bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outpatient and Ambulatory Extended Recovery Robotic Hepatectomy: Multinational Study of 307 Cases
Authors: Park James O , Lafaro Kelly , Hagendoorn Jeroen , Melstrom Laleh , Gerhards Michael F , Görgec Burak , Marsman Hendrik A , Thornblade Lucas W , Pilz da Cunha Gabriela , Yang Frank F , Labadie Kevin P , Sham Jonathan G , Swijnenburg Rutger-Jan , He Jin , Fong Yuman 
Published: May 2024

BACKGROUND:
For open minor hepatectomy, morbidity and recovery are dominated by the incision. The robotic approach may transform this “incision dominant procedure” into a safe outpatient procedure.

STUDY DESIGN:
We audited outpatient (less than 2 midnights) robotic hepatectomy at 6 hepatobiliary centers in 2 nations to test the hypothesis that the robotic approach can be a safe and effective short-stay procedure. Establishing early recovery after surgery programs were active at all sites, and home digital monitoring was available at 1 of the institutions.

RESULTS:
A total of 307 outpatient (26 same-day and 281 next-day discharge) robotic hepatectomies were identified (2013 to 2023). Most were minor hepatectomies (194 single segments, 90 bi-segmentectomies, 14 three segments, and 8 four segments). Thirty-nine (13%) were for benign histology, whereas 268 were for cancer (33 hepatocellular carcinoma, 27 biliary, and 208 metastatic disease). Patient characteristics were a median age of 60 years (18 to 93 years), 55% male, and a median BMI of 26 kg/m2 (14 to 63 kg/m2). Thirty (10%) patients had cirrhosis. One hundred eighty-seven (61%) had previous abdominal operation. Median operative time was 163 minutes (30 to 433 minutes), with a median blood loss of 50 mL (10 to 900 mL). There were no deaths and 6 complications (2%): 2 wound infections, 1 failure to thrive, and 3 perihepatic abscesses. Readmission was required in 5 (1.6%) patients. Of the 268 malignancy cases, 25 (9%) were R1 resections. Of the 128 with superior segment resections (segments 7, 8, 4A, 2, and 1), there were 12 positive margins (9%) and 2 readmissions for abscess.

CONCLUSIONS:
Outpatient robotic hepatectomy in well-selected cases is safe (0 mortality, 2% complication, and 1.6% readmission), including resection in the superior or posterior portions of the liver that is challenging with nonarticulating laparoscopic instruments.
Systemic Inflammatory Effect of Hypobaria During Aeromedical Evacuation after Porcine Traumatic Brain Injury
Authors: Price Adam D , Baucom Matthew R , Becker Ellen R , Archdeacon Chad M , Smith Maia P , Caskey Chelsea , Schuster Rebecca , Blakeman Thomas C , Strilka Richard J , Pritts Timothy A , Goodman Michael D 
Published: May 2024

BACKGROUND:
Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is used by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation after TBI that could contribute to more severe TBI-related secondary injury.

STUDY DESIGN:
Thirty-six female pigs were used to test TBI vs Sham TBI, hypoxia vs normoxia, and hypobaria vs ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 ft were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO2 while at altitude. Serum cytokines, ubiquitin C-terminal hydrolase L1, and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein and phosphorylated tau.

RESULTS:
Serum interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly elevated after TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared with ground level/normoxia. No difference in TBI biomarkers after TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue glial fibrillary acidic protein or phosphorylated tau when comparing the most different conditions of Sham TBI + ground or normoxia with the TBI + hypobaria/hypoxia group was noted.

CONCLUSIONS:
The hypobaric environment of AE induces systemic inflammation after TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE after TBI.
Quantifying Differential Rhythmicity based on Effect Sizes with LimoRhyde2
Authors: Obodo Dora , Asiaee Amir 
Published: May 2024

ABSTRACTCurrent methods for assessing differential rhythmicity in genomic data focus on hypothesis testing and model selection, often assuming sinusoidal rhythms. A more appropriate approach is to estimate differences in rhythmic properties between two or more conditions using effect sizes. To address this gap, we extend LimoRhyde2, a method for quantifying rhythm-related effect sizes and their uncertainty in genome-scale data, to enable differential rhythmicity analyses. Through extensive testing, we validate the method for differential rhythmicity analysis and showcase how it improves biological interpretation for circadian systems biology.
ISGylation of the SARS-CoV-2 N protein by HERC5 impedes N oligomerization and thereby viral RNA synthesis
Authors: Zhu Junji , Liu Guan Qun , Goins Christopher M. , Stauffer Shaun R. , Gack Michaela U. 
Published: May 2024

AbstractInterferon (IFN)-stimulated gene 15 (ISG15), a ubiquitin-like protein, is covalently conjugated to host (immune) proteins such as MDA5 and IRF3 in a process called ISGylation, thereby limiting the replication of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, whether SARS-CoV-2 proteins can be directly targeted for ISGylation remains elusive. In this study, we identified the nucleocapsid (N) protein of SARS-CoV-2 as a major substrate of ISGylation catalyzed by the host E3 ligase HERC5; however, N ISGylation is readily removed through de-ISGylation by the papain-like protease (PLpro) activity of NSP3. Mass spectrometry analysis identified that the N protein undergoes ISGylation at four lysine residues (K266, K355, K387 and K388), and mutational analysis of these sites in the context of a SARS-CoV-2 replicon (N-4KR) abolished N ISGylation and alleviated ISGylation-mediated inhibition of viral RNA synthesis. Furthermore, our results indicated that HERC5 targets preferentially phosphorylated N protein for ISGylation to regulate its oligomeric assembly. These findings reveal a novel mechanism by which the host ISGylation machinery directly targets SARS-CoV-2 proteins to restrict viral replication and illuminate how an intricate interplay of host (HERC5) and viral (PLpro) enzymes coordinates viral protein ISGylation and thereby regulates virus replication.
The roles of an extended N-terminal region and ETD motif in a pump-like cation channelrhodopsin discovered in a lake microbiome
Authors: Takaramoto Shunki , Fainsod Shai , Nagata Takashi , Rozenberg Andrey , Béjà Oded , Inoue Keiichi 
Published: May 2024

AbstractChannelrhodopsins are light-gated ion channels consisting of seven-transmembrane helices and a retinal chromophore, which are used as popular optogenetic tools for modulating neuronal activity. Cation channelrhodopsins (CCRs), first recognized as the photoreceptors in the chlorophyteChlamydomonas reinhardtii, have since been identified in diverse species of green algae, as well in other unicellular eukaryotes. The CCRs from non-chlorophyte species are commonly referred to as bacteriorhodopsin-like channelrhodopsins, or BCCRs, as most of them feature the three characteristic amino acid residues of the “DTD motif” in the third transmembrane helix (TM3 or helix C) matching the canonical DTD motif of the well-studied archaeal light-driven proton pump bacteriorhodopsin. Here, we report characterization of HulaCCR1, a novel BCCR identified through metatranscriptomic analysis of a unicellular eukaryotic community in Lake Hula, Israel. Interestingly, HulaCCR1 has an ETD motif in which the first residue of the canonical motif is substituted for glutamate. Electrophysiological measurements of the wild-type and a mutant with a DTD motif of HulaCCR1 suggest the critical role of the first glutamate in spectral tuning and channel gating. Additionally, HulaCCR1 exhibits long extensions at the N– and C-termini. Photocurrents recorded from a truncated variant without the signal peptide predicted at the N-terminus were diminished, and membrane localization of the truncated variant significantly decreased, indicating that the signal peptide is important for membrane trafficking of HulaCCR1. These characteristics of HulaCCR1 would be related to a new biological significance in the original unidentified species, distinct from those known for other BCCRs.
A Novel GeneARHGAP44for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)
Authors: Wang Siyu , Lenzini Petra , Thygarajan Bharat , Lee Joseph H. , Vardarajan Badri N. , Yashin Anatoli , Miljkovic Iva , Daw E. Warwick , Lin Shiow J. , Patti Gary , Brent Michael , Zmuda Joseph M. , Perls Thomas T. , Christensen Kaare , Province Michael A. , An Ping 
Published: May 2024

AbstractGlycated hemoglobin (HbA1c) indicates average glucose levels over three months and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal changes in HbA1c (ΔHbA1c) are also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 non-diabetic Europeans from the Long Life Family Study to uncover gene variants influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on17p12. In-depth analysis of this locus revealed a variant rs56340929 (explaining 27% of the linkage peak) in theARHGAP44gene that was significantly associated with ΔHbA1c. RNA transcription ofARHGAP44was associated with ΔHbA1c. The Framingham Offspring Study data further supported these findings on the gene level. Together, we found a novel geneARHGAP44for ΔHbA1c in family members without T2D. Follow-up studies using longitudinal omics data in large independent cohorts are warranted.
IL-23 drives uveitis by acting on a novel population of tissue-resident entheseal T cells
Authors: Hedley Robert , Ward Amy , Chu Colin J , Coupland Sarah E , Kiriakidis Serafim , Taylor Peter C , Dakin Stephanie G ,   The ORBIT consortium, Buckley Christopher D , Sherlock Jonathan , Dick Andrew D , Copland David A 
Published: May 2024

AbstractRecurrent acute anterior uveitis is a frequent extra-articular manifestation of the axial spondyloarthropathies (AxSpA); chronic inflammatory diseases affecting the spine, enthesis, peripheral joints, skin, and gastrointestinal tract. Pathology in AxSpA has been associated with local tissue-resident populations of interleukin (IL)-23 responsive lymphoid cells. Here we reveal a novel population of ocular T cells defined by CD3+CD4-CD8-γδTCR+IL-23R+ that reside within the anterior uvea as an ocular entheseal analogue of the mouse eye. Localised cytokine expression demonstrates that uveal IL-23R+ IL-17A-producing cells are both necessary and sufficient to drive uveitis in response to IL-23. This T cell population is also present in humans, occupying extravascular tissues of the anterior uveal compartment. Consistent with the concept of IL-23 as a unifying mediator in AxSpA, we present evidence that IL-23 can also act locally on tissue resident T cells in the anterior compartment of the eye at sites analogous to the enthesis to drive ocular inflammation.
A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints
Authors: Joshi Nitin , Yan Jing , Dang Mickael , Slaughter Kai , Wang Yufeng , Wu Dana , Ung Trevor , Pandya Virja , Chen Mu Xian , Kaur Shahdeep , Bhagchandani Sachin , Alfassam Haya A , Joseph John , Gao Jingjing , Dewani Mahima , Yip Ryan Chak Sang , Weldon Eli , Shah Purna , Shukla Chetan , Sherman Nicholas E , Luo James N , Conway Thomas , Eickhoff James P. , Botelho Luis , Alhasan Ali H , Karp Jeffrey M , Ermann Joerg 
Published: May 2024

AbstractIntra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel’s potential for PTOA treatment in active patients.
Supporting Self-management Through eHealth - Exploring the Needs, Challenges and Solutions in General Practice: A Qualitative and Participatory Design Study
Authors: Djurtoft Chris , Sørensen Kristine , Odgaard Christian , Hoegh Morten , Rathleff Michael S. , Johansen Simon K. 
Published: May 2024

AbstractIntroductionDigital transformation and integration of eHealth solutions into chronic pain management faces significant challenges that have not yet been met. To realize the potential of eHealth solutions there is a need to understand the challenges, needs and care processes of eHealth into specific contexts and specific purposes. The objective of this study was to explore challenges, barriers, support needs, and visions experienced by patients and general practitioners (GPs) in the context of an eHealth solution designed for chronic pain management in general practice.MethodsThe study used action-research as a methodological framework. We conducted two future workshops involving eight patients living with chronic pain and seven GPs with clinical experience in managing chronic pain. Through case vignettes and inspiration cards, these workshops stimulated discussions and shared knowledge construction. Data were analysed using reflexive thematic analysis, separated by the groups, and were synthesized via a matrix analysis.ResultsThe analysis revealed five content summary themes: Theme 1—patients’ experience of challenges in life with pain; Theme 2—challenges in treating patients with chronic pain; Theme 3—patients’ suggestions for the structure of the eHealth solution; Theme 4—GP’ suggestions for the structure of the eHealth solution; and Theme 5—differences and similarities: Visions for an eHealth solution. The analysis generated several touchpoints and tension within the patient-physician encounter.ConclusionIn conclusion, these themes provide distinct narratives, offering valuable insights into the design objectives. Our study represents a significant advancement in developing personalized and innovative eHealth solutions for general practice, addressing key clinical challenges.PerspectiveRealizing the potential of eHealth solutions, these findings highlight both contrasting and shared viewpoints on design objectives, providing crucial insight into end-user perspectives for effective pain management. Additionally, the study underscores the importance of supported self-management and clinical communication in understanding each patient’s overall presentation within the healthcare system.
Maternal Western-style diet programs skeletal muscle gene expression in lean adolescent Japanese macaque offspring
Authors: Beck Emily A. , Hetrick Byron , Nassar Luis , Turnbull Douglas W. , Dean Tyler A. , Gannon Maureen , Aagaard Kjersti M. , Wesolowski Stephanie R. , Friedman Jacob E. , Kievit Paul , McCurdy Carrie E. 
Published: May 2024

ABSTRACTEarly-life exposure to maternal obesity or a maternal calorically dense Western-style diet (WSD) is strongly associated with a greater risk of metabolic diseases in offspring, most notably insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). Prior studies in our well-characterized Japanese macaque model demonstrated that offspring of dams fed a WSD, even when weaned onto a control (CTR) diet, had reductions in skeletal muscle mitochondrial metabolism and increased skeletal muscle insulin resistance compared to offspring of dams on CTR diet. In the current study, we employed a nested design to test for differences in gene expression in skeletal muscle from lean 3-year-old adolescent offspring from dams fed a maternal WSD in both the presence and absence of maternal obesity or lean dams fed a CTR diet. We included offspring weaned to both a WSD or CTR diet to further account for differences in response to post-weaning diet and interaction effects between diets. Overall, we found that a maternal WSD fed to dams during pregnancy and lactation was the principal driver of differential gene expression (DEG) in offspring muscle at this time point. We identified key gene pathways important in insulin signaling including PI3K-Akt and MAP-kinase, regulation of muscle regeneration, and transcription-translation feedback loops, in both male and female offspring. Muscle DEG showed no measurable difference between offspring of obese dams on WSD compared to those of lean dams fed WSD. A post-weaning WSD effected offspring transcription only in individuals from the maternal CTR diet group but not in maternal WSD group. Collectively, we identify that maternal diet composition has a significant and lasting impact on offspring muscle transcriptome and influences later transcriptional response to WSD in muscle, which may underlie the increased metabolic disease risk in offspring.
TRAPT: A multi-stage fused deep learning framework for transcriptional regulators prediction via integrating large-scale epigenomic data
Authors: Zhang Guorui , Song Chao , Yin Mingxue , Liu Liyuan , Zhang Yuexin , Li Ye , Zhang Jianing , Guo Maozu , Li Chunquan 
Published: May 2024

AbstractIt is a challenging task to identify functional transcriptional regulators, which control expression of gene sets via regulatory elements and epigenomic signals, involving context-specific studies such as development and diseases. Integrating large-scale multi-omics epigenomic data enables the elucidation of the complex epigenomic control patterns of regulatory elements and regulators. Here, we propose TRAPT, a multi-modality deep learning framework that predicts functional transcriptional regulators from a queried gene set by integrating large-scale multi-omics epigenomic data, including histone modifications, ATAC-seq and TR-ChIP-seq. We design two-stage self-knowledge distillation model to learn nonlinear embedded representation of upstream and downstream regulatory element activity, and merge multi-modality epigenomic features from TR and the queried gene sets for inferring regulator activity. Experimental results on 1072 TR-related datasets demonstrate that TRAPT outperforms current state-of-the-art methods in predicting transcriptional regulators, especially in the prediction of transcription co-factors and chromatin regulators. Additionally, we have successfully identified key transcriptional regulators associated with the disease, genetic variation, cell fate decisions, and tissues. Our method provides an innovative perspective for integrating epigenomic data and has the potential to significantly assist researchers in deepening their understanding of gene expression regulation mechanisms.
The impact of ancestral, environmental and genetic influences on germlinede novomutation rates and spectra
Authors: Garcia-Salinas O. Isaac , Hwang Seongwon , Huang Qin Qin , Kaplanis Joanna , Neville Matthew D.C. , Sanghvi Rashesh , Day Felix , Rahbari Raheleh , Scally Aylwyn , Martin Hilary C. 
Published: May 2024

AbstractDe novogermline mutation is an important factor in the evolution of allelic diversity and disease predisposition in a population. Here, we study the influence of genetically-inferred ancestry and environmental factors onde novomutation rates and spectra. Using a genetically diverse sample of ∼10K whole-genome sequenced trios, one of the largestde novomutation catalogues to date, we found that genetically-inferred ancestry is associated with modest but significant changes in both germline mutation rate and spectra across continental populations. These effects may be due to genetic or environmental factors correlated with ancestry. We find epidemiological evidence that exposure to tobacco smoke is significantly associated with increasedde novomutation rate, but it does not mediate the observed ancestry effects. Investigation of several other potential mutagenic factors using Mendelian randomisation showed no consistent effects, except for age of menopause, where increased age corresponded to a reduction inde novomutation rate. Overall, our study presents evidence on new factors influencingde novomutational rate and spectra.
Scalable Screening of Ternary-Code DNA Methylation Dynamics Associated with Human Traits
Authors: Goldberg David C , Cloud Cameron , Lee Sol Moe , Barnes Bret , Gruber Steven , Kim Elliot , Pottekat Anita , Westphal Maximillian S , McAuliffe Luana , Majounie Elisa , KalayilManian Manesh , Zhu Qingdi , Tran Christine , Hansen Mark , Stojakovic Jelena , Parker Jared B , Kohli Rahul M , Porecha Rishi , Renke Nicole , Zhou Wanding 
Published: May 2024

SUMMARYEpigenome-wide association studies (EWAS) are transforming our understanding of the interplay between epigenetics and complex human traits and phenotypes. We introduce the Methylation Screening Array (MSA), a new iteration of the Infinium technology for scalable and quantitative screening of trait associations of nuanced ternary-code cytosine modifications in larger, more inclusive, and stratified human populations. MSA integrates EWAS, single-cell, and cell-type-resolved methylome profiles, covering diverse human traits and diseases. Our first MSA applications yield multiple biological insights: we revealed a previously unappreciated role of 5-hydroxymethylcytosine (5hmC) in trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5-methylcytosines (5mCs) in defining tissues and cells’ epigenetic identities. In-depth analyses highlighted the cell type context of EWAS and GWAS hits. Using this platform, we conducted a comprehensive human 5hmC aging EWAS, discovering tissue-invariant and tissue-specific aging dynamics, including distinct tissue-specific rates of mitotic hyper- and hypomethylation rates. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.