bluuebunny/crossref_metadata_2025_split huggingface dataset:
The G9a histone methyltransferase represses osteoclastogenesis and bone resorption by regulating NFATc1 function
Authors: Komatsu Koichiro , Ideno Hisashi , Nakashima Kazuhisa , Udagawa Nobuyuki , Kobayashi Yasuhiro , Kimura Hiroshi , Tachibana Makoto , Yamashita Teruhito , Nifuji Akira 
Published: July 2024

AbstractEpigenetic modifications affect cell differentiation via transcriptional regulation. G9a/EHMT2 is an important epigenetic modifier that catalyzes the methylation of histone 3 lysine 9 (H3K9) and interacts with various nuclear proteins. In this study, we investigated the role of G9a in osteoclast differentiation. When we deleted G9a by infection of Cre‐expressing adenovirus into bone marrow macrophages (BMMs) from G9afl/fl (Ehmt2fl/fl) and induced osteoclastic differentiation by the addition of macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL), the number of TRAP‐positive multinucleated osteoclasts significantly increased compared with control. Furthermore, the mRNA expression of osteoclast markers, TRAP, and cathepsin K, and to a lesser extent, NFATc1, a critical transcription factor, increased in G9a KO cells. Infection of wild‐type (WT) G9a‐expressing adenovirus in G9a KO cells restored the number of TRAP‐positive multinucleated cells. In G9a KO cells, increased nuclear accumulation of NFATc1 protein and decreased H3K9me2 accumulation were observed. Furthermore, ChIP experiments revealed that NFATc1 binding to its target, Ctsk promoter, was enhanced by G9a deletion. For in vivo experiments, we created G9a conditional knock‐out (cKO) mice by crossing G9afl/fl mice with Rank Cre/+ (Tnfrsf11aCre/+) mice, in which G9a is deleted in osteoclast lineage cells. The trabecular bone volume was significantly reduced in female G9a cKO mice. The serum concentration of the C‐terminal telopeptide of type I collagen (CTX), a bone‐resorbing indicator, was higher in G9a cKO mice. In addition, osteoclasts differentiated from G9a cKO BMMs exhibited greater bone‐resorbing activity. Our findings suggest that G9a plays a repressive role in osteoclastogenesis by modulating NFATc1 function.
Moving Accreditation Forward With Accreditation Scholarship
Authors: Graves Lisa , Rudkowski Jill 
Published: July 2024

Abstract
Accreditation in medical education serves to create and sustain a culture of excellence in medical education endeavors. Accreditors in undergraduate medical education, graduate medical education, and continuing professional development spaces on the medical education continuum need to enhance collaboration across international boundaries to develop and implement best practices in medical education accreditation. One opportunity that exists to achieve this is the emerging field of accreditation research, and more broadly, accreditation scholarship. In this commentary, the authors, both professional members of Canadian accreditation committee secretariats (the Committee on the Accreditation of Canadian Medical Schools and the Committee on the Accreditation of Continuing Medical Education), highlight accreditation scholarship as tool to support medical education accreditation improvement, growth, and innovation.
Using Natural Language Processing to Visualize Narrative Feedback in a Medical Student Performance Dashboard
Authors: Maimone Christina , Dolan Brigid M. , Green Marianne M. , Sanguino Sandra M. , O’Brien Celia Laird 
Published: July 2024

Abstract

Problem
Clinical competency committees rely on narrative feedback for important insight into learner performance, but reviewing comments can be time-consuming. Techniques such as natural language processing (NLP) could create efficiencies in narrative feedback review. In this study, the authors explored whether using NLP to create a visual dashboard of narrative feedback to preclerkship medical students would improve the competency review efficiency.

Approach
Preclerkship competency review data collected at the Northwestern University Feinberg School of Medicine from 2014 to 2021 were used to identify relevant features of narrative data associated with review outcome (ready or not ready) and draft visual summary reports of the findings. A user needs analysis was held with experienced reviewers to better understand work processes in December 2019. Dashboards were designed based on this input to help reviewers efficiently navigate large amounts of narrative data. The dashboards displayed the model’s prediction of the review outcome along with visualizations of how narratives in a student’s portfolio compared with previous students’ narratives. Excerpts of the most relevant comments were also provided. Six faculty reviewers who comprised the competency committee in spring 2023 were surveyed on the dashboard’s utility.

Outcomes
Reviewers found the predictive component of the dashboard most useful. Only 1 of 6 reviewers (17%) agreed that the dashboard improved process efficiency. However, 3 (50%) thought the visuals made them more confident in decisions about competence, and 3 (50%) thought they would use the visual summaries for future reviews. The outcomes highlight limitations of visualizing and summarizing narrative feedback in a comprehensive assessment system.

Next Steps
Future work will explore how to optimize the dashboards to meet reviewer needs. Ongoing advancements in large language models may facilitate these efforts. Opportunities to collaborate with other institutions to apply the model to an external context will also be sought.
Changes in the Objective Vision Quality of Adolescents in a Mesopic Visual Environment After Wearing Orthokeratology Lenses: A Prospective Study
Authors: Cheng Zhi'ang , Meng Jing , Ye Linyu , Wang Xinyu , Gong Yiqiang , Liu Xiaoyong 
Published: July 2024

Purpose:
This study aimed to investigate changes in objective vision quality in mesopic environments in teenagers with myopia after wearing orthokeratology (OK) lenses.

Methods:
This prospective clinical study included 45 patients (80 eyes) who received OK lenses at the First Affiliated Hospital of Jinan University from March 2021 to September 2021. An Optical Path Difference-Scan III refractive power/corneal analyzer was used to determine the corneal topographic parameters (corneal e, corneal Q, surface asymmetry index (SAI), and surface regularity index (SRI)), higher-order aberrations (HOAs), axial length (AL) change, lens decentration, induced astigmatism, target power, and Strehl ratio (SR) in a mesopic visual environment after wearing OK lenses for 6 months. In addition, corneal morphological parameters, HOAs, and SR were analyzed in a mesopic visual environment. Finally, we investigated the correlations among corneal morphology, HOAs, AL change, lens decentration, induced astigmatism, and SR.

Results:
The SAI value was significantly higher (P<0.01), and the corneal e was significantly lower (P<0.01), in a mesopic visual environment after wearing OK lenses for 1 week than baseline. A significant increase was observed in total HOAs and spherical aberrations, compared with before the OK lenses were worn (P<0.01). In addition, SR in the mesopic visual environment decreased significantly after wearing the lenses (P<0.01). No significant differences were observed (P>0.05) among the 1-week, 1-month, 3-month, and 6-month follow-up findings. After 6 months, AL and lens decentration did not differ significantly compared with before (P>0.05), whereas induced astigmatism significantly increased (P<0.05). Negative correlations were observed between corneal Q, SAI, SRI, HOAs, induced astigmatism, and SR, and positive correlations were found between corneal e, AL change, lens decentration, and SR, after wearing OK lenses.

Key Points:
• Wearing orthokeratology lenses significantly altered corneal morphology and HOAs in myopic teenagers within 1 week. • The changes that we observed in the eyes of adolescents with myopia after wearing orthokeratology lenses decreased vision quality in mesopic environments. • Strehl ratio is significantly correlated with multiple parameters, including HOAs, AL change, and lens decentration.

Conclusions:
In teenagers with myopia wearing OK lenses, significant changes in vision quality and corneal morphology were observed, leading to increased aberrations and affecting optical imaging quality. Furthermore, SR is significantly correlated with multiple parameters, including HOAs, AL change, and lens decentration.

Registration Number:
This study is registered with the United States Clinical Trials Registry under registration number NCT04929119.
A cellular mechanism contributing to pain-induced analgesia
Authors: Franciosa Federica , Acuña Mario A. , Nevian Natalie E. , Nevian Thomas 
Published: July 2024

Abstract
The anterior cingulate cortex (ACC) plays a crucial role in the perception of pain. It is consistently activated by noxious stimuli and its hyperactivity in chronic pain indicates plasticity in the local neuronal network. However, the way persistent pain effects and modifies different neuronal cell types in the ACC and how this contributes to sensory sensitization is not completely understood. This study confirms the existence of 2 primary subtypes of pyramidal neurons in layer 5 of the rostral, agranular ACC, which we could classify as intratelencephalic (IT) and cortico-subcortical (SC) projecting neurons, similar to other cortical brain areas. Through retrograde labeling, whole-cell patch-clamp recording, and morphological analysis, we thoroughly characterized their different electrophysiological and morphological properties. When examining the effects of peripheral inflammatory pain on these neuronal subtypes, we observed time-dependent plastic changes in excitability. During the acute phase, both subtypes exhibited reduced excitability, which normalized to pre-inflammatory levels after day 7. Daily conditioning with nociceptive stimuli during this period induced an increase in excitability specifically in SC neurons, which was correlated with a decrease in mechanical sensitization. Subsequent inhibition of the activity of SC neurons projecting to the periaqueductal gray with in vivo chemogenetics, resulted in reinstatement of the hypersensitivity. Accordingly, it was sufficient to enhance the excitability of these neurons chemogenetically in the inflammatory pain condition to induce hypoalgesia. These findings suggest a cell type–specific effect on the descending control of nociception and a cellular mechanism for pain-induced analgesia. Furthermore, increased excitability in this neuronal population is hypoalgesic rather than hyperalgesic.
Identification of Drugs and Patient Profiles at Risk for Severe Skin Injuries Due to Extravasation
Authors: Maezawa Mika , Miyasaka Koumi , Hirofuji Sakiko , Wakabayashi Wataru , Iwata Mari , Nakao Satoshi , Akase Tomoko , Iguchi Kazuhiro , Nakamura Mitsuhiro 
Published: July 2024

This study aimed to identify risk factors and combinations thereof that are associated with severe skin injuries due to the extravasation of injectable drugs. A cross-sectional study using the Japanese Adverse Drug Event Report database was conducted according to the RECORD-PE checklist. Adverse event reports related to necrosis, ulcers, or erosions due to extravasation were considered “with severe skin injury,” and others were considered “without severe skin injury.” Approximately 255 cases “with” and 260 cases “without” severe skin injury were identified. The relationship between the incidence of severe skin injury and age, sex, drugs, and primary disease was evaluated using the χ2 test. Association rule mining was used to evaluate the correlation between each combination of factors and skin injury. Nine factors were identified as independent risk factors for severe skin injury, including age (<10 or ≥70 years), peripheral parenteral nutrition use, and mental disorders. The association rule mining results suggested that a combination of specific patient backgrounds and drug use was associated with the incidence of necrosis or ulcers. The findings of this study reiterate that nurses might consider closely observing patients with the risk factors identified in this study for the prevention and early detection of extravasation-related skin injuries.
Skull Base Aspergillus Infection Mimicking Tumor Recurrence
Authors: Chuang Tzyy-Ling , Wang Yuh-Feng 
Published: July 2024

Abstract
We report a case of recurrent nasopharyngeal carcinoma postnasopharyngectomy, presenting with headaches. MRI revealed abnormal signals of the clivus with enhancement, and FDG PET/CT indicated intense uptake in the nasopharynx, clivus, and left neck lymph nodes. Bone SPECT/CT showed bony erosion and uptake in bilateral skull base areas. Biopsy confirmed aspergillosis. Despite the challenges in distinguishing tumor invasion from Aspergillus infection on MRI, bone SPECT/CT, and FDG PET/CT, the short postsurgery period and extensive uptake suggested skull base osteomyelitis.
Number of ICD-10 diagnosis fields required to capture sepsis in administrative data and truncation bias: A nationwide prospective registry study
Authors: Skei Nina Vibeche , Damås Jan Kristian , Gustad Lise Tuset 
Published: July 2024

AbstractBackgroundIn observational studies that uses administrative data, it is essential to report technical details such as the number of International Classification of Disease (ICD) coding fields extracted. This information is crucial for ensuring comparability between studies and for avoiding truncation bias in estimates, particularly for complex conditions like sepsis. Specific sepsis codes (explicit sepsis) is suggested identified by extracting 15 diagnosis fields, while for implicit sepsis, comprising an infection code combined with an acute organ failure, the number of diagnosis field remains unknown.ObjectiveThe objective was to explore the necessary number of diagnosis fields to capture explicit and implicit sepsis.Materials and methodsWe conducted a study utilizing The Norwegian Patient Register (NPR), which encompasses all medical ICD-10 codes from specialized health services in Norway. Data was extracted for all adult patients with hospital admissions registered under explicit and implicit sepsis codes from all Norwegian hospitals between 2008 through 2021.ResultsIn 317,705 sepsis admissions, we observed that 105,499 ICD-10 codes were identified for explicit sepsis, while implicit sepsis was identified through 270,346 codes for infection in combination with 240,586 codes for acute organ failure. Through our analysis, we found that 55.3%, 37.0%, and 10.0% of the explicit, infection, and acute organ failure codes, respectively, were documented as the main diagnosis. The proportion of explicit and infection codes peaked in main diagnosis field, while for acute organ failure codes this was true in the third diagnosis field. Notably, the cumulative proportion reached 99% in diagnosis field 11 for explicit codes and in diagnosis field 14 for implicit codes.ConclusionExpanding the utilization of multiple diagnosis fields can enhance the comparability of data in epidemiological studies, both internationally and within countries. To make truncation bias visible, reporting guidelines should specify the number of diagnosis fields when extracting ICD-10 codes.
A Label-free Optical Biosensor-Based Point-of-Care Test for the Rapid Detection of Monkeypox Virus
Authors: Aslan Mete , Seymour Elif , Brickner Howard , Clark Alex E. , Celebi Iris , Townsend Michael B. , Satheshkumar Panayampalli S. , Riley Megan , Carlin Aaron F. , Ünlü M. Selim , Ray Partha 
Published: July 2024

ABSTRACTDiagnostic approaches that combine the high sensitivity and specificity of laboratory-based digital detection with the ease of use and affordability of point-of-care (POC) technologies could revolutionize disease diagnostics. This is especially true in infectious disease diagnostics, where rapid and accurate pathogen detection is critical to curbing the spread of disease. We have pioneered an innovative label-free digital detection platform that utilizes Interferometric Reflectance Imaging Sensor (IRIS) technology. IRIS leverages light interference from an optically transparent thin film, eliminating the need for complex optical resonances to enhance the signal by harnessing light interference and the power of signal averaging in shot-noise-limited operation to achieve virtually unlimited sensitivity. In our latest work, we have further improved our previous ‘Single-Particle’ IRIS (SP-IRIS) technology by allowing the construction of the optical signature of target nanoparticles (whole virus) from a single image. This new platform, ‘Pixel-Diversity’ IRIS (PD-IRIS), eliminated the need for z-scan acquisition, required in SP-IRIS, a time-consuming and expensive process, and made our technology more applicable to POC settings. Using PD-IRIS, we quantitatively detected the Monkeypox virus (MPXV), the etiological agent for Monkeypox (Mpox) infection. MPXV was captured by anti-A29 monoclonal antibody (mAb 69-126-3) on Protein G spots on the sensor chips and were detected at a limit-of-detection (LOD) - of 200 PFU/ml (∼3.3 attomolar). PD-IRIS was superior to the laboratory-based ELISA (LOD - 1800 PFU/mL) used as a comparator. The specificity of PD-IRIS in MPXV detection was demonstrated using Herpes simplex virus, type 1 (HSV-1), and Cowpox virus (CPXV). This work establishes the effectiveness of PD-IRIS and opens possibilities for its advancement in clinical diagnostics of Mpox at POC. Moreover, PD-IRIS is a modular technology that can be adapted for the multiplex detection of pathogens for which high-affinity ligands are available that can bind their surface antigens to capture them on the sensor surface.
Resource competition in CRISPRa genetic circuits
Authors: Manoj Krishna , Del Vecchio Domitilla 
Published: July 2024

ABSTRACTCRISPR-mediated gene activation (CRISPRa) allows concurrent regulation of transcription of many gene targets and has found widespread applications in genome-wide screening, bioproduction, and therapeutics. In principle, multiple gene targets can be regulated independently by choosing orthogonal scaffold RNA (scRNA); in practice, this is not the case due to competition for dCas9 and activator protein. While prior studies have extensively characterized competition effects in CRISPRi circuits such an investigation in CRISPRa circuits is still lacking. In this paper, we investigate the on-target and off-target effects of competition for the two resources during CRISPRa. We observe a biphasic response in the on-target response of a CRISPRa module, wherein increased expression of scRNA leads to target repression instead of activation. The addition of a competitor further leads to the repression of any other CRISPRa system, showing the lack of modularity of concurrent CRISPRa systems. These effects are significant even when both resources are expressed at their maximum tolerable limit. We finally show that competition can also be used to design the response of a CRISPRa module by reducing leakiness while keeping the same maximal activation. The results from this study can significantly affect the interpretation of data obtained when using multiple CRISPRi/a modules and can be used as a predictive tool to determine how the operation of any such module in a concurrent configuration is different from the one expected in isolation.
Ion and water permeation through Claudin-10b paracellular channels
Authors: Berselli Alessandro , Alberini Giulio , Benfenati Fabio , Maragliano Luca 
Published: July 2024

AbstractThe structural scaffold of epithelial and endothelial tight junctions (TJ) comprises multimeric strands of claudin (Cldn) proteins, which anchor adjacent cells and control the paracellular flux of water and solutes. Based on the permeability properties they confer to the TJs, Cldns are classified as channel- or barrier-forming. Some of them, however, show mixed features. For instance, Cldn10b, expressed in kidneys, lungs, and other tissues, displays high permeability for cations and low permeability for water. Along with its high sequence similarity to the cation- and water-permeable Cldn15, this makes Cldn10b a valuable test case for investigating the molecular determinants of paracellular transport. In lack of high-resolution experimental information on TJ architectures, here we use Molecular Dynamics simulations to study two atomistic models of Cldn10b strands and compare their ion and water transport with those of Cldn15. Our data, based on extensive standard simulations and Free Energy calculations, reveal that both Cldn10b models form cation-permeable pores narrower than Cldn15, which, together with the stable coordination of Na+ions to acidic pore-lining residues (E153, D36, D56), limit the passage of water molecules. By providing a mechanism driving a peculiar case of paracellular transport, these results provide a structural basis for the specific permeability properties of Cldn isoforms that define their physiological role.Graphical abstract
Conserved loop of a phase modifier endows protein condensates with fluidity
Authors: Kawamukai Honoka , Matsusaki Motonori , Tanimoto Takanari , Watabe Mai , Morishima Ken , Tomita Shunsuke , Shinkai Yoichi , Niwa Tatsuya , Mannen Taro , Kumeta Hiroyuki , Nanaura Hitoki , Kato Kotona , Mabuchi Takuya , Aiba Yuichiro , Uehara Takeru , Isozumi Noriyoshi , Hara Yoshika , Kanemura Shingo , Matsumura Hiroyoshi , Sugie Kazuma , Ishimori Koichiro , Muraoka Takahiro , Sugiyama Masaaki , Okumura Masaki , Mori Eiichiro , Yoshizawa Takuya , Saio Tomohide 
Published: July 2024

AbstractDipeptide repeats (DPRs) that are gene products from abnormal hexanucleotide repeat expansion inC9orf72trigger amyotrophic lateral sclerosis (ALS) through unknown mechanism. This study highlights, importin Karyopherinβ2 (Kapβ2), which is responsible for nuclear transport and phase modification of RNA-binding proteins (RBPs), as a major DPR target. We demonstrate DPR accumulation in the nucleus via Kapβ2-mediated transport, which results in dose-dependent toxicity observed in nematode and yeast models. In vitro interaction studies exploiting chemical probe arrays and biophysical measurements reveal multivalent DPR binding to Kapβ2, including at the conserved acidic loop. Refractive index and fluorescence imaging coupled with biochemical assays unveiled that binding of excess DPRs to the acidic loop turns a phase modifier Kapβ2 into phase disrupter, resulting more condensed and viscous RBP condensates. Our findings provides molecular insight intoC9orf72-ALS related to age and repeat expansion.