bluuebunny/crossref_metadata_2025 huggingface dataset:
Recognizing rare rashes
Authors: Roth Maleah , Anderson Adrijana
Published: April 2024

Acute generalized exanthematous pustulosis (AGEP) is a rare, pustular rash that occurs most commonly after exposure to a medication (typically antibiotics or diltiazem). This case describes a patient who developed a widespread pustular eruption shortly after beginning empiric antibiotics for community-acquired pneumonia. Diagnosis of AGEP was difficult in this scenario due to the patient's pulmonary infection and atypical skin biopsy results. However, after AGEP was correctly identified, the offending agents were discontinued and the patient had subsequent resolution of her symptoms.
Early and aggressive treatment for Crohn disease using biologics and immunomodulators
Authors: Martin Erin , Sadowski Catherine K.
Published: April 2024

Traditionally, medical providers have used the step-up approach to manage patients with Crohn disease, starting with 5-aminosalicylic acid derivatives, progressing to corticosteroids, and eventually to immunomodulators and biologics. However, a new top-down approach focuses on early and aggressive therapy with biologics and immunomodulators to reduce the rate of mucosal and intestinal damage. This article describes early and aggressive biologic and immunomodulator therapies and new therapeutic parameters compared with traditional step-up treatment for patients with Crohn disease.
Chondrocyte Invasion May Be a Mechanism for Persistent Staphylococcus Aureus Infection In Vitro
Authors: Chang Jerry , Kerr David , Zheng Megan , Seyler Thorsten
Published: April 2024

Background

Recurrent bone and joint infection with Staphylococcus aureus is common. S. aureus can invade and persist in osteoblasts and fibroblasts, but little is known about this mechanism in chondrocytes. If S. aureus were able to invade and persist within chondrocytes, this could be a difficult compartment to treat.

Question/purpose

Can S. aureus infiltrate and persist intracellularly within chondrocytes in vitro?

Methods

Cell lines were cultured in vitro and infected with S. aureus. Human chondrocytes (C20A4) were compared with positive controls of human osteoblasts (MG63) and mouse fibroblasts (NIH3T3), which have previously demonstrated S. aureus invasion and persistence (human fibroblasts were not available to us). Six replicates per cell type were followed for 6 days after infection. Cells were treated daily with antibiotic media for extracellular killing. To determine whether S. aureus can infiltrate chondrocytes, fluorescence microscopy was performed to qualitatively assess the presence of intracellular bacteria, and intracellular colony-forming units (CFU) were enumerated 2 hours after infection. To determine whether S. aureus can persist within chondrocytes, intracellular CFUs were enumerated from infected host cells each day postinfection.

Results

S. aureus invaded human chondrocytes (C20A4) at a level (2.8 x 105 ± 5.5 x 104 CFUs/mL) greater than positive controls of human osteoblasts (MG63) (9.5 x 102 ± 2.5 x 102 CFUs/mL; p = 0.01) and mouse fibroblasts (NIH3T3) (9.1 x 104 ± 2.5 x 104 CFUs/mL; p = 0.02). S. aureus also persisted within human chondrocytes (C20A4) for 6 days at a level (1.4 x 103 ± 5.3 x 102 CFUs/mL) greater than that of human osteoblasts (MG63) (4.3 x 102 ± 3.5 x 101 CFUs/mL; p = 0.02) and mouse fibroblasts (NIH3T3) (0 CFUs/mL; p < 0.01). S. aureus was undetectable within mouse fibroblasts (NIH3T3) after 4 days. There were 0 CFUs yielded from cell media, confirming extracellular antibiotic treatment was effective.

Conclusion

S. aureus readily invaded human chondrocytes (C20A4) in vitro and persisted viably for 6 days after infection, evading extracellular antibiotics. Chondrocytes demonstrated a greater level of intracellular invasion and persistence by S. aureus than positive control human osteoblast (MG63) and mouse fibroblast (NIH3T3) cell lines.

Clinical Relevance

Chondrocyte invasion and persistence may contribute to recurrent bone and joint infections. Additional research should assess longer periods of persistence and whether this mechanism is present in vivo.
Continuous Corneal Endothelial Damage by Chlorhexidine Alcohol Used for Disinfection in Nonophthalmic Surgery
Authors: Yoshinaga Yu , Soma Takeshi , Oie Yoshinori , Koh Shizuka , Nishida Kohji
Published: April 2024

Purpose:

To report a case of corneal endothelial damage caused by alcohol-containing chlorhexidine gluconate (CG-A) and its progression over time.

Methods:

This was a case report.

Results:

A 22-year-old man underwent neurosurgery under general anesthesia. CG-A (1%) was used for disinfection after the application of corneal protection tape. Postoperatively, the patient presented with hyperemia and swelling of the left conjunctiva and was referred to our department. Initial examination revealed left corneal epithelial erosion and corneal edema, which improved on postoperative day 14. The corneal endothelial cell density (ECD) was 3,345 cells/mm2 on day 14, decreased rapidly to 2,090 cells/mm2 on day 42, and slowly reduced to 1,122 cells/mm2 on day 168. Thereafter, no decrease in ECD was observed.

Conclusions:

CG formulations can lead to a persistent decrease in ECD over several months, even after improvement of acute corneal edema.
The Incidence of Cervical Intraepithelial Neoplasia or Cervical Cancer in Women Referred With Postcoital Bleeding
Authors: Mohammad Hajer , Espensen Anne Sofie , Arnardóttir Margrét Björg , Bergholdt Stinne Holm , Petersen Lone Kjeld
Published: April 2024

Objectives

The incidence of cervical cancer among patients with postcoital bleeding (PCB) was the primary objective of this study. Furthermore, the proportion of cervical intraepithelial neoplasia requiring treatment and the correlation between PCB and the presence of high-risk human papillomavirus (HPV) was determined. Lastly, the study aimed to identify risk factors among the referred women.

Methods

A retrospective cohort study was conducted at a university hospital in Denmark between January 1, 2017 and December 31, 2019. Women referred with PCB were identified with the ICD diagnosis codes “DN930 Postcoital and contact bleeding” and “DN930B Contact bleeding.” Demographic and paraclinical data were extracted from the journals and the supportive systems: Patoweb and the Danish Microbiology Database.

Results

A total of 789 women were included in this study, with only 0.25% (n = 2) diagnosed with cervical cancer and 2.5% (n = 20) diagnosed with cervical intraepithelial neoplasia II–III and adenocarcinoma in situ. Human papillomavirus testing was only conducted in a minority of cases, and a low incidence of high-risk human papilloma virus was detected in the 22 cases, n = 5.

Conclusions

A very low incidence of cervical cancer and high-grade cervical intraepithelial neoplasia reported among women referred with PCB. Prognostic factors as body mass index, smoking, and HPV vaccination status may predict the risk of cervical cancer. Selection criteria like primary testing for hrHPV and cytology as cotests before referral to colposcopy may reduce the number of unnecessary colposcopies.
Evaluating the Quality of Narrative Feedback for Entrustable Professional Activities in a Surgery Residency Program
Authors: Fernandes Rosephine Del , de Vries Ingrid , McEwen Laura , Mann Steve , Phillips Timothy , Zevin Boris
Published: April 2024

Objective:

To assess the quality of narrative feedback given to surgical residents during the first 5 years of competency-based medical education implementation.

Background:

Competency-based medical education requires ongoing formative assessments and feedback on learners’ performance.

Methods:

We conducted a retrospective cross-sectional study using assessments of entrustable professional activities (EPAs) in the Surgical Foundations curriculum at Queen’s University from 2017 to 2022. Two raters independently evaluated the quality of narrative feedback using the Quality of Assessment of Learning score (0–5).

Results:

A total of 3900 EPA assessments were completed over 5 years. Of assessments, 57% (2229/3900) had narrative feedback documented with a mean Quality of Assessment of Learning score of 2.16 ± 1.49. Of these, 1614 (72.4%) provided evidence about the resident’s performance, 951 (42.7%) provided suggestions for improvement, and 499/2229 (22.4%) connected suggestions to the evidence. There was no meaningful change in narrative feedback quality over time (r = 0.067, P = 0.002). Variables associated with lower quality of narrative feedback include: attending role (2.04 ± 1.48) compared with the medical student (3.13 ± 1.12, P < 0.001) and clinical fellow (2.47 ± 1.54, P < 0.001), concordant specialties between the assessor and learner (2.06 ± 1.50 vs 2.21 ± 1.49, P = 0.025), completion of the assessment 1 month or more after the encounter versus 1 week (1.85 ± 1.48 vs 2.23 ± 1.49, P < 0.001), and resident entrusted versus not entrusted to perform the assessed EPA (2.13 ± 1.45 vs 2.35 ± 1.66; P = 0.008). The quality of narrative feedback was similar for assessments completed under direct and indirect observation (2.18 ± 1.47 vs 2.06 ± 1.54; P = 0.153).

Conclusions:

Just over half of the EPA assessments of surgery residents contained narrative feedback with overall fair quality. There was no meaningful change in the quality of feedback over 5 years. These findings prompt future research and faculty development.
National Football League Game Officials Self-Rating of Knowledge in Neuro-Ophthalmic Principles and Practice: A Pilot Program to Improve Precision and Accuracy of Game Official Calls
Authors: Carrabba Nicole V. , Ong Joshua , Vogt Ashtyn Z. , Panzo Nicholas J. , Memon Hamza , Lee Virginia A. , Waisberg Ethan , Sarker Prithul , Zaman Nasif , Tavakkoli Alireza , Laylani Noor A. , Lee Andrew G.
Published: April 2024

Background:

To determine whether a neuro-ophthalmic curriculum would improve National Football League (NFL) game officials' self-rated knowledge and interest in neuro-ophthalmic principles to improve precision and accuracy of NFL play-calling.

Methods:

The formalized and structured neuro-ophthalmic principles (NOP) curriculum was introduced to 121 NFL game officials, 17 replay officials, and 4 officiating staff who attended the NFL Official Training Camp in Irving, Texas, on September 8 and 9, 2023. Before and after the lecture and videos were introduced, participants completed an optional hard-copy feedback form pertaining to self-reported NOP knowledge, likelihood of using said terms, and interest in future content of NOP applicable NFL officiating. Paired 2-tailed t tests were used for statistical analysis to directly compare the self-reported knowledge before and after the neuro-ophthalmic curriculum introduction.

Results:

One hundred forty-two participants completed the prelecture and postlecture feedback forms self-reported knowledge after the NOP curriculum was given to the NFL officiating staff. All (142/142) participants completed a survey. There was a statistically significant improvement in the mean ratings of the prelecture vs. postlecture understanding of the specific neuro-ophthalmic terms pertinent to NFL game officials (2.6 [95% CI, 2.3–3.0] vs. 7.9 [95% CI, 7.6–8.2], P < 0.001) and 2.7 [95% CI, 2.3–3.0] vs. 7.7 [95% CI, 7.4–8.0]), respectively. There was a statistically significant greater likelihood of using said terms prelecture vs. postlecture (2.9 [95% CI, 2.4–3.4] vs. 7.5 [95% CI, 7.2–7.9], P < 0.001).

Conclusions:

This study found a statistically significant improvement in neuro-ophthalmic knowledge and a greater likelihood of using NOP terms following the NOP curriculum. NFL game officials, replay officials, and staff are interested in expanding their knowledge in the vision science of neuro-ophthalmic concepts and applications involved in play-calling. We hope that our pilot data will lead to a model of education that will improve the precision and accuracy of NFL play-calls by officials on game days.
Non-resolving neuroinflammation regulates axon regeneration in chronic spinal cord injury
Authors: Stewart Andrew N. , Bosse-Joseph Christopher C. , Kumari Reena , Bailey William M. , Park Kennedy A. , Slone Victoria K. , Gensel John C.
Published: April 2024

Chronic spinal cord injury (SCI) lesions retain increased densities of microglia and macrophages. In acute SCI, macrophages induce growth cone collapse, facilitate axon retraction away from lesion boundaries, as well as play a key role in orchestrating the growth-inhibitory glial scar. Little is known about the role of sustained inflammation in chronic SCI, or whether chronic inflammation affects repair and regeneration. We performed transcriptional analysis using the Nanostring Neuropathology panel to characterize the resolution of inflammation into chronic SCI, to characterize the chronic SCI microenvironment, as well as to identify spinal cord responses to macrophage depletion and repopulation using the CSF1R inhibitor, PLX-5622. We determined the ability for macrophage depletion and repopulation to augment axon growth into chronic lesions both with and without regenerative stimulation using neuronal-specific PTEN knockout (PTEN-KO). PTEN-KO was delivered with spinal injections of retrogradely transported adeno associated viruses (AAVrg’s). Both transcriptional analyses and immunohistochemistry revealed the ability for PLX-5622 to significantly deplete inflammation around and within chronic SCI lesions, with a return to pre-depleted inflammatory densities after treatment removal. Neuronal-specific transcripts were significantly elevated in mice after inflammatory repopulation, but no significant effects were observed with macrophage depletion alone. Axon densities significantly increased within the lesion after PLX-5622 treatment with a more consistent effect observed in mice with inflammatory repopulation. PTEN-KO did not further increase axon densities within the lesion beyond effects induced by PLX-5622. We identified that PLX-5622 increased axon densities within the lesion that are histologically identified as 5-HT+and CGRP+, both of which are not robustly transduced by AAVrg’s. Our work identified that increased macrophage/microglia densities in the chronic SCI environment may be actively retained by homeostatic mechanisms likely affiliated with a sustained elevated expression of CSF1 and other chemokines. Finally, we identify a novel role of sustained inflammation as a prospective barrier to axon regeneration in chronic SCI.

Highlights

Macrophages and microglia repopulate the chronically injured spinal cord after depletion.

CSF1R antagonism in chronic SCI augments the growth of specific axon types in the lesion.

CSF1R antagonism does not augment a PTEN-knockout-induced functional recovery.
Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition
Authors: Zhang Xiaotian , Jeong Heykyeong , Niu Jingwen , Holland Sabrina M. , Rotanz Brittany N. , Gordon John , Einarson Margret B. , Childers Wayne E. , Thomas Gareth M.
Published: April 2024

Dual leucine-zipper kinase (DLK) drives acute and chronic forms of neurodegeneration, suggesting that inhibiting DLK signaling could ameliorate diverse neuropathological conditions. However, direct inhibition of DLK’s kinase domain in human patients and conditional knockout of DLK in mice both cause unintended side effects, including elevated plasma neurofilament levels, indicative of neuronal cytoskeletal disruption. Indeed, we found that a DLK kinase domain inhibitor acutely disrupted the axonal cytoskeleton and caused vesicle aggregation in cultured dorsal root ganglion (DRG) neurons, further cautioning against this therapeutic strategy. In seeking a more precise intervention, we found that retrograde (axon-to-soma) pro-degenerative signaling requires acute, axonal palmitoylation of DLK and hypothesized that modulating this post-translational modification might be more specifically neuroprotective than cell-wide DLK inhibition. To address this possibility, we screened >28,000 compounds using a high-content imaging assay that quantitatively evaluates DLK’s palmitoylation-dependent subcellular localization. Of the 33 hits that significantly altered DLK localization in non-neuronal cells, several reduced DLK retrograde signaling and protected cultured DRG neurons from DLK-dependent neurodegeneration. Mechanistically, the two most neuroprotective compounds selectively prevent stimulus-dependent palmitoylation of axonal pools of DLK, a process crucial for DLK’s recruitment to axonal vesicles. In contrast, these compounds minimally impact DLK localization and signaling in healthy neurons and avoid the cytoskeletal disruption associated with direct DLK inhibition. Importantly, our hit compounds also reduce pro-degenerative retrograde signaling in vivo, suggesting that modulating DLK’s palmitoylation-dependent localization could be a novel neuroprotective strategy.
A straightforward cell culture insert model to incorporate biochemical and biophysical stromal properties into transplacental transport studies
Authors: Nelson Katherine M. , Ferrick Bryan J. , Karimi Hassan , Hatem Christine L. , Gleghorn Jason P.
Published: April 2024

Introduction

The placental extracellular matrix (ECM) dynamically remodels over pregnancy and in disease. How these changes impact placental barrier function is poorly understood as there are limitedin vitromodels of the placenta with a modifiable stromal compartment to mechanistically investigate these extracellular factors. We developed a straightforward method to incorporate uniform hydrogels into standard cell culture inserts for transplacental transport studies.

Methods

Uniform polyacrylamide (PAA) gels were polymerized within cell culture inserts by (re)using the insert packaging to create a closed, controllable environmental chamber. PAA pre-polymer solution was added dropwise via a syringe to the cell culture insert and the atmosphere was purged with an inert gas. Transport and cell culture studies were conducted to validate the model.

Results

We successfully incorporated and ECM functionalized uniform PAA gels to cell culture inserts enable cell adhesion and monolayer formation. Imaging and analyte transport studies validated gel formation and expected mass transport results and successful cell studies confirmed cell viability, monolayer formation, and that the model could be used transplacental transport studies. Detailed methods and validation protocols are included.

Discussion

It is well appreciated that ECM biophysical and biochemical properties impact cell phenotype and cell signaling in many tissues including the placenta. The incorporation of a PAA gel within a cell culture insert enables independent study of placental ECM biophysical and biochemical properties in the context of transplacental transport. These straightforward and low-cost methods to build three dimensional cellular models are readily adoptable by the wider scientific community.
Quantifying and controlling the proteolytic degradation of cell adhesion peptides
Authors: Rozans Samuel J. , Moghaddam Abolfazl Salehi , Wu Yingjie , Atanasoff Kayleigh , Nino Liliana , Dunne Katelyn , Pashuck E. Thomas
Published: April 2024

Peptides are widely used within biomaterials to improve cell adhesion, incorporate bioactive ligands, and enable cell-mediated degradation of the matrix. While many of the peptides incorporated into biomaterials are intended to be present throughout the life of the material, their stability is not typically quantified during culture. In this work we designed a series of peptide libraries containing four different N-terminal peptide functionalizations and three C-terminal functionalization to better understand how simple modifications can be used to reduce non-specific degradation of peptides. We tested these libraries with three cell types commonly used in biomaterials research, including mesenchymal stem/stromal cells (hMSCs), endothelial cells, and macrophages, and quantified how these cell types non-specifically degraded peptide as a function of terminal amino acid and chemistry. We found that peptides in solution which contained N-terminal amines were almost entirely degraded by 48 hours, irrespective of the terminal amino acid, and that degradation occurred even at high peptide concentrations. Peptides with C-terminal carboxylic acids also had significant degradation when cultured with cells. We found that simple modifications to the termini could significantly reduce or completely abolish non-specific degradation when soluble peptides were added to cells cultured on tissue culture plastic or within hydrogel matrices, and that functionalizations which mimicked peptide conjugations to hydrogel matrices significantly slowed non-specific degradation. We also found that there were minimal differences across cell donors, and that sequences mimicking different peptides commonly-used to functionalized biomaterials all had significant non-specific degradation. Finally, we saw that there was a positive trend between RGD stability and hMSC spreading within hydrogels, indicating that improving the stability of peptides within biomaterial matrices may improve the performance of engineered matrices.
300 Hz transcutaneous auricular vagus nerve stimulation (taVNS) impacts pupil size nonlinearly as a function of intensity
Authors: Phillips Ian , Johns Michael A. , Pandža Nick B. , Calloway Regina C. , Karuzis Valerie P. , Kuchinsky Stefanie E.
Published: April 2024

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neuromodulatory technique that may have numerous potential health and human performance benefits. However, optimal stimulation parameters for maximizing taVNS efficacy are unknown. Progress is impeded by disagreement on the identification of a biomarker that reliably indexes activation of neuromodulatory systems targeted by taVNS, including the locus coeruleus-norepinephrine (LC-NE) system. Pupil size varies with LC-NE activity and is one potential taVNS biomarker that has shown inconsistent sensitivity to taVNS in prior studies. The present study examined the relationship between pupil size and taVNS using stimulation parameters that have shown promising behavioral effects in prior studies but have received comparatively little attention. Participants received 30-second trains of 50 μs taVNS pulses delivered below perceptual threshold at 300 Hz to the left external acoustic meatus (EAM) while pupil size was recorded during a pupillary light reflex task. Analysis of pupil size using generalized additive mixed modelling (GAMM) revealed a nonlinear relationship between taVNS intensity and pupil diameter. Active taVNS increased pupil size during stimulation for participants who received taVNS between 2 and approximately 4.8 mA, but not for participants who received higher intensity taVNS (up to 8.1 mA). In addition, taVNS effects persisted in subsequent blocks, mitigating decreases in pupil size over the course of the task. These findings suggest 300 Hz taVNS activates the LC-NE system when applied to the EAM, but its effects may be counteracted at higher intensities.
The spatial and cellular portrait of Transposable Element expression during Gastric Cancer
Authors: Valdebenito-Maturana Braulio
Published: April 2024

Gastric Cancer (GC) is a lethal malignancy, with urgent need for the discovery of novel biomarkers for its early detection. I previously showed that Transposable Elements (TEs) become activated in early GC (EGC), suggesting a role in gene expression. Here, I follow-up on that evidence using single-cell data from gastritis to EGC, and show that TEs are expressed and follow the disease progression, with 2,430 of them being cell populations markers. Pseudotemporal trajectory modeling revealed 111 TEs associated with the origination of cancer cells. Analysis of spatial data from GC also confirms TE expression, with 204 TEs being spatially enriched. Finally, a network of TE-mediated gene regulation was modeled, indicating that ∼2,000 genes could be modulated by TEs, with ∼500 of them already implicated in cancer. These results suggest that TEs might play a functional role in GC progression, and highlights them as potential biomarker for its early detection.
A recurrent neural circuit inDrosophiladeblurs visual inputs
Authors: Pang Michelle M. , Chen Feng , Xie Marjorie , Druckmann Shaul , Clandinin Thomas R. , Yang Helen H.
Published: April 2024

A critical goal of vision is to detect changes in light intensity, even when these changes are blurred by the spatial resolution of the eye and the motion of the animal. Here we describe a recurrent neural circuit inDrosophilathat compensates for blur and thereby selectively enhances the perceived contrast of moving edges. Usingin vivo, two-photon voltage imaging, we measured the temporal response properties of L1 and L2, two cell types that receive direct synaptic input from photoreceptors. These neurons have biphasic responses to brief flashes of light, a hallmark of cells that encode changes in stimulus intensity. However, the second phase was often much larger than the first, creating an unusual temporal filter. Genetic dissection revealed that recurrent neural circuitry strongly shapes the second phase of the response, informing the structure of a dynamical model. By applying this model to moving natural images, we demonstrate that rather than veridically representing stimulus changes, this temporal processing strategy systematically enhances them, amplifying and sharpening responses. Comparing the measured responses of L2 to model predictions across both artificial and natural stimuli revealed that L2 tunes its properties as the model predicts in order to deblur images. Since this strategy is tunable to behavioral context, generalizable to any time-varying sensory input, and implementable with a common circuit motif, we propose that it could be broadly used to selectively enhance sharp and salient changes.
PLM_Sol: predicting protein solubility by benchmarking multiple protein language models with the updatedEscherichia coliprotein solubility dataset
Authors: Zhang Xuechun , Hu Xiaoxuan , Zhang Tongtong , Yang Ling , Liu Chunhong , Xu Ning , Wang Haoyi , Sun Wen
Published: April 2024

Protein solubility plays a crucial role in various biotechnological, industrial and biomedical applications. With the reduction in sequencing and gene synthesis costs, the adoption of high-throughput experimental screening coupled with tailored bioinformatic prediction has witnessed a rapidly growing trend for the development of novel functional enzymes of interest (EOI). High protein solubility rates are essential in this process and accurate prediction of solubility is a challenging task. As deep learning technology continues to evolve, attention-based protein language models (PLMs) can extract intrinsic information from protein sequences to a greater extent. Leveraging these models along with the increasing availability of protein solubility data inferred from structural database like the Protein Data Bank (PDB), holds great potential to enhance the prediction of protein solubility. In this study, we curated an UpdatedEscherichia coli(E.coli) protein Solubility DataSet (UESolDS) and employed a combination of multiple PLMs and classification layers to predict protein solubility. The resulting best-performing model, named Protein Language Model-based protein Solubility prediction model (PLM_Sol), demonstrated significant improvements over previous reported models, achieving a notable 5.7% increase in accuracy, 9% increase in F1_score, and 10.4% increase in MCC score on the independent test set. Moreover, additional evaluation utilizing our in-house synthesized protein resource as test data, encompassing diverse types of enzymes, also showcased the superior performance of PLM_Sol. Overall, PLM_Sol exhibited consistent and promising performance across both independent test set and experimental set, thereby making it well-suited for facilitating large-scale EOI studies. PLM_Sol is available as a standalone program and as an easy-to-use model athttps://zenodo.org/doi/10.5281/zenodo.10675340.
Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma
Authors: Poklepovic Andrew S. , Shah Palak , Tombes Mary Beth , Shrader Ellen , Bandyopadhyay Dipankar , Deng Xiaoyan , Roberts Catherine H. , Ryan Alison A. , Hudson Daniel , Sankala Heidi , Kmieciak Maciej , Dent Paul , Malkin Mark G.
Published: April 2024

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.
ExpOmics: a comprehensive web platform empowering biologists with robust multi-omics data analysis capabilities
Authors: Li Douyue , Min Zhuochao , Guo Jia , Chen Yubin , Zhang Wenliang
Published: April 2024

Motivation

High-throughput technologies have yielded a broad spectrum of multi-omics datasets, offering unparalleled insights into complex biological systems. However, effectively analyzing this diverse array of data presents challenges, given factors such as species diversity, data types, costs, and limitations of available tools.

Results

We propose ExpOmics, a comprehensive web platform featuring seven applications and four toolkits with 28 customizable analysis functions, spanning various aspects of differential expression, co-expression, WGCNA analysis, feature selection, and functional enrichment analysis. ExpOmics empowers users to effortlessly upload and explore multi-omics data without organism restriction, supporting a wide array of data types including gene, mRNA, lncRNA, miRNA, circRNA, piRNA, and protein expression data. It is compatible with diverse gene nomenclatures and expression value types. Moreover, ExpOmics enables users to comprehensive analysis of 22,427 transcriptomic datasets sourced from 63 projects and 196 cancer subtypes in TCGA, discovering cancer biomarkers and targets. The analysis results from ExpOmics are visually presented in high-quality graphical formats suitable for publication, available for free download. In summary, ExpOmics can serves as a robust platform for global researchers to delve into diverse expression datasets, gain biological insights, and formulate testable hypotheses.

Availability and implementation

ExpOmics is available athttp://www.biomedical-web.com/expomics.
SARS-CoV-2 Omicron Envelope T9I adaptation confers resistance to autophagy
Authors: Klute Susanne , Nchioua Rayhane , Cordsmeier Arne , Vishwakarma Jyoti , Koepke Lennart , Alshammary Hala , Jung Christoph , Hirschenberger Maximilian , Hoenigsperger Helene , Fischer Jana-Romana , Zech Fabian , Stenger Steffen , Serra-Moreno Ruth , Gonzalez-Reiche Ana S. , Sordillo Emilia Mia , van Bakel Harm , Simon Viviana , Kirchhoff Frank , Jacob Timo , Kmiec Dorota , Pichlmair Andreas , Ensser Armin , Sparrer Konstantin MJ
Published: April 2024

To date, five variants of concern (VOCs) of SARS-CoV-2 have emerged that show increased fitness and/or immune evasion. While the continuously evolving escape from humoral immune responses has been analyzed in detail, adaptation of SARS-CoV-2 to human innate immune defenses such as autophagy is less understood. Here, we demonstrate that mutation T9I in the structural envelope (E) protein confers autophagy resistance of Omicron VOCs (BA.1, BA.5 and XBB.1.5) compared to 2020 SARS-CoV-2 or the Delta VOC. Mechanistic analyses revealed that Omicron-associated E T9I shows increased inhibition of autophagic flux and colocalization/interaction with autophagosomes, thus shielding incoming SARS-CoV-2 S pseudotyped virions from autophagy. Rare Omicron isolates carrying ancestral E T9 remain sensitive towards autophagy whereas recombinant early 2020 SARS-CoV-2 expressing E T9I shows increases resistance against autophagy. Our data indicate that the E T9I mutation drives autophagy resistance of the Omicron variants and thus may have contributed to their effective spread.
Reproducible, data-driven characterization of sleep based on brain dynamics and transitions from whole-night fMRI
Authors: Yang Fan Nils , Picchioni Dante , de Zwart Jacco A. , Wang Yicun , van Gelderen Peter , Duyn Jeff H.
Published: April 2024

Understanding the function of sleep requires studying the dynamics of brain activity across whole-night sleep and their transitions. However, current gold standard polysomnography (PSG) has limited spatial resolution to track brain activity. Additionally, previous fMRI studies were too short to capture full sleep stages and their cycling. To study whole-brain dynamics and transitions across whole-night sleep, we used an unsupervised learning approach, the Hidden Markov model (HMM), on two-night, 16-hour fMRI recordings of 12 non-sleep-deprived participants who reached all PSG-based sleep stages. This method identified 21 recurring brain states and their transition probabilities, beyond PSG-defined sleep stages. The HMM trained on one night accurately predicted the other, demonstrating unprecedented reproducibility. We also found functionally relevant subdivisions within rapid eye movement (REM) and within non-REM 2 stages. This study provides new insights into brain dynamics and transitions during sleep, aiding our understanding of sleep disorders that impact sleep transitions.

Teaser

An unsupervised learning model provides new insights into brain activity during human nocturnal sleep
Income inequality and access to advanced immunotherapy for lung cancer: the case of Durvalumab in the Netherlands
Authors: Katsimpokis Dimitris , Aarts Mieke J. , Geleijnse Gijs , Kunst Peter , Bijlsma Maarten J.
Published: April 2024

With the introduction of immunotherapy with non-small lung cancer, prognosis of these patients has improved. However, socio-economic differences in access to various immunotherapy treatments have been reported. In the Netherlands, such differences are not expected due to universal insurance coverage. We investigated the existence of differential susceptibility by socioeconomic status (SES) of the effect of distance to treatment hospital on access to Durvalumab in patients with stage III non-small lung cancer who received chemoradiation, and the influence of differential mortality. We used data from the Netherlands Cancer Registry (n = 3774) from the period 2017-2021. First, we fitted Bayesian discrete failure time models and compared SES-by-distance-to-hospital interaction to a baseline model including age, distance, SES and performance score. We then fitted a time to mortality model and used both models in a g-formula to simulate a scenario where mortality levels were equalized. Our results showed that the high SES group received Durvalumab more often than the low SES group (HR = 1.23, CI95% = [1.07, 1.53]), and even 4 kilometer distance increase leads to less Durvalumab (HR = 0.93, CI95% = [0.86, 0.99]). Bayes factor < 3 indicated inconclusive evidence for a SES by distance interaction effect, while g-formula results showed that differential mortality does not affect SES differences. Secondary analyses showed strong evidence that SES differences in using Durvalumab were constant over the years (Bayes factor > 17). Overall, these results are significant for understanding how socio-economic inequality affects proper care and can be vital for public policy.
Severe Maternal Morbidity Disparities Before and During the COVID Pandemic in a Medicaid Population
Authors: Meghea Cristian I. , Johnson Jennifer E. , Roman Lee Anne , Bolder Hannah , Key Kent , McCoy White Jonne , Yu Xiao
Published: April 2024

This study assessed racial and ethnic disparities in severe maternal mortality during delivery through 6 weeks postpartum, before and during the COVID pandemic, in a statewide Medicaid population. This retrospective, population-based, cohort study used Medicaid claims data linked to birth certificates from the Michigan Department of Health and Human Services Health Services Data Warehouse that included all individuals giving birth between January 1, 2017, and October 31, 2021, in Michigan who had Medicaid insurance during the month of childbirth. The SMM rate increased more during the COVID pandemic for Black (1.36 [1.26-1.46]) compared to White individuals (1.17 [1.09-1.26], p-value<0.01 Black vs White). The Black-White and Hispanic-White disparities in severe maternal morbidity, already high in the Medicaid population, widened during the COVID pandemic. Multilevel interventions are needed to reduce disparities in maternal morbidity and mortality.

Conflict of interest disclosure

No conflicts to disclose.
Validity of self-screening with the KOJI AWARENES™ test for range of motion and strength in healthy subjects
Authors: Hirohata Kenji , Furuya Hidetaka , Mitomo Sho , Osaka Yuki , Murofushi Koji , Yagishita Kazuyoshi
Published: April 2024

Objective

This study aimed to establish the validity of the KOJI AWARENESSTM sub-components by determining whether there is a connection between the sub-component scores and joint range of motion, muscle strength, and balance.

Methods

Fifty healthy adults (17 females and 33 males) participated in the study, completing both the KOJI AWARENESSTMand measurements of joint range of motion, muscle strength, and balance. The range of motion of the upper and lower extremities and trunk was measured using either a goniometer or an inclinometer. A handheld dynamometer was used to measure muscle strength. Balance ability was assessed using a modified balance error scoring system. Using the Mann–Whitney U test or Jonckheere–Terpstra test, we compared the KOJI AWARENESS™ score and the corresponding body segments, with a significance level of P ≤ 0.05.

Results

Our results indicated that there were associations between external references and many items, but no associations were found for flexion, extension, and rotation of the "neck mobility," extension and external rotation of the "hip mobility," and strength of the "mid-section stability strength" in the KOJI AWARENESSTM.

Conclusion

Overall, the KOJI AWARENESSTMsub-component scores showed good validity, with the exception of the items related to neck and hip flexibility and trunk muscle strength. Future analyses should include a wider range of age groups, such as middle-aged and elderly individuals.
Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci
Authors: Francis Michael , Gorman Bryan R. , Bigdeli Tim B. , Genovese Giulio , Voloudakis Georgios , Bendl Jaroslav , Zeng Biao , Venkatesh Sanan , Chatzinakos Chris , McAuley Erin , Ji Sun-Gou , Markianos Kyriacos , Schreiner Patrick A. , Partan Elizabeth , Shi Yunling , Devineni Poornima ,   VA Million Veteran Program, Moser Jennifer , Muralidhar Sumitra , Ramoni Rachel , Bick Alexander G. , Natarajan Pradeep , Assimes Themistocles L. , Tsao Philip S. , Klarin Derek , Tcheandjieu Catherine , Peachey Neal S. , Iyengar Sudha K. , Roussos Panos , Pyarajan Saiju
Published: April 2024

Mosaic loss of chromosome Y (mLOY) is a common somatic mutation in leukocytes of older males. mLOY was detected in 126,108 participants of the Million Veteran Program: 106,054 European (EUR), 13,927 admixed African (AFR), and 6,127 Hispanic. In multi-ancestry genome-wide association analysis, we identified 323 genome-wide significant loci, 167 of which were novel–more than doubling the number of known mLOY loci. Tract-based ancestry deconvolution resolved local inflation at AFR lead SNPs. Transcriptome-wide associations yielded 2,297 significant genes, including seven additional novel genes; integrative eQTL analyses highlighted 51 genes that causally influence mLOY via differential expression. Thirty-two significant traits found in a phenome-wide polygenic score scan were used in Mendelian randomization (MR). MR implicated six traits as causal influences on mLOY: triglycerides, high-density lipoprotein, smoking, body mass index, testosterone, and sex hormone-binding globulin; and found influence of mLOY on plateletcrit, prostate cancer, lymphocyte percentage, and neutrophil percentage. These results mark a major step forward in our understanding of the genetic architecture of mLOY and its associated risks.
Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression
Authors: Cenzano Itziar , Cócera Miguel , Bantan Azari , Larrayoz Marta , Vilas-Zornoza Amaia , San-Martin Patxi , Aguirre-Ruiz Paula , Alignani Diego , Lopez Aitziber , Barrios Marta Miñana , Agreda Delia Quilez , González Ignacio Sancho , Ruiz Javier , Lagani Vincenzo , Tegner Jesper , Martín-Subero Ignacio , Agirre Xabier , Paiva Bruno , Rodriguez-Otero Paula , Tamariz-Amador Luis-Esteban , San-Miguel Jesús , Martinez-Climent Jose A. , Saez Borja , Hernáez Mikel , Calvo Isabel A. , Gomez-Cabrero David , Prosper Felipe
Published: April 2024

The role of the bone marrow microenvironment (BME) in the transition from monoclonal gammopathy of undetermined significance (MGUS) into clinically active multiple myeloma (MM) is not completely determined. To address this issue, we performed single-cell RNA sequencing (scRNA-seq) of non-hematopoietic BME cells as well as plasma cells (PC) from two genetically engineered mouse models of MM termed BIcγ1and MIcγ1that recapitulate the progression of MGUS into MM. Our results identify distinct transcriptional dynamics between endothelial cells (EC) and mesenchymal stem cells (MSC). While EC acquire a stress state during MGUS, a proliferating and angiogenic profile characterizes MM. On the other hand, MSC compromised their differentiation potential, exhibiting a more inflammatory profile that initiates from the MGUS stage. Interestingly, we identified an interferon (IFN)-related myeloma signature in malignant EC of the BIcγ1model, which is also expressed in MSC but not observed in the more aggressive MIcγ1model and can be identified in MSC from a subgroup of MM patients. The analysis of the EC and MSC interactions with malignant PC revealed stage-specific interactions that contribute to angiogenesis, immunomodulation, and MM extravasation. Finally, the translational relevance of our results in humans was confirmed on MSC from newly diagnosed patients with monoclonal gammopathies at different stages of the disease. In summary, these results show a remodeling of the non-hematopoietic BME in MM progression, providing potential targets at the tumor-niche interface that may hold clinical significance and complement existing immunotherapies.

Abstract Figure

KEY POINTS

EC stress pre-vascular state in MGUS, shifts to angiogenic in MM, while MSC early transcriptional changes in MGUS persist in overt MM.

Identification of a myeloma-specific IFN signature in the non-hematopoietic BME that could define a subgroup of MM patients.
Carbonic anhydrase plays multiple roles in acetotrophic growth of a model marine methanogen from the domainArchaea
Authors: Santiago-Martínez Michel Geovanni , Zimmerman Sabrina , Apolinario Ethel E. , Sowers Kevin R. , Ferry James G.
Published: April 2024

Carbonic anhydrase (CA) catalyzes the reversible hydration of CO2to bicarbonate and a proton. The enzyme is universally distributed in all three domains of life and plays diverse physiological roles in the domainsEukaryaandBacteria. Remarkably, a physiological role has not been identified for any CA from the domainArchaea. Herein are described roles for a gamma class CA (Cam) from the methane-producing marine archaeonMethanosarcina acetivorans. Acetate-dependent growth of a Δcammutant showed an extended lag phase, lower final cell density, and metabolized acetate to a threshold of 20.0 mM compared to 1.0 mM for wild-type. Molar growth yields (Ymethane) were substantially greater for wild-type compared to the mutant. In contrast, growth parameters were identical for the methanol-grown wild-type and mutant. Rates of methane formation in resting cell suspensions containing 20.0 mM acetate were significantly less in the mutantversuswild-type and dependent on the presence of CO2. Rates for the wild-type decreased with increasing pH that was more pronounced for the mutant. CA activity was 100-fold greater in the membraneversussoluble fraction of acetate-grown cells. Addition of a surrogate CA stimulated acetate-dependent methanogenesis in resting cell suspensions of the mutant. The results support a role for Cam to supply protons for symport of acetate by the AceP symporter that also optimizes and facilitates growth at low acetate concentrations and high pH values encountered in the marine environment whereM. acetivoranswas isolated.

Significance Statement

Although CA plays major physiological roles in the domainsEukaryaandBacteria, a role has not been reported for the domainArchaeain which methanogens comprise the major group with abundant genomic annotations for CAs. Acetotrophic methanogens account for most of the methane produced in Earth’s biosphere where it is a major greenhouse gas. Although the biochemistry of the conversion of acetate to methane and carbon dioxide is well known, little is understood of acetate transport. The finding that CA has multiple roles facilitating thermodynamically constrained growth of a model marine acetotrophic methanogen has implications for advancing ecological understanding of the methane cycle that impacts global warming and climate change. Finally, the work is an introduction to anticipated physiological roles of CAs in the domainArchaeafor which genomic annotations are abundant.