bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrodin attenuates diabetic cardiomyopathy characterized by myocardial fibrosis by inhibiting the KLK8-PAR1 signaling axis
Authors: Zhang MingShan , Zhang YuFei , He JingGang , Wang XinRui , Wang YinYin , Li LinYan , Tao Ling , Zhang Min , Shen Xiangchun 
Published: November 2024

Abstract
Background
Diabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated.

Methods
In vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS.

Results
GAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling.

Conclusion
GAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved.

Graphical Abstract
Associations between genetic variants of Toll-interacting proteins and interstitial lung diseases: a systematic review and meta-analysis
Authors: Li Xiaoyuan , Cui Beibei , Jiang Lili 
Published: November 2024

Abstract
Background
Genetic polymorphisms in Toll-interacting protein (TOLLIP) have been documented in relation to clinical manifestations of interstitial lung disease (ILD). Nevertheless, the findings across studies present inconsistencies. The present meta-analysis endeavors to elucidate the nexus between genetic variations in TOLLIP and the onset and prognosis of interstitial lung disease (ILD), with the overarching aim of providing insight into the pathophysiological underpinnings of ILD.

Method
This systematic review was registered in PROSPERO. The OVID MEDLINE, OVID EMBASE, and Web of Science electronic databases were searched.

Results
Fourteen studies with a total of 4821 cases and 9765 controls were examined. The final TOLLIP variants to be included in this meta-analysis were rs5743890, rs111521887, and rs3750920. There were significantly fewer TOLLIP rs5743890 minor allele C carriers among individuals with interstitial lung disease (ILD) than among those without this condition (11.42% vs. 18.92%). Conversely, patients with ILD exhibited higher frequencies of rs111521887 minor allele G carriers (28.92% vs. 22.44%) and rs3750920 minor allele T carriers (40.06% vs. 34.00%). A potential association between rs5743890_C and a reduced incidence of ILD was plausible (p = 0.04, OR = 0.72, 95% CI = 0.53–0.99). Furthermore, a stratified analysis revealed that rs5743890_C was significantly associated with a decreased risk of IPF (p = 0.004, OR = 0.62, 95% CI = 0.44–0.86). There was a significant correlation between susceptibility to ILD and rs111521887 G (p < 0.00001, OR = 1.48, 95% CI = 1.33–1.65) and rs3750920 T (p < 0.00001, OR = 1.34, 95% CI = 1.26–1.44). The survival of IPF patients was correlated with the TOLLIP rs5743890 SNP, and patients with the rs5743890_C genotype had worse survival (p = 0.02, HR = 1.59, 95% CI = 1.07–2.36).

Conclusion
This study showed that rs5743890_C was associated with a lower incidence of ILD and a worse survival rate in patients with IPF. Rs111521887_G and rs3750920_T were found to be associated with an elevated risk of ILD incidence, while no significant association was observed with ILD prognosis. Furthermore, studies are warranted to validate our results and assess the effects of TOLLIP genetic variants on ILD.
AKAP6 controls NFATc4 activity for BDNF-mediated neuroprotection
Authors: Mackiewicz Joanna , Tomczak Julia , Lisek Malwina , Guo Feng , Boczek Tomasz 
Published: November 2024

AbstractBrain-derived neurotrophic factor (BDNF) is known for its potent prosurvival effect. Despite successfully replicating this effect in various clinical and pre-clinical models, the complete characterization of the molecular mechanisms underlying its neuroprotective action remains incomplete. Emerging research suggests a vital role for A-kinase anchoring proteins (AKAPs) as central nodal points orchestrating BDNF-dependent signaling. Among the over 50 identified AKAPs, AKAP6 has recently gained special attention due to its involvement in the neurotrophin-mediated survival of injured retinal ganglion cells (RGCs). However, the mechanisms by which AKAP6 responds to pro-survival BDNF signaling remain unknown. In this study, we shown that AKAP6 plays a crucial role in regulating BDNF-mediated NFAT transcriptional activity in neuronal survival by anchoring protein phosphatase calcineurin (CaN) and nuclear factor of activated T cells (NFATc4). Furthermore, we demonstrate that disrupting the anchoring of CaN diminishes the pro-survival effect of BDNF. Lastly, through experiments with NFATc4−/− mice, we provide evidence that NFATc4 acts downstream to BDNF’s neuroprotection in vivo. These findings could offer valuable insights for developing neuroprotective strategies aimed at preserving injured neurons from degeneration and promoting their regeneration.
Intravitreal injection of the Galectin-3 inhibitor TD139 provides neuroprotection in a rat model of ocular hypertensive glaucoma
Authors: Rombaut Anne , Brautaset Rune , Williams Pete A. , Tribble James R. 
Published: November 2024

AbstractNeuroinflammation is a significant contributor to the pathology of glaucoma. Targeting key-mediators in this process is a realistic option to slow disease progression. Galectin-3 is a β-galactoside binding lectin that has been associated with inflammation in both systemic and central nervous system diseases. Elevated Galectin-3 has recently been detected in multiple animal models of glaucoma and inhibiting Galectin-3 using an intravitreal injection of TD139 (a Galectin-3 small molecule inhibitor) is neuroprotective. We queried whether this neuroprotective effect was translatable to another animal model and species. TD139 was intravitreally injected, in a rat ocular hypertensive model of glaucoma, 3 days after the induction of ocular hypertension (at peak intraocular pressure). Retinal ganglion cell survival and glial morphological markers were quantified. The degeneration of retinal ganglion cells was prevented by TD139 injection, but gross glial markers remained unaffected. These data confirm that the intravitreal injection of TD139 is neuroprotective in a rat ocular hypertensive model of glaucoma, while suggesting that the inhibition of Galectin-3 is not sufficient to alter the gross inflammatory outcome.
Experience of patent ductus arteriosus ligation during extracorporeal membrane oxygenation treatment in newborns with severe respiratory failure due to persistent pulmonary hypertension: a single-center retrospective study
Authors: Zhang Qi-Liang , Liu Yi-Nan , Zeng Ya-Ting , Zheng Yi-Rong , Chen Qiang 
Published: November 2024

Abstract
Background
The aim of this study is to summarize our center’s experience with patent ductus arteriosus (PDA) ligation during extracorporeal membrane oxygenation (ECMO) treatment in newborns with severe respiratory failure due to persistent pulmonary hypertension of the newborn (PPHN).

Methods
We retrospectively collected and analyzed clinical data from five newborns with severe respiratory failure due to PPHN who underwent PDA ligation during ECMO treatment at our hospital between January 2021 and August 2023.

Results
All five patients had large PDAs, measuring 10 mm, 6 mm, 6 mm, 7 mm, and 6 mm, respectively. Significant left-to-right shunting through the PDA was observed after 29 h, 14 h, 3 h, 7 h, and 5 h of ECMO treatment, respectively, at which point successful PDA ligation was performed. The surgical durations were 52 min, 45 min, 55 min, 50 min, and 40 min, respectively. Post-ligation, blood lactate levels significantly decreased compared to preoperative values. Four patients were successfully weaned off ECMO, with ECMO support durations of 64 h, 92 h, 70 h, and 87 h, respectively. After ECMO removal, mechanical ventilation was discontinued after 5.2 days, 7.2 days, 9.5 days, and 5.5 days, respectively. None of the four surviving patients experienced complications such as residual shunting, bleeding, chylothorax, neurologic injury, pneumothorax, poor wound healing, or sepsis.

Conclusion
During ECMO treatment for PPHN in newborns with large PDAs, the direction of blood flow through the PDA should be closely monitored. PDA ligation is a feasible and reasonable intervention when pulmonary artery pressure decreases and left-to-right shunting through the PDA becomes evident.
Deprescribing anticholinergics to preserve brain health: reducing the risk of dementia through deprescribing (R2D2): study protocol for a randomized clinical trial
Authors: Campbell Noll L. , Holden Richard J. , Gao Sujuan , Unverzagt Frederick W. , Lane Kathleen A. , Carter Allie , Harrington Addison B. , Manoharan Sneha , Manoharan Neha , Rosenthal Danielle L. , Pitts Christopher , Pelkey Kathryn , Papineau Emily , Lauck David M. , Keshk Noha , Alamer Khalid , Khalil Hussein , Boustani Malaz A. 
Published: November 2024

Abstract
Background
Older adults commonly experience chronic medical conditions and are at risk of cognitive impairment as a result of age, chronic comorbidity, and medications prescribed to manage multiple chronic conditions. Anticholinergic medications are common treatments for chronic conditions and have been repeatedly associated with poor cognitive outcomes, including delirium and dementia, in epidemiologic studies. However, no study has definitively evaluated the causal relationship between anticholinergics and cognition in a randomized controlled trial design. Utilizing our prior experience in deprescribing anticholinergic medications in various clinical environments, we designed an outpatient deprescribing intervention to prospectively test the potential causal relationship between anticholinergics and cognition in primary care older adults.

Methods
This cluster randomized clinical trial will be conducted to evaluate the impact of an anticholinergic deprescribing intervention compared to usual care on outcomes of cognition and safety in primary care older adults. Participants will include those aged 65 years and over, receiving primary care in the greater Indianapolis area, using a strong anticholinergic within the last 2 weeks or with evidence of high-risk exposure in the past year. Those excluded will have a diagnosis of Alzheimer’s disease or related dementia, or serious mental illness. The trial plans to enroll 344 participants who will be cluster-randomized at the level of primary care physician to avoid contamination. Participants will complete outcome assessments every 6 months up to 2 years by blinded outcome assessors. The primary outcome of the study is a composite measure of cognition that includes domains assessing executive cognitive function, language, and memory. Secondary outcomes include patient-reported measures of pain intensity, depression, anxiety, sleep disturbance, and health-related quality of life.

Discussion
The R2D2 trial will be the largest and longest prospective randomized trial testing the impact of an anticholinergic-specific deprescribing intervention on cognition in primary care older adults. Results could influence deprescribing methodology and provide new insight on the relationship between anticholinergics and cognition.

Trial registration
ClinicalTrials.gov NCT04270474. Registered on February 17, 2020.
Complete genome sequence of Bacillus pumilus NWMCC0302, a strain for degrading bovine blood
Authors: Xiang Jun , Liao Qingyan , Zeng Songyu , Zhou Wei , Ma Zhongren , Ding Gongtao , Zhou Xueyan 
Published: November 2024

Abstract
Background
Directly discharging livestock and poultry slaughter blood without proper treatment can cause severe ecological damage. Exploring the use of microorganisms to break down waste blood into smaller molecules such as peptides and amino acids, as well as investigating the possibility of transforming these small molecules into water-soluble fertilizers containing amino acids, holds significant research value in the comprehensive utilization of livestock and poultry blood.

Results
In this study, a single strain of Bacillus pumilus NWMCC0302, which has effectively degraded bovine blood, was isolated from abattoir blood sludge using casein agar plates and Columbia blood agar plates. The degradation test was carried out using bovine raw blood as a nitrogen source in the medium, and the results showed that the strain degraded 53.83% of bovine blood under optimal degradation conditions. The whole genome sequencing of Bacillus pumilus NWMCC0302 was conducted using the second-generation DNBSEQ platform and the third-generation PacBio platform, employing high-throughput sequencing technology. The size of the strain's entire genome was determined to be 3 868 814 bp with a G-C content of 41.63%. The total gene length accounted for 88.98% of the genome length at 3 442 341 bp and encoded 4 113 genes. The strain contained 79 tRNAs, 24 rRNAs, 7 sRNAs, and 296 repetitive sequences. The gene data obtained from sequencing were also functionally annotated using the COG, KEGG, and VFDB databases. In the COG database, 310 genes were involved in amino acid transport and metabolism, including 10 catabolic proteins related to COGs. In the KEGG database, were 201 genes involved in amino acid metabolism pathways, including 8 genes in nitrogen metabolism pathways and 2 genes in oxidative pathways. The VFDB database contains two lysostaphin genes and one serine protease-hydrolyzed ClpP gene.

Conclusions
In summary, Bacillus pumilus NWMCC0302 was screened for its efficient ability to degrade bovine blood. Additionally, the genetic information of Bacillus pumilus NWMCC0302 was revealed at the genetic level, providing a feasible experimental method for applying this strain to the degradation of blood from slaughtered livestock and poultry. Moreover, it is a potential functional strain for producing amino acid-containing water-soluble fertilisers.
Exosome crosstalk between cancer stem cells and tumor microenvironment: cancer progression and therapeutic strategies
Authors: Li Qi , He Guangpeng , Yu Yifan , Li Xinyu , Peng Xueqiang , Yang Liang 
Published: November 2024

AbstractCancer stem cells (CSCs) represent a small yet pivotal subset of tumor cells endowed with self-renewal capabilities. These cells are intricately linked to tumor progression and are central to drug resistance, metastasis, and recurrence. The tumor microenvironment (TME) encompasses the cancer cells and their surrounding milieu, including immune and inflammatory cells, cancer-associated fibroblasts, adjacent stromal tissues, tumor vasculature, and a variety of cytokines and chemokines. Within the TME, cells such as immune and inflammatory cells, endothelial cells, adipocytes, and fibroblasts release growth factors, cytokines, chemokines, and exosomes, which can either sustain or disrupt CSCs, thereby influencing tumor progression. Conversely, CSCs can also secrete cytokines, chemokines, and exosomes, affecting various components of the TME. Exosomes, a subset of extracellular vesicles (EVs), carry a complex cargo of nucleic acids, proteins, and lipids, playing a crucial role in the communication between CSCs and the TME. This review primarily focuses on the impact of exosomes secreted by CSCs (CSC-exo) on tumor progression, including their roles in maintaining stemness, promoting angiogenesis, facilitating metastasis, inducing immune suppression, and contributing to drug resistance. Additionally, we discuss how exosomes secreted by different cells within the TME affect CSCs. Finally, we explore the potential of utilizing exosomes to mitigate the detrimental effects of CSCs or to target and eliminate them. A thorough understanding of the exosome-mediated crosstalk between CSCs and the TME could provide valuable insights for developing targeted therapies against CSCs.
SCAN: a nanopore-based, cost effective decision-supporting tool for mass screening of aneuploidies
Authors: Schack Anne Kristine , Garrido-Navas M. Carmen , Galevski David , Madjarov Gjorgji , Krych Lukasz 
Published: November 2024

AbstractIn developed countries, Newborn Screening (NBS) programs aim to detect treatable yet clinically silent disorders. The selection of disorders to be included in NBS considers severity, treatment availability, prevalence, and analysis cost. However, numerous genetic disorders remain excluded from routine testing due to high expenses and specialized equipment requirements. Here we present SCAN, a novel, non-invasive, and cost-effective decision-support tool utilizing nanopore sequencing for estimating proportions of chromosomes responsible for the most common aneuploidies. SCAN combines DNA enrichment (amplification), barcoding, nanopore sequencing, and machine learning predictive modeling. In a proof-of-concept study for Klinefelter Syndrome, SCAN achieved 100% sensitivity, specificity, and accuracy, becoming the world’s first IVD-certified genetic test utilising nanopore sequencing. Further model training shows promise in expanding this assay to detect other chromosomal aneuploidies included in the protocol.
Noninvasive biomarkers implicated in urea and TCA cycles for metabolic liver disease
Authors: Yang Guiyan , Wan Yu-Jui Yvonne 
Published: November 2024

AbstractBile acid (BA) and its receptor FXR play crucial roles in metabolism, and dysregulated BA synthesis regulated by hepatic and bacterial enzymes causes metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Moreover, because ~ 75% of hepatic blood is from the gut, liver metabolism is influenced by intestinal bacteria and their metabolites. Thus, we used gut microbiota and metabolites from the urine and serum to uncover biomarkers for metabolic distress caused by Western diet (WD) intake, aging, and FXR inactivity. Hepatic transcriptomes were profiled to define liver phenotypes. There were 654 transcriptomes commonly altered by differential diet intake, ages, and FXR functional status, representing the signatures of liver dysfunction, and 76 of them were differentially expressed in healthy human livers and HCC. Machine learning approaches classified urine and serum metabolites for differential dietary intake and age difference. Additionally, the gut microbiota could predict FXR functional status. Furthermore, FXR was essential for differentiating dietary effects in colonizing age-related gut microbes. The integrated analysis established the relationships between the metabolites and gut microbiota correlated with hepatic transcripts commonly altered by diet, age, and FXR functionality. Remarkably, the changes in metabolites involved in the urea cycle, mitochondrial metabolism, and amino acid metabolism are associated with hepatic dysfunction (i.e. FXF deactivation). Taken together, noninvasive specimens and biomarkers are promising resources for identifying metabolic distress.
Stable-to-dynamic expansion of fault slipping area through fluid injection observed in laboratory experiments using a sub-meter scale specimen
Authors: Ito Takatoshi , Aoki Koji , Mukuhira Yusuke , Yabe Yasuo 
Published: November 2024

AbstractIn the field, locally applied fluid pressure can initiate fault slip, which may expand unstably over a wide area under certain conditions, generating elastic waves and inducing earthquakes. Therefore, examining the unstable expansion of the initial slip is important. However, reproducing this process in laboratory experiments, such as triaxial loading tests on small cylindrical specimens with inclined faults, is challenging. To achieve this, we prepared a sub-meter-scale cubic specimen, which was separated into two triangular prisms by a model fault. The specimen was subjected to biaxial compression of different magnitudes. A 2D array of strain gauges was embedded beneath the fault plane to measure the changes in shear strain with fault slip driven by fluid injection. Based on the experimental results, we discussed the features of the injection-induced fault slips that lead to earthquakes. The strain increased locally around the edge of the fault slipping area by approximately 10 με, which is equivalent to a shear stress of ~ 0.1 MPa. The fault slipping area first expanded gradually and then unstably beyond the fluid invasion area approximately 3 s after the slip was initiated. The unstable expansion of initial slips was suppressed by reducing the initial shear stress on the fault by 0.3 MPa. In this case, the initial shear stress was possibly too small for additional stress to accumulate at the edge of the fault-slipping area to overcome the static frictional strength of the fault. Our experimental study explicitly confirms that injection-induced aseismic slip can outpace the fluid migration front, finally leading up to a runaway rupture. It also confirms that the level of initial shear stress is important in controlling the rupture size under fluid injection.
Graphical Abstract