bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term increase in soluble interleukin-6 receptor levels in convalescents after mild COVID-19 infection
Authors: Lokau Juliane , Garbers Yvonne , Vicente Manuel M. , Dittrich Anna , Meltendorf Stefan , Lingel Holger , Münster-Kühnel Anja K. , Brunner-Weinzierl Monika , Garbers Christoph
Published: January 2025

Introduction

Serum levels of interleukin-6 (IL-6) are increased in COVID-19 patients. IL-6 is an effective therapeutic target in inflammatory diseases and tocilizumab, a monoclonal antibody that blocks signaling via the IL-6 receptor (IL-6R), is used to treat patients with severe COVID-19. However, the IL-6R exists in membrane-bound and soluble forms (sIL-6R), and the sIL-6R in combination with soluble glycoprotein 130 (sgp130) forms an IL-6-neutralizing buffer system capable of neutralizing small amounts of IL-6.

Methods

In this study, we analyzed serum levels of IL-6, sIL-6R and sgp130 in the serum of COVID-19 convalescent individuals with a history of mild COVID-19 disease and in acute severely ill COVID-19 patients compared to uninfected control subjects. Furthermore, we used single cell RNA sequencing data in order to determine which immune cell types are sources and targets of the individual cytokines and whether their expression is altered in severe COVID-19 patients.

Results

We find that sIL-6R levels are not only increased in acute severely ill patients, but also in convalescents after a mild COVID-19 infection. We show that this increase in sIL-6R results in an enhanced capacity of the sIL-6R/sgp130 buffer system, but that significantly enhanced free IL-6 is still present due to an overload of the buffer. Further, we identify IL-6 serum levels, age and the number of known pre-existing medical conditions as crucial determinants of disease outcome for the patients. We also show that IL-11 has no major systemic role in COVID-19 patients and that sCD25 is only increased in acute severely ill COVID-19 patients, but not in mild convalescent individuals.

Discussion

In conclusion, our study shows long-lasting alterations of the IL-6 system after COVID-19 disease, which might be relevant when applying anti-IL-6 or anti-IL-6R therapy.
Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors
Authors: Khan Safwaan H. , Choi Yeonjoo , Veena Mysore , Lee John K. , Shin Daniel Sanghoon
Published: January 2025

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, the extension of these successes to solid tumors remains limited due to several intrinsic challenges, including antigen heterogeneity and immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview of recent advances in CAR T cell therapy aimed at overcoming these obstacles. We discuss the importance of antigen identification by emphasizing the identification of tumor-specific and tumor-associated antigens and the development of CAR T therapies targeting these antigens. Furthermore, we highlight key structural innovations, including cytokine-armored CARs, protease-regulated CARs, and CARs engineered with chemokine receptors, to enhance tumor infiltration and activity within the immunosuppressive microenvironment. Additionally, novel manufacturing approaches, such as the Sleeping Beauty transposon system, mRNA-based CAR transfection, and in vivo CAR T cell production, are discussed as scalable solution to improve the accessibility of CAR T cell therapies. Finally, we address critical therapeutic limitations, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and suboptimal persistence of CAR T cells. An examination of emerging strategies for countering these limitations reveals that CRISPR-Cas9-mediated genetic modifications and combination therapies utilizing checkpoint inhibitors can improve CAR T cell functionality and durability. By integrating insights from preclinical models, clinical trials, and innovative engineering approaches, this review addresses advances in CAR T cell therapies and their performance in solid tumors.
Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation
Authors: Hangiu Oana , Navarro Rocío , Frago Susana , Rubio-Pérez Laura , Tapia-Galisteo Antonio , Díez-Alonso Laura , Gómez-Rosel Marina , Silva-Pilipich Noelia , Vanrell Lucía , Smerdou Cristian , Howard Kenneth A. , Sanz Laura , Álvarez-Vallina Luis , Compte Marta
Published: January 2025

Background

Immune checkpoint inhibitors have revolutionized cancer therapy, but many patients fail to respond or develop resistance, often due to reduced T cell activity. Costimulation via 4-1BB has emerged as a promising approach to enhance the effector function of antigen-primed T cells. Bispecific T cell-engaging (TCE) antibodies are an effective way to provide tumor-specific T cell receptor-mediated signaling to tumor-infiltrating lymphocytes. mRNA-based delivery of bispecific antibodies, offer a novel approach to enhance tumor-specific immune responses while minimizing adverse effects.

Methods

Two bispecific antibodies were generated: the EGFR x CD3 TCE antibody (LiTE) and the PD-L1 x 4-1BB costimulatory antibody (LiTCo), which was further fused to a high FcRn albumin variant (Albu-LiTCo). The mRNA encoding these bispecific antibodies contains an N1-methylpseudouridine modified nucleoside and regulatory sequences to ensure proper expression and stability. A series of in vitro assays and cell-based analyses were performed to characterize both antibodies. The in vivo efficacy of the mRNA-encoded bispecific antibodies was evaluated in xenograft tumor models expressing EGFR.

Results

We investigated the combined effect of two mRNA-encoded Fc-free bispecific antibodies with complementary mechanisms of action: an EGFR-targeting TCE and a half-life extended PD-L1 x 4-1BB costimulatory antibody. The mRNAs encoding both bispecific LiTERNA and Albu-LiTCoRNA, showed similar binding specificity and in vitro function to their protein analogues. Pharmacokinetic studies demonstrated sustained expression of both bispecific antibodies following intravenous administration of the mRNAs formulated using a polymer/lipid-based nanoparticle (LNP) but different pharmacokinetic profiles, shorter for the TCE and longer for the PD-L1 x 4-1BB. When administered as a mRNA-LNP combination (ComboRNA), the growth of EGFR-positive tumors in immunocompetent mice was significantly inhibited, resulting in tumor regression in 20% of cases with no associated toxicity. Histological analysis confirmed increased T cell infiltration in the tumors treated with LITERNA and ComboRNA. Repeated administration resulted in sustained production of bispecific antibodies with different exposure cycles and potent antitumor activity with a favorable safety profile.

Conclusions

These results highlight the potential of combining two mRNA-encoded bispecific antibodies with different mechanisms of action and programmable half-life for cancer immunotherapy.
The global trends and distribution in tumor-infiltrating lymphocytes over the past 49 years: bibliometric and visualized analysis
Authors: Wu Beibei , Luo Ding , Wang Xuejie , Qiao Chen , Li Rui , Liu Jian
Published: January 2025

Background

The body of research on tumor-infiltrating lymphocytes (TILs) is expanding rapidly; yet, a comprehensive analysis of related publications has been notably absent.

Objective

This study utilizes bibliometric methodologies to identify emerging research hotspots and to map the distribution of tumor-infiltrating lymphocyte research.

Methods

Literature from the Web of Science database was analyzed and visualized using VOSviewer, CiteSpace, Scimago Graphica, R-bibliometrix, and R packages.

Results

Research on tumor-infiltrating lymphocytes began in 1975 and has experienced significant growth, particularly after 2015. Leading contributors include the United States, the National Cancer Institute, the journal Cancer Immunology Immunotherapy, and researcher Steven A. Rosenberg. Other prominent contributors include China, the National Institutes of Health, researcher Roberto Salgado, and the Journal of Immunology. Prominent institutions in the USA and Europe occupy central roles within collaborative networks. Financial support plays a pivotal role in driving research advancements. Keyword clustering analysis reveals four primary knowledge domains: adoptive cell therapy; the prognostic value of TILs; PD-1/PD-L1 and TILs; and prognostic studies of TILs across various cancers. Keyword and reference analyses further indicate that “adoptive cell therapy,” “the prognostic value of TILs,” and “immune checkpoint inhibitors and TILs” are central themes in current and future research. Combination therapies; tumor neoantigens; gene editing; dominant population selection of TILs therapy; TILs in Tumor microenvironment; emerging predictive biomarkers; TILs in predicting the efficacy of neoadjuvant chemotherapy and immunotherapy; the relationship between TILs and PD-L1; TIL-based patient stratification; tertiary lymphoid structures; and TIL evaluation through digital pathology and artificial intelligence are identified as key areas of interest.

Conclusions

This analysis highlights the increasing academic focus on tumor-infiltrating lymphocyte research and identifies key recent themes in the field such as prognostic value of TILs, personalized treatments, and combination therapies.
Advancing diagnosis and treatment for human African trypanosomiasis in Nigeria: challenges and future directions
Authors: Zongo Kelly , Emmanuel Rolayo Toyin
Published: January 2025

Human African trypanosomiasis (HAT), commonly known as sleeping sickness, remains a significant health threat in sub-Saharan Africa. In Nigeria, the challenges of diagnosing and treating HAT are profound, especially in resource-constrained, remote areas. This article offers a perspective on the barriers to timely diagnosis and treatment of HAT in Nigeria, drawing from recent developments in diagnostic techniques and case management approaches. The focus is on improving the current diagnostic framework, decentralizing the validation process, and streamlining drug distribution to effectively halt the transmission of HAT. We discuss the potential of simple and rapid molecular diagnostics, particularly the lyophilized LAMP test, as a game-changer in resource-limited settings and the need for a national repository of drugs to ensure timely therapeutic interventions. This article also explores future directions for the elimination of HAT in Nigeria, highlighting the importance of policy reforms and increased investment in diagnostic infrastructure.
Plasticity of thermal tolerance and associated gill transcriptome in ballan wrasse (Labrus bergylta)
Authors: Palma Peter Almaiz , Bekaert Michaël , Gutierrez Alejandro P. , Abacan Elfred John C. , Migaud Herve , Betancor Mónica B.
Published: January 2025

Thermal condition has profound influence on physiology and behaviour of ballan wrasse (Labrus bergylta), a cleaner fish commonly deployed in salmon cages to control sea lice infection. To address knowledge gaps on the species thermal biology, critical thermal limits were determined by acclimating fish (21.5 ± 3.1 g, 10.5 ± 0.4 cm) at a range of temperatures (6, 10, or 14°C) found in its natural habitat on the west coast of Scotland for one week and subjecting them to ramping temperature (~0.3°C/min) until loss of equilibrium. Critical thermal maxima (CTmax), minima (CTmin), and thermal breadth values increased with acclimation temperature. Thermal tolerance polygon was constructed and showed the intrinsic (7.9 to 16.8°C) and acquired (3.4°C and 22.8°C) thermal tolerance zones, supporting the seasonal differences in behaviour and delousing efficacy of ballan wrasse deployed in salmon farms. Gill transcriptomic profiles of ballan wrasse were performed following thermal acclimation and subsequent exposure to CTmax and CTmin. Initial acclimation resulted in unique differentially expressed genes (DEGs) and enrichment of GO terms that were almost exclusively found in each acclimation group. Transcriptome response to CTmax and CTmin also varied between acclimation groups. CTmax and CTmin shared 0% DEGs at 6°C, 43% at 10°C, and 7% at 14°C, but some overlapping GO terms. This study is the first to investigate the thermal tolerance limits of ballan wrasse and provides new data into the plasticity of thermal tolerance limits and molecular response to thermal stimuli in fish.
Strength and durability of concrete with bentonite clay and quarry dust
Authors: Umar Muhammad , Qian Hui , Khan M. Nasir Ayaz , Siddique Muhammad Shahid , Almujibah Hamad , A. Elshekh Ali. E. , Bashir Maaz Osman , Vatin Nikolai Ivanovich
Published: January 2025

The research object is concrete with supplementary cementitious materials (SCMs) such as bentonite clay and quarry dust. The impact of incorporating these SCMs on fresh concrete properties, compressive, flexural, and split tensile strengths, and acid resistance was investigated. Microstructural analysis using Scanning Electron Microscopy (SEM) and X-ray radiography were used. Varying proportions of SCMs (5%–20%) were incorporated into the concrete mix while maintaining a constant water-to-cement ratio. Key findings reveal a 7.31% increase in compressive strength, a significant 19.7% improvement in flexural strength, and enhanced acid resistance. Utilizing Response Surface Methodology (RSM), the optimal mix design for achieving superior mechanical strength was identified. The quadratic model of RSM indicated that a combination of 10.29% bentonite clay, 7.20% quarry dust, and 8.19% fine aggregate replacement yielded the highest strength. Predictive and experimental results demonstrated strong agreement. Compared to the reference concrete, the optimized samples exhibited significant increases of 18.08%, 33.60%, and 11.15% in compressive, flexural, and tensile strengths, respectively. This research demonstrates the potential of locally available SCMs as viable and sustainable alternatives for concrete production, offering improved performance without compromising strength.
Comparison of the EQ-5D-3L and EQ-5D-5L instruments in patients undergoing unicompartmental knee arthroplasty
Authors: Tai Zhipeng , Wan Dongping , Zan Qiang , Huang Yuanchi , Xu Chao
Published: January 2025

Purpose

The purpose of this investigation is to assess and contrast the effectiveness of the two EuroQol five dimensions questionnaire (EQ-5D) versions—EQ-5D-3L and EQ-5D-5L—in assessing one-year quality of life outcomes for patients with knee osteoarthritis (KOA) undergoing unicompartmental knee arthroplasty (UKA).

Material and method

From the medical records at the Honghui Hospital, Xi’an Jiaotong University, 402 individuals aged 50 and above, who were one-year post-operation, were selected to fill out survey questionnaires during their return hospital visits. Of these, 231 respondents (57.5%) completed the questionnaire; 228 completed both versions, and 56 completed the EQ-5D retest questionnaire. The assessment included missing data, ceiling effects, informativity and discriminatory power, as well as response consistency, redistribution properties, and inconsistency. Reliability and validity were also evaluated.

Results

The results indicate that the EQ-5D-5L surpasses the EQ-5D-3L in construct validity, informativity, detection precision, and discriminatory power. Consistency reliability is also better in the EQ-5D-5L than in the EQ-5D-3L. Both instrument versions maintained reliable levels of test–retest reliability.

Conclusion

In patients with KOA undergoing UKA, the EQ-5D-5L has proven superior in measurement capabilities when compared with the EQ-5D-3L one-year post-operation. Thus, it is advised to utilize the EQ-5D-5L for ongoing assessments of quality of life in this specific group of patients.
Evaluation of the effectiveness of GASMAN anesthesia simulation software combined with case-based learning versus traditional lecture-based learning in inhalation anesthesia education
Authors: Chen Chao , Yang Shengfeng , Xiong Xinglong , Shi Yewei , Zhu Zhenyan , Shi Jing
Published: January 2025

Objective

To evaluate the effectiveness of integrating GASMAN anesthesia simulation software with case-based learning (IGC) compared to traditional lecture-based learning (LBL) in teaching inhalation anesthesia to undergraduate anesthesiology students.

Methods

Fourth-year students from two academic years (2022, n = 110; 2023, n = 131) enrolled in a five-year anesthesiology program were assigned to either traditional lecture-based learning (LBL) or IGC groups. The LBL group received traditional lectures using PowerPoint slides, while the IGC group engaged with GASMAN anesthesia simulation software (a tool designed for anesthesia simulation and gas monitoring) combined with case-based learning. The cases used in the IGC group were structured around realistic clinical scenarios, simulating real-world challenges in inhalation anesthesia. These scenarios were integrated with the GASMAN software to provide interactive simulations, enhancing students’ understanding of pharmacokinetics and pharmacodynamics. Teaching effectiveness was evaluated through expert assessments and student feedback, with learning outcomes compared via post-course assessments.

Results

The IGC group scored significantly higher in student evaluations in areas such as comprehending and mastering theoretical knowledge, resolving clinical challenges, nurturing clinical reasoning, increasing learning interest, enhancing learning efficiency, consolidating memory, improving analytical skills, and refining application proficiency (adjusted P < 0.001), however, there were no significant differences between the two groups in the improvement of practical skills. Post-course test scores were also higher in the IGC group for both total post-course test and subjective questions scores (adjusted P < 0.001), though no difference was found for objective question scores. After applying false discovery rate (FDR) correction, expert evaluation scores showed no significant differences between the two groups.

Conclusion

The integration of GASMAN software with case-based learning significantly enhances the quality of inhalation anesthesia education by improving student engagement, critical thinking, and conceptual understanding. This approach demonstrates promise for advancing clinical education, although further research is needed to evaluate its long-term impact.
Prevalence of psoriatic arthritis in Italy: insights from the multicentric MAPSI study
Authors: Serban Teodora , Tramontano Giuseppina , Pendolino Monica , Roccatello Dario , Epis Oscar Massimiliano , Iannone Florienzo , De Andres Ilenia , Favero Marta , Romeo Nicoletta , Rovera Guido , Santo Leonardo , Tirri Enrico , Bergamini Alberto , Foti Roberta , Schenone Carlotta , Bianchi Gerolamo
Published: January 2025

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with cutaneous psoriasis (PsO), first defined by Moll and Wright. Initially perceived as relatively benign, PsA is now recognized for its chronic, progressive, and destructive nature, significantly impacting patients' quality of life, similar to Rheumatoid Arthritis (RA). Globally, PsA represents about 20% of cases in early arthritis clinics, posing diagnostic and management challenges. Early diagnosis is crucial to prevent long-term disability and prevent comorbidities. While classification criteria for PsA are widely accepted, the lack of specific diagnostic criteria may delay diagnosis, with many patients experiencing delays of over a year before receiving an accurate diagnosis. For this reason, the exact prevalence of PsA remains uncertain.

Methods

The MAnagement of PSoriatic Arthritis in Italy (MAPSI) project is a multicenter observational study aimed to investigate the prevalence of PsA and characteristics in an Italian cohort. This study included 454 patients diagnosed or confirmed by a rheumatologist across 25 Rheumatology Units in Italy. Data were collected on demographics, clinical features, and treatment histories. In our cohort, distinct gender differences were observed in PsA phenotype and disease impact.

Results

Men had a higher prevalence of axial involvement and were more likely to be current or former smokers, while women showed greater rates of enthesitis and reported higher perceived disease activity. Additionally, women had a higher prevalence of psychological comorbidities, whereas men had more severe skin involvement; laboratory tests were often unhelpful in diagnosing PsA, with elevated inflammatory markers in only about half of the cases.

Discussion

These findings highlight the need for gender-sensitive approaches in the management of PsA. Our findings highlight the importance of comprehensive patient evaluation, including extramuscoloskeletal manifestation with a gender-sensitive approaches, focusing on a prompt diagnosis to prevent systemic comorbidities. Real-world data, such as those provided by the MAPSI study, are essential for understanding the burden of PsA and developing effective management strategies tailored to patient characteristics.
Impacts of intestinal microbiota metabolite trimethylamine N-oxide on cardiovascular disease: a bibliometric analysis
Authors: Leng Xiaohui , Wei Xiunan , Wang Jun , Yao Xiaodong , Zhang Miaomiao , Sun Dajuan , Liang Junwei , Chi Lili , Cheng Yan
Published: January 2025

Background

Trimethylamine N-oxide (TMAO), a metabolite dependent on intestinal microbiota, is closely related to the emergence, progression, and prognosis of cardiovascular disease (CVD), and has received increasing attention in recent years.

Objective

The current research hotspots and future development trends in TMAO and CVD field are found through bibliometrics analysis, which provides reference for further study.

Methods

The bibliometrics tools VOSviewer and CiteSpace were used to analyze the publications from the Web of Science Core Collection (WOSCC) database. The articles published from 2004 to 2024 about the relationship between TMAO and CVD were retrieved. Bibliometric analysis includes annual publications, countries/regions, institutions, authors and co-cited authors, journals and cited-journals, references and keywords.

Results

After searching and screening, 1,466 publications were included for subsequent bibliometric analysis. Since 2014, the number of publications exposing the relationship between TMAO and CVD has increased rapidly, as has the frequency of citations. China, USA and Italy are the countries that publish the most relevant research. Cleveland Clinic is the leading institution in this field. Stanley L Hazen, Zeneng Wang and W H Wilson Tang are the most prolific authors in this field, and the latter two have the closest academic cooperation. American Journal of Clinical Nutrition and Journal of the American Heart Association are influential journals that publish research in this field. “Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk” is the most frequently cited article. Keyword analysis shows that gut microbiota, metabolism, phosphatidylcholine and atherosclerosis (AS) are the hotspots in this field.

Conclusion

This study summarizes the research situation of TMAO and CVD in the past 20 years, focusing on the effect of TMAO on pathogenesis of AS, predictive value of TMAO on CVD risk, and dietary and drug intervention for TMAO. Probiotics and natural products may be the research focus of preventing and treating CVD by intervening TMAO in the future.
Marine actinobacteria metabolites: unlocking new treatments for acne vulgaris
Authors: De La Hoz-Romo María Clara , Díaz Luis , Gómez-León Javier , Quintero Marynes , Villamil Luisa
Published: January 2025

Marine-derived actinobacteria isolated from sponge Cliona varians and soft coral Eunicea fusca were screened for antibacterial activity against acne-related bacteria, specifically Staphylococcus epidermidis ATCC 14990, methicillin-resistant Staphylococcus aureus ATCC BAA44, and Cutibacterium acnes ATCC 6919. Cytotoxicity assays were performed on human dermal fibroblast (HDFa) and keratinocyte (HaCaT) cell lines to assess the safety profile of the extracts. Chemical characterization was conducted using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS/MS). Among the extracts, six derived from Kocuria sp., Rhodococcus sp., Nocardia sp., Micrococcus sp., and Streptomyces sp. demonstrated significant antibacterial activity. Notably, extract Z9.216 from Kocuria sp. exhibited the highest efficacy, inhibiting S. epidermidis by 68%, S. aureus by 93%, and C. acnes by 98.7% at a concentration of 0.003 mg/mL, which was comparable to the standard antibiotics erythromycin and vancomycin, while maintaining over 90% cell viability in both HDFa and HaCaT cell lines. Untargeted metabolomic analysis suggested that antibacterial activity might be associated with compounds from the chemical families of alkaloids, terpenoids, and fatty acids, among others. These findings highlight the therapeutic potential of marine actinobacteria in underexplored environments as a promising strategy for treating acne vulgaris, a chronic inflammatory skin condition.
Dietary supplementation with proanthocyanidins and rutin alleviates the symptoms of type 2 diabetes mice and regulates gut microbiota
Authors: Gao Yue , Huang Binbin , Qin Yunyi , Qiao Bing , Ren Mengfei , Cao Liqing , Zhang Yan , Han Maozhen
Published: January 2025

Background

Obesity and high fasting blood glucose (FBG) resulting from high-fat diets (HFDs) have emerged as significant public health concerns, garnering increasing attention. Recently, gut microbiota has been linked with metabolic diseases such as type 2 diabetes (T2DM), and its mediating role in dietary supplements has been confirmed. Seeking various dietary supplements to lose body weight (BW) and decrease FBG and explaining the underlying mechanism have become the research hotspots in T2DM studies.

Methods

In this study, rutin and proanthocyanidins (PA) were selected as dietary supplements (200 mg/kg × day, oral gavage, 6 weeks) in T2DM mice induced with HFD to assess their efficacy in weight loss, FBG reduction, gut microbiota alterations, and the associated underlying mechanisms.

Results

Our findings indicate that rutin was more effective than PA in relieving inflammation and fat hypertrophy, although both significantly reduced BW and FBG within 2 weeks after the intervention. Analysis of 16S rRNA amplicons revealed substantial alterations in the gut microbial community composition of mice administered with PA and rutin compared to HFD-fed mice. Importantly, several core microbes, particularly a series of probiotics, such as Akkermansia, Lactococcus, Odoribacter, Faecalibaculum, and Roseburia were identified, which were significantly correlated with the changes in BW and FBG.

Conclusion

Overall, our study highlights that rutin and PA can reduce BW, FBG, and inflammation by modulating the gut microbiota composition, providing novel perspectives for managing and treating weight and FBG concerns in obesity and T2DM patients through dietary supplements in clinical treatment.
Recombinant Marek’s disease virus expressing VP1 and VP2 proteins provides robust immune protection against chicken infectious anemia virus
Authors: Ge Chengfei , Lu Hangqiong , Han Jinze , Sun Guorong , Li Shihao , Lan Xingge , Liu Yongzhen , Yu Mengmeng , Hu Xinyun , Hu Mingxue , Qi Xiaole , Cui Hongyu , Duan Yulu , Wang Suyan , Chen Yuntong , Wang Xiaomei , Zhang Yanping , Gao Yulong , Liu Changjun
Published: January 2025

Chicken infectious anemia (CIA) is a highly contagious disease caused by the chicken infectious anemia virus (CIAV), and it poses a serious threat to the poultry industry. However, effective control measures and strategies have not been identified. In this study, a recombinant Marek’s disease virus (rMDV) expressing the VP1 and VP2 proteins of CIAV was successfully constructed using CRISPR/Cas9, and a commercial Marek’s disease virus (MDV) vaccine strain was used as the vector. VP1 and VP2 expression by rMDV was confirmed by immunofluorescence assay and western blot analysis, which revealed robust in vitro expression. Further analysis showed that the VP1 and VP2 genes integrated into the MDV genome did not alter the growth kinetics of the virus and remained stable even after 20 passages, indicating the genetic stability of the recombinant virus. In animal studies, vaccination of one-day-old specific-pathogen-free chickens with rMDV induced high levels of CIAV-specific antibodies (1 × 105) and neutralizing antibodies (1:25) and a potent cellular immune response. Moreover, rMDV vaccination conferred an 85% protective index against challenge with a highly virulent strain of CIAV, significantly reducing the occurrence of anemia and thymic atrophy caused by CIAV infection and dramatically suppressing CIAV replication in the thymus. Collectively, these results highlight the potential of rMDV as a vaccine candidate for preventing and controlling CIAV infection, thus offering a new avenue for mitigating the impact of CIA on the poultry industry.
The diagnostic accuracy of point-of-care nucleic acid-based isothermal amplification assays for scrub typhus: a systematic review and meta-analysis
Authors: Dixit Rashi , Manikandan Sandeep , Prakash John Antony Jude , Biswal Manisha , Mohapatra Dharitri , Gopalan Natarajan , Gnanamani G. , Behera Sujit Kumar
Published: January 2025

Introduction

The diagnosis and detection of pathogens such as Rickettsia and Orientia is a cause of major concern among the public health community. Unavailability of rapid, cost-effective diagnostic assays contributes to delayed diagnosis and timely treatment. Using the methodology of systematic reviewing and meta-analysis, the study aimed to synthesize and compare the diagnostic performances of all the available isothermal assays for the detection of classical rickettsial diseases.

Methods

Studies were retrieved from PubMed and Scopus, and selection and screening were conducted using pre-determined inclusion and exclusion criteria. Analysis was performed using Meta-DiSc 2.0 for the assessment and comparison of diagnostic performance of the isothermal assays.

Results

Overall, six studies were selected as a part of this systematic review. All the selected studies (n = 6) optimized LAMP as their index test to detect scrub typhus. The quality assessment of the selected studies revealed only (n = 1) study to be of poor quality with a QUADAS-2 score of (<2). Meta-analysis revealed the pooled sensitivity of LAMP to be 66% [95% CI (0.40–0.85)] with a pooled specificity of 94% [95% CI (0.81–0.98)]. LAMP was estimated with a positive likelihood ratio of 8.3 [95% CI (3.8–18.1)] and a negative likelihood ratio of 0.3 [95% CI (0.2–0.7)] with a false positivity rate of 0.07 [95% CI (0.02–0.2)]. The diagnostic odds ratio was reported to be 21.96 [95% CI (10.2–47.3)]. Due to severe heterogeneity in the body of evidence (I2 = 0.77), a meta-regression was performed with certain covariates to explore the potential causes. A case–control design was found to exaggerate the sensitivity {0.84 [95% CI (0.5–0.9)]} and specificity {0.73 [95% CI (0.6–0.8)]}.

Conclusion

The findings reveal subpar performance of LAMP for the detection of scrub typhus. Active research and development focused on optimization of novel molecular diagnosis that are efficient, rapid, and cost-effective shall foster timely diagnosis and aid in reduction of the overall burden of scrub typhus.

Protocol and registration

A detailed protocol of this review is registered and available in Prospero at: https://www.crd.york.ac.uk/prospero/. (registration number CRD42024511706).
Immune-checkpoint-inhibitor therapy directed against PD-L1 is tolerated in the heart without manifestation of cardiac inflammation in a preclinical reversible melanoma mouse model
Authors: Schoenherr Caroline , Pietzsch Stefan , Barca Cristina , Müller Franziska E. , Bahr Frauke S. , Kasten Martina , Zeug Andre , Erschow Sergej , Falk Christine S. , Ponimaskin Evgeni , Thackeray James T. , Hilfiker-Kleiner Denise , Ricke-Hoch Melanie
Published: January 2025

Immune-checkpoint-inhibitors (ICI) target key regulators of the immune system expressed by cancer cells that mask those from recognition by the immune system. They have improved the outcome for patients with various cancer types, such as melanoma. ICI-based therapy is frequently accompanied by immune-related adverse side effects (IRAEs). The reversible melanoma cancer mouse model (B16F10 cells stably expressing a ganciclovir (GCV)-inducible suicide gene in C57BL/6N mice: B16F10-GCV) allows chemotherapy-free tumor elimination in advanced disease stage and demonstrates almost complete recovery of the mouse heart from cancer-induced atrophy, molecular impairment and heart failure. Thus, enabling the study of anti-cancer-therapy effects. Here, we analyzed potential cardiac side effects of antibody-mediated PD-L1 inhibition in the preclinical B16F10-GCV mouse model after tumor elimination and 2 weeks recovery (50 days after tumor inoculation). Anti-PD-L1 treatment was associated with improved survival as compared to isotype control (Ctrl) treated mice. Surviving anti-PD-L1 and Ctrl mice showed similar cardiac function, dimensions and the expression of cardiac stress and hypertrophy markers. Although anti-PD-L1 treatment was associated with increased troponin I type 3 cardiac (TNNI3) blood levels, cardiac mRNA expression of macrophage markers and elevated cardiac levels of secreted inflammatory factors compared to Ctrl treatment, both groups showed a comparable density of inflammatory cells in the heart (using CXCR4-ligand 68Ga-Pentixafor in PET-CT and immunohistochemistry). Thus, anti-PD-L1 therapy improved survival in mice with advanced melanoma cancer with no major cardiac phenotype or inflammation 50 days after tumor inoculation. Without a second hit that triggers the inflammatory response, anti-PD-L1 treatment appears to be safe for the heart in the preclinical melanoma mouse model.
An innovative advance in bone grafting: initial clinical results using a novel integrative bone graft in spinal fusion
Authors: Passias Peter G. , Onafowokan Oluwatobi O. , Das Ankita , Mir Jamshaid M. , Yung Anthony , Fisher Max
Published: January 2025

Introduction

Although autologous iliac crest bone graft (ICBG) has long been the gold standard for spinal fusion, complications related to its harvest and availability issues with local bone autograft have encouraged the development of bone graft substitutes that provide safer alternatives with consistent clinical efficacy and potential for applications across musculoskeletal health, including spinal fusion. This study evaluates the initial safety and efficacy of a novel integrative bone matrix (IBM) in spinal fusion procedures.

Methods

The charts of twenty patients who underwent spinal fusion surgery at 1–5 contiguous interbody levels and/or 1–15 contiguous posterolateral levels with the novel IBM between November 2022 and May 2023 were retrospectively evaluated for safety and efficacy endpoints at standard of care 3, 6, and 12 months postoperative follow up visits. Radiographic fusion rate was evaluated by plain radiographs using the Bridwell interbody fusion grading system and/or the Glassman posterolateral fusion grading system, as appropriate. Subjective pain, disability, and quality of life assessments included the EuroQoL 5 Dimensions Visual Analogue Scale (EQ-5D VAS), Oswestry Disability Index (ODI), and the revised Scoliosis Research Society Score (SRS-22r).

Results

No adverse events occurred that were related to the graft, and no subjects required unplanned revision surgery. Radiographic fusion was achieved in all (100%) of the interbody and posterolateral levels by 12 months. There was no significant difference in overall fusion rate between subjects receiving short vs. long segment constructs. At 3, 6, and 12 month follow up, significant (p < 0.001) improvements were observed compared to baseline values for all patient reported outcome measures, and the cohort reached the minimum clinically significant mean improvements.

Discussion

This study highlights the potential of this novel IBM as a safe and effective bone graft substitute in spinal arthrodesis procedures. Patients had a high rate of fusion without any graft-related adverse events. Larger, controlled studies with longer-term follow-up are warranted for further validation.
Role of metabolic characteristics in the co-occurrence of insomnia, Alzheimer’s disease, and Parkinson’s disease: a Mendelian randomization study
Authors: Liu Chengyong , Wang Chi , Jiang Jing , Bo Yuyang , Nan Lixiu , Zhang Ying , Zhu Kongxi , Wang Xiaoqiu , Feng Xinxin , Lian Xiaoyang , Qin Shan
Published: January 2025

Objective

There reportedly exists a significant comorbidity between insomnia and neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), indicative of a potential link to serum metabolic dysregulation.

Method

To elucidate shared pathophysiological mechanisms between insomnia and AD/PD, we performed comprehensive two-sample Mendelian randomization (MR) analyses, investigating 1,400 serum metabolic characteristics for their causal relationships with the risks of insomnia, AD, widely defined AD (WDAD), and PD. We employed publicly available genetic data; the primary estimate was determined using inverse-variance weighting, supplemented by weighted median, simple mode, weighted mode, and the MR-PRESSO and MR-Egger methods to evaluate heterogeneity and pleiotropy.

Results

The ratio of N-palmitoyl-sphingosine to N-palmitoyl-sphinganine is linked to higher risks of insomnia (OR = 1.137, 95% CI = 1.015–1.273, p = 0.026) and AD (OR = 1.090, 95% CI = 1.005–1.183, p = 0.037). The acetylcarnitine to propionylcarnitine ratio is a risk factor for insomnia (OR = 1.190, 95% CI = 1.003–1.370, p = 0.016) but has protective effects against AD (OR = 0.868, 95% CI = 0.784–0.961, p = 0.006) and WDAD (OR = 0.892, 95% CI = 0.817–0.973, p = 0.010). Glutamine conjugate of C7H12O2 levels are associated with reduced risk of insomnia (OR = 0.863, 95% CI = 0.749–0.995, p = 0.042) and PD (OR = 0.856, 95% CI = 0.746–0.981, p = 0.026).

Conclusion

Our findings highlight the crucial role of serum metabolic characteristics in the comorbidity of insomnia with neurodegenerative diseases, providing valuable insights into prospective therapeutic targets and diagnostic markers.
An EEG-based framework for automated discrimination of conversion to Alzheimer’s disease in patients with amnestic mild cognitive impairment: an 18-month longitudinal study
Authors: Ge Yingfeng , Yin Jianan , Chen Caie , Yang Shuo , Han Yuduan , Ding Chonglong , Zheng Jiaming , Zheng Yifan , Zhang Jinxin
Published: January 2025

Background

As a clinical precursor to Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI) bears a considerably heightened risk of transitioning to AD compared to cognitively normal elders. Early prediction of whether aMCI will progress to AD is of paramount importance, as it can provide pivotal guidance for subsequent clinical interventions in an early and effective manner.

Methods

A total of 107 aMCI cases were enrolled and their electroencephalogram (EEG) data were collected at the time of the initial diagnosis. During 18-month follow-up period, 42 individuals progressed to AD (PMCI), while 65 remained in the aMCI stage (SMCI). Spectral, nonlinear, and functional connectivity features were extracted from the EEG data, subjected to feature selection and dimensionality reduction, and then fed into various machine learning classifiers for discrimination. The performance of each model was assessed using 10-fold cross-validation and evaluated in terms of accuracy (ACC), area under the curve (AUC), sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and F1-score.

Results

Compared to SMCI patients, PMCI patients exhibit a trend of “high to low” frequency shift, decreased complexity, and a disconnection phenomenon in EEG signals. An epoch-based classification procedure, utilizing the extracted EEG features and k-nearest neighbor (KNN) classifier, achieved the ACC of 99.96%, AUC of 99.97%, SEN of 99.98%, SPE of 99.95%, PPV of 99.93%, and F1-score of 99.96%. Meanwhile, the subject-based classification procedure also demonstrated commendable performance, achieving an ACC of 78.37%, an AUC of 83.89%, SEN of 77.68%, SPE of 76.24%, PPV of 82.55%, and F1-score of 78.47%.

Conclusion

Aiming to explore the EEG biomarkers with predictive value for AD in the early stages of aMCI, the proposed discriminant framework provided robust longitudinal evidence for the trajectory of the aMCI cases, aiding in the achievement of early diagnosis and proactive intervention.
Dynamic retinal vessel analysis: flickering a light into the brain
Authors: Peterfi Anna , Pinaffi-Langley Ana Clara da C. , Szarvas Zsofia , Muranyi Mihaly , Kaposzta Zalan , Adams Cheryl , Pinto Camila Bonin , Mukli Peter , Kotliar Konstantin , Yabluchanskiy Andriy
Published: January 2025

Introduction

Growing aging populations pose new challenges to public health as the number of people living with dementia grows in tandem. To alleviate the burden of dementia, prodromal signs of cognitive impairment must be recognized and risk factors reduced. In this context, non-invasive techniques may be used to identify early changes and monitor disease progression. Dynamic retinal vessel analysis (DVA) provides an opportunity to measure retinal vasoreactivity in a way that may be comparable to cerebral vasoreactivity, thus providing a window to the brain.

Methods

We conducted a literature search on PubMed and Scopus to identify studies utilizing DVA to describe retinal vasoreactivity in central nervous system diseases and compare it with brain function and structure. We included original papers with full text in English.

Results

We identified 11 studies, of which most employed a cross-sectional design (91%). Studies on cerebrovascular diseases reported that retinal vasoreactivity decreased in patient populations compared with that of healthy controls. Studies on cognitive impairment and dementia yielded mixed results, at least in part due to high population heterogeneity. There is also evidence for the association between DVA and brain and cognition parameters such as cerebral blood flow velocity, cerebral microvascular diffusivity, and cognitive function score.

Discussion

The reviewed papers on DVA and brain function, despite the mixed results, have demonstrated the relationship between retinal vasoreactivity and cerebrovascular function and cognition. Heterogeneity in study populations, procedures, and analyses make comparisons difficult. Studies with larger sample size, clear description of the population and methods, and standardized DVA analysis are needed to elucidate the eye–brain connection and to enhance the translational and clinical applications of DVA.
Advances in physiological and clinical relevance of hiPSC-derived brain models for precision medicine pipelines
Authors: Imani Farahani Negin , Lin Lisa , Nazir Shama , Naderi Alireza , Rokos Leanne , McIntosh Anthony Randal , Julian Lisa M.
Published: January 2025

Precision, or personalized, medicine aims to stratify patients based on variable pathogenic signatures to optimize the effectiveness of disease prevention and treatment. This approach is favorable in the context of brain disorders, which are often heterogeneous in their pathophysiological features, patterns of disease progression and treatment response, resulting in limited therapeutic standard-of-care. Here we highlight the transformative role that human induced pluripotent stem cell (hiPSC)-derived neural models are poised to play in advancing precision medicine for brain disorders, particularly emerging innovations that improve the relevance of hiPSC models to human physiology. hiPSCs derived from accessible patient somatic cells can produce various neural cell types and tissues; current efforts to increase the complexity of these models, incorporating region-specific neural tissues and non-neural cell types of the brain microenvironment, are providing increasingly relevant insights into human-specific neurobiology. Continued advances in tissue engineering combined with innovations in genomics, high-throughput screening and imaging strengthen the physiological relevance of hiPSC models and thus their ability to uncover disease mechanisms, therapeutic vulnerabilities, and tissue and fluid-based biomarkers that will have real impact on neurological disease treatment. True physiological understanding, however, necessitates integration of hiPSC-neural models with patient biophysical data, including quantitative neuroimaging representations. We discuss recent innovations in cellular neuroscience that can provide these direct connections through generative AI modeling. Our focus is to highlight the great potential of synergy between these emerging innovations to pave the way for personalized medicine becoming a viable option for patients suffering from neuropathologies, particularly rare epileptic and neurodegenerative disorders.
Astrocytes phenomics as new druggable targets in healthy aging and Alzheimer’s disease progression
Authors: Lana Daniele , Ugolini Filippo , Iovino Ludovica , Attorre Selene , Giovannini Maria Grazia
Published: January 2025

For over a century after their discovery astrocytes were regarded merely as cells located among other brain cells to hold and give support to neurons. Astrocytes activation, “astrocytosis” or A1 functional state, was considered a detrimental mechanism against neuronal survival. Recently, the scientific view on astrocytes has changed. Accumulating evidence indicate that astrocytes are not homogeneous, but rather encompass heterogeneous subpopulations of cells that differ from each other in terms of transcriptomics, molecular signature, function and response in physiological and pathological conditions. In this review, we report and discuss the recent literature on the phenomic differences of astrocytes in health and their modifications in disease conditions, focusing mainly on the hippocampus, a region involved in learning and memory encoding, in the age-related memory impairments, and in Alzheimer’s disease (AD) dementia. The morphological and functional heterogeneity of astrocytes in different brain regions may be related to their different housekeeping functions. Astrocytes that express diverse transcriptomics and phenomics are present in strictly correlated brain regions and they are likely responsible for interactions essential for the formation of the specialized neural circuits that drive complex behaviors. In the contiguous and interconnected hippocampal areas CA1 and CA3, astrocytes show different, finely regulated, and region-specific heterogeneity. Heterogeneous astrocytes have specific activities in the healthy brain, and respond differently to physiological or pathological stimuli, such as inflammaging present in normal brain aging or beta-amyloid-dependent neuroinflammation typical of AD. To become reactive, astrocytes undergo transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. Alterations of astrocytes affect the neurovascular unit, the blood–brain barrier and reverberate to other brain cell populations, favoring or dysregulating their activities. It will be of great interest to understand whether the differential phenomics of astrocytes in health and disease can explain the diverse vulnerability of the hippocampal areas to aging or to different damaging insults, in order to find new astrocyte-targeted therapies that might prevent or treat neurodegenerative disorders.