bluuebunny/crossref_metadata_2025_split huggingface dataset:
WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome
Authors: Lim Hui Dong , Lee So Min , Yun Ye Jin , Lee Dae Hee , Lee Jun Ho , Oh Seung-Ha , Lee Sang-Yeon 
Published: April 2023

AbstractBackgroundWolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome,WFS1heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified twoWFS1heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of theWFS1variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes inWFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.MethodsWe performed molecular genetic test and evaluated clinical phenotypes of threeWFS1-associated DFNA6/14/38 families. A putative WFS1–NCS1 interaction model was generated, and the impacts ofWFS1variants on stability were predicted by comparing intramolecular interactions. A total of 62WFS1variants associated with DFNA6/14/38 were included in a systematic review.ResultsOne variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7–9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val inWFS1is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.ConclusionsWe expanded the genotypic spectrum ofWFS1heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits forWFS1heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.
Cascade amplification of tumor chemodynamic therapy and starvation with re-educated TAMs via Fe-MOF based functional nanosystem
Authors: Zheng Xinmin , Li Xiang , Meng Siyu , Shi Guolin , Li Hui , Du Huiping , Dai Liangliang , Yang Hui 
Published: April 2023

AbstractTumor microenvironment is characterized by the high concentration of reactive oxygen species (ROS), which is an effective key used to open the Pandora’s Box against cancer. Herein, a tumor-targeted nanosystem HFNP@GOX@PFC composed of ROS-cleaved Fe-based metal–organic framework, hyaluronic acid (HA), glucose oxidase (GOX) and perfluorohexane (PFC) has been developed for tumor cascade amplified starvation and chemodynamic therapy (CDT). In response to the high concentration of hydrogen peroxide (H2O2) intratumorally, HFNP@GOX@PFC endocytosed by tumor cells can specially be disassembled and release GOX, PFC and Fe2+, which can collectively starve tumor and self-produce additional H2O2 via competitively glucose catalyzing, supply oxygen to continuous support GOX-mediated starvation therapy, initiate CDT and cascade amplify oxidative stress via Fe2+-mediated Fenton reaction, leading to the serious tumor damage with activated p53 signal pathway. Moreover, HFNP@GOX@PFC also significantly initiates antitumor immune response via re-educating tumor-associated macrophages (TAMs) by activating NF-κB and MAPK signal pathways. In vitro and in vivo results collectively demonstrate that nanosystem not only continuously initiates starvation therapy, but also pronouncedly cascade-amplify CDT and polarize TAMs, consequently efficiently inhibiting tumor growth with good biosafety. The functional nanosystem combined the cascade amplification of starvation and CDT provides a new nanoplatform for tumor therapy.
RA-RAR signaling promotes mouse vaginal opening through increasing β-catenin expression and vaginal epithelial cell apoptosis
Authors: Zheng Nana , Zhang Wenbo , Zhang Xiaodan , Li Biao , Wu Zhanying , Weng Yashuang , Wang Weiyong , Miao Jingjing , Yang Jing , Zhang Meijia , Xia Wei 
Published: April 2023

Abstract
Background
Retinoic acid (RA) plays important role in the maintenance and differentiation of the Müllerian ducts during the embryonic stage via RA receptors (RARs). However, the function and mechanism of RA-RAR signaling in the vaginal opening are unknown.

Method
We used the Rarα knockout mouse model and the wild-type ovariectomized mouse models with subcutaneous injection of RA (2.5 mg/kg) or E2 (0.1 µg/kg) to study the role and mechanism of RA-RAR signaling on the vaginal opening. The effects of Rarα deletion on Ctnnb1 mRNA levels and cell apoptosis in the vaginas were analyzed by real-time PCR and immunofluorescence, respectively. The effects of RA on the expression of β-catenin and apoptosis in the vaginas were analyzed by real-time PCR and western blotting. The effects of E2 on RA signaling molecules were analyzed by real-time PCR and western blotting.

Results
RA signaling molecules were expressed in vaginal epithelial cells, and the mRNA and/or protein levels of RALDH2, RALDH3, RARα and RARγ reached a peak at the time of vaginal opening. The deletion of Rarα resulted in 25.0% of females infertility due to vaginal closure, in which the mRNA (Ctnnb1, Bak and Bax) and protein (Cleaved Caspase-3) levels were significantly decreased, and Bcl2 mRNA levels were significantly increased in the vaginas. The percentage of vaginal epithelium with TUNEL- and Cleaved Caspase-3-positive signals were also significantly decreased in Rarα−/− females with vaginal closure. Furthermore, RA supplementation of ovariectomized wild-type (WT) females significantly increased the expression of β-catenin, active β-catenin, BAK and BAX, and significantly decreased BCL2 expression in the vaginas. Thus, the deletion of Rarα prevents vaginal opening by reducing the vaginal β-catenin expression and epithelial cell apoptosis. The deletion of Rarα also resulted in significant decreases in serum estradiol (E2) and vagina Raldh2/3 mRNA levels. E2 supplementation of ovariectomized WT females significantly increased the expression of RA signaling molecules in the vaginas, suggesting that the up-regulation of RA signaling molecules in the vaginas is dependent on E2 stimulation.

Conclusion
Taken together, we propose that RA-RAR signaling in the vaginas promotes vaginal opening through increasing β-catenin expression and vaginal epithelial cell apoptosis.
Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study
Authors: Sun Lulu , Guo Daoxia , Jia Yiming , Shi Mengyao , Yang Pinni , Wang Yu , Liu Fanghua , Zhu Zhengbao , Zheng Jin 
Published: April 2023

Abstract
Background
Experimental studies suggested that intercellular adhesion molecule 4 (ICAM-4) might be implicated in ischemic stroke, but the population-based evidence on the relationship between ICAM-4 and ischemic stroke were limited. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and its subtypes.

Methods
A total of 11 single-nucleotide polymorphisms associated with ICAM-4 were selected as instrumental variables based on the genome-wide association studies (GWAS) with 3,301 European individuals. Summary-level data about ischemic stroke and its subtypes were obtained from the Multi-ancestry GWAS launched by the International Stroke Genetics Consortium. We used the inverse-variance weighted method followed by a series of sensitivity analyses to evaluate the associations of genetically determined ICAM-4 with the risks of ischemic stroke and its subtypes.

Results
Genetically determined higher ICAM-4 levels were significantly associated with increased risks of ischemic stroke (in the IVW method fitted to multiplicative random effects model: odds ratio [OR] per standard deviation [SD] increase, 1.04; 95% confidence interval [CI], 1.01–1.07; P = 0.006; in the IVW analysis with fixed effects model: OR per SD increase, 1.04; 95% CI, 1.01–1.07; P = 0.003) and cardioembolic stroke (in multiplicative random effects model: OR per SD increase, 1.08; 95% CI, 1.02–1.14; P = 0.004; in fixed effects model: OR per SD increase, 1.08; 95% CI, 1.03–1.13; P = 0.003). There was no association of ICAM-4 with the risks of large artery stroke and small vessel stroke. MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different MR methods further confirmed these findings.

Conclusions
We found positive associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and cardioembolic stroke. Future studies are needed to explore the detailed mechanism and investigate the targeting effect of ICAM-4 on ischemic stroke.
Antibiotic use in acute mesenteric ischemia: a review of the evidence and call to action
Authors: Tian Yuqian , Dhara Sanjeev , Barrett Christopher D. , Richman Aaron P. , Brahmbhatt Tejal S. 
Published: April 2023

AbstractAcute mesenteric ischemia (AMI) is a life-threatening condition with a high mortality rate. The standard practice after making the diagnosis includes aggressive resuscitation, anticoagulation, followed by revascularization and resection of necrotic bowel. The role of empiric antibiotics in the management of AMI is not well defined in the literature. This review article aims to examine our current understanding on this matter, based on bench research and clinical studies. It is demonstrated in animal study model that the ischemia/reperfusion (I/R) injury damages intestinal epithelium, and subsequently lead to barrier dysfunction, a condition that can support bacterial translocation through a complex interplay between the intestinal epithelium, the intestinal immune system and the intestine’s endogenous bacterial population. Based on this mechanism, it is possible that the use of antibiotics may help mitigate the consequences of I/R injury, which is examined in few animal studies. In clinical practice, many guidelines support the use of prophylactic antibiotics, based on a meta-analysis of randomized control trials (RCTs) demonstrating the benefit of antibiotics in multi-organ dysfunction syndrome. However, there is no direct reference to AMI in this meta-analysis. Most clinical studies that focus on AMI and mentions the use of antibiotics are retrospective and single institution, and very few comments on the role of antibiotics in their discussions. We conclude that there is limited evidence in literature to support the use of prophylactic antibiotic in AMI to improve outcome. More clinical studies with high level of evidence and basic science research are needed to improve our understanding on this topic and ultimately help build a better clinical pathway for patients with AMI.
Insights into the impact of hepatitis B virus on hepatic stellate cell activation
Authors: You Hongjuan , Wang Xing , Ma Lihong , Zhang Fulong , Zhang Huanyang , Wang Yuxin , Pan Xiucheng , Zheng Kuiyang , Kong Fanyun , Tang Renxian 
Published: April 2023

AbstractDuring chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. The activation of hepatic stellate cells (HSCs) is a central event in the occurrence and progression of liver fibrosis. Although accumulating evidence has shown that HBV directly stimulates HSC activation, whether the virus infects and replicates in HSCs remains controversial. Inflammation is one of the obvious characteristics of chronic HBV infection, and it has been demonstrated that persistent inflammation has a predominant role in triggering and maintaining liver fibrosis. In particular, the regulation of HSC activation by HBV-related hepatocytes via various inflammatory modulators, including TGF-β and CTGF, in a paracrine manner has been reported. In addition to these inflammation-related molecules, several inflammatory cells are essential for the progression of HBV-associated liver fibrosis. Monocytes, macrophages, Th17 cells, NK cells, as well as NKT cells, participate in the modulation of HBV-related liver fibrosis by interacting with HSCs. This review summarizes current findings on the effects of HBV and the relevant molecular mechanisms involved in HSC activation. Because HSC activation is essential for liver fibrosis, targeting HSCs is an attractive therapeutic strategy to prevent and reverse hepatic fibrosis induced by HBV infection.
Generative adversarial networks in EEG analysis: an overview
Authors: Habashi Ahmed G. , Azab Ahmed M. , Eldawlatly Seif , Aly Gamal M. 
Published: April 2023

AbstractElectroencephalogram (EEG) signals have been utilized in a variety of medical as well as engineering applications. However, one of the challenges associated with recording EEG data is the difficulty of recording large amounts of data. Consequently, data augmentation is a potential solution to overcome this challenge in which the objective is to increase the amount of data. Inspired by the success of Generative Adversarial Networks (GANs) in image processing applications, generating artificial EEG data from the limited recorded data using GANs has seen recent success. This article provides an overview of various techniques and approaches of GANs for augmenting EEG signals. We focus on the utility of GANs in different applications including Brain-Computer Interface (BCI) paradigms such as motor imagery and P300-based systems, in addition to emotion recognition, epileptic seizures detection and prediction, and various other applications. We address in this article how GANs have been used in each study, the impact of using GANs on the model performance, the limitations of each algorithm, and future possibilities for developing new algorithms. We emphasize the utility of GANs in augmenting the limited EEG data typically available in the studied applications.
SARS-CoV-2 infection aggravates cigarette smoke-exposed cell damage in primary human airway epithelia
Authors: Chen Rui , Hui Kenrie Pui-Yan , Liang Yingmin , Ng Ka-Chun , Nicholls John Malcolm , Ip Mary Sau-Man , Peiris Malik , Chan Michael Chi-Wai , Mak Judith Choi-Wo 
Published: April 2023

Abstract
Background
The coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic with over 627 million cases and over 6.5 million deaths. It was reported that smoking-related chronic obstructive pulmonary disease (COPD) might be a crucial risk for COVID-19 patients to develop severe condition. As cigarette smoke (CS) is the major risk factor for COPD, we hypothesize that barrier dysfunction and an altered cytokine response in CS-exposed airway epithelial cells may contribute to increased SARS-CoV-2-induced immune response that may result in increased susceptibility to severe disease. The aim of this study was to evaluate the role of CS on SARS-CoV-2-induced immune and inflammatory responses, and epithelial barrier integrity leading to airway epithelial damage.

Methods
Primary human airway epithelial cells were differentiated under air-liquid interface culture. Cells were then exposed to cigarette smoke medium (CSM) before infection with SARS-CoV-2 isolated from a local patient. The infection susceptibility, morphology, and the expression of genes related to host immune response, airway inflammation and damages were evaluated.

Results
Cells pre-treated with CSM significantly caused higher replication of SARS-CoV-2 and more severe SARS-CoV-2-induced cellular morphological alteration. CSM exposure caused significant upregulation of long form angiotensin converting enzyme (ACE)2, a functional receptor for SARS-CoV-2 viral entry, transmembrane serine protease (TMPRSS)2 and TMPRSS4, which cleave the spike protein of SARS-CoV-2 to allow viral entry, leading to an aggravated immune response via inhibition of type I interferon pathway. In addition, CSM worsened SARS-CoV-2-induced airway epithelial cell damage, resulting in severe motile ciliary disorder, junctional disruption and mucus hypersecretion.

Conclusion
Smoking led to dysregulation of host immune response and cell damage as seen in SARS-CoV-2-infected primary human airway epithelia. These findings may contribute to increased disease susceptibility with severe condition and provide a better understanding of the pathogenesis of SARS-CoV-2 infection in smokers.
Movement of cerebrospinal fluid tracer into brain parenchyma and outflow to nasal mucosa is reduced at 24 h but not 2 weeks post-stroke in mice
Authors: Warren K. E. , Coupland K. G. , Hood R. J. , Kang L. , Walker F. R. , Spratt N. J. 
Published: April 2023

Abstract
Background
Recent data indicates that cerebrospinal fluid (CSF) dynamics are disturbed after stroke. Our lab has previously shown that intracranial pressure rises dramatically 24 h after experimental stroke and that this reduces blood flow to ischaemic tissue. CSF outflow resistance is increased at this time point. We hypothesised that reduced transit of CSF through brain parenchyma and reduced outflow of CSF via the cribriform plate at 24 h after stroke may contribute to the previously identified post-stroke intracranial pressure elevation.

Methods
Using a photothrombotic permanent occlusion model of stroke in C57BL/6 adult male mice, we examined the movement of an intracisternally infused 0.5% Texas Red dextran throughout the brain and measured tracer efflux into the nasal mucosa via the cribriform plate at 24 h or two weeks after stroke. Brain tissue and nasal mucosa were collected ex vivo and imaged using fluorescent microscopy to determine the change in CSF tracer intensity in these tissues.

Results
At 24 h after stroke, we found that CSF tracer load was significantly reduced in brain tissue from stroke animals in both the ipsilateral and contralateral hemispheres when compared to sham. CSF tracer load was also reduced in the lateral region of the ipsilateral hemisphere when compared to the contralateral hemisphere in stroke brains. In addition, we identified an 81% reduction in CSF tracer load in the nasal mucosa in stroke animals compared to sham. These alterations to the movement of CSF-borne tracer were not present at two weeks after stroke.

Conclusions
Our data indicates that influx of CSF into the brain tissue and efflux via the cribriform plate are reduced 24 h after stroke. This may contribute to reported increases in intracranial pressure at 24 h after stroke and thus worsen stroke outcomes.
Biomechanical study of different fixation constructs for anterior column and posterior hemi-transverse acetabular fractures: a finite element analysis
Authors: Chen Kaifang , Huang Guixiong , Wan Yizhou , Yao Sheng , Su Yanlin , Li Lianxin , Guo Xiaodong 
Published: April 2023

Abstract
Background
To compare the biomechanical properties and stability, using a finite element model, of four fixation constructs used for the treatment of anterior column and posterior hemi-transverse (ACPHT) acetabular fractures under two physiological loading conditions (standing and sitting).

Methods
A finite element model simulating ACPHT acetabular fractures was created for four different scenarios: a suprapectineal plate combined with posterior column and infra-acetabular screws (SP-PS-IS); an infrapectineal plate combined with posterior column and infra-acetabular screws (IP-PS-IS); a special infrapectineal quadrilateral surface buttress plate (IQP); and a suprapectineal plate combined with a posterior column plate (SP-PP). Three-dimensional finite element stress analysis was performed on these models with a load of 700 N in standing and sitting positions. Biomechanical stress distributions and fracture displacements were analysed and compared between these fixation techniques.

Results
In models simulating the standing position, high displacements and stress distributions were observed at the infra-acetabulum regions. The degree of these fracture displacements was low in the IQP (0.078 mm), as compared to either the IP-PS-IS (0.079 mm) or the SP & PP (0.413 mm) fixation constructs. However, the IP-PS-IS fixation construct had the highest effective stiffness. In models simulating the sitting position, high fracture displacements and stress distributions were observed at the regions of the anterior and posterior columns. The degree of these fracture displacements was low in the SP-PS-IS (0.101 mm), as compared to the IP-PS-IS (0.109 mm) and the SP-PP (0.196 mm) fixation constructs.

Conclusion
In both standing and sitting positions, the stability and stiffness index were comparable between the IQP, SP-PS-IS, and IP-PS-IS. These 3 fixation constructs had smaller fracture displacements than the SP-PP construct. The stress concentrations at the regions of quadrilateral surface and infra-acetabulum suggest that the buttressing fixation of quadrilateral plate was required for ACPHT fractures.
Baicalein alleviates TNF-α-induced apoptosis of human nucleus pulposus cells through PI3K/AKT signaling pathway
Authors: Liu Yang , Liu Dao-kuo , Wang Zhi-wei , Zhao Chong , Miao Jun 
Published: April 2023

AbstractBackgroundNucleus pulposus (NP) cell apoptosis contributed to disc degeneration. Baicalein, a natural steroid saponin, has been demonstrated to have anti-inflammatory, antiapoptotic, and antioxidative effects in various diseases.However, little is known about the roles of baicalein in intervertebral disc degeneration.MethodsTo evaluate the roles of baicalein in disc degeneration and its specific mechanism, human NP cells were incubated with TNF-α and various concentrations of baicalein. Cell viability, extracellular matrix protein expression, catabolic factors, degree of apoptosis, inflammatory factors, and related signaling pathways were evaluated by western blotting, fluorescence immunostaining, TUNEL staining, and reverse transcription PCR.ResultsBaicalein inhibited TNF-α-activated apoptotic signaling and catabolic activity in NP cells. Baicalein promoted PI3K/Akt signaling and attenuated the level of apoptosis-related markers in TNF-α-stimulated human NP cells.ConclusionOur work provides that baicalein attenuates TNF-α-activated apoptosis in human NP cells through promoting the PI3K/Akt pathway, indicating that baicalein is a new potential candidate for clinical therapy to attenuate disc degeneration.