bluuebunny/crossref_metadata_2025 huggingface dataset:
CAR-T therapy for endocrine neoplasms: novel targets and combination of therapies
Authors: Wang Fang , Zhang Ruiqi , Zhou Zhaokai , Shi Run , Peng Fu , Xu Yudi , Yang Shuai , Wang Zhan , Zhang Pengpeng , Tu Rui , Zhang Chun , Liu Xingchen , Cai Jun
Published: February 2025

Endocrine malignancies constitute a heterogeneous tumour group with diverse biological characteristics. While typically indolent, they encompass aggressive types and presence of any metastatic sign indicates a high probability of recurrence and a diminished response to conventional therapies. Chimeric antigen receptor (CAR)-T cell immunotherapy has constituted a revolutionary advance in cancer treatment and exhibited significant potential for application in endocrine cancer. However, limited effectiveness was displayed in clinical application, which necessitates the exploration of novel modalities. Identification of specific and safe targets for endocrine cancer is the initial stage towards establishing a successful CAR-T treatment. Various therapies under investigation offer potential enhancements to CAR T cell efficacy through diverse mechanisms. Herein, we summarize recent advances in identifying targets of endocrine cancer for CAR therapy and provide an overview of combinatorial approaches.
Electrochemotherapy with bleomycin, oxaliplatin, or cisplatin in mouse tumor models, from tumor ablation to in situ vaccination
Authors: Uršič Valentinuzzi Katja , Kamenšek Urška , Kranjc Brezar Simona , Heranney Chloe , Komel Tilen , Buček Simon , Čemažar Maja , Serša Gregor
Published: February 2025

Introduction

In addition to its direct cytotoxic effects, ablative therapies as electrochemotherapy (ECT) can elicit indirect antitumor effects by triggering immune system responses. Here, we comprehensively analyzed this dual effectiveness of intratumoral ECT with chemotherapeutic drugs bleomycin (BLM), oxaliplatin (OXA), and cisplatin (CDDP). Our aim was to determine if ECT can act as in situ vaccination and thereby induce an abscopal effect. By evaluating ECT’s potential for in situ vaccination, our goal was to pave the way for future advancements for its combination with emerging (immuno)therapies, leading to enhanced responses and outcomes.

Methods

We employed two mouse tumor models, the immunologically cold B16F10 melanoma and 4T1 mammary carcinoma, to explore both local and systemic (i.e., abscopal) antitumor effects following equieffective intratumoral ECT with BLM, OXA, and CDDP. Through histological analyses and the use of immunodeficient and metastatic (for abscopal effect) mouse models, we identified and compared both the cytotoxic and immunological components of ECT’s antitumor efficiency, such as immunologically recognizable cell deaths (immunogenic cell death and necrosis) and immune infiltrate (CD11+, CD4+, CD8+, GrB+).

Results

Differences in immunological involvement after equieffective intratumoral ECT were highlighted by variable kinetics of immunologically recognizable cell deaths and immune infiltrate across the studied tumor models. Particularly, the 4T1 tumor model exhibited a more pronounced involvement of the immune component compared to the B16F10 tumor model. Variances in the antitumor (immune) response were also detected based on the chemotherapeutic drug used in ECT. Collectively, ECT demonstrated effectiveness in inducing in situ vaccination in both tumor models; however, an abscopal effect was observed in the 4T1 tumor model only.

Conclusions

This is the first preclinical study systematically comparing the immune involvement in intratumoral ECT’s efficiency using three distinct chemotherapeutic drugs in mouse tumor models. The demonstrated variability in immune response to ECT across different tumor models and chemotherapeutic drugs provides a basis for future investigations aimed at enhancing the effectiveness of combined treatments.
Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis
Authors: Dumut Daciana C. , Hajduch Marian , Zacharias Amanda M. , Duan Qingling , Frydrych Ivo , Rozankova Zuzana , Popper Miroslav , Garic Dusan , Paun Radu Alexandru , Centorame Amanda , Shah Juhi , Mistrik Martin , Dzubak Petr , De Sanctis Juan B. , Radzioch Danuta
Published: February 2025

Advanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are characterized by low immunogenicity. This study investigates bis-diethyldithiocarbamate (CuET), a novel anticancer compound, and its impact on the colorectal cancer tumor microenvironment (TME). CuET is shown to convert immunologically inactive tumors into hotbeds of antitumor immune responses, marked by increased lymphocyte infiltration, heightened cytotoxicity of natural killer (NK) and T cells, and enhanced non-self recognition by lymphocytes. The potent anticancer cytotoxicity and in vivo safety and efficacy of CuET are established. In summary, CuET transforms the colorectal cancer TME, bolstering NK and T cell cytotoxicity and refining tumor cell recognition through non-classical activation via the NKG2D/NKG2DL axis. This study unveils a novel mechanism of action for CuET: a potent immunomodulator capable of turning cold tumors hot.
Monoclonal anti-CD38 therapy in human myeloma: retrospects and prospects
Authors: Horenstein Alberto L. , Faini Angelo C. , Morandi Fabio , Ortolan Erika , Storti Paola , Giuliani Nicola , Richardson Paul G. , Malavasi Fabio
Published: February 2025

Monoclonal antibody therapy using CD38 as a target remains central to managing human multiple myeloma (MM). CD38 was selected early on as a target for mAb-mediated therapy for MM, driven by findings from an early Cluster of Differentiation (CD) Workshop. The first CD38-targeting antibody to be approved yielded strong trial results, significantly improving survival rates and earning widespread patient acceptance. However, resistance to the therapy later emerged, complicating treatment management. Despite CD38’s still central role in MM therapy, too little attention has been paid to its broader roles–not only as a myeloma marker but also as an enzyme and adhesion molecule in physiology. This review, a collaborative effort between basic scientists and clinical experts, explores some of the lesser-known mechanisms of antibody action and interactions with CD38 at key stages of treatment. The review also highlights the relevance of the MM environment, focusing on the importance of the bone marrow (BM) niche. The goal is to identify new agents whose unique properties may enhance tumor eradication. By gaining a deeper understanding of interactions between therapeutic antibodies, myeloma cells, and the tumor microenvironment (TME), it is hoped that previously unrecognized vulnerabilities within the disease may be revealed, paving the way to more effective treatment strategies.
AAV-based vectors for human diseases modeling in laboratory animals
Authors: Aliev Timur I. , Yudkin Dmitry V.
Published: February 2025

The development of therapeutic drugs and vaccines requires the availability of appropriate model animals that replicate the pathogenesis of human diseases. Both native and transgenic animals can be utilized as models. The advantage of transgenic animals lies in their ability to simulate specific properties desired by researchers. However, there is often a need for the rapid production of transgenic animal models, especially in situations like a pandemic, as was evident during COVID-19. An important tool for transgenesis is the adeno-associated virus. The genome of adeno-associated virus serves as a convenient expression cassette for delivering various DNA constructs into cells, and this method has proven effective in practice. This review analyzes the features of the adeno-associated virus genome that make it an advantageous vector for transgenesis. Additionally, examples of utilizing adeno-associated viral vectors to create animal models for hereditary, oncological, and viral human diseases are provided.
Associations between asthma and Life’s Essential 8: a cross-sectional study
Authors: Xu Jiao , Tang Jianlei
Published: February 2025

Background

Asthma is a serious respiratory disease attributed to multiple factors. The Life’s Essential 8 (LE8), introduced by the American Heart Association, aims to improve and maintain cardiovascular health. However, the correlation between LE8 components and asthma remains unclear. We hypothesized that LE8 is a protective factor against asthma.

Materials and methods

Multiple logistic regression analysis, restricted cubic spline (RCS) analysis, and subgroup analysis were used to analyze the data collected from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018.

Results

A total of 3,360 participants with asthma were included in the analysis. With all confounders controlled for, LE8 scores were negatively correlated with asthma prevalence (odds ratio (OR) per 10-point increment, 0.85 [95% confidence interval (CI), 0.82–0.88]). Compared to low LE8 scores, moderate and high LE8 scores were associated with reduced asthma risk, with adjusted ORs (95% CIs) of 0.59 (0.51–0.68) and 0.48 (0.39–0.58), respectively. Non-linear correlations were observed between LE8 scores and asthma (p non-linear = 0.01) and between health factor scores and asthma (p non-linear = 0.01). However, a linear dose–response correlation was noted between health behavior scores and asthma (p non-linear = 0.30). Subgroup analysis showed no significant interaction effects (p > 0.05), except in the sex and drinking status subgroups (p for interaction = 0.02).

Conclusion

Asthma is associated with components of LE8, which warrants further attention and may contribute to reducing asthma prevalence.
Airway clearance technique therapy for atelectasis induced by scoliosis surgery: a case report
Authors: Zhai Rui , Su Hairong , Wu Yaxu , Tan Rong , Zhang Xiaoli , Tian Ye , Hu Mei
Published: February 2025

The patient, a 55-year-old female presenting with spinal deformity and exertional dyspnea, was referred to the hospital. Radiographic evaluation of her spine revealed an “S”-shaped scoliosis with a Cobb angle measuring 68°, indicative of severe scoliosis. Despite receiving medication for expectoration, postoperative symptoms including chest tightness, breathlessness, and ineffective coughing persisted and progressively worsened. Subsequent chest CT scans demonstrated extensive atelectasis, and pharmacological interventions proved to be ineffective. Considering the patient’s clinical condition, we implemented airway clearance technique (ACT) along with prone ventilation to optimize cough effectiveness and mitigate atelectasis formation. The airway clearance techniques (ACT) employed include nebulization, continuous positive expiratory pressure (CPEP), and continuous high frequency oscillation (CHFO). Chest CT imaging confirmed that ACT substantially alleviated the patient’s pulmonary atelectasis. Moreover, blood gas analysis indicated significant improvements in both the PaO2/FiO2 ratio and base excess of whole blood. Follow-up evaluation 1 year post-discharge revealed a favorable prognosis for the patient. We anticipate that our experience utilizing these novel therapeutic modalities will provide valuable insights for clinicians managing similar complications.
Does viral circulation in slums have a global impact? The lesson learned from SARS-CoV-2 circulation in Complexo de favelas da Maré, Rio de Janeiro, Brazil
Authors: dos Santos Monique Cristina , Fintelman-Rodrigues Natalia , Silva Aline de Paula Dias da , Silva Rodolfo Leandro Nascimento , Seixas Victor Corrêa , Batista-da-Silva Amanda A. , Ferreira Marcelo Alves , Bozza Patrícia T. , Bozza Fernando A. , Souza Thiago Moreno L.
Published: February 2025

Because of growing inequalities, more than one-third of the worldwide population is expected to live in slums by 2050. Although slum dwellers are at increased risk of infectious diseases, this population may have been overlooked with respect to the sustainability of virus evolution. In this study, we aimed to analyze the genetic diversity and evolution of SARS-CoV-2 in the Complexo de Favelas da Maré slum, Rio de Janeiro, Brazil, and assess its impact on the global spread of the virus. We found that this slum harbored multiple strains of SARS-CoV-2, and its amplification and genetic diversity connected with the global circulation from 2020 to 2022. Thus, enhancing surveillance in slums could be important for future epidemic/pandemic preparedness by connecting virus genetic diversity in this region with its circulation at divergent locations.
Characterization and genomic analysis of a Herelleviridae bacteriophage UHP46 infecting mastitis-causing Staphylococcus aureus
Authors: Najeeb Sara , Khan Imran , Muhammad Javed , Jahangir Muhammad , Alvi Iqbal Ahmad , Abbas Anza , Ullah Aman , Ullah Arif , Sajjad Wajiha , Khan Hashir , Khan Amjad
Published: February 2025

Background

Mastitis is a widespread disease on a global scale, significantly impacting the dairy industry. Mastitis in dairy cattle is caused by over 150 different bacteria, with Staphylococcus aureus (S. aureus) playing a significant role in financial losses, problems with animal welfare, and challenges with food safety. Phage treatment is thus being investigated as an effective replacement for reducing contaminants and illnesses caused by bacteria. In this study, we identified a phage UHP46, that effectively targets mastitis-causing S. aureus.

Methods

S. aureus S46 was used to screen for the wastewater lytic phages. The isolated lytic phage UHP46, which formed clear plaques and spots, was further characterized.

Results

Phage UHP46, belonging to the Herelleviridae family, forms clear, circular plaques in bacterial lawn. UHP46 showed stability under various range of temperature and pH levels, with maximum activity observed at pH 7 and temperature 37°C. Genomic analysis revealed that phage UHP46 is a dsDNA virus with an approximate genome size of 139,731 bp, and it encodes 72 proteins with known functions and 136 hypothetical proteins. One-step growth curve analysis indicated latent period of approximately 20 mins and burst size of about 27 progeny/cell. In organic stability test, UHP46 showed stability in DMSO and acetone. Furthermore, it effectively inhibited S. aureus growth for up to 16 h, suggesting its suitability for therapeutic applications against S. aureus infections.

Conclusion

These findings suggest that phage UHP46 could serve as a promising alternative to antibiotics for managing S. aureus- induced mastitis, contributing to dairy production and improved animal health.
New insights into microbial bile salt hydrolases: from physiological roles to potential applications
Authors: Dong Zixing , Yang Shuangshuang , Tang Cunduo , Li Dandan , Kan Yunchao , Yao Lunguang
Published: February 2025

Gut microbiota has been increasingly linked to metabolic health and diseases over the past few decades. Bile acids (BAs), the major components of bile, are bidirectionally linked to intestinal microbiota, also known as the gut microbiome-BA metabolic axis. Gut microbiota-derived bile salt hydrolase (BSH, EC 3.5.1.24), which catalyzes the “gateway” reaction in a wider pathway of bile acid modification, not only shapes the bile acid landscape, but also modulates the crosstalk between gut microbiota and host health. Therefore, microbial BSHs exhibit the potential to directly or indirectly influence microbial and host physiologies, and have been increasingly considered as promising targets for the modulation of gut microbiota to benefit animal and human health. However, their physiological functions in bacterial and host physiologies are still controversial and not clear. In this review, we mainly discuss the current evidence related to the physiological roles that BSHs played in gut microbiota and human health, and the possible underlying mechanisms. Meanwhile, we also present the potential applications of BSHs and BSH-producing probiotics in various fields. Finally, we describe several important questions that need to be addressed by further investigations. A detailed exploration of the physiological significance of BSHs will contribute to their future diagnostic and therapeutic applications in improving animal and human health.
Whole genomic analysis uncovers high genetic diversity of rifampicin-resistant Mycobacterium tuberculosis strains in Botswana
Authors: Mogashoa Tuelo , Loubser Johannes , Choga Ontlametse T. , Ngom Justice Tresor , Choga Wonderful T. , Mbulawa Mpaphi B. , Molefi Tuduetso , Stephen One , Makhondo Topo , Seru Kedumetse , Motshosi Patience , Zuze Boitumelo , Makhema Joseph , Musonda Rosemary M. , Otukile Dimpho , Modongo Chawangwa , Kgwaadira Botshelo T. , Fane Keabetswe , Gaseitsiwe Simani , Warren Rob M. , Moyo Sikhulile , Dippenaar Anzaan , Streicher Elizabeth M.
Published: February 2025

Background

The emergence of drug-resistant Mycobacterium tuberculosis (M. tb) strains remains a threat to tuberculosis (TB) prevention and care. Understanding the drug resistance profiles of circulating strains is crucial for effective TB control. This study aimed to describe the genetic diversity of rifampicin-resistant M. tb strains circulating in Botswana using whole genome sequencing (WGS).

Methods

This study included 202 stored M. tb isolates from people diagnosed with rifampicin-resistant TB (RR-TB) between January 2016 and June 2023. Genomic DNA was extracted using the cetyltrimethylammonium bromide (CTAB) method. Library preparation was performed using the Illumina DNA prep kit following the manufacturer's instructions. Sequencing was done on Illumina NextSeq2000. TBProfiler software was used to identify known M. tb lineages and drug resistance profiles. Statistical analyses were performed on STATA version 18.

Results

WGS analysis revealed multidrug resistance (57.9%: 95% CI; 50.7–64.8), Pre-XDR (16.8%, 95% CI: 11.9–22.7), RR-TB (20.2%: 95% CI: 14.98–26.5), and HR-TB (0.5%, 95% CI; 0.01–2.7). We identified a high genetic diversity with three predominant lineages: lineage 4 (60.9%, 95% CI; 53.8–67.7), lineage 1 (22.8%: 95% CI; 17.2–29.2), and lineage 2 (13.9%, 95% CI: 9.4–19.4). The most frequently observed drug resistance mutations for rifampicin, isoniazid, ethambutol, streptomycin, pyrazinamide, and fluoroquinolones were rpoB S450L (28.6%), katG S315T (60.5%), embA_c.-29_-28delCT, embB Q497R (31.7%), rrs_n.517C>T (47.1%), pncA_c.375_389delCGATGAGGTCGATGT (36.0%) and gyrA A90V (79.4%), respectively. No bedaquiline and delamanid resistance-associated mutations were detected.

Conclusions

This study highlights the high genetic diversity of M. tb strains, with a predominance of lineage 4 among people with RR-TB in Botswana. It provides valuable insights into the genetic diversity of rifampicin-resistant M. tb strains circulating in Botswana.
IL-6/GATA2/SERPINE1 pathway is implicated in regulating cellular senescence after acute kidney injury
Authors: Su Hongshuang , Lin Xiaoxi , Paredong Ayinuer , Yao Congcong , Zhang Yan , Geng Mengke , Guan Yuqian , Gong Lichao , Jiang Feng , Lv Qi , Shou Songtao , Jin Heng
Published: February 2025

Purpose

Acute kidney injury (AKI) secondary to Rhabdomyolysis syndrome represents a life-threatening complication, characterized by notably high incidence and mortality rates. The role of cellular senescence in the progression of AKI has increasingly garnered attention in recent years. Our previous research has demonstrated that remote ischemic postconditioning (RIPC) can attenuate renal cellular senescence and elevation of serum level of interleukin-6 (IL-6) induced by ischemia-reperfusion injury following crush injury. The objective of this study is to investigate the specific role of IL-6 in Rhabdomyolysis-induced AKI (RM-AKI).

Methods

We established a mouse model of RM-AKI by intramuscular injection of glycerol and simulated RM-AKI at the cellular level by treating Hk-2 cells with myoglobin. Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, is a key substance. IL-6, a multifunctional cytokine, plays a crucial role in the occurrence and development of various kidney diseases. It can promote inflammatory responses, cell proliferation, fibrosis, and other processes. TCZ exerts a protective effect on the kidneys by specifically binding to the IL-6 receptor and blocking the signal transduction of IL-6. Additionally, the levels of IL-6 were detected by employing ELISA kits. RNA sequencing analysis was performed on cells treated with myoglobin and tocilizumab. Flow cytometry was utilized to assess cell cycle distribution and the percentage of senescent cells. The expression levels of SERPINE1, GATA2, p53, and p21 were determined by real-time quantitative PCR and Western blot. Additionally, a dual-luciferase reporter gene assay was conducted to validate the binding effect of SERPINE1 and GATA2.

Results

Transcriptome Analysis revealed that genes including GATA2 and SERPINE1 were downregulated in HK-2 cells following tocilizumab treatment. Inhibition of the IL-6 receptor by tocilizumab in these cells led to a reduction in cellular senescence, accompanied by decreased of the cell cycle regulatory proteins P53 and P21 in mRNA and protein levels, while alleviating cell cycle arrest. Additionally, a dual-luciferase reporter assay confirmed that GATA2 binds to the promoter of SERPINE1 (PAI-1), thereby initiating its transcription.

Conclusion

The IL-6/GATA2/SERPINE1 pathway mediates cellular senescence after acute kidney injury, and inhibiting IL-6 can alleviate AKI-induced cellular senescence, providing an important basis for exploring new therapeutic strategies.
Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential
Authors: Tang Mi-bo , Liu Yi-xuan , Hu Zheng-wei , Luo Hai-yang , Zhang Shuo , Shi Chang-he , Xu Yu-ming
Published: February 2025

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.
Bidirectional relationship between depression and activities of daily living and longitudinal mediation of cognitive function in patients with Parkinson’s disease
Authors: Xu Yue , Chen Durong , Dong Meiqi , Zhang Yun , Yu Hongmei , Han Yanqing
Published: February 2025

Objective

To investigate the bidirectional relationship between depression and activities of daily living (ADL) in Parkinson’s disease (PD) patients and explore the mediating role of cognitive function over time.

Methods

Data from 892 PD patients from the Parkinson’s Progression Markers Initiative (PPMI) database were included in this study, and depression, cognitive function, and ADL were measured using the Geriatric Depression Scale (GDS-15), Montreal Cognitive Assessment Scale (MoCA), and Unified Parkinson’s Disease Rating Scale, Part II (UPDRS II) respectively. The cross-lagged panel model (CLPM) was employed to analyze the reciprocal relationship between depression and ADL. Then, we explored the mediating role of cognitive function in the bidirectional relationship between depression and ADL in patients with PD, and the mediation effect test was carried out using a bias-corrected nonparametric percentile bootstrap approach.

Results

Depression in patients with PD predicted their subsequent ADL (β = 0.079, p < 0.01), and ADL also predicted their subsequent depression (β = 0.069, p < 0.05), In addition, Bootstrap analysis showed that cognitive function played a significant mediating role in prediction of depression to ADL in patients with PD (β = 0.006, p = 0.074, 95%CI = 0.001 ~ 0.014), and cognitive function also played a significant mediating role in prediction of depression to ADL (β = 0.006, p = 0.067, 95%CI = 0.001 ~ 0.013).

Conclusion

There is a bidirectional relationship between depression and ADL in patients with PD. Furthermore, we found that cognitive function mediates the relationship that exists between depression and ADL in patients with PD. Interventions aimed at enhancing cognitive function could potentially lessen the vicious cycle of depression and ADL in PD, thus improving patient quality of life (QOL).
Quantification and correlation of amyloid-β plaque load, glial activation, GABAergic interneuron numbers, and cognitive decline in the young TgF344-AD rat model of Alzheimer’s disease
Authors: Futácsi Anett , Rusznák Kitti , Szarka Gergely , Völgyi Béla , Wiborg Ove , Czéh Boldizsár
Published: February 2025

Background

Animal models of Alzheimer’s disease (AD) are essential tools for investigating disease pathophysiology and conducting preclinical drug testing. In this study, we examined neuronal and glial alterations in the hippocampus and medial prefrontal cortex (mPFC) of young TgF344-AD rats and correlated these changes with cognitive decline and amyloid-β plaque load.

Methods

We compared TgF344-AD and non-transgenic littermate rats aged 7–8 months of age. We systematically quantified β-amyloid plaques, astrocytes, microglia, four different subtypes of GABAergic interneurons (calretinin-, cholecystokinin-, parvalbumin-, and somatostatin-positive neurons), and newly generated neurons in the hippocampus. Spatial learning and memory were assessed using the Barnes maze test.

Results

Young TgF344-AD rats had a large number of amyloid plaques in both the hippocampus and mPFC, together with a pronounced increase in microglial cell numbers. Astrocytic activation was significant in the mPFC. Cholecystokinin-positive cell numbers were decreased in the hippocampus of transgenic rats, but calretinin-, parvalbumin-, and somatostatin-positive cell numbers were not altered. Adult neurogenesis was not affected by genotype. TgF344-AD rats had spatial learning and memory impairments, but this cognitive deficit did not correlate with amyloid plaque number or cellular changes in the brain. In the hippocampus, amyloid plaque numbers were negatively correlated with cholecystokinin-positive neuron and microglial cell numbers. In the mPFC, amyloid plaque number was negatively correlated with the number of astrocytes.

Conclusion

Pronounced neuropathological changes were found in the hippocampus and mPFC of young TgF344-AD rats, including the loss of hippocampal cholecystokinin-positive interneurons. Some of these neuropathological changes were negatively correlated with amyloid-β plaque load, but not with cognitive impairment.
Mechanistic insights into connexin-mediated neuroglia crosstalk in neurodegenerative diseases
Authors: Denaro Simona , D’Aprile Simona , Vicario Nunzio , Parenti Rosalba
Published: February 2025

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple Sclerosis (MS), and Huntington’s disease (HD), although distinct in their clinical manifestations, share a common hallmark: a disrupted neuroinflammatory environment orchestrated by dysregulation of neuroglial intercellular communication. Neuroglial crosstalk is physiologically ensured by extracellular mediators and by the activity of connexins (Cxs), the forming proteins of gap junctions (Gjs) and hemichannels (HCs), which maintain intracellular and extracellular homeostasis. However, accumulating evidence suggests that Cxs can also act as pathological pore in neuroinflammatory conditions, thereby contributing to neurodegenerative phenomena such as synaptic dysfunction, oxidative stress, and ultimately cell death. This review explores mechanistic insights of Cxs-mediated intercellular communication in the progression of neurodegenerative diseases and discusses the therapeutic potential of targeting Cxs to restore cellular homeostasis.
Prediction models for cognitive impairment in middle-aged patients with cerebral small vessel disease
Authors: Zheng Wei , Qin Xiaoyan , Mu Ronghua , Yang Peng , Huang Bingqin , Song Zhixuan , Zhu Xiqi
Published: February 2025

Purpose

This study aims to develop hippocampal texture model for predicting cognitive impairment in middle-aged patients with cerebral small vessel disease (CSVD).

Methods

The dataset included 145 CSVD patients (Age, 52.662 ± 5.151) and 99 control subjects (Age, 52.576±4.885). An Unet-based deep learning neural network model was developed to automate the segmentation of the hippocampus. Features were extracted for each subject, and the least absolute shrinkage and selection operator (LASSO) method was used to select radiomic features. This study also included the extraction of total intracranial volume, gray matter, white matter, cerebrospinal fluid, white matter hypertensit, and hippocampus volume. The performance of the models was assessed using the areas under the receiver operating characteristic curves (AUCs). Additionally, decision curve analysis (DCA) was conducted to justify the clinical relevance of the study, and the DeLong test was utilized to compare the areas under two correlated receiver operating characteristic (ROC) curves.

Results

Nine texture features of the hippocampus were selected to construct radiomics model. The AUC values of the brain volume, radiomics, and combined models in the test set were 0.593, 0.843, and 0.817, respectively. The combination model of imaging markers and hippocampal texture did not yield improved a better diagnosis compared to the individual model (p > 0.05).

Conclusion

The hippocampal texture model is a surrogate imaging marker for predicting cognitive impairment in middle-aged CSVD patients.
Awake brain MRSI reveals anesthetic sensitivity and regional aging effects on [13C]bicarbonate metabolism in mice
Authors: Ono Maiko , Kono Rena , Hirata Kosei , Saito Keita , Nakao Motonao , Takakusagi Yoichi , Araki Rikita , Sumiyoshi Akira , Takado Yuhei
Published: February 2025

Abnormalities and alterations in the glycolytic pathway in the pathology of neurodegenerative diseases and brain aging have received much attention, as clinical applications of proton-based magnetic resonance spectroscopy (MRS) have recently illuminated the elevation of lactate concentrations in the brains of patients with neurodegenerative diseases, including Alzheimer’s disease. Hyperpolarized [1-13C]pyruvate MRS has shown promise for neurological applications because it enables the real-time in vivo detection of glycolysis and oxidative phosphorylation flux. In studies of the mouse brain using hyperpolarized [1-13C]pyruvate, there are few reports that the signal of [13C]bicarbonate, a product of oxidative phosphorylation metabolized from [1-13C]pyruvate, was detected using MR spectroscopic imaging (MRSI) that allows spatial mapping of metabolism, although there have been reports of [13C]bicarbonate signals being detected by pulse-acquire sequences in the entire brain. In the present study, we compared hyperpolarized [1-13C]pyruvate metabolism between the brains of awake and isoflurane-anesthetized mice using a custom-made awake mouse restraint device with MRSI. Although the signal for [1-13C]lactate, a product of glycolysis metabolized from [1-13C]pyruvate, was detectable in multiple brain regions that include the orbitofrontal cortex and hippocampus in both awake and anesthetized mice, the signal for [13C]bicarbonate metabolized from [1-13C]pyruvate was only detectable in the brains of awake mice. Moreover, a comparison of hyperpolarized [1-13C]pyruvate metabolism in young and aged mouse brains using awake MRSI detected age-related decreases in oxidative phosphorylation flux in brain regions that include the hippocampus with variations in the extent of these changes across different brain regions. These results demonstrate that hyperpolarized [1-13C]pyruvate MRSI under awake conditions is useful for the spatial detection of abnormalities and alterations in glycolysis and oxidative phosphorylation flux in the brains of mice. Thus, the use of hyperpolarized [1-13C]pyruvate MRSI has potential in pathological and mechanistic studies of brain diseases and brain aging.
What can neurofeedback and transcranial alternating current stimulation reveal about cross-frequency coupling?
Authors: Orendáčová Mária , Kvašňák Eugen
Published: February 2025

In recent years, the dynamics and function of cross-frequency coupling (CFC) in electroencephalography (EEG) have emerged as a prevalent area of investigation within the research community. One possible approach in studying CFC is to utilize non-invasive neuromodulation methods such as transcranial alternating current stimulation (tACS) and neurofeedback (NFB). In this study, we address (1) the potential applicability of single and multifrequency tACS and NFB protocols in CFC research; (2) the prevalence of CFC types, such as phase–amplitude or amplitude–amplitude CFC, in tACS and NFB studies; and (3) factors that contribute to inter- and intraindividual variability in CFC and ways to address them potentially. Here we analyzed research studies on CFC, tACS, and neurofeedback. Based on current knowledge, CFC types have been reported in tACS and NFB studies. We hypothesize that direct and indirect effects of tACS and neurofeedback can induce CFC. Several variability factors such as health status, age, fatigue, personality traits, and eyes-closed (EC) vs. eyes-open (EO)condition may influence the CFC types. Modifying the duration of the tACS and neurofeedback intervention and selecting a specific demographic experimental group could reduce these sources of CFC variability. Neurofeedback and tACS appear to be promising tools for studying CFC.
Behavioral representations within the endogenous dual attentional pathways during audiovisual integration processing
Authors: Guan Zhongtian , Yan Mingli , He Miao , Liu Yubo , Zhang Zhixi , Li Chunlin
Published: February 2025

Introduction

Audiovisual integration processes are modulated by top-down attention and may involve different neural mechanisms under spatial, temporal, and neutral properties, which are externally manifested by subjects adopting different cognitive strategies. Composite behavioral indicators are able to assess the balance between speed and accuracy when subjects perform a task, thus further revealing behavioral representations of cognitive tasks. However, the cognitive strategies and neural mechanisms involved in audiovisual integration under endogenous attentional modulation are unclear, and in particular, the functional relationship between the dorsal and ventral pathways still needs to be thoroughly investigated.

Methods

We design only auditory (A), only visual (V), and audiovisual attention (VA) tasks based on the classical Posner paradigm with spatial, temporal and neutral cues for behavioral indicators, brain activation, and their correlations.

Results

Our results showed significant differences in behavioral performance between tasks, with weaker performance on the dual-channel task than on the single-channel task. The brain showed consistent activation in the frontal eye field, inferior parietal lobule, supplementary motor area, superior temporal gyrus, middle occipital gyrus and cuneus. The dorsal pathway is mainly associated with spatial processing and executive control, while the ventral pathway is involved in object recognition and semantic processing. In correlation analyses, proportions of correct responses (PC) showed a wider range of results. Spatio-temporal attention mobilized more cognitive resources than neutral attention in the audiovisual task and influenced execution strategies. Inverse efficiency score (IES) revealed endogenous attentional modulation of energy expenditure in the dual-channel task, whereas rate-correct score (RCS) revealed inter-task differences in correct response efficiency. Linear integrated speed–accuracy score (LISAS) and balanced integration score (BIS) showed different speed-accuracy balance in our task.

Conclusion

Our findings emphasize the synergy of functions and the dynamic synergy of cognitive processes in dorsal and ventral attentional pathways, which contribute to the management of cognitive flexibility and efficiency.
Disproportionality analysis of upadacitinib-related adverse events in inflammatory bowel disease using the FDA adverse event reporting system
Authors: Wang Shiyi , Wang Xiaojian , Ding Jing , Zhang Xudong , Zhu Hongmei , Fan Yihong , Sun Changbo
Published: February 2025

Background

Upadacitinib, a Janus kinase inhibitor, has been increasingly used over the past few years to treat moderate to severe ulcerative colitis and Crohn’s disease in patients who are insufficiently responsive or intolerant to tumor necrosis factor (TNF) antibodies, demonstrating notable clinical efficacy. The long-term safety of upadacitinib in extensive populations remains unexplored. This study evaluates upadacitinib-related adverse events (AEs) utilizing data from the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Methods

We employed disproportionality analyses, including the proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) algorithms to identify signals of upadacitinib-associated AEs for treating inflammatory bowel disease (IBD).

Results

From a total of 7,037,004 adverse event reports sourced from the FAERS database, 37,822 identified upadacitinib as the primary suspect drug in adverse drug events (ADEs), including 1,917 reports specifically related to the treatment of inflammatory bowel disease (IBD). The most commonly reported AEs were acne, product residue present, haematochezia, frequent bowel movements, flatulence, blood cholesterol increased, aligning with clinical trial outcomes. Notably, significant but unexpected AEs, such as rosacea, proctalgia, polyp, were also reported. Subgroup analysis indicated that the most prevalent AEs among the elderly included pulmonary embolism, cataract, and sepsis, whereas the 18–65 age group most frequently reported acne, abdominal pain, and nasopharyngitis. The median onset time for AEs related to upadacitinib was 41.00 days (interquartile range [IQR] 10–141.5 days), with the majority occurring within 3 months of treatment initiation (n = 269, 66.09%), particularly in the first month (n = 171, 42.01%).

Conclusion

Our findings affirm clinical observations and reveal potential new AE signals for upadacitinib, underscoring the need for prospective clinical studies to verify these results and clarify their clinical relevance. This study contributes valuable evidence for ongoing safety evaluations of upadacitinib.
Post-treatment of rat aflatoxicosis by camel milk and silymarin
Authors: Hassaneen Nahla H. , Hemeda Shabaan A. , El Nahas Abeer F. , Albadrani Ghadeer M. , Al-Ghadi Muath Q. , Mohammedsaleh Zuhair M. , Fadl Sabreen E. , El-Diasty Eman M. , Sakr Hader I.
Published: February 2025

Background

Aflatoxins are highly potent mycotoxins that can seriously harm the health of humans and a variety of animal species. On the other hand, camel milk and silymarin offer a variety of positive effects for many animal species. In addition, camel milk and silymarin reduce the impact of AFB1 on the hematology, serum biochemical markers, histopathology of the liver and testes, and expression of the inflammatory, antioxidant, and male reproductive genes.

Methods

40 rats were used to evaluate the beneficial effect of silymarin and camel milk against aflatoxin B1 (AFB1) toxicity in rats. The classified treatments were the control negative (no treatment) and the control positive (supplied with 1.4 mg aflatoxin/kg diet) for 28 days. Camel milk group (supplied with 1.4 mg aflatoxin/kg diet) for 28 days and camel milk (1 milliliter of camel milk per kilogram of body weight) orally, from day 29 to day 43). Silymarin (supplied with 1.4 mg aflatoxin/kg diet) for 28 days and silymarin (20 mg silymarin/kg b.wt), orally, from day 29 to day 43). The evaluation was done through measuring leukocyte count, liver function tests, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), ferritin, and testosterone. Moreover, the histopathology of the liver and testes was done along with expression levels of specific genes in the liver and testes.

Results

The outcomes showed that the post-treatment with silymarin and camel milk improved biochemical markers in serum and ability to reproduce.

Conclusion

In conclusion, post-treatment with camel milk and silymarin could mitigate the negative effect of AFB1 on rats.
The impact of local social spending on the political dissatisfaction of economically deprived individuals — Evidence from Dutch municipalities
Authors: Hummler Teresa , Vierus Paul
Published: February 2025

Previous research demonstrates that local conditions are highly visible and proximate for citizens and thus have a distinct impact on political attitude formation. However, we still lack knowledge of the interplay of the local and the individual level. In this study, we examine how a specific group (economically deprived individuals) responds to local social spending in the formation of political dissatisfaction. Research at the national level has provided contradictory findings concerning the influence of social policy measures. To shed new light on this interrelationship, we investigate the extent to which the individual link between economic hardship and political dissatisfaction is moderated by the level of local social spending. To empirically gauge this, we use panel data from the Netherlands merged with municipality-level data on social spending. Results from multilevel regressions reveal that the positive relationship between economic hardship and political dissatisfaction is mitigated in municipalities with higher levels of local social spending, suggesting a resource effect. Changes in the economic situation over time play a crucial role in this regard since the connection between economic hardship and political dissatisfaction is particularly pronounced for individuals in constant economic hardship.
Future anxiety and the motives for postponing parenthood: generational time perspective and life satisfaction as mediators
Authors: Szcześniak Małgorzata , Timoszyk-Tomczak Celina , Łoś Julia , Grzeczka Monika
Published: February 2025

Introduction

Research to date has focused largely on the consequences of delayed parenting. However, little is known about the reasons and relevant mechanisms that are involved in people’s decisions to delay parenthood. The aim of our study was to verify how anxiety about the future relates to the motives for deferred parenthood and how this relationship is mediated by generational time perspective and life satisfaction.

Methods

A total of 203 Polish adults between 18 and 40 years of age participated in the study. All of them were of reproductive age but did not yet have children. Respondents completed the following questionnaires: The Dark Future Scale, The Multidimensional Scale of Motives for Postponing Parenthood, The Generational Time Perspective Questionnaire, and The Riverside Life Satisfaction Scale.

Results

The results obtained in the study show that future anxiety correlates significantly and positively with all six motives for postponing parenthood, postponed parenthood overall, and generational affectivity. It is also associated with the generational cognitive perspective at the level of tendency, and negatively with life satisfaction. According to our findings, in all seven models, at least one of the factors mediated the relationship between future anxiety and motives for postponing parenthood/its total score.

Conclusion

The current study advances the understanding of how the subjective future time perspective is related to delayed parenthood through generational concern and reduced life satisfaction. Our findings may indicate that despite the importance of sociodemographic variables in postponing parenthood (e.g., lack of housing, financial instability, acquiring knowledge, education, etc.), variables related to personality and time perspective play a very important role in postponing the decision to have a child.
The multiple self and psychological openness
Authors: Suszek Hubert , Kopera Maciej , Jakubczyk Andrzej
Published: February 2025

Introduction

This research identifies and explores two distinct modes of self-experience and their influence on psychological openness. We distinguish between the unitary self-mode, where individuals perceive themselves as cohesive, stable entities, and the multiple self-mode, where they recognize their diverse, context-dependent aspects. These modes represent fundamentally different ways of experiencing and organizing self-knowledge that can be situationally activated. While both modes of self-experience have been theoretically described, their influence on psychological functioning remains empirically unexplored.

Methods

Through five experiments (N = 989), we tested whether activation of the multiple self-mode increases psychological openness compared to activation of the unitary self-mode using different experimental manipulations and measures.

Results

Induction of the multiple self enhanced psychological openness compared to induction of the unitary self. This effect was consistently observed across various domains of openness: openness as a state (Study 1, N = 204), openness to change (Studies 3 and 4, N = 230 and N = 184), range of values (Studies 2 and 3, N = 212 and N = 230), psychological mindedness and decentering (Study 5, N = 159). Results consistently showed moderate effect sizes (d = 0.31–0.44) across different operationalizations of both the multiple self-induction and openness measures.

Discussion

These findings indicate that the way in which individuals organize their self-knowledge has important implications for their cognitive and experiential flexibility, contributing to our understanding of personality plasticity and development.