bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial progenitor cell-derived conditioned medium mitigates chronic cerebral ischemic injury through macrophage migration inhibitory factor-activated AKT pathway
Authors: Cheng Ya-Wen , Yang Ling-Yu , Chen Yi-Tzu , Chou Sheng-Che , Chen Kuo-Wei , Chen Yi-Hsing , Deng Chuan-Rou , Chen I-Chin , Chou Wan-Ju , Chang Chen-Chih , Chen Yong-Ren , Hwa Hsiao-Lin , Wang Kuo-Chuan , Kuo Meng-Fai 
Published: November 2024

Abstract
Background
Chronic cerebral ischemia (CCI) is a significant health issue characterized by hypoperfusion due to damage or occlusion of the cerebral or carotid arteries. CCI may lead to progressive cognitive impairment that is considered as a prelude to neurodegenerative diseases, including dementia and Alzheimer's disease (AD). Endothelial progenitor cells (EPCs) have been implicated in vascular repair in ischemic cerebrovascular diseases, primarily by differentiating into endothelial cells (ECs) or through paracrine effects. However, the clinical transplantation of stem cell therapies remains limited. In this study, we investigated the effects of EPC-derived conditioned medium (EPC-CM) on the impaired vasculature and neurological function in a rodent model of CCI and the mechanism involved.

Methods
EPC-CM was analyzed by cytokine array to identify key factors involved in angiogenesis and cellular senescence. The effects and mechanism of the candidate factors in the EPC-CM were validated in vitro using oxygen–glucose deprivation (OGD)-injured ECs and EPCs. The therapeutic effects of EPC-CM and the identified key factor were further examined in a rat model of CCI, which was induced by bilateral internal carotid artery ligation (BICAL). EPC-CM was administered via intracisternal injection one week post BICAL. The cerebral microvasculature and neurobehavior of the rats were examined three weeks after BICAL.

Results
Macrophage migration inhibitory factor (MIF) was identified as a key factor in the EPC-CM. Recombinant MIF protein promoted angiogenesis and prevented senescence in the injured EPCs and ECs. The effect was similar to that of the EPC-CM. These therapeutic effects were diminished when the EPC-CM was co-treated with MIF-specific antibody (Ab). Additionally, the vascular, motor, and cognitive improvements observed in the BICAL rats treated with EPC-CM were abolished by co-treated with MIF Ab. Furthermore, we found MIF promoted angiogenesis and anti-senescence via activating the AKT pathway. Inhibition of the AKT pathway diminished the protective effects of MIF in the in vitro study.

Conclusions
We demonstrated that EPC-CM protected the brain from chronic ischemic injury and promoted functional recovery through MIF-mediated AKT pathway. These findings suggest EPC-CM holds potential as a novel cell-free therapeutic approach for treating CCI through the actions of MIF.
B2M or CIITA knockdown decreased the alloimmune response of dental pulp stem cells: an in vitro study
Authors: Hu Mingxin , Zhang Yuchen , Liu Junqing , Chen Yihan , Kang Jun , Zhong Jialin , Lin Shulan , Liang Ye , Cen Rong , Zhu Xiaofei , Zhang Chengfei 
Published: November 2024

Abstract
Background
Dental pulp stem cells (DPSCs) have acquired noteworthy attention for their application in treating ischemic diseases and facilitating tissue regeneration. However, the host’s immune response following allogenic DPSC transplantation often handicaps the long-term survival of transplanted cells, thereby limiting the application of DPSCs in cell therapy. This study aims to investigate whether genetic modification can alleviate the immunogenicity of DPSCs.

Methods
Beta 2-microglobulin (B2M) and the class II histocompatibility complex transactivator (CIITA) were individually knocked down in DPSCs by lentiviral particles encoding short hairpin (sh) RNAs. The self-renewal capacity and pluripotency of DPSCs-shB2M (B2M silenced DPSCs) and DPSCs-shCIITA (CIITA silenced DPSCs) were evaluated by CCK8 and differentiation assays including osteogenesis, adipogenesis, and neurogenesis. The expression of HLA-I and HLA-II in DPSCs-shB2M and DPSCs-shCIITA after IFN-γ treatment were analyzed by western blotting, immunofluorescence, and flow cytometry. The function of genetically modified cells was assessed by leukocyte-mediated cytotoxicity and T-cell proliferation assays.

Results
Western blotting, immunofluorescence, and flow cytometry revealed that DPSCs-shB2M and DPSCs-shCIITA exhibited impaired IFN-γ inducible HLA-I and HLA-II expression. There were no significant differences in the self-renewal capacity and pluripotency among DPSCs-shB2M, DPSCs-shCIITA, and control groups (p > 0.05). Lower leukocyte-mediated cytotoxicity and higher cell survival rates were found in DPSCs-shB2M and DPSCs-shCIITA groups compared to the control (p < 0.05). T cell proliferation was significantly inhibited in both DPSCs-shB2M and DPSCs-shCIITA groups (p < 0.05).

Conclusion
Genetic knockdown of B2M or CIITA in DPSCs substantially reduced their immunogenicity without compromising their stemness, thereby broadening the clinical application of DPSCs in cell therapy and tissue regeneration.
Ancestral retrovirus envelope protein ERVWE1 upregulates circ_0001810, a potential biomarker for schizophrenia, and induces neuronal mitochondrial dysfunction via activating AK2
Authors: Li Wenshi , Xue Xing , Li Xuhang , Wu Xiulin , Zhou Ping , Xia Yaru , Zhang Jiahang , Zhang Mengqi , Zhu Fan 
Published: November 2024

Abstract
Background
Increasingly studies highlight the crucial role of the ancestral retrovirus envelope protein ERVWE1 in the pathogenic mechanisms of schizophrenia, a severe psychiatric disorder affecting approximately 1% of the global population. Recent studies also underscore the significance of circular RNAs (circRNAs), crucial for neurogenesis and synaptogenesis, in maintaining neuronal functions. However, the precise relationship between ERVWE1 and circRNAs in the etiology of schizophrenia remains elusive.

Results
This study observed elevated levels of hsa_circ_0001810 (circ_0001810) in the blood samples of schizophrenia patients, displaying a significant positive correlation with ERVWE1 expression. Interestingly, in vivo studies demonstrated that ERVWE1 upregulated circ_0001810 in neuronal cells. Circ_0001810, acting as a competing endogenous RNA (ceRNA), bound to miR-1197 and facilitated the release of adenylate kinase 2 (AK2). The bioinformatics analysis of the schizophrenia datasets revealed increased levels of AK2 and enrichment of mitochondrial dynamics. Notably, miR-1197 was reduced in schizophrenia patients, while AK2 levels were increased. Additionally, AK2 showed positive correlations with ERVWE1 and circ_0001810. Further studies demonstrated that AK2 led to mitochondrial dysfunction, characterized by loss of intracellular ATP, mitochondrial depolarization, and disruption of mitochondrial dynamics. Our comprehensive investigation suggested that ERVWE1 influenced ATP levels, promoted mitochondrial depolarization, and disrupted mitochondrial dynamics through the circ_0001810/AK2 pathway.

Conclusions
Circ_0001810 and AK2 were increased in schizophrenia and positively correlated with ERVWE1. Importantly, ERVWE1 triggered mitochondrial dysfunction through circ_0001810/miR-1197/AK2 pathway. Recent focus on the impact of mitochondrial dynamics on schizophrenia development had led to our discovery of a novel mechanism by which ERVWE1 contributed to the etiology of schizophrenia, particularly through mitochondrial dynamics. Moreover, these findings collectively proposed that circ_0001810 might serve as a potential blood-based biomarker for schizophrenia. Consistent with our previous theories, ERVWE1 is increasingly recognized as a promising therapeutic target for schizophrenia.
Incorporating Limestone Powder and Ground Granulated Blast Furnace Slag in Ultra-high Performance Concrete to Enhance Sustainability
Authors: Sharma Yashovardhan , Yeluri Meghana , Allena Srinivas , Owusu-Danquah Josiah 
Published: November 2024

AbstractWhile ultra-high performance concrete (UHPC) offers numerous advantages, it also presents specific challenges, primarily due to its high cost and excessive cement content, which can pose sustainability concerns. To address this challenge, this study aims to develop cost-effective and sustainable UHPC mixtures by incorporating ground granulated blast furnace slag (GGBFS) and limestone powder (LP) as partial replacements for portland cement. Eight fiber-reinforced UHPC mixtures were investigated, with a water-to-cementitious materials (w/cm) ratio of 0.15. In four of the UHPC mixtures, 25% of the cement was replaced with GGBFS, and further, LP was added as a mineral filler, partially substituting up to 20% of the cement. In the remaining four mixtures, cement was replaced with only LP up to 20% (without GGBFS). The 28-day compressive strength of the UHPC mixture with 25% GGBFS and 20% LP was 149 MPa, 3.50% lower than the mixture without GGBFS. Its 28-day flexural strength decreased by 30%. Increasing LP replacement reduced drying and autogenous shrinkage, with a 29% shrinkage reduction at 20% LP replacement. Moreover, UHPC mixtures with GGBFS exhibited lower shrinkage compared to those without GGBFS for all LP replacements up to 20%. For evaluating the sustainability of UHPC mixtures, the cement composition index (CCI) and clinker to cement ratio (CCR) were determined. For 20% LP replacement with 25% GGBFS, CCI was 3.6 and the CCR was 0.5, 38% decrease from the global clinker to cement ratio. Overall, 20% LP replacement UHPC mixtures with and without GGBFS can produce UHPC class performance and reduce the environmental impact.
Effectiveness of cold atmospheric plasma in decontaminating enterococcus faecalis colonized collagen and PTFE membranes used in guided bone regeneration: a comparative in vitro investigation
Authors: Weitkamp Jan-Tobias , Hogreve Adrian , Spille Johannes , Veziroglu Salih , Aktas Oral Cenk , Flörke Christian , Liedtke Kim Rouven , Wiltfang Jörg , Gülses Aydin 
Published: November 2024

Abstract
Purpose
Wound healing disorders caused by bacterial infections in dental surgery, especially where membranes are used, are a common issue in oral surgery. Cold atmospheric plasma (CAP) offers a non-invasive solution for surface decontamination, including dental implants. The aim of this study was to evaluate the antibacterial effectiveness of CAP on various clinically applied membranes made of collagen and polytetrafluoroethylene (PTFE).

Materials and methods
To assess the antibacterial properties of CAP, enterococcus faecalis were seeded on different membranes: Memlock (collagen), Memlock Pliable (collagen), Agronaut (collagen), and PermaPro (PTFE); n = 4. After in vitro cultivation for 6 days, CAP using a kINPen® MED with an output of 5 W was applied 5 min and 10 min. Bacterial colony-forming units (CFU) were quantified to detect decontamination effectiveness. In addition, live and dead staining as well as scanning electron microscopy (SEM) of membranes was performed for validation and surface texture analysis.

Results
Bacterial colonization was highest on collagen-based membranes (CFU Memlock: 14.38 ± 8.91). The results showed that CAP significantly reduced bacterial colonization on all membrane types after 10 min application of CAP; Memlock (CFU after 10 min 0.22 ± 0.16^106; p = 0.0256), Argonaut (CFU after 10 min 0.02 ± 0.01^106; p = 0.0129) and PermaPro (complete bacterial decontamination; p = 0.0058). This was paralleled by fluorescence and scanning electron microscopy. CAP was most effective on smooth membrane surfaces as SEM revealed.

Conclusion
CAP thus offers a non-invasive, cost-effective method to reduce bacterial infections in guided bone regeneration using membranes.

Graphical Abstract
Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test
Authors: Kurakami Masaki , Hakura Atsushi , Sato Rika , Kawade Akihiro , Yamagata Takeshi , Koyama Naoki , Kakiuchi Dai , Asakura Shoji 
Published: November 2024

Abstract
Background
Although the in silico predictive ability of the Ames test results has recently made remarkable progress, there are still some chemical classes for which the predictive ability is not yet sufficient due to a lack of Ames test data. These classes include simple heterocyclic compounds. This study aimed to investigate the mutagenicity and structure-mutagenicity relationships for some heterocycles in the Ames test. In the present study, we selected 12 quinoline analogues containing one or two nitrogen atoms in the naphthalene ring and 12 indole analogues containing one to three nitrogen atoms in the indole ring, without any side moiety.

Results
The Ames test was performed with five standard bacterial strains (TA100, TA1535, TA98, TA1537, and WP2uvrA) using the pre-incubation method with and without rat liver S9. Five quinoline and two indole analogues were mutagenic. Among the five quinoline analogues, four were mutagenic in the presence of S9 mix with TA100, whereas cinnoline was mutagenic in the absence of S9 mix with TA1537. Among the two indole analogues, indazole was mutagenic in the presence and absence of S9 mix with WP2uvrA and 4-azaindole was mutagenic in the absence of S9 mix with TA1537. The mechanisms underlying the induction of mutagenesis appear to differ between quinoline and indole analogues. In addition, we performed in silico analysis of the mutagenicity of all these analogues using DEREK Nexus 6.1.1 (Lhasa Limited) and GT_EXPERT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as knowledge-based models and GT1_BMUT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as a statistical-based model. The knowledge-based model showed low sensitivity for both the quinoline and indole analogues (DEREK Nexus and GT_EXPERT: 20% for quinolines and 0% for indoles). Conversely, the statistical model showed high sensitivity (100% for both quinolines and indoles) and low specificity (43% for quinolines and 10% for indoles).

Conclusion
Based on the Ames test results, we proposed structural alerts noting that quinoline analogues were mutagenic when they had nitrogens in any of the positions 2, 5, 7, or 8 in addition to 1, and indole analogues were mutagenic when they had nitrogens at positions 2 or 4 in addition to 1.
DNA hypomethylation of INHBA promotes tumor progression and predicts prognosis and immune status of gastric cancer
Authors: Li Xueying , Jiang Haizhong , Fu Yangbo , Hu Qiying , Cai Xianlei , Xu Guoqiang 
Published: November 2024

Abstract
Objective
Gastric cancer (GC) is characterized by its high malignancy and poor prognosis. However, the role of Inhibin subunit beta A (INHBA) in GC remains insufficiently understood. This study aims to comprehensively evaluate the clinical significance, biological roles, and possible mechanisms of INHBA in GC.

Methods
Expression levels and survival analyses of the Inhibin beta family were assessed using online databases. A prediction model based on INHBA was developed. In addition, the associations between INHBA expression and immune status, and chemotherapy sensitivity were explored. In vitro experiments were conducted to investigate the biological impact of INHBA on GC cells. Pyrosequencing and the DNA methylation inhibitor, 5-AZA-2’-deoxycytidine (5-AZA-dC) were employed to elucidate the mechanisms underlying INHBA function.

Results
Our findings revealed that INHBA exhibited high expression in GC patients, and elevated INHBA expression correlated with worse outcomes. We developed a novel nomogram incorporating INHBA, age, and tumor node metastasis (TNM) stage to predict the prognosis of GC patients. Additionally, INHBA was found to be associated with suppressed infiltration of immune cells and chemosensitivity. Functionally, INHBA promoted the proliferation and invasiveness of GC cells. Mechanistically, pyrosequencing revealed DNA Hypomethylation of INHBA in the first exon region, and the effects of INHBA silencing were rescued by 5-AZA-dC treatment.

Conclusion
Our study suggests that DNA hypomethylation of INHBA contributes to the progression of GC. Furthermore, INHBA holds promise as a valuable biomarker for prognostic evaluation and immune status prediction in GC patients.
Erectile Dysfunction Therapy of Bariatric Patients: Tadalafil Biopharmaceutics and Pharmacokinetics Before vs. After Gastric Sleeve/Bypass
Authors: Porat Daniel , Dukhno Oleg , Cvijić Sandra , Dahan Arik 
Published: November 2024

AbstractBariatric surgery introduces significant changes in the gastrointestinal tract, which may affect oral drug absorption/bioavailability. Here we investigate the phosphodiesterase-5 inhibitor (PDE5i) tadalafil for potentially impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in vitro in different pHs, and ex vivo in gastric content aspirated from patients pre/post-surgery. Dissolution was studied in conditions mimicking pre/post-surgery stomach. Finally, the experimental data were used in physiologically-based pharmacokinetic (PBPK) model (GastroPlus®) to simulate pre- vs. post-surgery tadalafil PK. Tadalafil demonstrated low and pH-independent solubility, both in vitro and ex vivo. Tadalafil release from all drug products and under all gastric conditions was incomplete, with particularly poor dissolution (2%) of the highest dose under post-bariatric conditions. PBPK simulations revealed altered tadalafil PK after gastric bypass—but not after sleeve gastrectomy—compared to unoperated individuals, with 44–48% decreased Cmax, 35–56% decreased AUC and 44% shorter Tmax. This mechanistic analysis suggests that tadalafil may be as effective after sleeve gastrectomy as before the procedure; meanwhile, results after gastric bypass raise concerns regarding the bioperformance of the drug. In addition, the drug's duration of action may be much shorter after gastric bypass. Thus, the effectiveness of tadalafil, widely regarded as the ‘weekend pill’, may be shorter than expected among gastric bypass patients.
Graphical Abstract
USE OF THE TROCHANTERIC FIXATION NAIL ADVANCED (TFNA) MAY INCREASE THE RISK FOR NAIL BREAKAGE AND EARLY BREAKAGE TIME COMPARED TO OTHER FREQUENTLY USED IMPLANTS
Authors: Karjalainen L.i , Lähdesmäki M. , Ylitalo A. , Eskelinen A. , Mattila V. M. , Repo J. 
Published: November 2024

BackgroundCephalomedullary nails are widely used for fixation of unstable pertrochanteric fractures. In 2018, the Depuy Synthes Trochanteric Fixation Nail - Advanced (TFNA) implant was introduced at a level I academic trauma center. Thereafter, the TFNA swiftly replaced the older implant models used at the time. Subsequently, clinical concerns were raised about the use of the TFNA due to reports of nail breakage. The purpose of this study was to investigate whether the concerns raised about the performance of the TFNA were valid and to assess long-term outcomes.MethodsThe data consisted of 2397 patients who had undergone a proximal femoral hip fracture procedure between 2014 and 2020. Data were handpicked from patient records. TFNA was compared with TFN, PFNA, Gamma3, and Intertan regarding nail breakage, breakage time and long-term outcomes.ResultsAfter exclusion a total of 23/1667 (1.4%) nails broke during the follow-up period. The TFNA broke the most often with 15 cases (2.0%), followed by the Gamma3 with five cases (1.1 %) and the PFNA with three cases (1.3%). Overall, the mean (SD) nail breakage time was 233 (147.8) days. However, for the TFNA, PFNA, and Gamma3, the mean breakage times were 176.8 days (109.9), 419 days (108.6), and 291.8 (153.4), respectively. In cox regression analysis we observed significant reduction in nail breakage when using PFNA with adjusted hazard risk of 0.081 [95% Ci, 0.011-0.576, p=0.011].ConclusionsIn our data, the TFNA had a slightly higher risk for nail breakage when compared to the PFNA and the Gamma3, with a risk difference of 0.7% and 0.9%, respectively. On average, the TFNA broke nearly four months earlier than the Gamma3 and more than eight months earlier than the PFNA. It should be noted, however, that implant breakage is a relatively infrequent complication.
STUDY TO EVALUATE NONOPERATIVE MANAGEMENT OF STABLE ANKLE FRACTURES AT A UNIVERSITY HOSPITAL
Authors: Bhat S. S. , Mathai N. J. , Raghavendra R. , Hodgson P. 
Published: November 2024

IntroductionAs per national guidelines for Ankle fractures in the United Kingdom, fractures considered stable can be treated with analgesia, splinting and allowed to weight bear as tolerated. The guidelines also suggest further follow-up not mandatory. This study was aimed at evaluating the current clinical practice of managing stable ankle fractures at a university hospital against national guidelines.MethodThe study was undertaken using retrospectively collected data, the inclusion criteria being all adults with stable ankle fracture pattern treated non-operatively between December 2022 and April 2023. Collected data included age of patient, date of injury, type of immobilization, number of clinical visits and any complications.Results41 cases were identified and analyzed. The mean age of the cohort was 49.8 years (Standard deviation 20.01). Twelve percent (n = 5) were reviewed in clinic, treated and discharged as stable Weber B type fracture pattern as per national guidelines after the first visit. About 52% (n = 21) were seen in clinic twice before discharge, first visit between 1-2 weeks and the last clinic visit between 5-7 weeks. About a third of patients (30%, n = 12) were seen in clinic on more than two occasions. At the first clinic visit 87% (n = 36) were given a boot and allowed to weight bear as tolerated. Two patients were diagnosed with deep vein thrombosis/pulmonary embolism during the treatment duration. Three patients had extended duration of follow up for ongoing symptoms. None discharged after first or second visit needed surgery for displaced or malunited fracture.ConclusionPatients discharged from clinic after first or second visit did not need any further surgery. As per national guidelines, patients deemed stable weber B lateral malleolus fracture pattern after weight bearing radiograph can be treated safely with a weight bearing walking boot with no further follow up.