Level IV.
Unraveling the dynamic transcriptomic changes during the dimorphic transition ofTalaromyces marneffeithrough time-course analysis
Authors: Du Minghao , Tao Changyu , Hu Xueyan , Zhang Yun , Kan Jun , Wang Juan , Yang Ence 
Published: June 2023

AbstractSystemic dimorphic fungi pose a significant public health challenge, causing over one million new infections annually. The dimorphic transition between saprophytic mycelia and pathogenic yeasts is strongly associated with the pathogenesis of dimorphic fungi. However, despite the dynamic nature of dimorphic transition, the current omics studies focused on dimorphic transition primarily employ static strategies, partly due to the lack of suitable dynamic analytical methods. Here, we firstly conducted time-course transcriptional profiling during the dimorphic transition ofTalaromyces marneffei, a model organism for thermally dimorphic fungi. Then, we identified 5,223 dimorphic transition induced genes (DTIGs) by developing DyGAM-NS (dynamic optimized generalized additive model with natural cubic smoothing), a model that enables the capture of non-uniform and nonlinear transcriptional changes during intricate biological processes. Notably, the DyGAM-NS outperformed other commonly used models, achieving the highest F1-score in DTIGs identification. The cluster analysis of DTIGs suggests differential functional involvement of genes at distinct stages of dimorphic transition. Moreover, we observed divergent gene expression patterns between mycelium-to-yeast and yeast-to-mycelium transitions, indicating the asymmetrical nature of two transition directions. Additionally, leveraging the identified DTIGs, we constructed a regulatory network for the dimorphic transition and identified two zinc finger-containing transcription factors that potentially regulate dimorphic transition inT. marneffei. In summary, our study not only elucidates the dynamic changes in transcriptional profiles during the dimorphic transition ofT. marneffeibut also provides a novel perspective for unraveling the underlying mechanisms of fungal dimorphism.IMPORTANCEThe dimorphic transition, i.e., morphological switch between saprophytic mycelia and pathogenic yeasts, plays a pivotal role in the pathogenesis of dimorphic fungi. However, the underlying mechanisms of dimorphic transition remain poorly understood, partly due to the lack of dynamic analytical methods suitable for its intricate nature. In the current study, we dissected the dynamic transcriptional profiles of dimorphic transition with a model thermally dimorphic fungus,T. marneffei, by developing a novel analytical method, DyGAM-NS. We proved that DyGAM-NS was more powerful in capturing the non-uniform and nonlinear gene expression variations during the dimorphic transition. With DyGAM-NS, we identified a repertoire of genes associated with dimorphic transition, and comprehensively unraveled distinct functions and expression patterns at different transition stages ofT. marneffei, which offers novel perspectives regarding the mechanistic underpinnings of fungal dimorphism.
Pitch is Not (Always) a Helix: Probing the Structure of Musical Pitch Across Tasks and Experience
Authors: Marjieh Raja , Griffiths Thomas L. , Jacoby Nori 
Published: June 2023

AbstractPitch perception is at the core of our experience of both speech and music, and understanding the appropriate representation of musical pitch has intrigued scholars for centuries. The pitch helix, which jointly represents the logarithmic scaling of the periodicity of tones and the heightened similarity between tones separated by an octave, or octave equivalence, is often presented in textbooks as the underlying representation of pitch. However, prior research suggests that the representation of pitch is influenced by task context and musical expertise, although the evidence derives from disparate studies that are small-scale and sometimes contradictory. Here we systematically investigate how the representation of pitch varies across musical expertise levels and task demands. Drawing inspiration from representational similarity analysis in neuroscience, we revisit this problem through a series of nine experiments involving participants with varied levels of musical expertise (N= 592) and paradigms covering both perception and production. We show that, depending on task and musical experience, the best geometrical approximation to the representation of pitch can exhibit an array of structures ranging from linear to double-helical structures, providing strong evidence that a simple helical representation cannot explain the data. Surprisingly, we also found that octave equivalence was strongest in the singing task despite being the most challenging due to production noise. These results suggest a broader, more nuanced understanding of how we perceive pitch.
Rapid measurement and machine learning classification of color vision deficiency
Authors: He Jingyi , Bex Peter J. , Skerswetat Jan 
Published: June 2023

AbstractColor vision deficiencies (CVDs) indicate potential genetic variations and can be important biomarkers of acquired impairment in many neuro-ophthalmic diseases. However, CVDs are typically measured with insensitive or inefficient tools that are designed to classify dichromacy subtypes rather than track changes in sensitivity. We introduce FInD (Foraging Interactive D-prime), a novel computer-based, generalizable, rapid, self-administered vision assessment tool and applied it to color vision testing. This signal detection theory-based adaptive paradigm computes test stimulus intensity from d-prime analysis. Stimuli were chromatic gaussian blobs in dynamic luminance noise, and participants clicked on cells that contain chromatic blobs (detection) or blob pairs of differing colors (discrimination). Sensitivity and repeatability of FInD Color tasks were compared against HRR, FM100 hue tests in 19 color-normal and 18 color-atypical, age-matched observers. Rayleigh color match was completed as well. Detection and Discrimination thresholds were higher for atypical observers than for typical observers, with selective threshold elevations corresponding to unique CVD types. Classifications of CVD type and severity via unsupervised machine learning confirmed functional subtypes. FInD tasks reliably detect CVD and may serve as valuable tools in basic and clinical color vision science.
Analysis of follow-up data in large biobank cohorts: a review of methodology
Authors: Kolde Anastassia , Koitmäe Merli , Käärik Meelis , Möls Märt , Fischer Krista 
Published: June 2023

AbstractThis study focuses on key methodological challenges in genome-wide association studies (GWAS) of biobank data with time-to-event outcomes, analyzed using the Cox proportional hazards (CPH) model. We address four primary issues: left-truncation of the data, com-putational inefficiency of standard model-fitting algorithms, related-ness among individuals, and model misspecification. To manage left-truncation, the common practice is to use age as the timescale, with individuals entering the risk set at their age of recruitment. We assess how this choice of timescale influences bias and statistical power, under realistic GWAS conditions of varying effect sizes and censoring rates. In addition, to alleviate the computational burden typical in large-scale data, we propose and evaluate a two-step martingale residual (MR) approach for high-dimensional CPH modeling. Our results show that the timescale choice has minimal effect on accuracy for small hazard ratios, though using birth age as the timescale-ignoring recruitment age-yields the highest power for association detection. We find that relatedness, when ignored, does not substantially bias effect size estimates, while omitting key covariates introduces significant bias. The two-step MR approach proves to be computationally efficient, retaining power for detecting small effect sizes, making it suitable for large-scale association studies. However, when precise effect size estimates are critical, particularly for moderate or larger effect sizes, we recommend recalculating these estimates using the conventional CPH model, with careful attention to left-truncation and relatedness. These conclusions are drawn from simulations and illustrated with data from the Estonian Biobank cohort.
Identification of potential molecular mimicry in pathogen-host interactions
Authors: Rich Kaylee D. , Srivastava Shruti , Muthye Viraj , Wasmuth James D. 
Published: June 2023

ABSTRACTPathogens have evolved sophisticated strategies to manipulate host signaling pathways, including the phenomenon of molecular mimicry, where pathogen-derived biomolecules imitate host biomolecules. In this study, we used a sequence-based bioinformatics pipeline to identify potential molecular mimicry candidates between humans and 32 pathogenic species—bacteria, fungi, protozoa, and helminths—of global health importance. We observed considerable variation in the number of mimicry candidates across pathogenic species, with pathogenic bacteria exhibiting fewer candidates compared to fungi and protozoans. Further analysis revealed that the candidate mimicry regions were enriched in solvent-accessible regions, highlighting their potential functional relevance. We identified a total of 1878 mimicked regions in 1439 human proteins, and clustering analysis indicated diverse target proteins across pathogen species. The human proteins containing mimicked regions revealed significant associations between these proteins and various biological processes, with an emphasis on host extracellular matrix organization and cytoskeletal processes. However, immune-related proteins were underrepresented as targets of mimicry. Our findings provide insights into the broad range of host-pathogen interactions mediated by molecular mimicry and highlight potential targets for further investigation. This comprehensive analysis contributes to our understanding of the complex mechanisms employed by pathogens to subvert host defenses and promotes the development of novel therapeutic strategies.
Self-reversal facilitates the resolution of HMCES-DNA protein crosslinks in cells
Authors: Rua-Fernandez Jorge , Lovejoy Courtney A. , Mehta Kavi P.M. , Paulin Katherine A. , Toudji Yasmine T. , Eichman Brandt F. , Cortez David 
Published: June 2023

ABSTRACTAbasic sites are common DNA lesions that stall polymerases and threaten genome stability. When located in single-stranded DNA (ssDNA), they are shielded from aberrant processing by HMCES via a DNA-protein crosslink (DPC) that prevents double-strand breaks. Nevertheless, the HMCES-DPC must be removed to complete DNA repair. Here, we found that DNA polymerase α inhibition generates ssDNA abasic sites and HMCES-DPCs. These DPCs are resolved with a half-life of approximately 1.5 hours. Resolution does not require the proteasome or SPRTN protease. Instead, HMCES-DPC self-reversal is important for resolution. Biochemically, self-reversal is favored when the ssDNA is converted to duplex DNA. When the self-reversal mechanism is inactivated, HMCES-DPC removal is delayed, cell proliferation is slowed, and cells become hypersensitive to DNA damage agents that increase AP site formation. Thus, HMCES-DPC formation followed by self-reversal is an important mechanism for ssDNA AP site management.
Macromolecular Crowding Tailors the Microtubule Cytoskeleton Through Tubulin Modifications and Microtubule-Associated Proteins
Authors: Shen Yusheng , Ori-McKenney Kassandra M. 
Published: June 2023

AbstractCells remodel their cytoskeletal networks to adapt to their environment. Here, we analyze the mechanisms utilized by the cell to tailor its microtubule landscape in response to changes in osmolarity that alter macromolecular crowding. By integrating live cell imaging,ex vivoenzymatic assays, andin vitroreconstitution, we probe the impact of acute perturbations in cytoplasmic density on microtubule-associated proteins (MAPs) and tubulin posttranslational modifications (PTMs), unraveling the molecular underpinnings of cellular adaptation via the microtubule cytoskeleton. We find that cells respond to fluctuations in cytoplasmic density by modulating microtubule acetylation, detyrosination, or MAP7 association, without differentially affecting polyglutamylation, tyrosination, or MAP4 association. These MAP-PTM combinations alter intracellular cargo transport, enabling the cell to respond to osmotic challenges. We further dissect the molecular mechanisms governing tubulin PTM specification, and find that MAP7 promotes acetylation by biasing the conformation of the microtubule lattice, and directly inhibits detyrosination. Acetylation and detyrosination can therefore be decoupled and utilized for distinct cellular purposes. Our data reveal that the MAP code dictates the tubulin code, resulting in remodeling of the microtubule cytoskeleton and alteration of intracellular transport as an integrated mechanism of cellular adaptation.
Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles
Authors: Xie Jing , Xu Yafei , Liu Xuhua , Long Li , Chen Ji , Huang Chunyan , Shao Yan , Cai Zhiqing , Zhang Zhimin , Zhou Ruixin , Leng Jiarong , Bai Xiaochun , Song Qiancheng 
Published: June 2023

AbstractAlthough preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor microRNAs, such as miR-99b-3p. Furthermore, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.
The LINC complex ensures accurate centrosome positioning during prophase
Authors: Lima Joana T. , Pereira António J. , Ferreira Jorge G. 
Published: June 2023

AbstractAccurate centrosome separation and positioning during early mitosis relies on force- generating mechanisms regulated by a combination of extracellular, cytoplasmic, and nuclear cues. The identity of the nuclear cues involved in this process remains largely unknown. Here, we investigate how the prophase nucleus contributes to centrosome positioning during the initial stages of mitosis, by using a combination of cell micropatterning, high-resolution live-cell imaging and quantitative 3D cellular reconstruction. We show that in untransformed RPE-1 cells, centrosome positioning is regulated by a nuclear signal, independently of external cues. This nuclear mechanism relies on the linker of nucleoskeleton and cytoskeleton (LINC) complex that controls the timely loading of dynein on the nuclear envelope (NE), providing spatial cues for robust centrosome positioning on the shortest nuclear axis, prior to nuclear envelope permeabilization (NEP). Our results demonstrate how nuclear-cytoskeletal coupling maintains a robust centrosome positioning mechanism to ensure efficient mitotic spindle assembly.Summary blurbCentrosome positioning in prophase is essential for efficient spindle assembly. Here, we show that centrosome positioning requires LINC complex-mediated loading of dynein on the nuclear envelope.
Symbiotic nutrient exchange enhances the long-term survival of cassiosomes, the autonomous stinging-cell structures ofCassiopea
Authors: Toullec Gaëlle , Lyndby Niclas Heidelberg , Banc-Prandi Guilhem , Pogoreutz Claudia , Olmos Cristina Martin , Meibom Anders , Rädecker Nils 
Published: June 2023

AbstractMedusae of the widely distributed and locally invasive upside-down jellyfishCassiopearelease autonomous, mobile stinging structures. These so-called cassiosomes are a major contributor to ‘contactless’ stinging incidents in (sub-)tropical shallow waters. While the presence of endosymbiotic dinoflagellates in cassiosomes has previously been observed, their potential contribution to the metabolism and long-term survival of cassiosomes is unknown. Combining stable isotope labeling and correlative SEM and NanoSIMS imaging with a long-termin vitroexperiment, this study reveals a mutualistic symbiosis based on nutritional exchanges in dinoflagellate-bearing cassiosomes. We were able to show that organic carbon input from the dinoflagellates fuels the metabolism of the host tissue and enables anabolic nitrogen assimilation. Thanks to this symbiotic nutrient exchange, cassiosomes showed enhanced survival in the light compared to dark conditions for at least one monthin vitro. Overall, this study demonstrates that cassiosomes, in analogy withCassiopeamedusae, are photosymbiotic holobionts. Cassiosomes thus promise to be a powerful new miniaturized model system for in-depth ultrastructural and molecular investigation of cnidarian photosymbioses.
Quantifying innervation facilitated by deep learning in wound healing
Authors: Mehta Abijeet Singh , Teymoori Sam , Recendez Cynthia , Fregoso Daniel , Gallegos Anthony , Yang Hsin-Ya , Isseroff Roslyn Rivkah , Zhao Min , Gomez Marcella 
Published: June 2023

ABSTRACTThe peripheral nerves (PNs) innervate the dermis and epidermis, which have been suggested to play an important role in wound healing. Several methods to quantify skin innervation during wound healing have been reported. Those usually require multiple observers, are complex and labor-intensive, and noise/background associated with the Immunohistochemistry (IHC) images could cause quantification errors/user bias. In this study, we employed the state-of-the-art deep neural network, DnCNN, to perform pre-processing and effectively reduce the noise in the IHC images. Additionally, we utilized an automated image analysis tool, assisted by Matlab, to accurately determine the extent of skin innervation during various stages of wound healing. The 8mm wound is generated using a circular biopsy punch in the wild-type mouse. Skin samples were collected on days 3,7,10 and 15, and sections from paraffin-embedded tissues were stained against pan-neuronal marker- protein-gene-product 9.5 (PGP 9.5) antibody. On day 3 and day 7, negligible nerve fibers were present throughout the wound with few only on the lateral boundaries of the wound. On day 10, a slight increase in nerve fiber density appeared, which significantly increased on day 15. Importantly we found a positive correlation (R-2= 0.933) between nerve fiber density and re-epithelization, suggesting an association between re-innervation and re-epithelization. These results established a quantitative time course of re-innervation in wound healing, and the automated image analysis method offers a novel and useful tool to facilitate the quantification of innervation in the skin and other tissues.
Positive association between alleles at selectively neutral loci
Authors: Potapova Nadezhda A. , Kondrashov Alexey S. 
Published: June 2023

ABSTRACTLinkage disequilibrium (LD) is a non-independent distribution of alleles at different loci and might be defined using directional and directionless approaches. While analytical theory is available for directionless LD, analytical theory for directional LD is less developed. In this study we investigated directional LD generated by random drift between two selectively neutral loci. When the sign of LD is determined by the ancestral-derived status of these alleles, its expected value is zero. In contrast, computer simulations show that random drift leads to a tendency of rare, as well as of common, alleles to occur together. This observation is supported by a straightforward analytical argument. If only those generations where both loci are polymorphic are taken into account, the magnitude of the resulting directional LD depends only on Ne. These observations might give an opportunity to directly estimate Nefrom the data on genetic variation within a single generation.