bluuebunny/crossref_metadata_2025_split huggingface dataset:
M2 microglia-derived exosomes promote vascular remodeling in diabetic retinopathy
Authors: Wang Xingxing , Xu Changlin , Bian Cunxin , Ge Pengfei , Lei Jie , Wang Jingfan , Xiao Tianhao , Fan Yuanyuan , Gu Qinyuan , Li Hong-Ying , Xu Jingyi , Hu Zizhong , Xie Ping 
Published: February 2024

AbstractDiabetic retinopathy (DR) is a vision-threatening diabetic complication that is characterized by microvasculature impairment and immune dysfunction. The present study demonstrated that M2 microglia intensively participated in retinal microangiopathy in human diabetic proliferative membranes, mice retinas, retinas of mice with oxygen-induced retinopathy (OIR) mice, and retinas of streptozotocin-induced DR mice. Further in vivo and in vitro experiments showed that exosomes derived from M2 polarized microglia (M2-exo) could reduce pericyte apoptosis and promote endothelial cell proliferation, thereby promoting vascular remodeling and reducing vascular leakage from the diabetic retina. These effects were further enhanced by M2-exo that facilitated M2 polarization of retinal microglia. Collectively, the study demonstrated the capability of M2-exo to induce retinal microvascular remodeling, which may provide a new therapeutic strategy for the treatment of DR.
Graphical Abstract
Mitral valve repair for degenerative mitral regurgitation with Carpentier’s functional classification type II in elderly patients: a single center experience
Authors: Kawamura Masashi , Monta Osamu , Maeda Shusaku , Tsutsumi Yasushi 
Published: February 2024

Abstract
Objective
Mitral valve (MV) repair for Carpentier functional classification Type II (C-II) mitral regurgitation (MR) is widely accepted because of its efficacy. It is unclear whether MV repair has the same benefits in elderly patients as in younger patients because of their lower life expectancy. Herein, we examined the midterm results of MV repair for C-II mitral regurgitation, especially in patients aged ≧70 years.

Method
A retrospective review was performed on 176 patients who underwent MV repair for C-II mitral regurgitation with a median age of 65 years; 55 (31%) patients were ≧70 years, and 124 were male (71%). Lesions of the mitral valve were isolated from the anterior leaflet (48 patients), posterior leaflet (113 patients), and both leaflets (15 patients), and included seven patients with Barlow’s disease. We compared the outcomes between patients aged ≧70 years (≧70 years; median age, 76 years) and those aged < 70 years (median age, 60 years).

Results
In terms of the durability of MV repair in elderly patients, there were no significant differences in the rates of freedom from reoperation or MR recurrence at 5 years between patients aged < 70 years and those aged ≧70 years (reoperation:98% in < 70 years versus 89% in ≧70 years; P = 0.4053; MR recurrence:95% in < 70 years versus 81% in ≧70 years; P = 0.095). The mitral valve complexity was divided into two grades: Simple (isolated posterior mitral lesion) and Complex (isolated anterior lesion or both lesions). In patients aged < 70 years, there was no significant difference in the rate of freedom from MR recurrence at 5 years between the Simple and Complex groups (96% vs. 91%; P = 0.1029). In contrast, in patients aged ≧70 years, the MR recurrence rate at 3 years in Complex was significantly higher in the Complex group than in the Simple (100% vs. 80%; P = 0.0265).

Conclusions
We studied the outcomes of MV repair for C-II in MR. In elderly patients, MR recurrence was higher in complex lesions than in simple lesions. MV replacement may be considered for elderly patients with complex mitral valve lesions, if appropriately selected.
Risk factors associated with severe adverse events in patients with relapsing polychondritis undergoing flexible bronchoscopy
Authors: Wang Shao-Ting , Wang Jinglan , Gao Xiaoxing , Chen Keqi , Xu Kai-Feng , Tian Xinlun 
Published: February 2024

Abstract
Background
Patients with relapsing polychondritis (RP) sometimes experience upper airway collapse or lower airway stenosis, and bronchoscopy may provide a valuable typical image to confirm the diagnosis. This study aimed to identify potential risk factors associated with severe adverse effects during bronchoscopy.

Methods
We performed a retrospective cohort study of 82 consecutive patients with RP hospitalized at Peking Union Medical College Hospital between January 1, 2012 and December 31, 2022. Clinical features and disease patterns were compared among patients with RP undergoing bronchoscopy with or without severe adverse effects. Binary logistic regression analysis was performed to identify the associated risk factors.

Results
For patients with RP undergoing bronchoscopy with severe adverse effects, the forced vital capacity (FVC), forced vital capacity percent predicted values (FVC%), and peak expiratory flow were significantly lower (P = 0.001, P = 0.001, and P = 0.021, respectively) than those in the non-severe adverse effect subgroup. Binary logistic regression analysis revealed that low FVC% (odds ratio, 0.930; 95% confidence interval, 0.880–0.982; P = 0.009) was an independent risk factor for severe adverse events in patients undergoing bronchoscopy.

Conclusions
Low FVC or FVC% suggests a high risk of severe adverse effects in patients with RP undergoing bronchoscopy. Patients with such risk factors should be carefully evaluated before bronchoscopy and adequately prepared for emergency tracheal intubation or tracheostomy.
IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts
Authors: Van den Eynde Astrid , Gehrcken Laura , Verhezen Tias , Lau Ho Wa , Hermans Christophe , Lambrechts Hilde , Flieswasser Tal , Quatannens Delphine , Roex Gils , Zwaenepoel Karen , Marcq Elly , Joye Philippe , Cardenas De La Hoz Edgar , Deben Christophe , Gasparini Alessia , Montay-Gruel Pierre , Le Compte Maxim , Lion Eva , Lardon Filip , Van Laere Steven , Siozopoulou Vasiliki , Campillo-Davo Diana , De Waele Jorrit , Pauwels Patrick , Jacobs Julie , Smits Evelien , Van Audenaerde Jonas R. M. 
Published: February 2024

Abstract
Background
It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma.

Methods
RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70+ tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs.

Results
In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70+ tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70+ tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner.

Conclusions
We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70+ cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.
Calcium signaling positively regulates cellulase translation and secretion in a Clr-2-overexpressing, catabolically derepressed strain of Penicillium funiculosum
Authors: Randhawa Anmoldeep , A. Ogunyewo Olusola , Jawed Kamran , Yazdani Syed Shams 
Published: February 2024

Abstract
Background
Low-cost cellulase production is vital to sustainable second-generation biorefineries. The catabolically derepressed strain of Penicillium funiculosum NCIM1228 (PfMig188 or ∆Mig1) secretes a superior set of cellulolytic enzymes, that are most suitable for 2G biorefineries. At a 3% (w/w) load, the ∆Mig1 secretome can release > 80% of fermentable sugars from lignocellulose at a 15% (w/v) biomass load, irrespective of the type of biomass and pretreatment. The robustness of the secretome can be further increased by improving the cellulase production capacity of the fungal strain.

Results
We began by identifying the transcription factor responsible for cellulase production in NCIM1228. An advanced RNA-seq screen identified three genes, clr-2, ctf1a and ctf1b; the genes were cloned under their native promoters and transformed into NCIM1228. Of the three, clr-2 overexpression led to twofold higher cellulase production than the parent strain and was thus identified as the transcriptional activator of cellulase in NCIM1228. Next, we overexpressed clr-2 in ∆Mig1 and expected an exponential increase in cellulolytic attributes accredited to the reinforced activation mechanisms, conjoint with diminished negative regulation. Although clr-2 overexpression increased the transcript levels of cellulase genes in ∆Mig1, there was no increase in cellulase yield. Even a further increase in the transcript levels of clr-2 via a stronger promoter was ineffective. However, when the CaCO3 concentration was increased to 5 g/l in the growth medium, we achieved a 1.5-fold higher activity of 6.4 FPU/ml in the ∆Mig1 strain with clr-2 overexpression. Enthused by the calcium effect, a transcriptomic screen for genes encoding Ca2+-activated kinase identified ssp1, whose overexpression could further increase cellulase yield to ~ 7.5 FPU/ml. Investigation of the mechanism revealed that calcium signaling exclusively enhances the translation and secretion of cellulase in Penicillium funiculosum.

Conclusions
Our study identifies for the first time that cellulose activates two discrete signaling events to govern cellulase transcription and posttranscriptional processes (translation, processing and secretion) in P. funiculosum NCIM1228. Whereas Clr-2, the transcriptional activator of cellulase, governs transcription, calcium signaling specifically activates cellulase translation and secretion.
Intestinal metabolites predict treatment resistance of patients with depression and anxiety
Authors: Matsuzaki Juntaro , Kurokawa Shunya , Iwamoto Chiaki , Miyaho Katsuma , Takamiya Akihiro , Ishii Chiharu , Hirayama Akiyoshi , Sanada Kenji , Fukuda Shinji , Mimura Masaru , Kishimoto Taishiro , Saito Yoshimasa 
Published: February 2024

Abstract
Background
The impact of the gut microbiota on neuropsychiatric disorders has gained much attention in recent years; however, comprehensive data on the relationship between the gut microbiome and its metabolites and resistance to treatment for depression and anxiety is lacking. Here, we investigated intestinal metabolites in patients with depression and anxiety disorders, and their possible roles in treatment resistance.

Results
We analyzed fecal metabolites and microbiomes in 34 participants with depression and anxiety disorders. Fecal samples were obtained three times for each participant during the treatment. Propensity score matching led us to analyze data from nine treatment responders and nine non-responders, and the results were validated in the residual sample sets. Using elastic net regression analysis, we identified several metabolites, including N-ε-acetyllysine; baseline levels of the former were low in responders (AUC = 0.86; 95% confidence interval, 0.69–1). In addition, fecal levels of N-ε-acetyllysine were negatively associated with the abundance of Odoribacter. N-ε-acetyllysine levels increased as symptoms improved with treatment.

Conclusion
Fecal N-ε-acetyllysine levels before treatment may be a predictive biomarker of treatment-refractory depression and anxiety. Odoribacter may play a role in the homeostasis of intestinal L-lysine levels. More attention should be paid to the importance of L-lysine metabolism in those with depression and anxiety.
The impact of strategic napping on peak expiratory flow and respiratory function in young elite athletes
Authors: Kurtoğlu Ahmet , Eken Özgür , Aydın Engin , Çar Bekir , Nobari Hadi 
Published: February 2024

AbstractRespiratory health is a critical determinant of athletic performance, and the utilization of restorative strategies, such as strategic napping, may offer a competitive edge to athletes. This study investigates the effects of nap duration on the respiratory function of young elite athletes who have achieved top rankings national competitions. Participants engage in three test sessions with varying nap durations: no nap (N0), a 25-minute nap (N25), and a 45-minute nap (N45), with a minimum 72-hour interval between sessions. Respiratory parameters including Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), FEV1/FVC ratio, Peak Expiratory Flow rate (PEF), Forced Expiratory Flow at 25–75% of FVC (FEF25-75%), and Forced Expiratory Time (FET) are assessed. Results reveal a significant enhancement in PEF values following a 45-minute nap (N45) compared to the no-nap control (N0) [F1 − 11=7.356, p =.004, ηp2 = 0.401, (95% CI for difference: -1.56 to − 0.056)], indicating a potential positive influence of napping on maximum expiratory flow rate and, consequently, athletes’ respiratory performance. While no significant changes are observed in other respiratory parameters across different nap durations, these findings underscore the potential benefits of strategic napping in optimizing respiratory health in young elite athletes.
Remembering the null hypothesis when searching for brain sex differences
Authors: Eliot Lise 
Published: February 2024

AbstractHuman brain sex differences have fascinated scholars for centuries and become a key focus of neuroscientists since the dawn of MRI. We recently published a major review in Neuroscience and Biobehavioral Reviews showing that most male–female brain differences in humans are small and few have been reliably replicated. Although widely cited, this work was the target of a critical Commentary by DeCasien et al. (Biol Sex Differ 13:43, 2022). In this response, I update our findings and confirm the small effect sizes and pronounced scatter across recent large neuroimaging studies of human sex/gender difference. Based on the sum of data, neuroscientists would be well-advised to take the null hypothesis seriously: that men and women’s brains are fundamentally similar, or “monomorphic”. This perspective has important implications for how we study the genesis of behavioral and neuropsychiatric gender disparities.
A novel nanobody-based immunocytokine of a mutant interleukin-2 as a potential cancer therapeutic
Authors: Beig Parikhani Arezoo , Dehghan Rada , Talebkhan Yeganeh , Bayat Elham , Biglari Alireza , Shokrgozar Mohammad Ali , Ahangari Cohan Reza , Mirabzadeh Esmat , Ajdary Soheila , Behdani Mahdi 
Published: February 2024

AbstractThe immunotherapeutic application of interleukin-2 (IL-2) in cancer treatment is limited by its off-target effects on different cell populations and insufficient activation of anti-tumor effector cells at the site of the tumor upon tolerated doses. Targeting IL-2 to the tumor microenvironment by generating antibody-cytokine fusion proteins (immunocytokine) would be a promising approach to increase efficacy without associated toxicity. In this study, a novel nanobody-based immunocytokine is developed by the fusion of a mutant (m) IL-2 with a decreased affinity toward CD25 to an anti-vascular endothelial growth factor receptor-2 (VEGFR2) specific nanobody, denoted as VGRmIL2-IC. The antigen binding, cell proliferation, IFN-γ-secretion, and cytotoxicity of this new immunocytokine are evaluated and compared to mIL-2 alone. Furthermore, the pharmacokinetic properties are analyzed. Flow cytometry analysis shows that the VGRmIL2-IC molecule can selectively target VEGFR2-positive cells. The results reveal that the immunocytokine is comparable to mIL-2 alone in the stimulation of Primary Peripheral Blood Mononuclear Cells (PBMCs) and cytotoxicity in in vitro conditions. In vivo studies demonstrate improved pharmacokinetic properties of VGRmIL2-IC in comparison to the wild or mutant IL-2 proteins. The results presented here suggest VGRmIL2-IC could be considered a candidate for the treatment of VEGFR2-positive tumors.
Downregulation of salusins alleviates hypertrophic cardiomyopathy via attenuating oxidative stress and autophagy
Authors: Dang Jing-Yi , Zhang Wei , Chu Yi , Chen Jiang-Hong , Ji Zhao-Le , Feng Pin 
Published: February 2024

Abstract
Introduction
Salusins, which are translated from the alternatively spliced mRNA of torsin family 2 member A (TOR2A), play a vital role in regulation of various cardiovascular diseases. However, it remains unclear precisely regarding their roles in hypertrophic cardiomyopathy (HCM). Therefore, this study was conducted to explore therapeutic effect and the underlying mechanisms of salusins on HCM.

Material and methods
In vivo experiments, Sprague–Dawley rats were used to induce HCM model by angiotensin (Ang) II infusion for 4 weeks. The rats were randomly divided into four groups, namely, Saline + Control shRNA (n = 7), Ang II + Control shRNA (n = 8), Saline + TOR2A shRNA (n = 7), and Ang II + TOR2A shRNA groups (n = 8). After HCM induction, doppler echocardiography is recommended to evaluate heart function. In vitro experiments, primary neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (NRCFs) were obtained from newborn rats, and were treated with Ang II (10–6 M) for 24 h.

Results
After treatment with Ang II, levels of salusin-α and salusin-β were elevated in serum and cardiac tissues of rats and in the neonatal rat cardiomyocytes and cardiac fibroblasts. Downregulation of salusins alleviated the Ang II-induced cardiac hypertrophy by suppressing the increased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (β-MHC) and cardiac fibrosis by blocking collagen I, collagen III and transforming growth factor-beta (TGF-β), and it also attenuated oxidative stress by suppressing the increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels and reversing the decreased superoxide dismutase (SOD) activity and autophagy by inhibiting the increased microtubule-associated protein light chain 3B (LC3B), Beclin1, autophagy related gene (Atg) 3 and Atg5 in the cardiac tissues of Ang II-infused rats and in the Ang II-treated NRCMs.

Conclusions
All these findings suggest that the levels of salusins were elevated in the HCM, and targeting of salusins contributes to alleviation of cardiac hypertrophy and fibrosis probably via attenuating oxidative stress and autophagy. Accordingly, targeting of salusins may be a strategy for HCM therapy.
Detection of skin α-synuclein using RT-QuIC as a diagnostic biomarker for Parkinson’s disease in the Chinese population
Authors: Li Jiaqi , Duan Suying , Yang Jing , Zheng Honglin , Yuan Yanpeng , Tang Mibo , Wang Yanlin , Liu Yutao , Xia Zongping , Luo Haiyang , Xu Yuming 
Published: February 2024

Abstract
Background
Several studies have indicated that skin holds promise as a potential sample for detecting pathological α-Syn and serving as a diagnostic biomarker for α-synucleinopathies. Despite reports in Chinese PD patients, comprehensive research on skin α-Syn detection using RT-QuIC is lacking.

Objective
This study aimed to evaluate the diagnostic performance of skin samples using RT-QuIC from PD patients in the Chinese population.

Methods
Patients with sporadic PD and controls were included according to the British PD Association Brain Bank diagnostic criteria. The seeding activity of misfolded α-Syn in these skin samples was detected using the RT-QuIC assay after protein extraction. Biochemical and morphological analyses of RT-QuIC products were conducted by atomic force microscopy, transmission electron microscopy, Congo red staining, and dot blot analysis.

Result
30 patients clinically diagnosed with PD and 28 controls with non-α-synucleinopathies were included in this study. 28 of 30 PD patients demonstrated positive α-Syn seeding activity by RT-QuIC assay. In contrast, no α-Syn seeding activity was detected in the 28 control samples, with an overall sensitivity and specificity of 93.3% and 100%, respectively (P < 0.001). Biochemical characterization of the RT-QuIC product indicated fibrillary α-Syn species in PD-seeded reactions, while control samples failed in the conversion of recombinant α-Syn substrate.

Conclusion
This study applied RT-QuIC technology to identify misfolded α-Syn seeding activity in skin samples from Chinese PD patients, demonstrating high specificity and sensitivity. Skin α-Syn RT-QuIC is expected to be a reliable approach for the diagnosis of PD.
Counteracting mental fatigue for athletes: a systematic review of the interventions
Authors: Sun He , Soh Kim Geok , Mohammadi Alireza , Toumi Zakaria , Zhang Lingling , Ding Cong , Gao Xiaojuan , Tian Jian 
Published: February 2024

AbstractThe deleterious effects of mental fatigue (MF) on athletes have been carefully studied in various sports, such as soccer, badminton, and swimming. Even though many researchers have sought ways to ameliorate the negative impact of MF, there is still a lack of studies that review the interventions used to counteract MF among athletes. This review aims to report the current evidence exploring the effects of interventions on MF and sport-specific performance, including sport-specific motor performance and perceptual-cognitive skills. Web of Science, Scopus, PubMed, and SPORTDicus (EBSCOhost) were combed through to find relevant publications. Additionally, the references and Google Scholar were searched for any grey literature. For the current review, we included only randomized controlled trials that involved athletes, a primary task to induce MF, interventions to counter MF with comparable protocols, and the outcomes of sport-specific motor performance and perceptual-cognitive skill. The selection criteria resulted in the inclusion of 10 articles. The manipulations of autonomous self-control exertion, person-fit, nature exposure, mindfulness, and transactional direct current stimulation showed that positive interventions counteract MF and improve sport-specific performance in different domains, including strength, speed, skill, stamina, and perceptual-cognitive skills. The selected interventions could significantly counteract MF and improve subsequent sport-specific performance. Moreover, self-regulation and attention resources showed the importance of the potential mechanisms behind the relevant interventions.