bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of early rhythm control and healthy lifestyle on the risk of stroke in elderly patients with new-onset atrial fibrillation: a nationwide population-based cohort study
Authors: Lim Woo-Hyun , Lee So-Ryoung , Choi Eue-Keun , Lee Seung-Woo , Han Kyung-Do , Oh Seil , Lip Gregory Y. H.
Published: February 2024

Background

The impact of early rhythm control (ERC) combined with healthy lifestyle (HLS) on the risk of ischemic stroke in elderly patients with atrial fibrillation (AF) remains unaddressed.

Objective

To evaluate the impact of combined ERC and HLS on the risk of stroke in elderly patients with new-onset AF.

Methods

Using the Korean National Health Insurance Service database, we included patients aged ≥75 years with new-onset AF from January 2009 to December 2016 (n = 41,315). Patients who received rhythm control therapy within 2 years of AF diagnosis were defined as the ERC group. Non-smoking, non-to-mild alcohol consumption (<105 g/week), and regular exercise were defined as HLS. Subjects were categorized into four groups: group 1 (without ERC and HLS, n = 25,093), 2 (HLS alone, n = 8,351), 3 (ERC alone, n = 5,565), and 4 (both ERC and HLS, n = 2,306). We assessed the incidence of ischemic stroke as the primary outcome, along with admissions for heart failure, all-cause death, and the composite of ischemic stroke, admission for heart failure, and all-cause death.

Results

Median follow-up duration of the study cohort was 3.4 years. After adjusting for multiple variables, groups 2 and 3 were associated with a lower stroke risk (adjusted hazard ratio [aHR]: 95% confidence interval [CI]: 0.867, 0.794–0.948 and 0.713, 0.637–0.798, respectively) than that of group 1. Compared to Group 1, group 4 showed the lowest stroke risk (aHR: 0.694, 95% CI: 0.586–0.822) among all groups, followed by group 3 (0.713, 0.637–0.798) and group 2 (0.857, 0.794–0.948), respectively. Group 4 was associated with the lowest risk of all-cause death (aHR: 0.680, 95% CI: 0.613–0.754) and the composite outcome (aHR: 0.708, 95% CI: 0.649–0.772).

Conclusion

ERC and HLS were associated with a lower risk of ischemic stroke in elderly patients with new-onset AF. Concurrently implementing ERC and maintaining HLS was associated with the lowest risk of death and the composite outcome, with a modest synergistic effect on stroke prevention.
Hybrid PSO with tree-based models for predicting uniaxial compressive strength and elastic modulus of rock samples
Authors: Shahani Niaz Muhammad , Xiaowei Qin , Wei Xin , Jun Li , Aizitiliwumaier Tuerhong , Xiaohu Ma , Shigui Qiu , Weikang Cao , Longhe Liu
Published: February 2024

The mechanical characteristics of rocks, specifically uniaxial compressive strength (UCS) and elastic modulus (E), serve as crucial factors in ensuring the integrity and stability of relevant projects in mining and civil engineering. This study proposes a novel hybrid PSO (particle swarm optimization) with tree-based models, such as gradient boosting regressor (GBR), light gradient boosting machine (LightGBM), random forest (RF), and extreme gradient boosting (XGBoost) for predicting UCS and E of rock samples from Block IX of the Thar Coalfield in Pakistan. A total of 122 datasets were divided into training and testing sets, with an 80:20 ratio, respectively, to develop the predictive models. Key performance metrics, including the coefficient of determination (R2), mean absolute error (MAE), and root mean square error (RMSE), were employed to assess the model’s predictive performance. The results indicate that the PSO-XGBoost model demonstrated the highest accuracy in predicting UCS and E, outperforming the other models, which exhibited inferior predictive performance. Furthermore, this study utilized the SHAP (Shapley Additive exPlanations) machine learning method to enhance our understanding of how each input feature variable influences the output values of UCS and E. In conclusion, the proposed framework offers significant advantages in evaluating the strength and deformation of rocks at Thar Coalfield, with promising applications in the field of mining and rock engineering.
Four novel mutations identification in 17 beta-hydroxysteroid dehydrogenase-3 deficiency and our clinical experience: possible benefits of early treatment
Authors: Wang Yunpeng , Xu Yu , Zhang Huijiao , Yin Danyang , Pan Yiming , He Xiwen , Li Shuaiting , Cheng Zhi , Zhu Gaohui , Zhao Ting , Huang Huizhe , Zhu Min
Published: February 2024

Introduction

Individuals with 17-beta-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency face a multitude of challenges, primarily concerning genital appearance, potential malignancy risks, and fertility issues. This study reports our findings from an investigation involving five individuals affected by 17β-HSD3 deficiency, ranging in age from pre-adolescence to adolescence. Notably, we identified four previously unreported mutations in these subjects.

Methods

Our study included a comprehensive evaluation to determine the potential occurrence of testicular tumors. The methods involved clinical examinations, genetic testing, hormone profiling, and patient history assessments. We closely monitored the progress of the study subjects throughout their treatment.

Results

The results of this evaluation conclusively ruled out the presence of testicular tumors among our study subjects. Moreover, four of these individuals successfully underwent gender transition. Furthermore, we observed significant improvements in genital appearance following testosterone treatment, particularly among patients in the younger age groups who received appropriate treatment interventions.

Discussion

These findings underscore the critical importance of early intervention in addressing concerns related to genital appearance, based on our extensive clinical experience and assessments. In summary, our study provides insights into the clinical aspects of 17β-HSD3 deficiency, emphasizing the vital significance of early intervention in addressing genital appearance concerns. This recommendation is supported by our comprehensive clinical assessments and experience.
Recent advances in the treatment and delivery system of diabetic retinopathy
Authors: Wang Zhiyi , Zhang Ningzhi , Lin Pei , Xing Yiqiao , Yang Ning
Published: February 2024

Diabetic retinopathy (DR) is a highly tissue-specific neurovascular complication of type 1 and type 2 diabetes mellitus and is among the leading causes of blindness worldwide. Pathophysiological changes in DR encompass neurodegeneration, inflammation, and oxidative stress. Current treatments for DR, including anti-vascular endothelial growth factor, steroids, laser photocoagulation, and vitrectomy have limitations and adverse reactions, necessitating the exploration of novel treatment strategies. This review aims to summarize the current pathophysiology, therapeutic approaches, and available drug-delivery methods for treating DR, and discuss their respective development potentials. Recent research indicates the efficacy of novel receptor inhibitors and agonists, such as aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, peroxisome proliferator-activated receptor alpha agonists, and novel drugs in delaying DR. Furthermore, with continuous advancements in nanotechnology, a new form of drug delivery has been developed that can address certain limitations of clinical drug therapy, such as low solubility and poor penetration. This review serves as a theoretical foundation for future research on DR treatment. While highlighting promising therapeutic targets, it underscores the need for continuous exploration to enhance our understanding of DR pathogenesis. The limitations of current treatments and the potential for future advancements emphasize the importance of ongoing research in this field.
What are the environmental factors that affect respiratory viral pathogen transmission and outcomes? A scoping review of the published literature
Authors: Spencer Elizabeth , Brassey Jon , Pluddemann Annette
Published: February 2024

Introduction

Respiratory viral pathogens are a major cause of morbidity and mortality, and there is a need to understand how to prevent their transmission.

Methods

We performed a scoping review to assess the amount and scope of published research literature on environmental factors, including meteorological factors and pollution, that affect the transmission of respiratory viral pathogens. We used Joanna Briggs Institute methodology for conducting a scoping review. We searched the electronic databases: MEDLINE, Register of Controlled Trials (Cochrane CENTRAL), TRIP database, WHO Covid-19 Database, Global Index Medicus, LitCovid, medRxiv, and Google Scholar. We included studies on environmental exposures and transmission of respiratory viruses (including but not restricted to: influenza, respiratory syncytial virus (RSV), human coronaviruses, viral pneumonia).

Results

The searches identified 880 studies for screening; after screening we included 481 studies, including 395 primary studies and 86 reviews. Data were extracted by one reviewer (ES) and independently checked by a second reviewer for accuracy (AP). All primary studies were observational, mostly using an ecological design; 2/395 primary studies were prospective cohorts. Among the primary studies, 241/395 were on SARS-CoV-2/COVID-19; 95 focussed on influenza; the remaining 59 reported on RSV, other coronaviruses, and other respiratory viruses. Exposures were most commonly temperature (306 primary studies) and humidity (201 primary studies); other commonly reported exposures were air pollution, wind speed, precipitation, season, and UV radiation. It was frequently reported, but not consistently, that temperature, humidity and air pollution were positively correlated with COVID-19 cases/deaths; for influenza, season/seasonality was commonly reported to be associated with cases/deaths.

Discussion

The majority of studies reported on SARS-CoV-2/COVID-19 and were of ecological design. Few prospective cohort studies have been done for any respiratory virus and environmental exposures. Understanding the role of environmental factors on transmission is limited by the lack of prospective cohort studies to inform decision making.

Systematic Review Registration

https://osf.io/ntdjx/, identifier: 10.17605/OSF.IO/NTDJX.
Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report
Authors: Bouhamdani Nadia , McConkey Haley , Leblanc Amélie , Sadikovic Bekim , Amor Mouna Ben
Published: February 2024

The lysine methyltransferase 2B (KMT2B) gene product is important for epigenetic modifications associated with active gene transcription in normal development and in maintaining proper neural function. Pathogenic variants in KMT2B have been associated with childhood-onset Dystonia-28 and Intellectual developmental disorder, autosomal dominant 68 (MRD 68) for cases of neurodevelopmental impairment without dystonia (DYT28; OMIM 617284 and MRD68; OMIM 619934, respectively). Since its first description in 2016, approximately one hundred KMT2B genetic variants have been reported with heterogeneous phenotypes, including atypical patterns of dystonia evolution and non-dystonic neurodevelopmental phenotypes. KMT2B-related disorders share many overlapping phenotypic characteristics with other neurodevelopmental disorders and delayed dystonia, that can appear later in childhood, often delaying clinical diagnosis. Furthermore, conventional genetic testing may not always provide actionable information (e.g., gene panel selection based on early clinical presentation or variants of uncertain significance), which prevents patients and families from obtaining early access to treatments and support. Herein, we describe the early diagnosis of KMT2B-related neurodevelopmental disorder by DNA methylation episignature testing in a 4-year-old patient without features of dystonia at diagnosis, which is reported to develop in more than 80% of KMT2B-related disorder cases. The proband, a 4-year-old female of Jewish-Israeli descent, presented with speech delay, microcephaly, poor weight gain, attention-deficit and hyperactivity disorder, dysmorphism, intellectual disabilities and joint hyperlaxity, but presented no signs of dystonia at initial evaluation. Episignature screening in this pre-symptomatic patient enabled accurate genetic diagnosis and timely and actionable intervention earlier in the natural history of Childhood-onset Dystonia-28.
Immune checkpoint inhibitor-related pneumonitis: research advances in prediction and management
Authors: Lin Mei-Xi , Zang Dan , Liu Chen-Guang , Han Xu , Chen Jun
Published: February 2024

The advent of immune-checkpoint inhibitors (ICIs) has revolutionized the treatment of malignant solid tumors in the last decade, producing lasting benefits in a subset of patients. However, unattended excessive immune responses may lead to immune-related adverse events (irAEs). IrAEs can manifest in different organs within the body, with pulmonary toxicity commonly referred to as immune checkpoint inhibitor-related pneumonitis (CIP). The CIP incidence remains high and is anticipated to rise further as the therapeutic indications for ICIs expand to encompass a wider range of malignancies. The diagnosis and treatment of CIP is difficult due to the large individual differences in its pathogenesis and severity, and severe CIP often leads to a poor prognosis for patients. This review summarizes the current state of clinical research on the incidence, risk factors, predictive biomarkers, diagnosis, and treatment for CIP, and we address future directions for the prevention and accurate prediction of CIP.
CXCR5+TIM-3-PD-1+ stem-like cytotoxic CD8+ T cells: elevated in chronic rhinosinusitis and associated with disease severity
Authors: Liu Zhichen , Zhao Zixuan , Xie Huanxia , Lu Ning , Liu Jisheng , Jiao Qingqing
Published: February 2024

Background

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease with an autoimmune background. Altered expression levels of T cell immunoglobulin and mucin-domain containing-3 (TIM-3), C-X-C chemokine receptor type 5 (CXCR5), and programmed cell death protein 1 (PD-1) are implicated in the progression of inflammatory and autoimmune diseases. Moreover, CXCR5+TIM-3-PD-1+ stem-like cytotoxic T cells function as memory stem cells during chronic disease processes and retain cytotoxicity-related gene networks.

Objectives

To explore the expressions of CXCR5, TIM-3, and PD-1 on T cells and their correlation with clinical parameters in CRS.

Methods

Flow cytometry was used to assess the expressions and co-expressions of CXCR5, TIM-3, and PD-1 on T cells in the tissues of the paranasal sinus and peripheral blood of patients with CRS as well as healthy controls. Immunofluorescence was used to assess the co-localization of TIM-3, CXCR5, and PD-1 with T cells. The disease severity of our patients with CRS was evaluated using the Lund-Mackay score. A complete blood count was also performed for the patients with CRS.

Results

Expression levels of CXCR5 and PD-1 on T cells were significantly increased in the nasal tissues of patients with CRS. Compared with those in healthy controls, patients with CRS had high percentages of CXCR5+TIM-3-PD-1+ CD8+ and CD4+ T cells in nasal tissues, while no significant difference was observed in peripheral blood levels. Patients with CRS had a higher density of nasal CXCR5+TIM-3-PD-1+ T cells than that in healthy controls. CXCR5+TIM-3-PD-1+ CD8+ T cell levels in the nasal polyps of patients with CRS were negatively correlated with the patients’ Lund-Mackay scores. The levels of CXCR5+TIM-3-PD-1+ T cells in nasal tissues were also negatively associated with disease duration and positively associated with the chronic inflammatory state of CRS.

Conclusions

The level of CXCR5+TIM-3-PD-1+ stem cell-like T cells, especially CXCR5+TIM-3-PD-1+ CD8+ T cells, is increased in CRS. Therefore, inducing CXCR5+TIM-3-PD-1+ T cell exhaustion may be an effective immunotherapy for CRS.
Somatostatin-SSTR3-GSK3 modulates human T-cell responses by inhibiting OXPHOS
Authors: Zhang Bo , Feng Huiru , Lin Hui , Li Rui
Published: February 2024

Introduction

Somatostatin (SST) is a peptide hormone primarily synthesized in the digestive and nervous systems. While its impact on the endocrine system is well-established, accumulating evidence suggests a crucial role for SST and its analogues in modulating immune responses. Despite this, the precise mechanism through which SST regulates T cells has remained largely unknown.

Methods

To elucidate the impact of SST on human T cells, we conducted a series of experiments involving cell culture assays, molecular analyses, and metabolic profiling. Human T cells were treated with SST, and various parameters including proliferation, cytokine production, and metabolic activities were assessed. Additionally, we employed pharmacological inhibitors and genetic manipulations to dissect the signaling pathways mediating SST's effects on T cells.

Results

We showed that SST diminishes T-cell proliferation by influencing IL-2 production and T-cell mitochondrial respiration, while having no discernible impact on TCR-induced glycolysis. Our findings also identified that the regulatory influence of SST on T-cell responses and metabolism is contingent on its receptor, SSTR3. Moreover, we demonstrated that SST governs T-cell responses and metabolism by acting through the T-cell metabolic checkpoint GSK3.

Discussion

Our study provides novel insights into the immunoregulatory function of SST in human T cells, highlighting the complex interplay between hormonal signaling and immune regulation. Understanding the molecular mechanisms underlying SST's effects on T cells may offer therapeutic opportunities for manipulating immune responses in various pathological conditions.
Structural–functional diversity of CD47 proteoforms
Authors: Zhang Ting , Wang Feng , Xu Lu , Yang Yong-Guang
Published: February 2024

The ubiquitously expressed transmembrane glycoprotein CD47 participates in various important physiological cell functions, including phagocytosis, apoptosis, proliferation, adhesion, and migration, through interactions with its ligands, including the inhibitory receptor signal regulatory protein α (SIRPα), secreted glycoprotein thrombospondin-1 (TSP-1), and integrins. Elevated expression of CD47 is observed in a wide range of cancer cells as a mechanism for evading the immune system, blocking the interaction between the CD47 and SIRPα is the most advanced and promising therapeutic approach currently investigated in multiple clinical trials. The widely held view that a single type of CD47 protein acts through membrane interactions has been challenged by the discovery of a large cohort of CD47 proteins with cell-, tissue-, and temporal-specific expression and functional profiles. These profiles have been derived from a single gene through alternative splicing and post-translational modifications, such as glycosylation, pyroglutamate modification, glycosaminoglycan modification, and proteolytic cleavage and, to some extent, via specific CD47 clustering in aging and tumor cells and the regulation of its subcellular localization by a pre-translational modification, alternative cleavage and polyadenylation (APA). This review explores the origins and molecular properties of CD47 proteoforms and their roles under physiological and pathological conditions, mentioning the new methods to improve the response to the therapeutic inhibition of CD47–SIRPα immune checkpoints, contributing to the understanding of CD47 proteoform diversity and identification of novel clinical targets and immune-related therapeutic candidates.
Immunometabolic features of natural killer cells are associated with infection outcomes in critical illness
Authors: Chung Kuei-Pin , Su Jia-Ying , Wang Yi-Fu , Budiarto Bugi Ratno , Yeh Yu-Chang , Cheng Jui-Chen , Keng Li-Ta , Chen Yi-Jung , Lu Ya-Ting , Juan Yi-Hsiu , Nakahira Kiichi , Ruan Sheng-Yuan , Chien Jung-Yien , Chang Hou-Tai , Jerng Jih-Shuin , Huang Yen-Tsung , Chen Shih-Yu , Yu Chong-Jen
Published: February 2024

Immunosuppression increases the risk of nosocomial infection in patients with chronic critical illness. This exploratory study aimed to determine the immunometabolic signature associated with nosocomial infection during chronic critical illness. We prospectively recruited patients who were admitted to the respiratory care center and who had received mechanical ventilator support for more than 10 days in the intensive care unit. The study subjects were followed for the occurrence of nosocomial infection until 6 weeks after admission, hospital discharge, or death. The cytokine levels in the plasma samples were measured. Single-cell immunometabolic regulome profiling by mass cytometry, which analyzed 16 metabolic regulators in 21 immune subsets, was performed to identify immunometabolic features associated with the risk of nosocomial infection. During the study period, 37 patients were enrolled, and 16 patients (43.2%) developed nosocomial infection. Unsupervised immunologic clustering using multidimensional scaling and logistic regression analyses revealed that expression of nuclear respiratory factor 1 (NRF1) and carnitine palmitoyltransferase 1a (CPT1a), key regulators of mitochondrial biogenesis and fatty acid transport, respectively, in natural killer (NK) cells was significantly associated with nosocomial infection. Downregulated NRF1 and upregulated CPT1a were found in all subsets of NK cells from patients who developed a nosocomial infection. The risk of nosocomial infection is significantly correlated with the predictive score developed by selecting NK cell-specific features using an elastic net algorithm. Findings were further examined in an independent cohort of COVID-19-infected patients, and the results confirm that COVID-19-related mortality is significantly associated with mitochondria biogenesis and fatty acid oxidation pathways in NK cells. In conclusion, this study uncovers that NK cell-specific immunometabolic features are significantly associated with the occurrence and fatal outcomes of infection in critically ill population, and provides mechanistic insights into NK cell-specific immunity against microbial invasion in critical illness.
Inflammasome modulation with P2X7 inhibitor A438079-loaded dressings for diabetic wound healing
Authors: Yaron Jordan R. , Bakkaloglu Selin , Grigaitis Nicole A. , Babur Farhan H. , Macko Sophia , Rhodes Samantha , Norvor-Davis Solenne , Rege Kaushal
Published: February 2024

The inflammasome is a multiprotein complex critical for the innate immune response to injury. Inflammasome activation initiates healthy wound healing, but comorbidities with poor healing, including diabetes, exhibit pathologic, sustained activation with delayed resolution that prevents healing progression. In prior work, we reported the allosteric P2X7 antagonist A438079 inhibits extracellular ATP-evoked NLRP3 signaling by preventing ion flux, mitochondrial reactive oxygen species generation, NLRP3 assembly, mature IL-1β release, and pyroptosis. However, the short half-life in vivo limits clinical translation of this promising molecule. Here, we develop a controlled release scaffold to deliver A438079 as an inflammasome-modulating wound dressing for applications in poorly healing wounds. We fabricated and characterized tunable thickness, long-lasting silk fibroin dressings and evaluated A438079 loading and release kinetics. We characterized A438079-loaded silk dressings in vitro by measuring IL-1β release and inflammasome assembly by perinuclear ASC speck formation. We further evaluated the performance of A438079-loaded silk dressings in a full-thickness model of wound healing in genetically diabetic mice and observed acceleration of wound closure by 10 days post-wounding with reduced levels of IL-1β at the wound edge. This work provides a proof-of-principle for translating pharmacologic inhibition of ATP-induced inflammation in diabetic wounds and represents a novel approach to therapeutically targeting a dysregulated mechanism in diabetic wound impairment.
Purinergic enzymes on extracellular vesicles: immune modulation on the go
Authors: Winzer Riekje , Nguyen Du Hanh , Schoppmeier Felix , Cortesi Filippo , Gagliani Nicola , Tolosa Eva
Published: February 2024

An increase in the extracellular concentration of ATP as a consequence of cellular stress or cell death results in the activation of immune cells. To prevent inflammation, extracellular ATP is rapidly metabolized to adenosine, which deploys an anti-inflammatory signaling cascade upon binding to P1 receptors on immune cells. The ectonucleotidases necessary for the degradation of ATP and generation of adenosine are present on the cell membrane of many immune cells, and their expression is tightly regulated under conditions of inflammation. The discovery that extracellular vesicles (EVs) carry purinergic enzyme activity has brought forward the concept of EVs as a new player in immune regulation. Adenosine-generating EVs derived from cancer cells suppress the anti-tumor response, while EVs derived from immune or mesenchymal stem cells contribute to the restoration of homeostasis after infection. Here we will review the existing knowledge on EVs containing purinergic enzymes and molecules, and discuss the relevance of these EVs in immune modulation and their potential for therapy.
The effects of atmospheric nitrogen deposition in coral-algal phase shifts on remote coral reefs
Authors: Fu Yichen , Chen Xiaoyan , Liu Yuchen , Li Yuxiao , Yu Kefu
Published: February 2024

Remote seawater has been considered a potential refuge for corals in the face of anthropogenic disturbances. However, these remote areas may receive increased atmospheric N deposition, and the ecological consequences remain unclear. This field survey revealed coral-algal phase shifts in the mid-north of the South China Sea. These shifts were observed in 44%, 13.6%, and 26.5% of the sampled reef sites at depths of 1-4 m, 5-8 m, and 10-15 m, respectively. Over 50% of sections in the deeper depths hosted fewer corals compared to shallower areas, coinciding with a higher abundance of macroalgae in the deeper layers. Furthermore, based on long-term observation of atmospheric N flux, laboratory experiments were conducted to explore the cause of coral declines. The results indicate that N supply efficiently promoted macroalgae growth. The saturation of N absorption by macroalgae occurred within 2 weeks, leading to nutrient accumulation in seawater, especially nitrate, which had a direct impact on corals. While moderate N fluxes appeared to mitigate coral bleaching, high N fluxes, even with a balanced P supply or medium level of nutrients with an imbalanced N/P ratio, can both increase the susceptibility of corals to heat bleaching. This study explains the coral-algal phase shift in remote and relatively deep seawater and improves understanding of the cause-and-effect relationship between atmospheric N deposition and coral reef decline.
Positron emission tomography and its role in the assessment of vulnerable plaques in comparison to other imaging modalities
Authors: Proaño-Bernal Leonardo , Gilabert-García Ana , Sharma-Sharma Shubhang , Mora-Barrera Citlali M. , Singer-De-la-Garza Jethro , Beristain-de-la-Rosa P. Yael , Basile-Alvarez Martín Roberto , Guerra Enrique C. , Bermudez-Gonzalez Jorge Luis , Luna-Alcala Santiago , Espinola-Zavaleta Nilda , Alexanderson-Rosas Erick
Published: February 2024

The diagnosis and management of vulnerable plaques are topics of high interest in the cardiovascular field. Although imaging techniques like computed tomography angiography (MCTA) and ultrasonography (USG) can structurally evaluate atherosclerotic plaques, they are limited in examining internal cellular processes. Positron emission tomography (PET) molecular imaging, on the other hand, can highlight these cellular processes, including inflammation, angiogenesis, and lipid oxidation. Magnetic resonance imaging (MRI) is also a valuable non-invasive imaging technique that can provide detailed anatomical and functional information on the cardiovascular system. In this review, we compare the advantages and drawbacks of MCTA, USG and MRI imaging techniques with PET molecular imaging in evaluating vulnerable plaques. PET imaging allows physicians to measure different pathophysiological events within the plaque using intravenous radiotracers, of which 18F-fluorodeoxyglucose (18F-FDG) is the most validated one. By using 18F-FDG, physicians can understand the formation of the plaque, assess the accumulation of macrophages, and predict major cardiovascular events. However, some limitations exist in using 18F-FDG, including myocardial uptake and low sensitivity in imaging coronary arteries. We also mention other radiotracers that can help in evaluating vulnerable plaques, including 18F-NaF. Although PET imaging is still challenging, it has shown promise in evaluating vulnerable plaques and could be used to intervene in high-risk patients before major cardiovascular events occur.
Effects of Caragana korshinskii tannin on fermentation, methane emission, community of methanogens, and metabolome of rumen in sheep
Authors: Niu Xiaoyu , Xing Yuanyaun , Wang Jingyao , Bai Lili , Xie Yongfang , Zhu Shouqian , Sun Mei , Yang Jing , Li Dabiao , Liu Yuanyuan
Published: February 2024

The purpose of this research was to investigate the impact of dietary supplementation of Caragana korshinskii tannin (CKT) on rumen fermentation, methane emission, methanogen community and metabolome in rumen of sheep. A total of 15 crossbred sheep of the Dumont breed with similar body conditions, were divided into three groups (n = 5), which were fed with CKT addition at 0, 2 and 4%/kg DM. The study spanned a total of 74 days, with a 14-day period dedicated to adaptation and a subsequent 60-day period for conducting treatments. The results indicated that the levels of ammonia nitrogen (NH3-N) and acetate were reduced (p < 0.05) in rumen sheep fed with 2 and 4% CKT; The crude protein (CP) digestibility of sheep in 2 and 4% CKT groups was decreased(p < 0.05); while the neutral detergent fiber (NDF) digestibility was increased (p < 0.05) in 4% CKT group. Furthermore, the supplementation of CKT resulted in a decrease (p < 0.05) in daily CH4 emissions from sheep by reducing the richness and diversity of ruminal methanogens community, meanwhile decreasing (p < 0.05) concentrations of tyramine that contribute to methane synthesis and increasing (p < 0.05) concentrations of N-methy-L-glutamic acid that do not contribute to CH4 synthesis. However, CH4 production of DMI, OMI, NDFI and metabolic weight did not differ significantly across the various treatments. To sum up, the addition of 4% CKT appeared to be a viable approach for reducing CH4 emissions from sheep without no negative effects. These findings suggest that CKT hold promise in mitigating methane emissions of ruminant. Further investigation is required to evaluate it effectiveness in practical feeding strategies for livestock.
Engineering circular bacteriocins: structural and functional effects of α-helix exchanges and disulfide introductions in circularin A
Authors: Liu Fangfang , van Heel Auke J. , Kuipers Oscar P.
Published: February 2024

Circular bacteriocins form a distinct group of antimicrobial peptides (AMPs) characterized by their unique head-to-tail ligated circular structure and functional properties. They belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) family. The ribosomal origin of these peptides facilitates rapid diversification through mutations in the precursor genes combined with specific modification enzymes. In this study, we primarily explored the bacteriocin engineering potential of circularin A, a circular bacteriocin produced by Clostridium beijerinckii ATCC 25752. Specifically, we employed strategies involving α-helix replacements and disulfide bond introductions to investigate their effects on both biosynthesis and bioactivity of the bacteriocin. The results show the feasibility of peptide engineering to introduce certain structural properties into circularin A through carefully designed approaches. The introduction of cysteines for potential disulfide bonds resulted in a substantial reduction in bacteriocin biosynthesis and/or bioactivity, indicating the importance of maintaining dynamic flexibility of α-helices in circularin A, while reduction of the potential disulfide in one case increased the activity. The 5 α-helices of circularin A were respectively replaced by corresponding helices from another circular peptide, enterocin AS-48, and modestly active peptides were obtained in a few cases. Overall, this study provides valuable insights into the engineering potential of circular bacteriocins as antimicrobial agents, including their structural and functional restrictions and their suitability as peptide engineering scaffolds. This helps to pave the way for the development of novel antimicrobial peptides with tailored properties based on circular bacteriocins.
Case report: Dihydropyridine receptor (CACNA1S) congenital myopathy, a novel phenotype with early onset periodic paralysis
Authors: Aburahma Samah K. , Rousan Liqa A. , Shboul Mohammad , Biella Fabio , Lucchiari Sabrina , Comi Giacomo Pietro , Meola Giovanni , Pagliarani Serena
Published: February 2024

Introduction

CACNA1S related congenital myopathy is an emerging recently described entity. In this report we describe 2 sisters with mutations in the CACNA1S gene and the novel phenotype of congenital myopathy and infantile onset episodic weakness.

Clinical description

Both sisters had neonatal onset hypotonia, muscle weakness, and delayed walking. Episodic weakness started in infancy and continued thereafter, provoked mostly by cold exposure. Muscle imaging revealed fat replacement of gluteus maximus muscles. Next generation sequencing found the missense p.Cys944Tyr variant and the novel splicing variant c.3526-2A>G in CACNA1S. Minigene assay revealed the splicing variant caused skipping of exon 28 from the transcript, potentially affecting protein folding and/or voltage dependent activation.

Conclusion

This novel phenotype supports the notion that there are age related differences in the clinical expression of CACNA1S gene mutations. This expands our understanding of mutations located in regions of the CACNA1S outside the highly conserved S4 segment, where most mutations thus far have been identified.
Embodied metacognition as strengthened functional connection between neural correlates of metacognition and dance in dancers: exploring creativity implications
Authors: Yang Ching-Ju , Yu Hsin-Yen , Hong Tzu-Yi , Cheng Li-Kai , Li Wei-Chi , Yeh Tzu-Chen , Chen Li-Fen , Hsieh Jen-Chuen
Published: February 2024

Introduction

Dance education fosters embodied metacognition, enhancing student’s creativity. This study examines the crucial role of functional connectivity (FC) between the neural correlates of metacognition (NCM) and dance (NCD) as the neurological foundation for dancers’ embodied metacognition. The investigation also explores whether these consolidated FCs inform the general creativity in dancers.

Methods

The research involved 29 dancers and 28 non-dancer controls. The study examined resting-state connections of the NCM through seed-based FC analysis. Correlation analyses were employed to investigate the connections between the targeted NCM-NCD FCs, initiated from the a priori NCM seed, and general creativity.

Results

Dancers demonstrated heightened FC between NCM and NCD compared to non-dancer controls. The targeted regions included the putamen, globus pallidus, posterior cerebellum, and anterior insula of NCD. The dancers exhibited higher originality scores. In dancers, the enhanced FC showed a negative correlation with originality and a positive correlation with flexibility. Conversely, the controls exhibited no significant correlations.

Discussion

Extended dance training enhances the NCM-NCD connection signifying embodied metacognition. This interconnectedness may serve as the neural predisposition for fostering general creativity performance in dancers. Dancers with heightened levels of originality could leverage the relatively weaker NCM-NCD FCs to facilitate better integration and coordination of creative cognitive processes. Our findings suggest that the consolidated functional connections as sculpted by domain-specific training may inform general creativity.
The GLP-1 receptor agonist exenatide improves recovery from spinal cord injury by inducing macrophage polarization toward the M2 phenotype
Authors: Noguchi Toshihiro , Katoh Hiroyuki , Nomura Satoshi , Okada Keiko , Watanabe Masahiko
Published: February 2024

Although a wide variety of mechanisms take part in the secondary injury phase of spinal cord injury (SCI), inflammation is the most important factor implicated in the sequelae after SCI. Being central to the inflammation reaction, macrophages and their polarization are a topic that has garnered wide interest in the studies of SCI secondary injury. The glucagon-like peptide 1 (GLP-1) receptor agonist exenatide has been shown to enhance the endoplasmic reticulum stress response and improve motor function recovery after spinal cord injury (SCI). Since exenatide has also been reported to induce the production of M2 cells in models of cerebral infarction and neurodegenerative diseases, this study was conducted to examine the effects of exenatide administration on the inflammation process that ensues after spinal cord injury. In a rat contusion model of spinal cord injury, the exenatide group received a subcutaneous injection of 10 μg exenatide immediately after injury while those in the control group received 1 mL of phosphate-buffered saline. Quantitative RT-PCR and immunohistochemical staining were used to evaluate the effects of exenatide administration on the macrophages infiltrating the injured spinal cord, especially with regard to macrophage M1 and M2 profiles. The changes in hind limb motor function were assessed based on Basso, Beattie, Bresnahan locomotor rating scale (BBB scale) scores. The improvement in BBB scale scores was significantly higher in the exenatide group from day 7 after injury and onwards. Quantitative RT-PCR revealed an increase in the expression of M2 markers and anti-inflammatory interleukins in the exenatide group that was accompanied by a decrease in the expression of M1 markers and inflammatory cytokines. Immunohistochemical staining showed no significant difference in M1 macrophage numbers between the two groups, but a significantly higher number of M2 macrophages was observed in the exenatide group on day 3 after injury. Our findings suggest that exenatide administration promoted the number of M2-phenotype macrophages after SCI, which may have led to the observed improvement in hind limb motor function in a rat model of SCI.
Absence of GATA3/FOXA1 co-expression predicts poor prognosis in upper tract urothelial carcinoma
Authors: Wang Yue , Wang Yunfan , He Huiying , Xiong Yan
Published: February 2024

Objective

GATA binding protein 3 (GATA3) and forkhead box A1 (FOXA1) have been individually implicated in the progression of upper tract urothelial carcinoma (UTUC). This study aims to evaluate the prognostic value of GATA3/FOXA1 co-expression in UTUC patients.

Methods

We collected 108 UTUC pathological tissue samples with complete follow-up data and 24 normal control urothelial tissues. We created a 132-site microarray and performed immunohistochemistry (IHC) to measure GATA3 and FOXA1 expression levels. Kaplan-Meier survival and Cox regression analyses were conducted to assess UTUC prognosis.

Results

GATA3 expression was positively correlated with FOXA1 (P=0.031). Absence of GATA3/FOXA1 co-expression (GATA3-/FOXA1-) was associated with tumor extensive necrosis (P=0.001) after Bonferroni correction for multiple comparisons. GATA3-/FOXA1- was associated with shorter Disease-Free Survival (DFS) (P=0.001) and Cancer-Specific Survival (CSS) (P<0.001) than other combination groups. Multivariate analyses identified extensive necrosis as an independent prognostic factor for CSS (P=0.030).

Conclusions

Our study revealed a positive correlation between GATA3 and FOXA1 expression in UTUC. GATA3-/FOXA1- is linked to tumor extensive necrosis and poor prognosis in UTUC and may serve as a potential biomarker for UTUC patients.
Platinum-based neoadjuvant chemotherapy upregulates STING/IFN pathway expression and promotes TILs infiltration in NSCLC
Authors: Gao Huan , Zhang Xiaoni , Ren Mengdi , Jiang Aimin , Liu Na , Wang Jingjing , Zheng Xiaoqiang , Liang Xuan , Ruan Zhiping , Tian Tao , Fu Xiao , Yao Yu
Published: February 2024

Objectives

To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival.

Materials and methods

A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-β, and the infiltration density of CD3+ TILs and CD8+TILs. The correlation between the expression of STING, PD-L1, IFN-β and the infiltration density of CD3+ TILs and CD8+ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed.

Results

NACT increased the expression of STING, IFN-β and PD-L1 in tumor cells, and the infiltration of CD3+ and CD8+ TILs. In addition, ypTNM stage, ypN stage, changes in CD3+ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3+ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3+ TILs changes were independent prognostic factors for DFS and OS.

Conclusion

NACT stimulates STING/IFN-β pathway, promotes infiltration of CD3+ and CD8+ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3+TILs after NACT. Patients with ypN0 and elevated CD3+ TILs after NACT had better OS benefits.
Norovirus in children under 2 years of age: an epidemiological study in Panama during the COVID-19 pandemic
Authors: DeAntonio Rodrigo , Hess-Holtz Morgan , Abrego Leyda , Capitan-Barrios Zeuz , Donoso Leyla Hernandez , De León Tirza , Sáez Llorens Xavier , Moreno Brechla , Weil John Gerard
Published: February 2024

Introduction

Norovirus infection is a common cause of acute gastroenteritis (AGE). Surveillance activities are important to aid investigation into effective norovirus control strategies, including vaccination. Here, we report ancillary findings related to the incidence, prevalence, and etiology of AGE caused by norovirus in Panama after adjustment of study methodology to comply with national coronavirus disease 2019 (COVID-19) mandates.

Methods

In January 2020, children aged <2 years began enrolling into an epidemiological study in Panama to estimate the burden of norovirus in preparation for evaluating upcoming prevention strategies. This included an observational, longitudinal, community-based AGE surveillance study and a hospital-based AGE surveillance study. For the longitudinal study, healthy children aged 5–18 months were enrolled from January 6 through March 23, 2020, with a follow-up of approximately 6 months. The last participant was contacted on September 23, 2020. For the hospital-based study, starting on January 21, 2020, children aged <2 years who were admitted to the Hospital del Niño Dr. José Renán Esquivel in Panama City due to AGE were evaluated. The last sample was collected on September 29, 2020. Collected stool samples were tested for norovirus as well as astrovirus, sapovirus, and various enteropathogens. Unfortunately, this study was disrupted by the subsequent implementation of disease transmission control procedures for the COVID-19 pandemic, and the study methodology was revised to comply with COVID-19 mandates.

Results

In the longitudinal surveillance cohort [N = 400 (Chiriquí, n = 239; Panama, n = 161)], a total of 185 AGE episodes were documented (Chiriquí, n = 85; Panama, n = 100) resulting in an overall AGE incidence of 11.6 (95% CI: 9.99–13.4) episodes per 100 child-months. The norovirus-related AGE incidence was 0.3 (95% CI: 0.10–0.73) episodes per 100 child-months (5/185 AGE episodes) and the prevalence of norovirus was 4.6% (13/282 stool samples collected). In the hospital-based surveillance cohort, at least one pathogen was detected in 50% of samples (44/88 stool samples collected) and norovirus prevalence was 6.8% (6/88 stool samples collected).

Discussion

This report demonstrates how the occurrence of the COVID-19 pandemic hindered the conduct of clinical trials. However, this also created unique research opportunities to investigate the potential impact of pandemic control measures on the etiology of infectious diarrheal disease.
Optic nerve sheath diameter and its association with brain swelling in pediatric cerebral malaria: a retrospective study
Authors: Raees Madiha Q. , Gushu Montfort Benard , Taylor Terrie E. , Seydel Karl B. , Wynkoop Hunter J. , O’Brien Nicole F.
Published: February 2024

Introduction

Mortality in pediatric cerebral malaria (CM) in low- and middle-income countries (LMICs) is associated with brain swelling on magnetic resonance imaging (MRI); however, MRI is unavailable in most LMICs. Optic nerve sheath diameter (ONSD) measurement is an inexpensive method of detecting increased intracranial pressure compared with the invasive opening pressure (OP). Our primary objective was to determine if increased ONSD correlated with brain swelling on MRI in pediatric CM. Our secondary objective was to determine if increased ONSD correlated with increased OP and/or poor neurological outcome in pediatric CM. We hypothesized that increased ONSD would correlate with brain swelling on MRI and increased OP and that ONSD would be higher in survivors with sequelae and non-survivors.

Methods

We performed a retrospective chart review of children aged 0–12 years in Blantyre, Malawi, from 2013 to 2022 with CM as defined by the World Health Organization. Brain swelling on admission MRI was characterized by brain volume scores (BVS); severe swelling was scored as 7–8, mild-to-moderate as 4–6, normal as 3. The admission ONSD was measured via ultrasound; it was defined as abnormal if it was >4.5 mm in children >1 year and >4 mm in children <1 year. Favorable outcome was defined as a normal neurological exam on discharge in survivors. The primary and secondary objectives were evaluated using Spearman's correlation; and the demographics were compared using chi-square and the Kruskal–Wallis test (Stata, College Station, TX, USA).

Results

Median age of the 207-patients cohort was 50 months [interquartile range (IQR) 35–75]; 49% (n = 102) were female. Of those, 73% (n = 152) had a favorable outcome, and 14% (n = 30) died. Twenty-nine (14%) had a normal BVS, 134 (65%) had mild-to-moderate swelling, and 44 (21%) had severe swelling. ONSD was elevated in 86% (n = 178) of patients, while 12% of patients had increased OP. There was a weakly positive correlation between BVS and ONSD (r = 0.14, p = 0.05). The median ONSD was not significantly different compared by discharge outcome (p = 0.11) or by BVS (p = 0.18).

Conclusion

ONSD was not a reliable tool to correlate with BVS, neurological outcome, or OP in children with CM. Future studies to identify alternative methods of early identification of CM patients at highest risk for morbidity and mortality are urgently needed.