bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomechanical Evaluation of Femoral Neck Fracture Fixation Based on Finite Element Analysis
Authors: Rao Laureb , Mittal Samarth , Kabra Apoorva , Trikha Vivek , Chawla Anoop , Mukherjee Kaushik 
Published: December 2024

AbstractPauwels type III fracture, wherein the fracture plane makes an angle of 50°-70° with the transverse plane, is the most unstable femoral neck fracture. Although there are various types of internal fixation devices, including Cannulated cancellous screws (CCS), dynamic hip screw (DHS), dynamic hip screw along with anti-rotation screws (DHS+ARS), and a newly introduced femoral neck system (FNS), patients with Pauwels type III fracture often experience implant failure. There was no study investigating the performance of these internal fixators under physiological musculoskeletal loading. The objective of the present study was to compare the biomechanical performance of CCS, DHS, DHS+ARS and FNS under daily physiological activities like normal walking and stair climbing.The unstable Pauwels type III fracture was virtually induced in a composite femur bone model and was fixed with all four internal fixators. Second-order tetrahedral elements were used to develop the FE models. The stresses, strains, and deformations of intact and reconstructed femur and implant components were compared to understand the biomechanical efficacy.FNS showed the highest inferior axial displacement of the femoral head while DHS+ARS exhibited the least inferior axial displacement. Among the four fracture fixation systems, DHS+ARS offered the highest post-fixation stability in terms of fracture gap opening (normal walking: 0.82mm and stair climbing: 0.95mm) and contact sliding, while the performance of single hole locking plated FNS was the worst (normal walking: 2.65mm, stair climbing: 3.72mm). Based on this computational study, DHS+ARS seems to be a better performing system in Pauwels type III fracture fixation.
Defining Mechanistic Links Between the Non-Coding Variant rs17673553 inCLEC16Aand Lupus Susceptibility
Authors: Reddy-Rallabandi Harikrishna , Singh Manish K. , Looger Loren L. , Nath Swapan K. 
Published: December 2024

AbstractSystemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by widespread inflammation and autoantibody production. Its development and progression involve genetic, epigenetic, and environmental factors. Although genome-wide association studies (GWAS) have repeatedly identified a susceptibility signal at 16p13, its fine-scale source and its functional and mechanistic role in SLE remain unclear. We used bioinformatics to prioritize likely functional variants and validated the top candidate through various experimental techniques, including CRISPR-based genome editing in B cells. To assess the functional impact of the proposed causal variant inCLEC16A, we compared autophagy levels between wild-type (WT) and knock-out (KO) cells. Systematic bioinformatics analysis identified the highly conserved non-coding intronic variant rs17673553, with the risk allele apparently affecting enhancer function and regulating several target genes, includingCLEC16Aitself. Luciferase reporter assays followed by ChIP-qPCR validated this enhancer activity, demonstrating that the risk allele increases the binding of enhancer histone marks (H3K27ac and H3K4me1), CTCF-binding factor, and key immune transcription factors (GATA3 and STAT3). Knock-down ofGATA3andSTAT3 viasiRNA led to a significant decrease inCLEC16Aexpression. These regulatory effects on the target gene were further confirmed using CRISPR-based genome editing and CRISPR-dCas9-based epigenetic activation/silencing. Functionally, WT cells exhibited higher levels of starvation-induced autophagy compared to KO cells, highlighting the role ofCLEC16Aand the rs17673553 locus in autophagy regulation. These findings suggest that the rs17673553 locus – particularly the risk allele – drives significant allele-specific chromatin modifications and binding of multiple transcription factors, thereby mechanistically regulating the expression of target autophagy-associated genes, includingCLEC16Aitself. This mechanism could potentially explain the association between rs17673553 and SLE, and underlie the signal at 16p13.
A minimalist binary/digital approach to large-scale single molecule protein identification with optically labeled tRNAs and multiple carboxypeptidases and its extension to peptide sequencing
Authors: Sampath G. 
Published: December 2024

AbstractRecently a binary/digital scheme based on the superspecificity property of transfer RNAs (tRNAs) was proposed for the identification of single amino acids (AAs) from binary-valued measurements (Eur. Phys. J. E45, 94, 2022). There are two formulations, they can be used to sequence short peptides and/or identify their parent proteins. In one of them an array of peptides is sequenced in 20 cycles by adding 20 different tRNAs carrying a fluorescent tag, optically recognizing the C-terminal residues, and cleaving the latter with a carboxypeptidase; the process is repeated over the peptides in parallel. Here this scheme is used to develop in theory a minimalist approach to protein identification that uses only two tRNAs and the carboxypeptidases A, B, and C. The latter form a complete and mutually exclusive set capable of cleaving all 20 AA types; this divides the 20 AAs into three classes. The sequences obtained are partial sequences in the reduced alphabet, their parent proteins can be obtained by search through a proteome database. The AA class of the terminal residue of every peptide in the array can be identified in a single cycle by using the three carboxypeptidases in the order C-B-A. With peptide lengths of ∼20 and a cycle time of ∼1 hour, the parent proteins of K peptides can be obtained in about 20 hours. This is independent of K (within the limits imposed by the imaging method used) and the dynamic range of a proteome; thus in theory a whole proteome can be processed in less than a day. Computational results suggest that the parent proteins of over 92% of peptides from the human proteome (Uniprot id UP000005640_9606) can be identified. The identification rate when residues are skipped due to carboxypeptidases cleaving the second and later residues in delayed reactions is about ∼90% with 1 or 2 skips. Full sequencing without skipped residues can be done by using all 20 tRNA types over 20 cycles in increasing order of cleavage time of the 20 AA types; a recursive procedure is given.
PTTG1-Mediated Pericyte Dysfunction Drives Diabetes-Induced Microvascular Dysfunction
Authors: Zhang Linyu , Ren Ling , Zhang Jingyue , Xia Min , Li Xiaosa , Yao Mudi , Ma Fanfei , Jiang Chang , Yao Jin , Yan Biao 
Published: December 2024

AbstractBackgroundPericytes are crucial for the development, stabilization, and functional regulation of microvasculature, especially in the retina. In diabetic retinopathy (DR), early loss of pericytes is a key event that drives microvascular dysfunction. Despite their critical role, the mechanisms underlying the functional heterogeneity of pericytes in DR remain poorly understood, impeding the development of effective therapeutic strategies.MethodsWe employed single-cell RNA sequencing to construct a comprehensive single- cell atlas of non-diabetic and diabetic retinas. Using bioinformatic clustering and subcluster analysis, we identified a specific pericyte subcluster associated with diabetic microvascular complications. Differential gene expression analysis and immunofluorescence validation highlighted PTTG1 as a potential key regulator of pericyte dysfunction. To investigate its functional role, we emplyed CRISPR/Cas9 and adenoviral vectors to modulate PTTG1 expression in vitro and in vivo. Combined transcriptomic and metabolomic approaches were used to explore the mechanistic pathways through which PTTG1 influences pericyte biology and vascular function.ResultsWe identified a novel pericyte subcluster characterized by elevated expression of PTTG1, which was strongly correlated with diabetic microvascular dysfunction. Silencing PTTG1 using CRISPR/Cas9 and siRNA in vitro mitigated pericyte dysfunction under high- glucose conditions. Targeted knockdown of PTTG1 using viral vectors improved retinal vascular integrity and reduced neovascularization in diabetic mice. Transcriptomic and untargeted metabolomic analyses revealed that PTTG1 knockdown reprogrammed pericyte energy metabolism by modulating glycolysis pathway genes, reducing oxidative stress, and restoring pericyte function, ultimately alleviating microvascular dysfunction in DR.ConclusionsPTTG1 plays a critical role in regulating pericyte dysfunction and maintaining vascular homeostasis in diabetic retinopathy. By modulating key metabolic pathways and pericyte phenotypes, PTTG1 represents a promising therapeutic target for treating diabetic microvascular complications. These insights offer a novel molecular framework for developing targeted therapies aimed at restoring retinal vascular health in diabetic patients.
Conflicting Timelines: Exploring patterns of mito-nuclear discordance in divergence estimates among tetrapods
Authors: Ranganathan Ekadh , Karanth Praveen 
Published: December 2024

AbstractPhylogenetic studies across a range of tetrapod groups have historically utilised either mitochondrial DNA, concatenated mito-nuclear matrices, or nuclear loci to infer divergence estimates. As such, the discordance between estimates inferred using differing data types has been a topic of interest over the past decade. Although several studies have looked into divergence disparities in smaller taxonomic groups, often with mixed results, a systematic investigation of the pattern of mito-nuclear divergence discordance in tetrapods across deep-time remains to be undertaken. In this study, we aimed to quantify the extent of divergence disparity inferred by the aforementioned data types in each of the four major tetrapod groups, namely primates (OrderPrimates), birds (ClassAves), squamates (OrderSquamata), and anurans (OrderAnura), while controlling for calibration strategies, taxon sampling and othera prioridistributions. We also calculated substitution saturation for all groups across data types in order to elucidate its role in generating unreliable divergence estimates. Our findings indicate that mitochondrial estimates consistently underestimate basal divergence times and overestimate recent divergences across all groups (apart from anurans) as compared to the nuclear datasets. We also find that divergence times estimated using concatenated matrices skew in favour of the nuclear tree. Furthermore, substitution saturation is substantial in all of the mitochondrial datasets across groups, and interestingly present in the nuclear dataset for Anurans, resulting in a reduction in overall mito-nuclear divergence disparity for the crown ages of the group. These results call for a revisit of divergence dates estimated using mitochondrial DNA, while advocating for saturation testing prior to divergence dating and highlighting the inherent bias in divergence dates estimated using concatenated mito-nuclear matrices.
Safety and efficacy of high frequency jet ventilation: a systematic and narrative review
Authors: Spaar Jasmin , Biro Peter , Sander Michael , Gross Volker , Scholtes Michael , Sohrabi Keywan 
Published: December 2024

AbstractHigh frequency jet ventilation (HFJV) is an unconventional mechanical ventilation technique increasingly utilized in complex medical fields such as airway surgery and intensive care.This systematic review analyzes the safety and efficacy of HFJV, focusing on its application in both adult and pediatric populations. Through systematic searches of PubMed, Cochrane Library, and Livivo databases, 41 studies meeting the inclusion criteria were identified. Key parameters analyzed included complications, CO₂ and O₂ levels, pH values, FiO₂, treatment course, and duration. Studies were selected that evaluated HFJV both as a standalone method and in comparison, with conventional ventilation techniques.The findings suggest that HFJV offers significant advantages in maintaining low alveolar pressures and improving surgical conditions, particularly in procedures requiring minimal organ movement. While most studies reported no significant difference in complication rates between HFJV and conventional ventilation, HFJV was associated with a more favorable treatment course and duration. Despite these positive outcomes, the data highlight challenges in the use of HFJV, particularly the complexity of the technique and the necessity for precise ventilatory parameter settings. Inappropriate settings can lead to suboptimal ventilation and oxygenation, increasing the risk of complications such as pneumothorax.This review underscores the need for further research to optimize HFJV application and better understand its long-term clinical impacts. The insights gained provide valuable guidance for future clinical use.Key MessageThis systematic review examines the safety and efficacy of high frequency jet ventilation in adult and paediatric patients. The findings indicate that HFJV offers advantages in complex procedures, such as airway surgery and intensive care, by providing lower alveolar pressures and improved surgical conditions without significantly increased complication rates compared to conventional ventilation. However, HFJV requires precise parameter controls to avoid complications such as pneumothorax. Further research is needed to optimise its long-term clinical effects.
Deciphering Risk of Recurrent Bone Stress Injury in Female Runners Using Serum Proteomics Analysis and Predictive Models
Authors: Romanowicz Genevieve E. , Popp Kristin , Dinh Ethan , Harker Isabella R. , Leguineche Kelly , Hughes Julie M. , Ackerman Kathryn E. , Bouxsein Mary L. , Guldberg Robert E. 
Published: December 2024

AbstractUp to 40% of elite athletes experience bone stress injuries (BSIs), with 20-30% facing reinjury. Early identification of runners at high risk of subsequent BSI could improve prevention strategies. However, the complex etiology and multifactorial risk factors of BSIs makes identifying predictive risk factors challenging. In a study of 30 female recreational athletes with tibial BSIs, 10 experienced additional BSIs over a 1-year period, prompting investigation of systemic biomarkers of subsequent BSIs using aptamer-based proteomic technology. We hypothesized that early proteomic signatures could discriminate runners who experienced subsequent BSIs. 1,500 proteins related to metabolic, immune, and bone healing pathways were examined. Using supervised machine learning and genetic programming methods, we analyzed serum protein signatures over the 1-year monitoring period. Models were also created with clinical metrics, including standard-of-care blood analysis, bone density measures, and health histories. Protein signatures collected within three weeks of BSI diagnosis achieved the greatest separation by sparse partial least squares discriminant analysis (sPLS-DA), clustering single and recurrent BSI individuals with a mean accuracy of 96 ± 0.02%. Genetic programming models independently verified the presence of candidate biomarkers, including fumarylacetoacetase, osteopontin, and trypsin-2, which significantly outperformed clinical metrics. Time-course differential expression analysis highlighted 112 differentially expressed proteins in individuals with additional BSIs. Gene set enrichment analysis mapped these proteins to pathways indicating increased fibrin clot formation and decreased immune signaling in recurrent BSI individuals. These findings provide new insights into biomarkers and dysregulated protein pathways associated with recurrent BSI and may lead to new preventative or therapeutic intervention strategies.One Sentence SummaryOur study identified candidate serum biomarkers to predict subsequent bone stress injuries in female runners, offering new insights for clinical monitoring and interventions.
Sex-specific proteomic signatures improve cardiovascular risk prediction for the general population without cardiovascular disease or diabetes
Authors: Xie Ruijie , Vlaski Tomislav , Sha Sha , Brenner Hermann , Schöttker Ben 
Published: December 2024

AbstractImportanceAccurate prediction of 10-year major adverse cardiovascular events (MACE) is crucial for effective cardiovascular disease prevention and management.ObjectiveTo evaluate whether adding sex-specific proteomic profiles to the SCORE2 model enhances 10-year MACE risk prediction in the large UK Biobank (UKB) cohort.Design, Setting, and ParticipantsData from 47,382 UKB participants, aged 40 to 69 years without prior cardiovascular disease or diabetes, were utilized. The cohort was randomly divided into derivation (70%) and validation (30%) sets.ExposuresProteomic profiling of plasma samples was conducted using the Olink Explore 3072 platform, measuring 2,923 unique proteins, of which 2,085 could be used. Sex-specific Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for biomarker selection.Main Outcomes and MeasuresThe primary outcome was 10-year MACE incidence, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Model performance was assessed by changes in Harrell’s C-index, net reclassification index (NRI), and integrated discrimination index (IDI).ResultsDuring 10-year follow-up, 2,163 participants experienced MACE. Overall, 18 proteins were selected by LASSO regression, with 5 of them identified in both sexes, 7 only in males, and 6 only in females. Incorporating these proteins, significantly improved the C-index of the SCORE2 model from 0.713 to 0.778 (P□<□0.001) in the total population. The improvement was greater in males (C-index increase from 0.684 to 0.771; Δ□=□+0.087) than in females (from 0.720 to 0.769; Δ□=□+0.049). The NRI was 19.9% for the total population, 36.3% for males, and 18.2% for females. The WAP four-disulfide core domain protein (WFDC2), which modulates extracellular matrix degradation, impacting fibrosis and plaque stability, and the growth/differentiation factor 15 (GDF15), reflecting increased inflammatory activity, were the proteins contributing the strongest C-index increase in both sexes; even more than the N-terminal prohormone of brain natriuretic peptide (NTproBNP), which was also selected.Conclusions and RelevanceThe derivedsex-specific 10-year MACE risk prediction models, combining 12 protein concentrations among men and 11 protein concentrations among women with the SCORE2 model, significantly improved the discriminative abilities of the SCORE2 model. This study shows the potential of sex-specific proteomic profiles for enhanced cardiovascular risk stratification and personalized prevention strategies.
Multi-omic analysis identifies a multi-step pathology in a case of multiple chorangioma syndrome in monochorionic twins
Authors: Wilk Brandon M. , Gajapathy Manavalan , Brown Donna M. , Duncan Virginia E. , Worthey Elizabeth A. 
Published: December 2024

AbstractBackgroundChorangiomas, benign proliferative capillary lesions in the placenta, occur in approximately 1% of births, typically as a solitary nodule. In rare cases, multiple nodules develop, posing risks of fetal heart failure, hydrops fetalis, and intrauterine death due to altered placental hemodynamics. Although genetic and hypoxic factors have been hypothesized to drive aberrant angiogenesis, definitive evidence has been lacking. We report on a unique case of multiple chorangiomas in half of a shared placenta in monozygotic, monochorionic diamniotic (MCDA) twins, providing an unprecedented opportunity to explore impacts that molecular variation has on chorangioma formation.ResultsWhole genome and bulk RNA sequencing supported identification of early embryonic or germline and somatic variation. It revealed a likely pathogenic heterozygous frameshift deletion in EPAS1, a hypoxia-sensing transcription factor, with an early embryonic or germline origin. This variant likely impaired placental oxygen regulation and angiogenesis through its impact on VEGF-related pathways. Deleterious somatic mutations in COL1A1, FBXO11, and TRIM71 were observed within the chorangioma-affected tissue, along with increased expression of Leptin and DNA damage signatures consistent with oxidative stress. In contrast, the unaffected twin’s placental territory showed a different pattern of pathogenic somatic variation with the presence of a known pathogenic variant in MUTYH and signs of repair deficiencies. These findings highlight the presence of predisposing events and distinct molecular processes within each domain of the shared placenta. We propose that these molecular events, combined with environmental factors intensified by the MCDA pregnancy, likely contributed to chorangioma development..ConclusionsOur study provides novel insights into the molecular basis of multiple chorangioma syndrome. To our knowledge, this is the first molecular evidence implicating both germline and somatic genetic involvement in this condition. The identification of molecular signatures previously associated with malignancy suggests that chorangiomas may share pathways with oncogenic processes. These findings highlight the importance of considering both genetic and environmental interactions in placental pathologies, offering potential implications for understanding and managing complex vascular and placental conditions, including preeclampsia, intrauterine growth restriction, and fetal vascular malperfusion.
Is the Official Development Assistance in Guinea-Bissau “emergency” or “indispensable”? Perceptions of key stakeholders in the healthcare sector
Authors: Casimiro Anaxore , Cane Réka Maulide , Jareski Andrade Michel , Varandas Luís , Craveiro Isabel 
Published: December 2024

AbstractOfficial Development Assistance (ODA) is a type of financial support for low and medium-income countries to promote economic development and well-being. This study explores the perceptions of key healthcare stakeholders on the role of ODA in the health sector in Guinea-Bissau, focusing on maternal and child health. This qualitative study, conducted in May 2022 and February 2024, utilized semi-structured interviews with ten national and international healthcare stakeholders. Participants included present and past Ministry of Public Health officials and global partners in Guinea-Bissau. An interview script was used, including questions about the role and effectiveness of ODA in development, challenges in implementing health programs, coordination mechanisms, alignment of assistance with countries’ strategic documents, and recommendations for future improvements. Thematic categorical analysis, identification of standards, themes, and emerging relationships were identified in the participants’ responses. Findings reveal as main topics: (1) Participants considered that foreign aid is seen as a “humanitarian” or “emergency” assistance that complements the government and has been indispensable for project implementation and improvement of health indicators (2) Stakeholders reported significant challenges, including inadequate alignment of donor agendas with national health strategies, insufficient coordination among actors, and limited government ownership. Political instability undermines projects’ sustainability and long-term impact (3). It is necessary to reinforce the management capacity of the Ministry of Health and ensure that the guiding tools are used. ODA has been crucial to avoid the collapse of the health sector in Guinea-Bissau. However, a more cohesive strategy is essential to enhance ODA effectiveness in Guinea-Bissau. Recommendations include strengthening government leadership, aligning donor programs with national health priorities, and fostering improved coordination among health actors. Increasing government ownership of ODA projects could improve sustainability. This research offers crucial insights for policymakers, emphasizing the balance between ODA and long-term health improvements in Guinea-Bissau.