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.

Heat Waves Alter Macrophyte-Derived Detrital Nutrients Release under Future Climate Warming Scenarios.

In addition to a rise in global air and water mean temperatures, extreme climate events such as heat waves are increasing in frequency, intensity, and duration in many regions of the globe. Developing a mechanistic understanding of the impacts of heat waves on key ecosystem processes and how they differ from just an increase in mean temperatures is therefore of utmost importance for adaptive management against effects of global change. However, little is known about the impact of extreme events on freshwater ecosystem processes, particularly the decomposition of macrophyte detritus. We performed a mesocosm experiment to evaluate the impact of warming and heat waves on macrophyte detrital decomposition, applied as a fixed increment (+4 °C) above ambient and a fluctuating treatment with similar energy input, ranging from 0 to 6 °C above ambient (i.e., simulating heat waves). We showed that both warming and heat waves significantly accelerate dry mass loss of the detritus and carbon (C) release but found no significant differences between the two heated treatments on the effects on detritus dry mass loss and C release amount. This suggests that moderate warming indirectly enhanced macrophyte detritus dry mass loss and C release mainly by the amount of energy input rather than by the way in which warming was provided (i.e., by a fixed increment or in heat waves). However, we found significantly different amounts of nitrogen (N) and phosphorus (P) released between the two warming treatments, and there was an asymmetric response of N and P release patterns to the two warming treatments, possibly due to species-specific responses of decomposers to short-term temperature fluctuations and litter quality. Our results conclude that future climate scenarios can significantly accelerate organic matter decomposition and C, N, and P release from decaying macrophytes, and more importantly, there are asymmetric alterations in macrophyte-derived detrital N and P release dynamic. Therefore, future climate change scenarios could lead to alterations in N/P ratios in the water column via macrophyte decomposition processes and ultimately affect the structure and function of aquatic ecosystems, especially in the plankton community.

Efficient NTRU Lattice-Based Certificateless Signature Scheme for Medical Cyber-Physical Systems.

An electronic health (e-health) system, such as a medical cyber-physical system, offers a number of benefits (e.g. inform medical diagnosis). There are, however, a number of considerations in the implementation of the medical cyber-physical system, such as the integrity of medical / healthcare data (e.g. manipulated data can result in misdiagnosis). A number of digital signature schemes have been proposed in recent years to mitigate some of these challenges. However, the security of existing signatures is mostly based on conventional difficult mathematical problems, which are known to be insecure against quantum attacks. In this paper, we propose a certificateless signature scheme, based on NTRU lattice. The latter is based on the difficulty of small integer solutions on the NTRU lattice, and is known to be quantum attack resilience. Security analysis and performance evaluations demonstrate that our proposed scheme achieves significantly reduced communication and computation costs in comparison to two other competing quantum resilience schemes, while being quantum attack resilience.

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.

Atrophin protein RERE positively regulates Notch targets in the developing vertebrate spinal cord.

The Notch signaling pathway controls cell fate decision, proliferation, and other biological functions in both vertebrates and invertebrates. Precise regulation of the canonical Notch pathway ensures robustness of the signal throughout development and adult tissue homeostasis. Aberrant Notch signaling results in profound developmental defects and is linked to many human diseases. In this study, we identified the Atrophin family protein RERE (also called Atro2) as a positive regulator of Notch target Hes genes in the developing vertebrate spinal cord. Prior studies have shown that during early embryogenesis in mouse and zebrafish, deficit of RERE causes various patterning defects in multiple organs including the neural tube. Here, we detected the expression of RERE in the developing chick spinal cord, and found that normal RERE activity is needed for proper neural progenitor proliferation and neuronal differentiation possibly by affecting Notch-mediated Hes expression. In mammalian cells, RERE co-immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over-expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. Our findings suggest that RERE stimulates Notch target gene expression by preventing degradation of NICD protein, thereby facilitating the assembly of a transcriptional activating complex containing NICD, CBF1/RBPjκ in vertebrate, Su(H) in Drosophila melanogaster, Lag1 in C. elegans, and other coactivators.

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.

From wings to whiskers to stem cells: why every model matters in fragile X syndrome research.

Fragile X syndrome (FXS) is caused by epigenetic silencing of the X-linked fragile X messenger ribonucleoprotein 1 (FMR1) gene located on chromosome Xq27.3, which leads to the loss of its protein product, fragile X messenger ribonucleoprotein (FMRP). It is the most prevalent inherited form of intellectual disability and the highest single genetic cause of autism. Since the discovery of the genetic basis of FXS, extensive studies using animal models and human pluripotent stem cells have unveiled the functions of FMRP and mechanisms underlying FXS. However, clinical trials have not yielded successful treatment. Here we review what we have learned from commonly used models for FXS, potential limitations of these models, and recommendations for future steps.

Surface engineering of mesoporous bioactive glass nanoparticles with bacteriophages for enhanced antibacterial activity.

Binary SiO2-CaO mesoporous bioactive glass nanoparticles (MBGNs) are multifunctional biomaterials able to promote osteogenic, angiogenic, and immunomodulatory activities. MBGNs have been applied in a variety of tissue regeneration strategies. However, MBGNs lack strong antibacterial activity and current strategies (loading of antibacterial ions or antibiotics) toward enhanced antibacterial activity may cause cytotoxicity or antibiotic resistance. Here we engineered MBGNs using bacteriophages (phages) to enhance the antibacterial activity. Salmonella Typhimurium (S. T) phage PFPV25.1 that can infect Salmonella enterica serovar Typhimurium strain LT2 was used as a model phage to engineer MBGNs. MBGNs were first modified with amine groups to enhance the affinity between phages and MBGNs surfaces. Afterward, the physicochemical and antibacterial activity of phage-engineered MBGNs was evaluated. The results showed that S. T phage PFPV25.1 was successfully bound onto MBGNs surfaces without losing their bioactivity. A higher quantity of phages could be bounded onto amine-functionalized MBGNs than onto non-functionalized MBGNs. Phages on amine-functionalized MBGNs exhibited higher antibacterial activity. The stability test showed that phages could remain on amine-functionalized MBGNs for over 28 days. This work provides valuable information on developing phage-modified MBGNs as a new and effective antibacterial system for biomedical applications.

Responses of submerged macrophytes to different particle size microplastics and tetracycline co-pollutants at the community and population level.

Microplastics (MPs) and antibiotics are ubiquitous in aquatic ecosystems, and their accumulation and combined effects are considered emerging threats that may affect biodiversity and ecosystem function. The particle size of microplastics plays an important role in their combined effects with antibiotics. Submerged macrophytes are crucial in maintaining the health and stability of freshwater ecosystems. However, little is known about the combined effects of different particle size of MPs and antibiotics on freshwater plants, particularly their effects on submerged macrophyte communities. Thus, there is an urgent need to study their effects on the macrophyte communities to provide essential information for freshwater ecosystem management. In the present study, a mesocosm experiment was conducted to explore the effects of three particle sizes (5 µm, 50 µm, and 500 µm) of polystyrene-microplastics (PSMPs) (75 mg/L), tetracycline (TC) (50 mg/L), and their co-pollutants on interactions between Hydrilla verticillata and Elodea nuttallii. Our results showed that the effects of MPs are size-dependent on macrophytes at the community level rather than at the population level, and that small and medium sized MPs can promote the growth of the two test macrophytes at the community level. In addition, macrophytes at the community level have a stronger resistance to pollutant stress than those at the population level. Combined exposure to MPs and TC co-pollutants induces species-specific responses and antagonistic toxic effects on the physio-biochemical traits of submerged macrophytes. Our study provides evidence that MPs and co-pollutants not only affect the morphology and physiology at the population level but also the interactions between macrophytes. Thus, there are promising indications on the potential consequences of MPs and co-pollutants on macrophyte community structure, which suggests that future studies should focus on the effects of microplastics and their co-pollutants on aquatic macrophytes at the community level rather than only at the population level. This will improve our understanding of the profound effects of co-pollutants in aquatic environments on the structure and behavior of aquatic communities and ecosystems.

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.

Sol-gel derived B2O3-CaO borate bioactive glasses with hemostatic, antibacterial and pro-angiogenic activities.

Sol-gel borate bioactive glasses (BGs) are promising ion-releasing biomaterials for wound healing applications. Here, we report the synthesis of a series of binary B2O3-CaO borate BGs (CaO ranging from 50 to 90 mol%) using a sol-gel-based method. The influence of CaO content in B2O3-CaO borate BG on morphology, structure and ion release behavior was investigated in detail. Reduced dissolution (ion release) and crystallization could be observed in borate BGs when CaO content increased, while the morphology was not significantly altered by increasing CaO content. Our results evidenced that the ion release behavior of borate BGs could be tailored by tuning the B2O3/CaO molar ratio. We also evaluated the in vitro cytotoxicity, hemostatic, antibacterial and angiogenic activities of borate BGs. Cytocompatibility was validated for all borate BGs. However, borate BGs exhibited composition-dependent hemostatic, antibacterial and angiogenic activities. Generally, higher contents of Ca in borate BGs facilitated hemostatic activity, while higher contents of B2O3 were beneficial for pro-angiogenic activity. The synthesized sol-gel-derived borate BGs are promising materials for developing advanced wound healing dressings, given their fast ion release behavior and favorable hemostatic, antibacterial and angiogenic activities.

How do liquid mixtures solubilize insoluble gelators? Self-assembly properties of pyrenyl-linker-glucono gelators in tetrahydrofuran-water mixtures.

The self-assembly behavior of a series of glucono-appended 1-pyrenesulfonyl derivatives containing α,ω-diaminoalkane spacers (Pn, where n, the number of methylene units separating the amino groups, is 2, 3, 4, 6, 7, and 8) in v:v tetrahydrofuran (THF):water mixtures is examined at room temperature. The Pn at 2 w/v % concentrations do not dissolve in either THF or water at room temperature. However, the Pn can be dissolved in some THF:water mixtures, and they form gels spontaneously in other compositions without dissolving completely. The self-assembly of the Pn in the liquid mixtures has been investigated using a variety of techniques. The particle sizes of the Pn in their solutions/sols, critical gelation concentrations, microstructures, thermal and mechanical stabilities of the gels, and molecular packing modes of Pn molecules in their gel networks are found to be very dependent on the composition of the liquid mixtures. Correlations between the self-assembly behavior of the Pn and the polarity of the liquid mixtures, as probed by E(T)(30) and Hansen solubility parameters, yield both qualitative and quantitative insights into why self-assembly of the Pn can or cannot be achieved in different liquid compositions. As revealed by UV-vis and fluorescence spectroscopy studies, π-π stacking of the pyrenyl groups occurs as part of the aggregation process. Correlations between the rheological properties of the gels and the Hansen solubility parameters of the Pn and the solvent mixtures indicate that hydrogen-bonding interactions are a major contributor to the mechanical stability. Overall, the results of this study offer a new strategy to investigate the balance between dissolution and aggregation of molecular gelators. To the best of our knowledge, this is the first example of the spontaneous formation of molecular gels without heating by placing gelators in mixtures of liquids in which they are insoluble in the neat components.

Pyrenyl-linker-glucono gelators. Correlations of gel properties with gelator structures and characterization of solvent effects.

A series of glucono-appended 1-pyrenesulfonyl derivatives containing α,ω-diaminoalkane spacers (Pn, where n, the number of methylene units separating the amino groups, is 2, 3, 4, 6, 7, and 8) have been prepared. Careful analyses of correlations between the structures of these molecules and their gels have provided important insights into the factors responsible for one-dimensional aggregation of small molecules containing both lipophilic and hydrophilic parts. The gelation behavior has been examined in 30 liquids of diverse structure and polarity, and the properties of their gels and the gelation mechanisms have been investigated using a variety of techniques. Possible reasons are discussed regarding why the Pn are better gelators than the corresponding naphthyl analogues (Nn) which had been investigated previously. P2 and P3 are ambidextrous gelators (i.e., they gelate both water and some organic liquids), and P4-P8 gelate some organic liquids which are protic and aprotic, but not water. In at least one of the liquids examined, P3, P4, P6, P7, and P8 form gels at less than 1 w/v % concentrations, and some of the gels in 1-decanol are thixotropic. Analyses of the gelation abilities using Hansen solubility parameters yield both qualitative and quantitative insights into the role of liquid-gelator interactions. For example, the critical gelation concentrations increase generally with increasing polar and hydrogen bonding interactions between the gelators and their liquid components. As revealed by FT-IR, (1)H NMR, UV-vis, and fluorescence spectra, hydrogen-bonding between glucono units and π-π stacking between pyrenyl groups are important in the formation and maintenance of the gel networks. The results from this study, especially those relating the aggregation modes and liquid properties, offer insights for the design of new surfactant-containing low-molecular-mass gelators with predefined gelating abilities.

Certificateless Public Auditing Scheme With Data Privacy and Dynamics in Group User Model of Cloud-Assisted Medical WSNs.

With the application of wireless sensor network (WSN) in healthcare field, online sharing of medical data has attracted more and more attention. However, wearable sensor nodes are limited in energy, storage space and data processing capacity, which largely restricts their deployment in resource demand application scenarios. Fortunately, cloud storage services can enrich the capabilities of wearable sensors and provide an effective method for people to share data within a group. However, as medical data directly relates to patients' health and privacy information, ensuring the integrity and privacy of medical records stored in cloud servers becomes a key issue to be urgently solved. Many public data auditing schemes have been put forward to address the above issues. Unfortunately, most of them have security vulnerabilities or poor functionality and performance. In this paper, we come up with a secure and efficient certificateless public auditing scheme for cloud-assisted medical WSNs, which not only supports dynamic data sharingand privacy protection, but also achieves efficient group user revocation. Security analysis and performance evaluation demonstrate that our scheme significantly reduce the total computation cost while achieving a higher security level. Compared with other related schemes, our new proposal is more suitable for group user data sharing in cloud-assisted medical WSNs.

Microplastics and co-pollutant with ciprofloxacin affect interactions between free-floating macrophytes.

Microplastic and antibiotic contamination are considered an increasing environmental problem in aquatic systems, while little is known about the impact of microplastics and co-pollutant with antibiotics on freshwater vascular plants, particularly the effects of interactions between macrophytes. Here, we performed a mesocosm experiment to evaluate the impact of polyethylene-microplastics and their co-pollutants with ciprofloxacin on the growth and physiological characteristics of Spirodela polyrhiza and Lemna minor and the interactions between these two macrophytes. Our results showed that microplastics alone cannot significantly influence fresh weight and specific leaf area of the two test free-floating macrophytes, but the effects on photosynthetic pigments, malondialdehyde, catalase and soluble sugar contents were species-specific. Ciprofloxacin can significant adverse effects on the growth and physiological traits of the two test macrophytes and microplastic mitigated the toxicity of ciprofloxacin on the two free-floating plants to a certain extent. In addition, our studies showed that microplastics and co-pollutants can influence relative yield and competitiveness of S. polyrhiza and L. minor by directly or indirectly influencing their physiology and growth. Therefore our findings suggest that species-specific sensibility to microplastic and its co-pollutant among free-floating macrophytes may influence macrophyte population dynamics and thereby community structure and ecosystem functioning. And microplastics altered other contaminant behaviours and toxicity, and may directly or indirectly influence macrophytes interactions and community structure. The present study is the first experimental study exploring the effects of microplastics alone and with their co-pollutants on interactions between free-floating macrophytes, which can provide basic theoretical guidance for improving the stability of freshwater ecosystems.

Mussel-Inspired Polydopamine Composite Mesoporous Bioactive Glass Nanoparticles: An Exploration of Potential Metal-Ion Loading Platform and In Vitro Bioactivity.

Exploring new approaches to realize the possibility of incorporating biologically active elements into mesoporous silicate bioactive glass nanoparticles (MBG NPs) and guaranteeing their meso- structural integrity and dimensional stability has become an attractive and interesting challenge in biomaterials science. We present a postgrafting strategy for introducing different metal elements into MBG NPs. This strategy is mediated by polydopamine (PDA) coating, achieving uniform loading of copper or copper-cobalt on the particles efficiently and ensuring the stability of MBG NPs in terms of particle size, mesoporous structure, and chemical structure. However, the PDA coating reduced the ion-binding free energy of the MBG NPs for calcium and phosphate ions, resulting in the deposition of minimal CaP clusters on the PDA@MBG NP surface when immersed for 7 days in simulated body fluid, indicating the absence of hydroxyapatite mineralization.

Biomineralization inspired 3D printed bioactive glass nanocomposite scaffolds orchestrate diabetic bone regeneration by remodeling micromilieu.

Type II diabetes mellitus (TIIDM) remains a challenging clinical issue for both dentists and orthopedists. By virtue of persistent hyperglycemia and altered host metabolism, the pathologic diabetic micromilieu with chronic inflammation, advanced glycation end products accumulation, and attenuated biomineralization severely impairs bone regeneration efficiency. Aiming to "remodel" the pathologic diabetic micromilieu, we 3D-printed bioscaffolds composed of Sr-containing mesoporous bioactive glass nanoparticles (Sr-MBGNs) and gelatin methacrylate (GelMA). Sr-MBGNs act as a biomineralization precursor embedded in the GelMA-simulated extracellular matrix and release Sr, Ca, and Si ions enhancing osteogenic, angiogenic, and immunomodulatory properties. In addition to angiogenic and anti-inflammatory outcomes, this innovative design reveals that the nanocomposites can modulate extracellular matrix reconstruction and simulate biomineralization by activating lysyl oxidase to form healthy enzymatic crosslinked collagen, promoting cell focal adhesion, modulating osteoblast differentiation, and boosting the release of OCN, the noncollagenous proteins (intrafibrillar mineralization dependent), and thus orchestrating osteogenesis through the Kindlin-2/PTH1R/OCN axis. This 3D-printed bioscaffold provides a multifunctional biomineralization-inspired system that remodels the "barren" diabetic microenvironment and sheds light on the new bone regeneration approaches for TIIDM.

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.

Complement 3a Mediates CCN2/CTGF in Human Retinal Pigment Epithelial Cells.

Background: Complement 3 (C3) is the crucial component of the complement cascade when retina was exposed to external stimulus. Cellular communication network 2/connective tissue growth factor (CCN2/CTGF) is important in response of retinal stress and a fulcrum for angiogenesis and fibrosis scar formation. Our study aims to explore the interaction between C3 and CCN2/CTGF via bioinformatics analyses and in vitro cell experiments. Methods: The GSE dataset was selected to analyse the chemokine expression in human retinal pigment epithelium (ARPE-19) cells under stimulus. Then, RPE cells were further transfected with or without C3 siRNA, followed by C3a (0.1 µM or 0.3 µM) for 24, 48, and 72 hours. Reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to measure CCN2/CTGF mRNA and protein levels. Results: The GSE36331 revealed C3 expression was significantly elevated in RPE under stimulus. Compared with negative control, CCN2/CTGF mRNA was increased with all types of C3a treatments, whereas a significant increase of protein level was only observed with high concentration of 0.3 µM C3a for a prolonged 72-hour time. Compared with nontransfected cells, significant reductions of CCN2/CTGF mRNA were observed in the C3 siRNA transfected cells with 0.3 µM C3a for 24, 48, and 72 hours, and a significant reduction of CCN2/CTGF protein was observed with 0.3 µM C3a for 48 hours. Conclusions: C3 was elevated in RPE under environmental stimulus and long-term exposure to specified concentration of C3a increased CCN2/CTGF expression in RPE, which could be partially reversed by C3 siRNA.