An in-depth review of the function of RNA-binding protein FXR1 in neurodevelopment.

FMR1 autosomal homolog 1 (FXR1) is an RNA-binding protein that belongs to the Fragile X-related protein (FXR) family. FXR1 is critical for development, as its loss of function is intolerant in humans and results in neonatal death in mice. Although FXR1 is expressed widely including the brain, functional studies on FXR1 have been mostly performed in cancer cells. Limited studies have demonstrated the importance of FXR1 in the brain. In this review, we will focus on the roles of FXR1 in brain development and pathogenesis of brain disorders. We will summarize the current knowledge in FXR1 in the context of neural biology, including structural features, isoform diversity and nomenclature, expression patterns, post-translational modifications, regulatory mechanisms, and molecular functions. Overall, FXR1 emerges as an important regulator of RNA metabolism in the brain, with strong implications in neurodevelopmental and psychiatric disorders.

Electrically conductive coatings in tissue engineering.

Recent interest in tissue engineering (TE) has focused on electrically conductive biomaterials. This has been inspired by the characteristics of the cells' microenvironment where signalling is supported by electrical stimulation. Numerous studies have demonstrated the positive influence of electrical stimulation on cell excitation to proliferate, differentiate, and deposit extracellular matrix. Even without external electrical stimulation, research shows that electrically active scaffolds can improve tissue regeneration capacity. Tissues like bone, muscle, and neural contain electrically excitable cells that respond to electrical cues provided by implanted biomaterials. To introduce an electrical pathway, TE scaffolds can incorporate conductive polymers, metallic nanoparticles, and ceramic nanostructures. However, these materials often do not meet implantation criteria, such as maintaining mechanical durability and degradation characteristics, making them unsuitable as scaffold matrices. Instead, depositing conductive layers on TE scaffolds has shown promise as an efficient alternative to creating electrically conductive structures. A stratified scaffold with an electroactive surface synergistically excites the cells through active top-pathway, with/without electrical stimulation, providing an ideal matrix for cell growth, proliferation, and tissue deposition. Additionally, these conductive coatings can be enriched with bioactive or pharmaceutical components to enhance the scaffold's biomedical performance. This review covers recent developments in electrically active biomedical coatings for TE. The physicochemical and biological properties of conductive coating materials, including polymers (polypyrrole, polyaniline and PEDOT:PSS), metallic nanoparticles (gold, silver) and inorganic (ceramic) particles (carbon nanotubes, graphene-based materials and Mxenes) are examined. Each section explores the conductive coatings' deposition techniques, deposition parameters, conductivity ranges, deposit morphology, cell responses, and toxicity levels in detail. Furthermore, the applications of these conductive layers, primarily in bone, muscle, and neural TE are considered, and findings from in vitro and in vivo investigations are presented. STATEMENT OF SIGNIFICANCE: Tissue engineering (TE) scaffolds are crucial for human tissue replacement and acceleration of healing. Neural, muscle, bone, and skin tissues have electrically excitable cells, and their regeneration can be enhanced by electrically conductive scaffolds. However, standalone conductive materials often fall short for TE applications. An effective approach involves coating scaffolds with a conductive layer, finely tuning surface properties while leveraging the scaffold's innate biological and physical support. Further enhancement is achieved by modifying the conductive layer with pharmaceutical components. This review explores the under-reviewed topic of conductive coatings in tissue engineering, introducing conductive biomaterial coatings and analyzing their biological interactions. It provides insights into enhancing scaffold functionality for tissue regeneration, bridging a critical gap in current literature.

Extracellular and intracellular effects of bioactive glass nanoparticles on osteogenic differentiation of bone marrow mesenchymal stem cells and bone regeneration in zebrafish osteoporosis model.

Bioactive glass nanoparticles (BGNs) are well-recognized multifunctional biomaterials for bone tissue regeneration due to their capability to stimulate various cellular processes through released biologically active ions. Understanding the correlation between BGN composition and cellular responses is key to developing clinically usable BGN-based medical devices. This study investigated the influence of CaO content of binary SiO2-CaO BGNs (CaO ranging from 0 to 10 mol%) on osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) and in vivo bone regeneration in zebrafish osteoporosis model. The results showed that BGNs could promote osteogenic differentiation of rBMSCs by indirectly releasing active ions or directly interacting with rBMSCs by internalization. In both situations, BGNs of a higher CaO content could promote the osteogenic differentiation of rBMSCs to a greater extent. The internalized BGNs could activate the transcription factors RUNX2 and OSX, leading to the expression of osteogenesis-related genes. The results in the zebrafish osteoporosis model indicated that the presence of BGNs of higher CaO contents could enhance bone regeneration and rescue dexamethasone-induced osteoporosis to a greater extent. These findings demonstrate that BGNs can stimulate osteogenic differentiation of rBMSCs by releasing active ions or internalization. A higher CaO content facilitates osteogenesis and bone regeneration of zebrafish as well as relieving dexamethasone-induced osteoporosis. The zebrafish osteoporosis model can be a potent tool for evaluating the in vivo bone regeneration effects of bioactive materials. STATEMENT OF SIGNIFICANCE: Bioactive glass nanoparticles (BGNs) are increasingly used as fillers of nanocomposites or as delivery platforms of active ions to regenerate bone tissue. Various studies have shown that BGNs can enhance osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by releasing active ions. However, the correlation between BGN composition and cellular responses and in vivo bone regeneration effect has still not been well investigated. Establishment of a suitable in vivo animal model for investigating this correlation is also challenging. The present study reports the influence of CaO content in binary SiO2-CaO BGNs on osteogenic differentiation of BMSCs extracellularly and intracellularly. This study also demonstrates the suitability of zebrafish osteoporosis model to investigate in vivo bone regeneration effect of BGNs.

Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development.

Fragile X messenger ribonucleoprotein 1 protein (FMRP) deficiency leads to fragile X syndrome (FXS), an autism spectrum disorder. The role of FMRP in prenatal human brain development remains unclear. Here, we show that FMRP is important for human and macaque prenatal brain development. Both FMRP-deficient neurons in human fetal cortical slices and FXS patient stem cell-derived neurons exhibit mitochondrial dysfunctions and hyperexcitability. Using multiomics analyses, we have identified both FMRP-bound mRNAs and FMRP-interacting proteins in human neurons and unveiled a previously unknown role of FMRP in regulating essential genes during human prenatal development. We demonstrate that FMRP interaction with CNOT1 maintains the levels of receptor for activated C kinase 1 (RACK1), a species-specific FMRP target. Genetic reduction of RACK1 leads to both mitochondrial dysfunctions and hyperexcitability, resembling FXS neurons. Finally, enhancing mitochondrial functions rescues deficits of FMRP-deficient cortical neurons during prenatal development, demonstrating targeting mitochondrial dysfunction as a potential treatment.

Inactivation of Hedgehog signal transduction in adult astrocytes results in region-specific blood-brain barrier defects.

In this study, we use molecular genetic approaches to clarify the role of the Hedgehog (Hh) pathway in regulating the blood-brain/spinal cord barrier (BBB) in the adult mouse central nervous system (CNS). Our work confirms and extends prior studies to demonstrate that astrocytes are the predominant cell type in the adult CNS that transduce Hh signaling, revealed by the expression of Gli1, a target gene of the canonical pathway that is activated in cells receiving Hh, and other key pathway transduction components. Gli1+ (Hh-responsive) astrocytes are distributed in specific regions of the CNS parenchyma, including layers 4/5/6 of the neocortex, hypothalamus, thalamus, and spinal cord, among others. Notably, although BBB properties in endothelial cells are normally regulated by both paracellular and transcellular mechanisms, conditional inactivation of Hh signaling in astrocytes results in transient, region-specific BBB defects that affect transcytosis but not paracellular diffusion. These findings stand in contrast to prior studies that implicated astrocytes as a source of Sonic hedgehog that limited extravasation via both mechanisms [J. I. Alvarez et al., Science 334, 1727-1731 (2011)]. Furthermore, using three distinct Cre driver lines as well as pharmacological approaches to inactivate Hh-pathway transduction globally in CNS astrocytes, we find that these specific BBB defects are only detected in the rostral hypothalamus and spinal cord but not the cortex or other regions where Gli1+ astrocytes are found. Together, our data show that Gli1+ Hh-responsive astrocytes have regionally distinct molecular and functional properties and that the pathway is required to maintain BBB properties in specific regions of the adult mammalian CNS.

Fabrication of Submicro-Nano Structures on Polyetheretherketone Surface by Femtosecond Laser for Exciting Cellular Responses of MC3T3-E1 Cells/Gingival Epithelial Cells.

PURPOSE: Polyetheretherketone (PEEK) exhibits high mechanical strengths and outstanding biocompatibility but biological inertness that does not excite the cell responses and stimulate bone formation. The objective of this study was to construct submicro-nano structures on PEEK by femtosecond laser (FSL) for exciting the responses of MC3T3-E1 cells and gingival epithelial (GE) cells, which induce regeneration of bone/gingival tissues for long-term stability of dental implants. MATERIALS AND METHODS: In this study, submicro-nano structures were created on PEEK surface by FSL with power of 80 mW (80FPK) and 160 mW (160FPK). RESULTS: Compared with PEEK, both 80FPK and 160FPK with submicro-nano structures exhibited elevated surface performances (hydrophilicity, surface energy, roughness and protein absorption). Furthermore, in comparison with 80FPK, 160FPK further enhanced the surface performances. In addition, compared with PEEK, both 80FPK and 160FPK significantly excited not only the responses (adhesion, proliferation, alkaline phosphatase [ALP] activity and osteogenic gene expression) of MC3T3-E1 cells but also responses (adhesion as well as proliferation) of GE cells of human in vitro. Moreover, in comparison with 80FPK, 160FPK further enhanced the responses of MC3T3-E1 cells/GE cells. CONCLUSION: FSL created submicro-nano structures on PEEK with elevated surface performances, which played crucial roles in exciting the responses of MC3T3-E1 cells/GE cells. Consequently, 160FPK with elevated surface performances and outstanding cytocompatibility would have enormous potential as an implant for dental replacement.

Nanostructured Coating of Non-Crystalline Tantalum Pentoxide on Polyetheretherketone Enhances RBMS Cells/HGE Cells Adhesion.

PURPOSE: As a dental material, polyetheretherketone (PEEK) is bioinert that does not induce cellular response and bone/gingival tissues regeneration. This study was to develop bioactive coating on PEEK and investigate the effects of coating on cellular response. MATERIALS AND METHODS: Tantalum pentoxide (TP) coating was fabricated on PEEK surface by vacuum evaporation and responses of rat bone marrow mesenchymal stem (RBMS) cells/human gingival epithelial (HGE) were studied. RESULTS: A dense coating (around 400 nm in thickness) of TP was closely combined with PEEK (PKTP). Moreover, the coating was non-crystalline TP, which contained many small humps (around 10 nm in size), exhibiting a nanostructured surface. In addition, the roughness, hydrophilicity, surface energy, and protein adsorption of PKTP were remarkably higher than that of PEEK. Furthermore, the responses (adhesion, proliferation, and osteogenic gene expression) of RBMS cells, and responses (adhesion and proliferation) of HGE cells to PKTP were remarkably improved in comparison with PEEK. It could be suggested that the nanostructured coating of TP on PEEK played crucial roles in inducing the responses of RBMS/HGE cells. CONCLUSION: PKTP with elevated surface performances and outstanding cytocompatibility might have enormous potential for dental implant application.

Automated diagnoses of age-related macular degeneration and polypoidal choroidal vasculopathy using bi-modal deep convolutional neural networks.

AIMS: To investigate the efficacy of a bi-modality deep convolutional neural network (DCNN) framework to categorise age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) from colour fundus images and optical coherence tomography (OCT) images. METHODS: A retrospective cross-sectional study was proposed of patients with AMD or PCV who came to Peking Union Medical College Hospital. Diagnoses of all patients were confirmed by two retinal experts based on diagnostic gold standard for AMD and PCV. Patients with concurrent retinal vascular diseases were excluded. Colour fundus images and spectral domain OCT images were taken from dilated eyes of patients and healthy controls, and anonymised. All images were pre-labelled into normal, dry or wet AMD or PCV. ResNet-50 models were used as the backbone and alternate machine learning models including random forest classifiers were constructed for further comparison. For human-machine comparison, the same testing data set was diagnosed by three retinal experts independently. All images from the same participant were presented only within a single partition subset. RESULTS: On a test set of 143 fundus and OCT image pairs from 80 eyes (20 eyes per-group), the bi-modal DCNN demonstrated the best performance, with accuracy 87.4%, sensitivity 88.8% and specificity 95.6%, and a perfect agreement with diagnostic gold standard (Cohen's κ 0.828), exceeds slightly over the best expert (Human1, Cohen's κ 0.810). For recognising PCV, the model outperformed the best expert as well. CONCLUSION: A bi-modal DCNN for automated classification of AMD and PCV is accurate and promising in the realm of public health.

Characterization of CT scans of patients with Birt-Hogg-Dubé syndrome compared with those of Chinese patients with non-BHD diffuse cyst lung diseases.

BACKGROUND AND OBJECTIVE: The purpose of this study was to create a practical CT-based algorithm to differentiate Birt-Hogg-Dubé (BHD) syndrome from other diffuse cystic lung diseases (DCLD). METHODS: The study was a retrospective review of the CT images of 33 patients with BHD syndrome, 33 patients with LAM, and 23 patients with NBNL (non-BHD and non-LAM) among DCLD patients. On the basis of the data collected, the CT images were reviewed again to evaluate the characteristics (size, number, distribution, and morphology) of pulmonary cysts. RESULTS: Lower lung-predominant cysts were more likely to be found in patients with BHD syndrome than in patients with LAM or in the NBNL DCLD group. In the axial distribution, 18 of 33 patients in BHD group had cysts that were predominantly near the mediastinum, and all the patients in the LAM and NBNL DCLD groups had diffuse cysts. The appearance of fusiform cysts was more easily observed in patients in the BHD group. In total, 58% patients in the BHD group had less than 50 lung cysts, while all patients in the non-BHD group had more than 50 lung cysts. The biggest cyst was located in the lower lobe in 28 of 33 patients in the BHD group, while 11 of 33 patients in LAM group and 10 patients in the NBNL DCLD group had the biggest cyst in the lower lobe. CONCLUSION: The pulmonary cysts in patients with BHD tended to be fusiform, less numerous and located predominantly in the lower lobe and near the mediastinum. These radiologic pulmonary features could assist physicians in differentiating BHD from other DCLDs.

A hierarchical nanostructural coating of amorphous silicon nitride on polyetheretherketone with antibacterial activity and promoting responses of rBMSCs for orthopedic applications.

Silicon nitride (SN) with good osteoconductivity has been introduced as an implantable biomaterial for joint replacement and interbody fusion devices. In this study, SN was coated on a polyetheretherketone (PEEK) surface by inductively coupled plasma-enhanced chemical vapor deposition (ICPECVD). The results showed that a dense coating (thickness of about 500 nm) of amorphous SN was closely combined with a PEEK substrate (PKSN) with a binding strength of 6.88 N. In addition, the coating surface showed hierarchical nanostructures containing many spherical bulges (sizes about 150 nm), which were composed of many small humps (sizes about 10 nm). Moreover, the roughness, hydrophilicity, surface energy, surface charge and adsorption of bovine serum albumin (BSA) of PKSN were obviously higher than those of PEEK. After immersion into simulated body fluid (SBF), the Si ions were gradually released from PKSN into SBF and a weak alkaline environment was created. Antibacterial experiments showed that PKSN exhibited a greater antibacterial activity than that of PEEK. Moreover, compared with PEEK, PKSN significantly promoted adhesion, proliferation, differentiation and expression of osteogenic related genes of the rat bone marrow stromal cells (rBMSCs). In conclusion, the SN coating of PKSN with hierarchical nanostructures exhibited excellent antibacterial activity and cytocompatibility, which would make it a great candidate for orthopedic applications.

The Relationship of Serum Antigen-Specific and Total Immunoglobulin E with Adult Cardiovascular Diseases.

Background: The relationship of serum antigen-specific immunoglobulin E (IgE) with cardiovascular diseases (CVDs) remains poorly understood. This study aimed to explore the association of antigen-specific and total IgE with CVDs using data derived from the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Methods and Results: The association of serum total or antigen-specific IgE levels with CVDs was analyzed by survey-weighted logistic regression modeling, adjusted by age, sex, race, education, body mass index, blood pressure, total cholesterol, C-reactive protein, homocysteine, diabetes, smoking, and alcohol consumption. 4953 subjects were included. Coronary heart disease was significantly related to serum total IgE levels. The association of serum total IgE levels with coronary heart disease was further validated by negative, ≥1 and 1-6 positive antigen-specific IgE. Myocardial infarction was positively associated with serum total IgE levels only when all antigen-specific IgE were negative, but inversely associated with serum total IgE when plant-specific IgE test results were positive. More specifically, myocardial infarction was also inversely related to positive oak, birch, or peanut-specific IgE. In addition, serum total IgE are positively associated with angina when at least one specific IgE were positive. Conclusions: Serum antigen-specific IgE, as well as total IgE, is significantly associated with CVDs independently of a long list of established cardiovascular risk factors, which is more informative than total IgE per se.

Association between LRH-1 single nucleotide polymorphisms and unexplained recurrent spontaneous abortion in Chinese Han couples.

To explore the genetic relationships between LRH-1 (rs2816948), CYP19 (rs727479 and rs700518), and P450scc (rs4077582) as a potential mechanism behind unexplained recurrent spontaneous abortions in a Chinese Han population. A case-control study was used and featured two groups: Patients with unexplained recurrent miscarriage (n = 82, abortion group) and those who voluntary surrendered of a normal early pregnancy (n = 97, control group). Abortion villi samples were obtained from all patients. Genomic DNA was later extracted and sequenced, after which statistical analyses performed to assess the relationship between single nucleotide polymorphisms and unexplained recurrent spontaneous abortions. There were significant differences in the genotypic and allelic distribution (p < .05) for CYP19 (rs727479) between the abortion and the control groups. There were no significant differences in the genotypic or allelic distributions (p > .05) for either the LRH-1 (rs2816948) or CYP19 (rs700518). There were also significant genotypic differences (p < .05) for P450scc (rs4077582), but no significant differences for its allelic distribution (p > .05). There was a significant correlation between the occurrence of unexplained recurrent spontaneous abortion and CYP19 (rs727479) single nucleotide polymorphisms.

The effect of somatostatin analogues on postoperative outcomes following pancreatic surgery: A meta-analysis.

BACKGROUND: Leakage from the pancreatic stump is a leading cause of morbidity following pancreatic surgery. It is essential to evaluate the effect of somatostatin analogues (SAs) following pancreatic surgery by analyzing all recent clinical trials. DATA SOURCES: We performed a literature search in the Medline, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science databases up to May 29, 2016. Publication bias was assessed with Egger's test. Study quality was assessed using the Jadad Composite Scale. CONCLUSIONS: Twelve clinical trials involving 1703 patients from Jan 1st, 2000 to May 29th, 2016 were included in the study. With improvements in surgical management and peri-operative patient care, prophylactic use of somatostatin and its analogues reduced the overall incidence of pancreatic fistulas (RR 0.72, 95% CI 0.55-0.94; p = 0.02) and decreased the post-operative hospital stay after pancreatic surgery (the weighted mean difference was -1.06, 95% CI-1/88 to -0.23; p = 0.01). Other post-operative outcomes did not change significantly with the use of somatostatin analogues.

A retrospective study of elevated post-operative parathormone in primary hyperparathyroid patients.

We retrospectively analyzed the relationship between normocalcemic parathormone elevation (NPE) and recurrence of primary hyperparathyroidism (pHPT) after surgery, as well as the risk factors of NPE. Out of 309 patients with pHPT that underwent parathyroidectomy. Six months after surgery, 75 patients exhibited NPE with high preoperative serum levels of alkaline phosphatase, calcium and intact parathyroid hormone (iPTH), postoperative day 1 iPTH, and large parathyroid volume. 15 exhibited NPE at 2 years after surgery with low serum vitamin D levels. Postoperative serum iPTH levels gradually normalized in most patients. Multivariate analysis showed that male patients were at greater risk for postoperative NPE (p<0.05). Only 3 of 309 patients showed recurrence during the follow-up period. NPE may not predict recurrent hyperparathyroidism or incomplete parathyroidectomy for benign parathyroid lesions. Postoperative NPE thus appears to be a response to severe hyperparathyroidism and vitamin D deficiency.

Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax. The known causative gene for BHD syndrome is the folliculin (FLCN) gene on chromosome 17p11.2. Studies of the FLCN mutation for BHD syndrome are less prevalent in Chinese populations than in Caucasian populations. Our study aims to investigate the genotype spectrum in a group of Chinese patients with BHD. METHODS: We enrolled 51 patients with symptoms highly suggestive of BHD from January 2014 to February 2017. The FLCN gene was examined using PCR and Sanger sequencing in every patient, for those whose Sanger sequencing showed negative mutation results, multiplex ligation-dependent probe amplification (MLPA) testing was conducted to detect any losses of large segments. MAIN RESULTS: Among the 51 patients, 27 had FLCN germline mutations. In total, 20 mutations were identified: 14 were novel mutations, including 3 splice acceptor site mutations, 2 different deletions, 6 nonsense mutations, 1 missense mutation, 1 small insertion, and 1 deletion of the whole exon 8. CONCLUSIONS: We found a similar genotype spectrum but different mutant loci in Chinese patients with BHD compared with European and American patients, thus providing stronger evidence for the clinical molecular diagnosis of BHD in China. It suggests that mutation analysis of the FLCN gene should be systematically conducted in patients with cystic lung diseases.

Expression of Liver Receptor Homolog-1 (LRH-1) in Villi and Decidua of Patients with Unexplained Recurrent Spontaneous Abortion.

BACKGROUND In view of the important function of nuclear receptor liver receptor homolog 1 (LRH 1) in various biological processes and the physiological changes accompanying unexplained recurrent spontaneous abortion (USRA), our study was carried out to investigate the potential roles of LRH-1 in USRA. MATERIAL AND METHODS Thirty patients with URSA at early the early state of pregnancy were selected, and 30 patients with normal early pregnancy were also selected from Aug 2015 to Sep 2016 as a control group. The expression of LRH-1 protein in decidua and villi were detected by immunohistochemistry and Western blot analysis, and the expression of LRH-1 mRNA was detected by RT-PCR. The expression levels of CYP19 and P450scc were detected by RT-PCR and Western blot analysis at mRNA and protein levels, respectively. RESULTS The levels of LRH-1, CYP19, and P450scc mRNA and protein in villi of the patients in the URSA group were significantly lower than in the control group. There were no significant differences between the URSA group and control group in the levels of LRH-1, CYP19, and P450scc mRNA and protein in villi in decidua. CONCLUSIONS URSA was related to the reduced expression level of LRH-1 in villous tissues but not in decidua, and expression of LRH-1 may be related to the expression of CYP19 and P450scc. We believe that the expression level of LRH-1 can be used as a marker in the early diagnosis of URSA, and the regulation of LRH-1 expression many lead to new URSA treatments.