bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating genome-wide association and transcriptome analysis to provide molecular insights into heterophylly and eco-adaptability in woody plants
Authors: Hu Yanmin , Tang Feng , Zhang Dan , Shen Shihua , Peng Xianjun 
Published: November 2023

Abstract
Heterophylly is regard as an important adaptive mechanism in response to different environments within plants. However, the genetic mechanisms responsible for heterophylly in woody plants are still poorly understood. Herein, the divergence of heterophyllous leaves was investigated at morphogenesis and using microdissection and physiological indexes in paper mulberry, and the genetic basis of heterophylly was further revealed combined with genome-wide association study (GWAS), transcriptome analysis and weighted gene coexpression network analysis (WGCNA). Our results revealed that the flavonoid content and antioxidant activity increased gradually from the entire leaf to the palmatisect leaf, while the hormone content and net photosynthetic rate decreased. Through GWAS and transcriptome analysis, a total of 98 candidate genes and 2338 differentially expressed genes associated with heterophylly were identified. Importantly, we uncovered critical variations in the candidate genes Bp07g0981 (WOX) and Bp07g0920 (HHO), along with significant differences in haplotypes and expression levels among heterophyllous leaves. Our results also suggested that the genes involved in hormone signaling pathways, antioxidant activity, and flavonoid metabolism might be closely related to the heterophylly of paper mulberry, which could account for the physiological data. Indeed, CR-wox mutant lines showed significant changes in leaf phenotypes, and differential expression profile analysis also highlighted the expression of genes related to phytohormones and transcription factors. Together, the genetic variations and candidate genes detected in this study provide novel insights into the genetic mechanism of heterophylly, and would improve the understanding of eco-adaptability in heterophyllous woody plants.
Translating ethical and quality principles for the effective, safe and fair development, deployment and use of artificial intelligence technologies in healthcare
Authors: Economou-Zavlanos Nicoleta J , Bessias Sophia , Cary Michael P , Bedoya Armando D , Goldstein Benjamin A , Jelovsek John E , O’Brien Cara L , Walden Nancy , Elmore Matthew , Parrish Amanda B , Elengold Scott , Lytle Kay S , Balu Suresh , Lipkin Michael E , Shariff Afreen Idris , Gao Michael , Leverenz David , Henao Ricardo , Ming David Y , Gallagher David M , Pencina Michael J , Poon Eric G 
Published: November 2023

Abstract

Objective
The complexity and rapid pace of development of algorithmic technologies pose challenges for their regulation and oversight in healthcare settings. We sought to improve our institution’s approach to evaluation and governance of algorithmic technologies used in clinical care and operations by creating an Implementation Guide that standardizes evaluation criteria so that local oversight is performed in an objective fashion.

Materials and Methods
Building on a framework that applies key ethical and quality principles (clinical value and safety, fairness and equity, usability and adoption, transparency and accountability, and regulatory compliance), we created concrete guidelines for evaluating algorithmic technologies at our institution.

Results
An Implementation Guide articulates evaluation criteria used during review of algorithmic technologies and details what evidence supports the implementation of ethical and quality principles for trustworthy health AI. Application of the processes described in the Implementation Guide can lead to algorithms that are safer as well as more effective, fair, and equitable upon implementation, as illustrated through 4 examples of technologies at different phases of the algorithmic lifecycle that underwent evaluation at our academic medical center.

Discussion
By providing clear descriptions/definitions of evaluation criteria and embedding them within standardized processes, we streamlined oversight processes and educated communities using and developing algorithmic technologies within our institution.

Conclusions
We developed a scalable, adaptable framework for translating principles into evaluation criteria and specific requirements that support trustworthy implementation of algorithmic technologies in patient care and healthcare operations.
Substrate selectivity and catalytic activation of the type III CRISPR ancillary nuclease Can2
Authors: Jungfer Kenny , Sigg Annina , Jinek Martin 
Published: November 2023

Abstract
Type III CRISPR-Cas systems provide adaptive immunity against foreign mobile genetic elements through RNA-guided interference. Sequence-specific recognition of RNA targets by the type III effector complex triggers the generation of cyclic oligoadenylate (cOA) second messengers that activate ancillary effector proteins, thus reinforcing the host immune response. The ancillary nuclease Can2 is activated by cyclic tetra-AMP (cA4); however, the mechanisms underlying cA4-mediated activation and substrate selectivity remain elusive. Here we report crystal structures of Thermoanaerobacter brockii Can2 (TbrCan2) in substrate- and product-bound complexes. We show that TbrCan2 is a single strand-selective DNase and RNase that binds substrates via a conserved SxTTS active site motif, and reveal molecular interactions underpinning its sequence preference for CA dinucleotides. Furthermore, we identify a molecular interaction relay linking the cA4 binding site and the nuclease catalytic site to enable divalent metal cation coordination and catalytic activation. These findings provide key insights into the molecular mechanisms of Can2 nucleases in type III CRISPR-Cas immunity and may guide their technological development for nucleic acid detection applications.
The miRNA–target interactions: An underestimated intricacy
Authors: Diener Caroline , Keller Andreas , Meese Eckart 
Published: November 2023

AbstractMicroRNAs (miRNAs) play indispensable roles in posttranscriptional gene regulation. Their cellular regulatory impact is determined not solely by their sheer number, which likely amounts to &gt;2000 individual miRNAs in human, than by the regulatory effectiveness of single miRNAs. Although, one begins to develop an understanding of the complex mechanisms underlying miRNA–target interactions (MTIs), the overall knowledge of MTI functionality is still rather patchy. In this critical review, we summarize key features of mammalian MTIs. We especially highlight latest insights on (i) the dynamic make-up of miRNA binding sites including non-canonical binding sites, (ii) the cooperativity between miRNA binding sites, (iii) the adaptivity of MTIs through sequence modifications, (iv) the bearing of intra-cellular miRNA localization changes and (v) the role of cell type and cell status specific miRNA interaction partners. The MTI biology is discussed against the background of state-of-the-art approaches with particular emphasis on experimental strategies for evaluating miRNA functionality.
scPipe: an extended preprocessing pipeline for comprehensive single-cell ATAC-Seq data integration in R/Bioconductor
Authors: Amarasinghe Shanika L , Yang Phil , Voogd Oliver , Yang Haoyu , Du Mei R M , Su Shian , Brown Daniel V , Jabbari Jafar S , Bowden Rory , Ritchie Matthew E 
Published: November 2023

Abstract
scPipe is a flexible R/Bioconductor package originally developed to analyse platform-independent single-cell RNA-Seq data. To expand its preprocessing capability to accommodate new single-cell technologies, we further developed scPipe to handle single-cell ATAC-Seq and multi-modal (RNA-Seq and ATAC-Seq) data. After executing multiple data cleaning steps to remove duplicated reads, low abundance features and cells of poor quality, a SingleCellExperiment object is created that contains a sparse count matrix with features of interest in the rows and cells in the columns. Quality control information (e.g. counts per cell, features per cell, total number of fragments, fraction of fragments per peak) and any relevant feature annotations are stored as metadata. We demonstrate that scPipe can efficiently identify ‘true’ cells and provides flexibility for the user to fine-tune the quality control thresholds using various feature and cell-based metrics collected during data preprocessing. Researchers can then take advantage of various downstream single-cell tools available in Bioconductor for further analysis of scATAC-Seq data such as dimensionality reduction, clustering, motif enrichment, differential accessibility and cis-regulatory network analysis. The scPipe package enables a complete beginning-to-end pipeline for single-cell ATAC-Seq and RNA-Seq data analysis in R.
Rheumatoid arthritis, quantitative parenchymal lung features and mortality among smokers
Authors: McDermott Gregory C , Hayashi Keigo , Yoshida Kazuki , Juge Pierre-Antoine , Moll Matthew , Cho Michael H , Doyle Tracy J , Kinney Gregory L , Dellaripa Paul F , Wallace Zachary S , Regan Elizabeth A , Hunninghake Gary M , Silverman Edwin K , Ash Samuel Y , Estepar Raul San Jose , Washko George R , Sparks Jeffrey A 
Published: November 2023

Abstract

Objectives
There have been limited investigations of the prevalence and mortality impact of quantitative CT (QCT) parenchymal lung features in RA. We examined the cross-sectional prevalence and mortality associations of QCT features, comparing RA and non-RA participants.

Methods
We identified participants with and without RA in COPDGene, a multicentre cohort study of current or former smokers. Using a k-nearest neighbour quantifier, high resolution CT chest scans were scored for percentage of normal lung, interstitial changes and emphysema. We examined associations between QCT features and RA using multivariable linear regression. After dichotomizing participants at the 75th percentile for each QCT feature among non-RA participants, we investigated mortality associations by RA/non-RA status and quartile 4 vs quartiles 1–3 of QCT features using Cox regression. We assessed for statistical interactions between RA and QCT features.

Results
We identified 82 RA cases and 8820 non-RA comparators. In multivariable linear regression, RA was associated with higher percentage of interstitial changes (β = 1.7 [0.5], P = 0.0008) but not emphysema (β = 1.3 [1.7], P = 0.44). Participants with RA and &gt;75th percentile of emphysema had significantly higher mortality than non-RA participants (hazard ratio [HR] 5.86; 95% CI: 3.75, 9.13) as well as RA participants (HR 5.56; 95% CI: 2.71, 11.38) with ≤75th percentile of emphysema. There were statistical interactions between RA and emphysema for mortality (multiplicative P = 0.014; attributable proportion 0.53; 95% CI: 0.30, 0.70).

Conclusion
Using machine learning-derived QCT data in a cohort of smokers, RA was associated with higher percentage of interstitial changes. The combination of RA and emphysema conferred &gt;5-fold higher mortality.
Perivascular CLICK‐gelatin delivery of thrombospondin‐2 small interfering RNA decreases development of intimal hyperplasia after arterial injury
Authors: Mota Lucas , Zhu Max , Li Jennifer , Contreras Mauricio , Aridi Tarek , Tomeo John N. , Stafford Alexander , Mooney David J. , Pradhan‐Nabzdyk Leena , Ferran Christiane , LoGerfo Frank W. , Liang Patric 
Published: November 2023

AbstractBypass graft failure occurs in 20%–50% of coronary and lower extremity bypasses within the first‐year due to intimal hyperplasia (IH). TSP‐2 is a key regulatory protein that has been implicated in the development of IH following vessel injury. In this study, we developed a biodegradable CLICK‐chemistry gelatin‐based hydrogel to achieve sustained perivascular delivery of TSP‐2 siRNA to rat carotid arteries following endothelial denudation injury. At 21 days, perivascular application of TSP‐2 siRNA embedded hydrogels significantly downregulated TSP‐2 gene expression, cellular proliferation, as well as other associated mediators of IH including MMP‐9 and VEGF‐R2, ultimately resulting in a significant decrease in IH. Our data illustrates the ability of perivascular CLICK‐gelatin delivery of TSP‐2 siRNA to mitigate IH following arterial injury.
Brain iron acquisition depends on age and sex in iron‐deficient mice
Authors: Palsa Kondaiah , Neely Elizabeth B. , Baringer Stephanie L. , Helmuth Timothy B. , Simpson Ian A. , Connor James R. 
Published: November 2023

AbstractAdequate and timely delivery of iron is essential for brain development. The uptake of transferrin‐bound (Tf) iron into the brain peaks at the time of myelination, whereas the recently discovered H‐ferritin (FTH1) transport of iron into the brain continues to increase beyond the peak in myelination. Here, we interrogate the impact of dietary iron deficiency (ID) on the uptake of FTH1‐ and Tf‐bound iron. In the present study, we used C57BL/6J male and female mice at a developing (post‐natal day (PND) 15) and adult age (PND 85). In developing mice, ID results in increased iron delivery from both FTH1 and Tf for both males and females. The amount of iron uptake from FTH1 was higher than the Tf and this difference between the iron delivery was much greater in females. In contrast, in the adult model, ID was associated with increased brain iron uptake by both FTH1 and Tf but only in the males. There was no increased uptake from either protein in the females. Moreover, transferrin receptor expression on the microvasculature as well as whole brain iron, and H and L ferritin levels revealed the male brains became iron deficient but not the female brains. Last, under normal dietary conditions, 55Fe uptake was higher in the developing group from both delivery proteins than in the adult group. These results indicate that there are differences in iron acquisition between the developing and adult brain for FTH1 and Tf during nutritional ID and demonstrate a level of regulation of brain iron uptake that is age and sex‐dependent.
Does the OTA Open Fracture Classification Align With the Gustilo-Anderson Classification? A Study of 2215 Open Fractures
Authors: Kovvur Murali , Turner Kristin E. , Lawrence Joshua E. , O’Toole Robert V. , O’Hara Nathan N. , Slobogean Gerard P. 
Published: November 2023

OBJECTIVES:
To characterize the Orthopaedic Trauma Association Open Fracture Classification (OTA-OFC) and Gustilo-Anderson classification of open extremity fractures and determine if there is meaningful alignment between these grading systems.

METHODS:

Design
: Retrospective case series.

Setting
: Level I academic trauma center.

Patient Selection Criteria
: Adult patients with at least one operatively treated open extremity fracture and surgeon-assigned OTA-OFC and Gustilo-Anderson classification.

Outcome Measures and Comparisons
: Frequency, distribution, and association measures of OTA-OFC category scores and Gustilo-Anderson classification types.

RESULTS:
2027 patients (mean age, 43.1 ± 17.5 years) with 2215 fractures were included. Gustilo-Anderson Type I or II fractures (n = 961; 43%) most frequently had the least severe scores for all OTA-OFC categories. Type IIIA fractures (n = 978; 44%) were most often assigned intermediate scores for OTA-OFC Bone Loss (n = 564; 58%). Type IIIB fractures (n = 204, 9%) were most often assigned intermediate OTA-OFC Skin scores (n = 120; 59%). Type IIIC fractures (n = 72; 3%) were most often assigned the most severe OTA-OFC Arterial score (n = 60; 83%). In the multivariable model, OTA-OFC Contamination scores showed little association (β = 0.05; 95% confidence interval [CI], 0.01–0.09) with Gustilo-Anderson classification severity. Conversely, higher OTA-OFC Arterial (β = 0.50; 95% CI, 0.44–0.56) and Skin (β = 0.46; 95% CI, 0.40–0.51) scores were strongly associated with more severe Gustilo-Anderson classifications.

CONCLUSIONS:
OTA-OFC Contamination scores were weakly associated with Gustilo-Anderson classification severity for open fractures. The study findings suggest the current Gustilo-Anderson classification does not adequately account for injury contamination, a known predictor of infection.
Open versus Closed Geriatric Ankle Fractures
Authors: Bowers Mathew , Ta Canhnghi , Vasudevan Rajiv Siddhartha , Trimm Conner Dean , Kent William T 
Published: November 2023

OBJECTIVES
To determine if open (O) or closed (C) geriatric ankle fractures had different patient characteristics or outcomes.

METHODS
Design: Retrospective cohort study
Setting: Urban level 1 trauma center
Patient Selection Criteria: Patients, age 60 years and older, who underwent operative fixation of a rotational ankle fracture (OTA/AO 44A-C) between January 2012 and September 2021.
Outcome Measures and Comparisons: Morbidity, defined as 90-day reoperation, 90-day readmission, or loss of mobility, as well as 1-year mortality compared between patients with closed and open fractures.

RESULTS
The open cohort was older (75 years vs 68 years; p=.003) but had similar Charlson Comorbidity Indices (CCI) (4.6 O vs 4.0 C; p=.323) and pre-injury rates of independent ambulation (70.4% O vs 80.9% C; p=.363). There were higher rates of 1-year mortality (11% vs 0%; p<0.001), deep infection (14.8% vs 3.9%; p=.019), and loss of mobility (64.7% vs 23.0%; p<0.001) in the open cohort. Multivariate regression identified open fracture as an independent predictor of 90-day reoperation (OR: 20.6; p=.022) and loss of mobility (OR: 5.1; p=.011).

CONCLUSION
Despite having comorbidities and pre-injury function similar to the closed geriatric ankle fracture cohort, open ankle fracture was independently predictive of greater loss of mobility. Nearly two-thirds of geriatric patients with open ankle fractures experienced a decline in functional independence, compared with 1 in 4 of those with closed fractures. Open fracture was associated with higher rates of deep infection, reoperation, and 1-year mortality.

LEVEL OF EVIDENCE:
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Improved Patient-reported Outcomes in Patients Aged 16 and Younger at Two Years After Anterior Cruciate Ligament Reconstruction Despite Relatively High Rates of Reinjury and Repeat Surgery
Authors: Doxey Stephen A. , Kleinsmith Rebekah M. , Huyke-Hernández Fernando A. , Schweitzer Adam , Only Arthur J. , Tompkins Marc , Kweon Christopher Y. , Cunningham Brian P. 
Published: November 2023

Background:
Anterior cruciate ligament reconstruction (ACLR) in adolescent patients, particularly those aged 16 and under, are increasingly common procedure that lacks robust clinical and patient-reported outcome (PRO) data. The purpose of this study was to report 2-year PROs of patients receiving ACLR aged 16 or younger using the single assessment numerical evaluation (SANE) and knee injury and osteoarthritis outcome score (KOOS). Secondary aims included characterizing treatment characteristics, return to sport (RTS), and clinical outcomes.

Methods:
The institutional PRO database was queried for patients receiving ACLR from 2009 to 2020. Patients aged older than 16, revision procedures, concomitant ligament repairs/reconstructions, and patients without full outcome data at 2 years were excluded. Outcomes over 2 years after ACLR included SANE, KOOS, reinjuries, reoperations, and time to RTS.

Results:
A total of 98 patients were included with an average age of 15.0 years. Most patients were females (77.6%). Bone-tendon-bone autograft (69.4%) was the most used. Average RTS was 8.7 months (range: 4.8 to 24.0 mo), with 90% of patients eventually returning to sport. A total of 23 patients (23.5%) experienced a reinjury and 24.5% (n = 24) underwent reoperation. Timing to RTS was not associated with reinjury, but patients who returned between 9.5 and 13.7 months did not sustain reinjuries. Mean KOOS and SANE scores at 2 years were 87.1 and 89.1, respectively, with an average improvement of +18.4 and +22.9, respectively. Change in KOOS was negatively impacted by reinjury to the anterior cruciate ligament graft and reoperation (anterior cruciate ligament failure: +10.0 vs 19.3, P = 0.081, respectively; reoperation: +13.2 vs +20.1, P = 0.051, respectively), though these did not reach statistical significance.

Conclusion:
Patients experienced improved SANE and KOOS scores after ACLR. Rates of reinjury and reoperation were relatively high and negatively impacted PRO scores but were not associated with the timing of RTS. Adolescent patients should be counseled regarding the risk of subsequent ipsilateral and contralateral knee injury after ACLR.

Level of Evidence:
Level IV—case series.
Postoperative Sclerotic Modic Changes after Transforaminal Lumbar Interbody Fusion
Authors: Xiao Yang , Zhu Ce , Xiu Peng , Wang Liang , Zhang Zhuang , Deng Zhipeng , Song Yueming , Yang Xi 
Published: November 2023

Study Design.
A retrospective cohort study.

Objective.
This study aimed to assess postoperative sclerotic Modic changes (MCs) following transforaminal lumbar interbody fusion (TLIF) for lumbar degenerative disc disease (LDD), investigating their prevalence, risk factors and association with clinical outcomes.

Summary of Background Data.
Sclerotic MCs may occur in patients with LDD after lumbar interbody fusion. The incidence and characteristics of postoperative sclerotic MCs, as well as their clinical impact, are unknown.

Methods.
The study included 467 patients (510 levels) who underwent single or two-level TLIF surgery, divided into a postoperative sclerotic MC group (60 patients, 66 levels) and non-MC group (407 patients, 444 levels). The time of development and location of postoperative sclerotic MCs, fusion rate, cage subsidence, bilateral process decompression, and cross-link usage were recorded. Preoperative, postoperative, and follow-up VAS and ODI scores were collected. Multivaraible logistic regression was used to evaluate factors associated with the development of postoperative sclerotic MCs.

Results.
The prevalence of postoperative sclerotic MCs was 12.8%. The postoperative sclerotic MC group had higher BMI. The postoperative sclerotic MC group demonstrated a fusion rate of 47%, significantly lower than that of the non-MC group (71%) at 6 months post-operation. At final follow-up, the fusion rate in the postoperative sclerotic MC group was 62%, significantly lower than that of the non-MC group (86%). Post-operative VAS and ODI scores were significantly higher in the group with postoperative sclerotic MCs. BMI and osteoporosis were significantly associated with the development of postoperative sclerotic MCs.

Conclusion.
Postoperative sclerotic MCs generally appear within the first year after surgery, with a prevalence of 12.8%. The presence of postoperative sclerotic MCs can adversely impact post-operative outcomes. To prevent postoperative sclerotic MCs, we postulate extending the immobilization period with external bracing and improving the management of BMI and osteoporosis in the peri-operative time window.