bluuebunny/crossref_metadata_2025 huggingface dataset:
Photon-Counting Versus Energy-Integrating Detector CT Angiography of the Lower Extremity in a Human Cadaveric Model With Continuous Extracorporeal Perfusion
Authors: Gruschwitz Philipp , Hartung Viktor , Kleefeldt Florian , Ergün Süleyman , Huflage Henner , Peter Dominik , Hendel Robin , Patzer Theresa Sophie , Pannenbecker Pauline , Kuhl Philipp Josef , Bley Thorsten Alexander , Petritsch Bernhard , Grunz Jan-Peter
Published: September 2023

Objectives

Detailed visualization of the arterial runoff is mandatory for the assessment of peripheral arterial occlusive disease. This study aims to compare the performance of a first-generation photon-counting detector computed tomography (PCD-CT) to a third-generation energy-integrating detector CT (EID-CT).

Materials and Methods

Computed tomography angiographies of 8 upper leg arterial runoffs were performed on human cadaveric models with continuous extracorporeal perfusion. For both PCD-CT and EID-CT, radiation dose-equivalent 120 kVp acquisition protocols (low-/medium-/high-dose: CTDIVol= 3/5/10 mGy) were used. All scans were performed with standard collimation (PCD-CT: 144 × 0.4 mm; EID-CT: 96 × 0.6 mm), a pitch factor of 0.4, and a gantry rotation time of 1.0 second. Reformatting of data included the use of comparable vascular kernels (Bv 48/49), a slice thickness and increment of 1.0 mm, and a field of view of 150 × 150 mm. Eight radiologists evaluated image quality independently using a browser-based pairwise forced-choice comparison setup. Kendall concordance coefficient (W) was calculated to estimate interrater agreement. Signal-to-noise ratio and contrast-to-noise ratio (CNR) were compared based on 1-way analyses of variance and linear regression analysis.

Results

Low-dose PCD-CT achieved superior signal-to-noise ratio/CNR values compared with high-dose EID-CT (P< 0.001). Linear regression analysis suggested that an EID-CT scan with a CTDIVolof at least 15.5 mGy was required to match the CNR value of low-dose PCD-CT. Intraluminal contrast attenuation was higher in PCD-CT than EID-CT, irrespective of dose level (415.0 ± 31.9 HU vs 329.2 ± 29.4 HU;P< 0.001). Subjective image quality of low-dose PCD-CT was considered superior to high-dose EID-CT (P< 0.001). Interrater agreement was high (W= 0.989).

Conclusions

Using cadaveric models with continuous extracorporeal perfusion allows for intraindividual image quality comparisons between PCD-CT and EID-CT on variable dose levels. With superior luminal contrast attenuation and denoising in angiographies of the peripheral arterial runoff, PCD-CT displayed potential for radiation saving of up to 83% compared with EID-CT.
FDG-Avid Malakoplakia of the Ureter Mimicking Malignancy
Authors: Zhao Qian , Dong Aisheng , Zuo Changjing , Chen Haige
Published: September 2023

Malacoplakia is a rare chronic granulomatous disease and frequently associated withEscherichia coliinfection. We describe the contrast-enhanced CT and FDG PET/CT findings in a case of bladder and ureteral malakoplakia withE. coliurinary tract infection. Contrast-enhanced CT showed multiple enhancing mural nodules in the bladder and left ureter, ranging from several millimeters to 3.1 cm. The ureteral nodules showed significantly increased FDG uptake with SUVmaxof 20.4, due to histiocyte, lymphocyte, and plasma cell infiltrates revealed by histopathology.
Increased 18F-FAPI Uptake in Radiation-Induced Liver Injury
Authors: Zhang Jing , Jiang Shuqin , Zhang Rusen , Zhang Linqi
Published: September 2023

A 51-year-old woman with breast cancer underwent a complete surgical resection and chemoradiotherapy approximately 3 months ago. Follow-up abdominal ultrasound detected a new lesion with decreased echogenicity in the hepatic segment IV/VIII. 18F-FDG PET/CT showed the hepatic lesion without abnormal uptake. The patient was subsequently enrolled in a clinical trial of 18F-FAPI PET/CT to assess the hepatic lesion. An intense 18F-FAPI activity was identified in the hepatic lesion. Finally, pathological analysis combined with imaging follow-up confirmed the diagnosis of radiation-induced liver injury.
Topical 188Re Ionizing Radiation Therapy Exerts High Efficacy in Curing Nonmelanoma Skin Cancer
Authors: Tietze Julia K. , Heuschkel Martin , Krönert Maila I. C. , Kurth Jens , Bandow Gesine , Ojak Gregor , Grünwald Pavel , Herold Johanna Isabelle , Thiem Alexander , Dreßler Miriam , Krause Bernd J. , Emmert Steffen , Schwarzenböck Sarah M.
Published: September 2023

Purpose of the report

Nonmelanoma skin cancer (NMSC) is the most frequent malignancy. Surgical intervention is the common treatment but may lead to disappointing results; alternative treatment options are needed.

Methods

In this monocentric pilot study, topical 188Re resin was investigated as a treatment for invasive NMSC up to 3-mm thickness. Twenty-two patients with 40 histologically confirmed NMSCs with a median size of 1.25 cm2 (range, 0.04–16.8 cm2) and a median tumor thickness of 0.35 mm (range, 0.1–2.1 mm) were included. Patients were treated once with 188Re resin with a targeted dose of 50 Gy. The median applied activity was 111.4 MBq (range, 21.0–168.0 MBq), and the median treatment time was 89 minutes (range, 38–175 minutes). The response rate, adverse events, and cosmetic outcome were assessed at 14 days, 4 months, and 12 months.

Results

Response rate at 12 months was 97.5%, with 95% complete responses (clinically or histologically proven in case of clinical doubt). Most adverse events were reported at 14 days, with 20% itching and 12.5% mostly minor pain. Forty-nine percent of the lesions showed hypopigmentation only at 12 months. Forty-one percent of the lesions were graded as cosmetically superior to the expected result after surgery and 51.3% as comparable to successful surgery. The cosmetic outcome on the head and face was superior compared with the trunk and leg (P = 0.003).

Conclusion

188Re resin is a highly effective treatment for NMSC up to 3-mm thickness and a valid alternative to surgery, specifically for tumors located on sensitive areas such as nose or ear.
Dental Pulp Stem Cells and Current in vivo Approaches to Study Dental Pulp Stem Cells in Pulp Injury and Regeneration
Authors: Yang Dongwook , Solidum Jea Giezl Niedo , Park Dongsu
Published: September 2023

Dental pulp stem cells (DPSCs) have garnered significant interest in dental research for their unique characteristics and potential in tooth development and regeneration. While there were many studies to define their stem cell-like characteristics and osteogenic differentiation functions that are considered ideal candidates for regenerating damaged dental pulp tissue, how endogenous DPSCs respond to dental pulp injury and supply new dentin-forming cells has not been extensively investigated in vivo. Here, we review the recent progress in identity, function, and regulation of endogenous DPSCs and their clinical potential for pulp injury and regeneration. In addition, we discuss current advances in new mouse models, imaging techniques, and its practical uses and limitations in the analysis of DPSCs in pulp injury and regeneration in vivo.
Iris Koreana NAKAI Inhibits Osteoclast Formation via p38-Mediated Nuclear Factor of Activated T Cells 1 Signaling Pathway
Authors: Lee Hwa-Yeong , Jung Ji-Eun , Yim Mijung
Published: September 2023

Background: Iris Koreana NAKAI (IKN) is a flowering perennial plant that belongs to the Iridaceae family. In this study, we aimed to demonstrate the effects of IKN on osteoclast differentiation in vitro and in vivo. We also sought to verify the molecular mechanisms underlying its anti-osteoclastogenic effects.Methods: Osteoclasts were formed by culturing mouse bone marrow macrophage (BMM) cells with macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL). Bone resorption assays were performed on dentin slices. mRNA expression levels were analyzed by quantitative polymerase chain reaction. Western blotting was performed to detect protein expression or activation. Lipopolysaccharide (LPS)-induced osteoclast formation was performed using a mouse calvarial model.Results: In BMM cultures, an ethanol extract of the root part of IKN suppressed RANKL-induced osteoclast formation and bone resorptive activity. In contrast, an ethanol extract of the aerial parts of IKN had a minor effect on RANKL-induced osteoclast formation. Mechanistically, the root part of IKN suppressed RANKL-induced p38 mitogen-activated protein kinase (MAPK) activation, effectively abrogating the induction of c-Fos and nuclear factor of activated T cells 1 (NFATc1) expression. IKN administration decreased LPS-induced osteoclast formation in a calvarial osteolysis model in vivo.Conclusions: Our study suggested that the ethanol extract of the root part of IKN suppressed osteoclast differentiation and function partly by downregulating the p38 MAPK/c-Fos/NFATc1 signaling pathways. Thus, the root part
hART: Deep Learning-Informed Lifespan Heart Failure Risk Trajectories
Authors: Moroz Harry , Li Yue , Marelli Ariane
Published: September 2023

Heart failure (HF) results in persistent risk and long-term comorbidities. This is particularly true for patients with lifelong HF sequelae of cardiovascular disease such as patients with congenital heart disease (CHD). We developedhART(heart failure Attentive Risk Trajectory), a deep-learning model to predict HF trajectories in CHD patients.hARTis designed to capture the contextual relationships between medical events within a patient’s history. It is trained to predict future HF risk by using the masked self-attention mechanism that forces it to focus only on the most relevant segments of the past medical events. To demonstrate the utility ofhART, we used a large cohort containing healthcare administrative data from the Quebec CHD database (137,493 patients, 35-year follow-up).hARTachieves an area under the precision-recall of 28% for HF risk prediction, which is 33% improvement over existing methods. Patients with severe CHD lesion showed a consistently elevated predicted HF risks throughout their lifespan, and patients with genetic syndromes exhibited elevated HF risks until the age of 50. The impact of the birth condition decreases on long-term HF risk. The timing of interventions such as arrhythmia surgery had varying impacts on the lifespan HF risk among the individuals. Arrhythmic surgery performed at a younger age had minimal long-term effects on HF risk, while surgeries during adulthood had a significant lasting impact. Together, we show thathARTcan detect meaningful lifelong HF risk in CHD patients by capturing both long and short-range dependencies in their past medical events. Our code is available athttps://github.com/li-lab-mcgill/hART-heart-failure-Attentive-Risk-Trajectory.
ChatGPT 4 Versus ChatGPT 3.5 on The Final FRCR Part A Sample Questions. Assessing Performance and Accuracy of Explanations
Authors: Ghosn Youssef , Sardouk Omar El , Jabbour Yara , Jrad Manal , Kamareddine Mohammed Hussein , Abbas Nada , Saade Charbel , Ghanem Alain Abi
Published: September 2023

Objective

To evaluate the performance of two versions of ChatGPT, GPT4 and GPT3.5, on the Final FRCR (Part A) also referred to as FRCR Part 2A radiology exam. The primary objective is to assess whether these large language models (LLMs) can effectively answer radiology test questions while providing accurate explanations for the answers.

Methods

The evaluation involves a total of 281 multiple choice questions, combining the 41 FRCR sample questions found on The Royal Collage of Radiologists website and 240 questions from a supplementary test bank. Both GPT4 and GPT3.5 were given the 281 questions with the answer choices, and their responses were assessed for correctness and accuracy of the explanations provided. The 41 FRCR sample questions difficulty was ranked into “low order” and “high order” questions. A significance level of p<0.05 was used.

Results

GPT4 demonstrated significant improvement over GPT3.5 in answering the 281 questions, achieving 76.5% correct answers compared to 52.7%, respectively (p<0.001). GPT4 demonstrated significant improvement over GPT3.5 in providing accurate explanations for the 41 FRCR sample questions, with an accuracy of 65.9% and 31.7% respectively (p=0.002). The difficulty of the question did not significantly affect the models’ performances.

Conclusion

The findings of this study demonstrate a significant improvement in the performance of GPT4 compared to GPT3.5 on FRCR style examination. However, the accuracy of the provided explanations might limit the models’ reliability as learning tools.

Advances in Knowledge

The study indirectly explores the potential of LLMs to contribute to the diagnostic accuracy and efficiency of medical imaging while raising questions about the current LLMs limitations in providing reliable explanations for radiology related questions hindering its uses for learning and in clinical practice.

Highlights

ChatGPT4 passed an FRCR part 2A style exam while ChatGPT3.5 did not.

ChatGPT4 showed significantly higher correctness of answers and accuracy of explanations.

No significant difference in performance was observed between “high order” and “lower order” questions.

Explanation accuracy was lower than correct answers rate limiting the Models’ reliability as

learning tools.
Design, conduct, analysis, and reporting of therapeutic efficacy studies in Visceral Leishmaniasis: A systematic review of published reports, 2000-2021
Authors: Dahal Prabin , Singh-Phulgenda Sauman , Naylor Caitlin , Brack Matthew , Chatterjee Mitali , Alves Fabiana , Guerin Philippe J , Stepniewska Kasia
Published: September 2023

A systematic review (SR) of published efficacy studies in visceral leishmaniasis (VL) was carried out to describe methodological aspect of design, analysis, conduct and reporting. Studies published during 2000-2021 and indexed in the Infectious Diseases Data Observatory (IDDO) VL library of clinical studies were eligible for inclusion (n=89 studies). The IDDO VL library is a living SR of prospective therapeutic studies (PROSPERO: CRD42021284622) and is updated bi-annually. A total of 40 (44.9%) studies were randomised, 33 (37.1%) were single-armed, 14 (15.7%) were non-randomised multi-armed studies, and randomisation was unclear in 2 (2.2%). After initial screening, patients were enrolled into the study upon confirmation of VL using parasitological method in 26 (29.2%), and serological and parasitological method in 63 (70.8%). Post-treatment follow-up duration was <6months in 3 (3.3%) studies, 6-months in 75 (84.3%), and >6months in 11 (12.4%) studies. Relapse was defined solely based on clinical suspicion in 4 (4.5%) studies, parasitological demonstration in 64 (71.9%), using molecular/serological/parasitological in 6 (6.7%), and was unclear in 15 (16.9%). Quality control of laboratory measures adopted was unclear in 66 (74.2%) studies, sample size calculation was reported in only 34 (38.2%) studies, and cured proportion was presented only as a point estimate in 39 (43.8%) studies. This review highlights substantial variations in definitions adopted for patient screening, disease diagnosis and therapeutic outcomes suggesting an urgent need for harmonisation of VL clinical trials protocol.
Algorithmic identification of treatment-emergent adverse events from clinical notes using large language models: a pilot study in inflammatory bowel disease
Authors: Silverman Anna L , Sushil Madhumita , Bhasuran Balu , Ludwig Dana , Buchanan James , Racz Rebecca , Parakala Mahalakshmi , El-Kamary Samer , Ahima Ohenewaa , Belov Artur , Choi Lauren , Billings Monisha , Li Yan , Habal Nadia , Liu Qi , Tiwari Jawahar , Butte Atul J , Rudrapatna Vivek A
Published: September 2023

Background and Aims

Outpatient clinical notes are a rich source of information regarding drug safety. However, data in these notes are currently underutilized for pharmacovigilance due to methodological limitations in text mining. Large language models (LLM) like BERT have shown progress in a range of natural language processing tasks but have not yet been evaluated on adverse event detection.

Methods

We adapted a new clinical LLM, UCSF BERT, to identify serious adverse events (SAEs) occurring after treatment with a non-steroid immunosuppressant for inflammatory bowel disease (IBD). We compared this model to other language models that have previously been applied to AE detection.

Results

We annotated 928 outpatient IBD notes corresponding to 928 individual IBD patients for all SAE-associated hospitalizations occurring after treatment with a non-steroid immunosuppressant. These notes contained 703 SAEs in total, the most common of which was failure of intended efficacy. Out of 8 candidate models, UCSF BERT achieved the highest numerical performance on identifying drug-SAE pairs from this corpus (accuracy 88-92%, macro F1 61-68%), with 5-10% greater accuracy than previously published models. UCSF BERT was significantly superior at identifying hospitalization events emergent to medication use (p < 0.01).

Conclusions

LLMs like UCSF BERT achieve numerically superior accuracy on the challenging task of SAE detection from clinical notes compared to prior methods. Future work is needed to adapt this methodology to improve model performance and evaluation using multi-center data and newer architectures like GPT. Our findings support the potential value of using large language models to enhance pharmacovigilance.
Cryoballoon Ablation of RooF line combined with pulmonary vein Isolation for persistent atrial fibrillation (The CARFI-PerAF Randomized Clinical Trial)
Authors: Huang Songqun , Zhao Yao , Ju Ruihan , Liu Chao , Dong Shaohua , Qin Aihong , Cao Jiang , Yu Manli , Guo Zhifu , Huang Xinmiao
Published: September 2023

Background

The limited effectiveness of pulmonary vein isolation (PVI) alone using cryoballoon ablation (CBA) led to addictive ablation in procedures of persistent atrial fibrillation (AF) ablation. Roof line (RL) ablation in addition to PVI hold great promise for reduction of AF recurrence after CBA. The randomized controlled CARFI-PerAF trial aimed to prospectively investigate the efficacy of a novel CBA strategy for block of RL and reduction of AF recurrence.

Methods

One hundred and ten patients who were diagnosed with persistent AF were randomized into PVI group and PVI+RL group. ‘Quarter balloon ablation technique’ and ‘roof distortion technique’ were used to improve quality of RL ablation. Conduction block of RL was confirmed by both voltage mapping and upper right atrial septum pacing. Primary effectiveness was freedom from AF or atrial tachycardia absent class I/III antiarrhythmic drugs through 12-month follow-up according to ECGs collected by portable device and 24-hour Holter.

Results

There was no significant difference in AF recurrence between PVI group and PVI+RL group (63.5% vs 76.2%, P = 0.296) after 532.7 ± 171.0 days of follow-up. However, blocked RL was associated with a significant reduction in risk of AF recurrence in the PVI+RL group (84.0% vs 45.5%, P = 0.025). The shape of RL was the only factor affecting the success rate of RL block. Patients with ‘Regular’ shape of RL predicted a higher rate of RL block than other types (89.7% vs 56.3%, P = 0.014).

Conclusions

Blocked roof line ablation was associated with a significant reduction in risk of atrial fibrillation recurrence after cryoballoon ablation. Patients with ‘Regular’ shape of roof line may benefit more from roof line ablation.
The Value of the Gensini Score For Prognostic Assessment in Patients with Acute Coronary Syndrome--A Retrospective Cohort Study Based on Machine Learning Methods
Authors: Chen Lixia , Jia Sixiang , Mou Xuanting , Tu Yiting , Lin Wenting , Chao Feng , Xia Shudong
Published: September 2023

Background

The Gensini score (GS) provides a good assessment of the degree of coronary plate loading. However, its clinical significance has been little explored.

Methods

In this retrospective cohort study, we implemented model development and performance comparison on database of The Fourth Affiliated Hospital of Zhejiang University School of Medicine (2019.1-2020.12). The patients were followed up for 2 years. Follow-up endpoint was the occurrence of MACCEs. We extracted clinical baseline data from each ACS patient within 24 hours of hospital admission and randomly divided the datasets into 70% for model training and 30% for model validation. Area under the curve (AUC) was used to compare the prediction performance of XGBoost, SGD and KNN. A decision tree model was constructed to predict the probability of MACCEs using a combination of weight features picked by XGBoost and clinical significance.

Results

A total of 361 ACS patients who met the study criteria were included in this study. It could be observed that the probability of a recurrent MACCEs within 2 years was 25.2%. XGboost had the best predictive efficacy (AUC:0.97). GS has high clinical significance. Then we used GS, Age and CK-MB to construct a decision tree model to predict the probability model of MACCEs reoccurring, and the final AUC value reached 0.771.

Conclusions

GS is a powerful indicator for assessing the prognosis of patients with ACS. The cut-off value of GS in the decision tree model provides a reference standard for grading the risk level of patients with ACS.
Genome-Wide Association Study and Meta-Analysis of Phytosterols Identifies a Novel Locus for Serum Levels of Campesterol
Authors: Alenbawi Jamil , Al-Sarraj Yasser A. , Umlai Umm-Kulthum I. , Kadhi Ayat , Hendi Nagham N. , Nemer Georges , Albagha Omar M. E.
Published: September 2023

Background

Sitosterolemia is a rare inherited disorder caused by mutations in theABCG5/ABCG8genes. These genes encode proteins that are involved in the transport of plant sterols (phytosterols) out of the body. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including xanthoma formation, atherosclerosis, and premature coronary artery disease.

Methods

We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa (MENA) population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol measured using the Metabolon platform from the Qatar Biobank Cohort and genome sequence data provided by Qatar Genome Program. Furthermore, a trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9,758 subjects) of European ancestry was conducted.

Results

Using conditional analysis, we identified two independent single nucleotide polymorphisms (SNPs) associated with β-sitosterol (rs145164937 and rs4299376), and two independent SNPs associated with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to two previously reported variants (rs199689137 and rs4245791). All of them map to theABCG5/8locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants inSCARB1andABOwith sitosterolemia.

Conclusions

This is the first study to shed light on genetic determinants of phytosterols in the MENA region using a genome-wide association approach. We also established the first polygenic risk score for this trait using the European large cohort study. These findings may have future implications on the personalized treatment of hyperlipidemia in general while showing the importance of building population-specific multi-omics databases.

Clinical Perspective

The formulation of the first polygenic risk score for sitosterolemia provides an exceptionally reliable tool for polygenic evaluation.

Plant sterol measurement should be included in lipid panel checkups and genetic screening for patients with tendon xanthomas to ensure an accurate diagnosis.

The establishment of regional and national registries for sitosterolemia in the Qatari community is essential for effective monitoring of the incidence of the disease and reducing the risk of early coronary artery disease.
Poor Accuracy of Triage Blood Pressure Measurements in a Pediatric Obesity Hypertension Clinic
Authors: Wen William , Psoter Kevin J. , Solomon Barry S. , Urbina Elaine M. , Brady Tammy M.
Published: September 2023

Accurate triage blood pressure (BP) measurements are essential for clinical decision making. We investigated the agreement and diagnostic accuracy of usual triage vs. standardized BP measurements in an obesity-related hypertension clinic.

This was a retrospective study of paired triage and standardized BP measurements from patients 4-21 years old. Triage BPs are measured by a medical assistant or nurse, often by automated device. Triplicate manual BP measurements are obtained by the clinic physician. Bland-Altman analyses determined mean differences between paired triage and mean standardized BPs. GEE- based multivariable relative risk (RR) regression determined the RR of triage BP overestimation by ≥5mmHg. Overall agreement, sensitivity, specificity, positive predictive value, and negative predictive value of usual triage BP measurements identifying hypertensive BP were determined.

130 participants with 347 clinic encounters were included. Mean age was 13.3 years (standard deviation 3.94), 76% were Black race, 58% were male. Overall mean systolic and diastolic BP difference was 8.7 mmHg (95% limits on agreement: −16.66, 34.07) and 4.1 mmHg (95% limits on agreement: −18.56, 26.68), respectively. Triage systolic BP was more likely overestimated by ≥5mmHg when a large adult (RR=1.49; 95% confidence interval: 1.00, 2.21) or thigh cuff (RR=1.94; 95% confidence interval: 1.08, 3.51) was required vs. when a child/adult cuff was required. Overall agreement in identifying hypertensive BP was 57.6%. Sensitivity (52.6%), specificity (63.4%), positive predictive value (60.8%), and negative predictive value (55.3%) were low across all cuff sizes.

There was poor agreement between usual triage and standardized BP measurements, with potential for significant clinical implications.

Clinical Trial Registration

ReNEW Clinic Cohort Study (ReNEW),NCT03816462,https://clinicaltrials.gov/ct2/show/NCT03816462
Knot or Not? Sequence-Based Identification of Knotted Proteins With Machine Learning
Authors: Šrámková Denisa , Sikora Maciej , Uchal Dawid , Klimentová Eva , Perlinska Agata P. , Nguyen Mai Lan , Korpacz Marta , Malinowska Roksana , Rubach Pawel , Šimeček Petr , Sulkowska Joanna I.
Published: September 2023

Knotted proteins, although scarce, are crucial structural components of certain protein families, and their roles remain a topic of intense research. Capitalizing on the vast collection of protein structure predictions offered by AlphaFold, this study computationally examines the entire UniProt database to create a robust dataset of knotted and unknotted proteins. Utilizing this dataset, we develop a machine learning model capable of accurately predicting the presence of knots in protein structures solely from their amino acid sequences, with our best-performing model demonstrating a 98.5% overall accuracy. Unveiling the sequence factors that contribute to knot formation, we discover that proteins predicted to be unknotted from known knotted families are typically non-functional fragments missing a significant portion of the knot core. The study further explores the significance of the substrate binding site in knot formation, particularly within the SPOUT protein family. Our findings spotlight the potential of machine learning in enhancing our understanding of protein topology and propose further investigation into the role of knotted structures across other protein families.

TOC Graphic
Japanese Encephalitis Virus: A pan-proteome analysis for aggregation propensities and in vitro validation with Capsid anchor and 2K peptide
Authors: Saumya Kumar Udit , Bharadwaj Taniya , Thakur Duni Chand , Verma Deepanshu , Giri Rajanish
Published: September 2023

Japanese encephalitis infection is a vector-borne disease caused by the flavivirus Japanese encephalitis virus (JEV). It is responsible for severe brain infections in humans worldwide. Given the ubiquitous nature of complications and tropism associated with Japanese encephalitis (JE) infection, a holistic understanding of its molecular mechanism is essential. The phenomenon of abnormal protein aggregation into pathogenic amyloids is now increasingly linked to multiple human diseases, also known as Amyloidosis. Most are neurodegenerative disorders, but amyloidosis is not restricted to a specific organ or tissue type. The overlap of viral protein aggregation with human pathologies remains limited, and it is gaining momentum, especially after the devastating Covid-19 pandemic. Therefore, in this study, we have examined the likelihood of aggregation for the entire collection of proteins in JEV. Multiple independent web server tools were employed to scan for potential amyloid-prone regions (APRs), and it was followed by in vitro validation using two JEV transmembrane domains, Capsid anchor, and 2K peptides. These synthetic viral peptides were introduced to artificial aggregation-inducing conditions and then analyzed using different dye-based assays and microscopy methods confirming amyloid-like fibril structure formation. We found these aggregates cytotoxic to human neuronal cell lines and membrane damaging to human blood-derived RBCs. The aggregation kinetics of both peptides is enhanced in the presence of artificial membrane models and seeds of self and diabetes hallmark protein Amylin. Our findings thereby strongly suggest the possibility of JEV protein aggregation playing a vital role in its pathogenesis, opening up a broad scope of future study. Also, the interplay between JEV protein aggregation and initiation/progression of other proteopathies is possible and needs further exploration.
Dual Roles of the Conditional Exosomes Derived fromPseudomonas aeruginosaBiofilms: Promoting and Inhibiting Bacterial Biofilm Growth
Authors: Saad Marwa Gamal , Beyenal Haluk , Dong Wen-Ji
Published: September 2023

Antibiotic-resistant biofilm infections have emerged as public health concerns because of their enhanced tolerance of high-dose antibiotic treatments. The biofilm life cycle involves multiple developmental stages, which are tightly regulated by active cell-cell communication via specific extracellular signal messengers such as exosomes. This study was aimed at exploring the roles ofPseudomonas aeruginosaexosomes secreted at different developmental stages in controlling biofilm growth. Our results show that exosomes secreted byP. aeruginosabiofilms during their exponential growth phase (G-Exo) enhance biofilm growth. In contrast, exosomes secreted byP. aeruginosabiofilms during their death/survival phase (D-Exo) can effectively inhibit/eliminateP. aeruginosaPAO1 biofilms up to 4.8-log10CFU/cm2. The inhibition effectiveness of D-Exo againstP. aeruginosabiofilms grown for 96 hours improved further in the presence of 10-50 μM Fe3+ions. Proteomic analysis suggests the inhibition involves an iron-dependent ferroptosis mechanism. This study is the first to report the functional role of bacterial exosomes in bacterial growth, which depends on the developmental stage of the parent bacteria. The finding of D-Exo-activated ferroptosis-based bacterial death may have significant implications for preventing antibiotic resistance in biofilms.

Significance statement

Antibiotic-resistant bacterial infections caused 1.27 million deaths in 2019 [1], and this number is projected to increase to 10 million deaths annually worldwide by 2050 [2]. Of these infections, up to 80% are caused by biofilm-associated infections [3, 4], which pose a significant challenge to human health. The treatment of biofilm infections remains a formidable problem because of the limited effectiveness of the currently available antibiotics against drug-resistant biofilms [5, 6]. The development of new therapeutic approaches that can effectively combat biofilm infections is required. This study represents a promising solution to antibiotic-resistant biofilm infections. The successful use of exosomes against biofilms opens new possibilities for combating challenging antibiotic-resistant biofilm infections.
Systematic review and meta-analysis of intraventricular antibiotics for neonatal meningitis and ventriculitis
Authors: Valdivia Doriam Alejandrino Perera , Pérez Edgar Abraham Herrera , Vega Luis Roberto Zapata , García José Miguel Hurtado , Herrera Karen Vanessa
Published: September 2023

Background

Many pediatric and neurosurgical studies have been published regarding intraventricular antibiotics in neonatal meningitis and ventriculitis. We aimed to determine the safety and effectiveness of intraventricular antibiotics in neonates with meningitis and/or ventriculitis and analyze the quality of available evidence.

Methods

We systematically reviewed scientific literature from the PubMed, EMBASE, LILACS, and SCOPUS databases. Randomized experimental and observational studies were included. The Cochrane methodology was used for systematic reviews.

Results

Twenty six observational studies and one randomized clinical trial involving 272 patients were included. The risk of bias in both pediatric and neurosurgical studies was high, and the quality of evidence was low (evidence level C). In the pediatric studies, no significant differences in mortality were found between intraventricular antibiotics and only systemic antibiotic [25.4% vs 16.1%, OR=0.96 (0.42– 2.24),P=0.93]. However, when analyzing the minimum administered doses, we found a lower mortality when a minimum duration of 3 days for intraventricular antibiotics was used compared to only systemic antibiotic [4.3% vs 17%, OR=0.22 (0.07–0.72),P=0.01]. In the neurosurgical studies, the use of intraventricular antibiotics in ventriculitis generally results in a mortality of 5% and a morbidity of 25%, which is lower than that in cases where intraventricular antibiotics were not used, with an average mortality of 37.3% and a morbidity of 50%.

Conclusion

Considering the low quality of evidence in pediatric and neurosurgical studies, we can conclude with a low level of certainty that intraventricular antibiotics may not significantly impact mortality in neonatal meningitis and ventriculitis. However, reduced mortality was observed in cases treated with a minimum duration of 3 days of intraventricular antibiotic, particularly the multidrug-resistant or treatment-refractory infections. Higher-quality studies are needed to improve the quality of evidence and certainty regarding the use of intraventricular antibiotics for treating neonatal meningitis and ventriculitis.
Smoking Habits and the Onset of Stroke: Insights from the Kyoto Stroke Registry
Authors: Shigematsu Kazuo , Nakano Hiromi
Published: September 2023

Cigarette smoking is a well-established risk factor for stroke due to its contribution to atherosclerosis. This study utilized data from the Kyoto Stroke Registry (KSR) spanning April 1997 to March 2020 to investigate the relationship between smoking history and the age at which stroke occurs.

The study focused on stroke patients registered in the KSR, categorizing them into four groups based on their smoking history: those with no smoking history, individuals who quit smoking more than one year ago, those who smoked fewer than 20 cigarettes per day, and those who smoked more than 20 cigarettes per day. The primary objective was to compare the age at which stroke onset occurred among these groups, employing statistical analysis through a Student t-test to identify significant differences.

After excluding patients with missing smoking status information, the analysis involved 30,491 stroke patients. The results revealed a noteworthy association: individuals with a smoking history, particularly heavy smokers, experienced a significantly younger age at stroke onset compared to those who had never smoked. Moreover, the study found that quitting smoking for more than one year was linked to a later onset of stroke compared to continuing to smoke. This observation held true even among those who smoked less than 20 cigarettes per day. Furthermore, the study’s findings remained consistent across all stroke types, including cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage, regardless of gender.

In conclusion, this comprehensive analysis of the KSR data reinforces the well-established notion that smoking history plays a critical role in the timing of stroke onset. Importantly, it underscores the potential benefits of smoking cessation, as well as the avoidance of smoking altogether, in reducing the risk of stroke. These findings carry significant implications for public health initiatives aimed at stroke prevention and emphasize the pivotal role of smoking cessation programs in mitigating the risk of stroke-associated morbidity and mortality.
A novel interpretable deep transfer learning combining diverse learnable parameters for improved T2D prediction based on single-cell gene regulatory networks
Authors: Alghamdi Sumaya , Turki Turki
Published: September 2023

Accurate deep learning (DL) models to predict type 2 diabetes (T2D) are concerned not only with targeting the discrimination task but also with learning useful feature representation. However, existing DL tools are far from perfect and do not provide appropriate interpretation as a guideline to explain and promote superior performance in the target task. Therefore, we provide an interpretable approach for our presented deep transfer learning (DTL) models to overcome such drawbacks, working as follows. We utilize several pre-trained models including SEResNet152, and SEResNeXt101. Then, we transfer knowledge from pre-trained models via keeping the weights in the convolutional base (i.e., feature extraction part) while modifying the classification part with the use of Adam optimizer to deal with classifying healthy controls and T2D based on single-cell gene regulatory network (SCGRN) images. Another DTL models work in a similar manner but just with keeping weights of the bottom layers in the feature extraction unaltered while updating weights of consecutive layers through training from scratch. Experimental results on the whole 224 SCGRN images using 5-fold cross-validation show that our model (TFeSEResNeXT101) achieving the highest average balanced accuracy (BAC) of 0.97 and thereby significantly outperforming the baseline that resulted in an average BAC of 0.86. Moreover, the simulation study demonstrated that the superiority is attributed to the distributional conformance of model weight parameters obtained with Adam optimizer when coupled with weights from a pre-trained model.
EpiSegMix: A Flexible Distribution Hidden Markov Model with Duration Modeling for Chromatin State Discovery
Authors: Schmitz Johanna Elena , Aggarwal Nihit , Laufer Lukas , Walter Jörn , Salhab Abdulrahman , Rahmann Sven
Published: September 2023

Motivation

Automated chromatin segmentation based on ChIP-seq data reveals insights into the epigenetic regulation of chromatin accessibility. Existing segmentation methods are constrained by simplifying modeling assumptions, which may have a negative impact on the segmentation quality.

Results

We introduce EpiSegMix, a novel segmentation method based on a hidden Markov model with flexible read count distribution types and state duration modeling, allowing for a more flexible modeling of both histone signals and segment lengths. In a comparison with two existing tools, ChromHMM, Segway and EpiCSeg, we show that EpiSegMix is more predictive of cell biology, such as gene expression. Its flexible framework enables it to fit an accurate probabilistic model, which has the potential to increase the biological interpretability of chromatin states.

Availability and implementation

Source code:https://gitlab.com/rahmannlab/episegmix.
Dietary Pyruvate Targets Cytosolic Phospholipase A2 to Mitigate Inflammation and Obesity in Mice
Authors: Hasan Sadaf , Ghani Nabil , Zhao Xiangli , Good Julia , Huang Amanda , Wrona Hailey Lynn , Liu Jody , Liu Chuan-ju
Published: September 2023

Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiationin vitroand its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity, but it also sheds light on the mechanism of its action. Pyruvate’s prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.
Gαi2 Interaction with EB1 Controls Microtubule Dynamics and Rac1 Activity inXenopusNeural Crest Cell Migration
Authors: Villaseca Soraya , Leal Juan Ignacio , Tovar Lina Mariana , Ruiz María José , Guajardo Jossef , Morales-Navarrete Hernan , Mayor Roberto , Torrejón Marcela
Published: September 2023

Cell migration is a complex and essential process in various biological contexts, from embryonic development to tissue repair and cancer metastasis. Central to this process are the actin and tubulin cytoskeletons, which control cell morphology, polarity, focal adhesion dynamics, and overall motility in response to diverse chemical and mechanical cues. Despite the well-established involvement of heterotrimeric G proteins in cell migration, the precise underlying mechanism remains elusive, particularly in the context of development. This study explores the involvement of Gαi2, a subunit of heterotrimeric G proteins, in cranial neural crest cell migration, a critical event in embryonic development. Our research uncovers the intricate mechanisms underlying Gαi2 influence, revealing a direct interaction with the microtubule-associated protein EB1, and through this with tubulin, suggesting a regulatory function in microtubule dynamics modulation. Here, we show that Gαi2 knockdown leads to microtubule stabilization, alterations in cell polarity and morphology with an increased Rac1-GTP concentration at the leading edge and cell-cell contacts, impaired cortical actin localization and focal adhesion disassembly. Interestingly, in Gαi2 knockdown cells, RhoA-GTP was found to be reduced at cell-cell contacts and concentrated at the leading edge, providing evidence of Gαi2 significant role in polarity. Remarkably, treatment with nocodazole, a microtubule-depolymerizing agent, effectively reduces Rac1 activity, restoring cranial NC cell morphology, actin distribution, and overall migration. Collectively, our findings shed light on the intricate molecular mechanisms underlying cranial neural crest cell migration and highlight the pivotal role of Gαi2 in orchestrating microtubule dynamics through EB1 and EB3 interaction, modulating Rac1 activity during this crucial developmental process.
Systematical assessment of the impact of single spike mutations of SARS-CoV-2 Omicron sub-variants on the neutralization capacity of post-vaccination sera
Authors: Katzmarzyk Maeva , Clesle Denise Christine , van den Heuvel Joop , Hoffmann Markus , Garritsen Henk , Pöhlmann Stefan , Jacobsen Henning , Cicin-Sain Luka
Published: September 2023

The evolution of novel SARS-CoV-2 variants significantly affects vaccine effectiveness. While these effects can only be studied retrospectively, neutralizing antibody titers are most used as correlates of protection. However, studies assessing neutralizing antibody titers often show heterogeneous data. To address this, we investigated assay variance and identified virus infection time and dose as factors affecting assay robustness. We next measured neutralization against Omicron sub-variants in cohorts with hybrid or vaccine induced immunity, identifying a gradient of immune escape potential. To evaluate the effect of individual mutations on this immune escape potential of Omicron variants, we systematically assessed the effect of each individual mutation specific to Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5. We cloned a library of pseudo-viruses expressing spikes with single point mutations, and subjected it to pooled sera from vaccinated hosts, thereby identifying multiple mutations that independently affect neutralization potency. These data might help to predict antigenic features of novel viral variants carrying these mutations and support the development of broad monoclonal antibodies.
Phenome-wide association study of ovarian cancer identifies common comorbidities and reveals shared genetics with complex diseases and biomarkers
Authors: Mulugeta Anwar , Lumsden Amanda L , Madakkatel Iqbal , Stacey David , Lee S. Hong , Mäenpää Johanna , Oehler Martin K. , Hyppönen Elina
Published: September 2023

Background

Ovarian cancer (OC) is commonly diagnosed among older women who have comorbidities. This hypothesis-free phenome-wide association study (PheWAS) aimed to identify comorbidities associated with OC, as well as traits that share a genetic architecture with OC.

Methods

We used data from 181,203 white British female UK Biobank participants and analysed OC and OC subtype-specific genetic risk scores (OC-GRS) for an association with 889 diseases and 43 other traits. We conducted PheWAS and colocalisation analyses for individual variants to identify evidence for shared genetic architecture.

Results

The OC-GRS was associated with 10 diseases, and the clear cell OC-GRS was associated with five diseases at the FDR threshold (p =5.6×10−4). Mendelian randomisaiton analysis (MR) provided robust evidence for the association of OC with higher risk of “secondary malignant neoplasm of digestive systems” (OR 1.64, 95% CI 1.33, 2.02), “ascites” (1.48, 95% CI 1.17, 1.86), “chronic airway obstruction” (1.17, 95% CI 1.07, 1.29), and “abnormal findings on examination of the lung” (1.51, 95% CI 1.22, 1.87). Analyses of lung spirometry measures provided further support for compromised respiratory function. PheWAS on individual OC variants identified five genetic variants associated with other diseases, and seven variants associated with biomarkers (all, p ≤4.5×10−8). Colocalisation analysis identified rs4449583 as the shared causal variant for OC and seborrheic keratosis.

Conclusions

OC is associated with digestive and respiratory comorbidities. Several variants affecting OC risk were associated with other diseases and biomarkers, with this study identifying a novel genetic locus shared between OC and skin conditions.