Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis.

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.

Efficacy and safety of celecoxib for treatment of mild to moderate postpartum depression: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Evidence has demonstrated the roles of inflammatory processes in pathogenesis of depression. We aim to assess the effects of adjunctive celecoxib with cognitive behavioral therapy (CBT), an anti-inflammatory agent, in treatment of postpartum depression and on levels of Brain-derived neurotrophic factor (BDNF) and inflammatory cytokines. METHODS: This was a randomized, double-blind, placebo-controlled trial to investigate the effects of adjunctive celecoxib with CBT on postpartum depression. Fifty outpatient women with postpartum depression, participated in this study. Patients randomly received either a celecoxib capsule twice a day or a placebo capsule twice a day for 6 weeks. Patients were assessed using the Hamilton Depression Rating Scale (HDRS) and the adverse event checklist at baseline and weeks 2, 4, and 6. RESULTS: Patients in the celecoxib group showed a greater decline in HDRS scores from baseline to all three study time points compared to the placebo group (p = 0.12 for week 2, p = 0.001 for week 4, p < 0.001 for week 6). Rate of response to treatment was significantly higher in the celecoxib group compared to the placebo group at week 4 (60 vs 24%, p = 0.010) and week 6 (96 vs 44%, p < 0.001). Rate of remission was significantly higher in the celecoxib group compared to the placebo group at week 4 (52 vs 20%, p = 0.018) and week 6 (96 vs 36%, p < 0.001). Levels of most inflammatory markers were significantly lower in the celecoxib group compared to the placebo group at week 6. Levels of BDNF were significantly higher in the celecoxib group compared to the placebo group at week 6 (p < 0.001). CONCLUSIONS: Findings suggest adjunctive celecoxib is an effective treatment for the improvement of postpartum depressive symptoms.

Evaluation of mechanical, optical, and fluoride-releasing properties of a translucent bulk fill glass hybrid restorative dental material.

OBJECTIVE: Measure and compare the mechanical properties, translucency, and fluoride-releasing capabilities of EQUIA Forte HT against Fuji IX GP and ChemFil Rock. MATERIALS AND METHODS: Ten specimens of each material were fabricated for compressive strength (CS), flexural strength (FS), and surface hardness analysis at 24 h and 7 days. The L*a*b* values were measured against a black-and-white background using a spectrophotometer to analyze the translucency parameter (TP). Fluoride release was recorded after 2 months of immersion in distilled water. The mean data was analyzed by 1- and 2-way ANOVA (α = 0.5). RESULTS: EQUIA Forte HT showed higher CS, surface hardness, and FS values (p < 0.05) compared with Fuji IX GIC, while no significant difference was found in FS values between EQUIA Forte HT and Chemfil Rock (p > 0.05). The EQUIA Forte HT exhibited significantly higher translucency in comparison to both ChemFil Rock (p < 0.001) and Fuji IX GICs (p < 0.05). An increase (p > 0.05) of fluoride release was observed for EQUIA Forte HT. CONCLUSION: The EQUIA Forte HT Glass-ionomer cements (GIC) offers enhanced translucency, improved strength, and enhanced fluoride-releasing properties compared to the traditionally used Fuji IX GIC and ChemFil Rock GICs. This material might have a wide range of clinical applications due to its improved strength and optical properties. CLINICAL SIGNIFICANCE: Glass-ionomer dental restorative materials possess unique advantageous characteristics. However, its poor mechanical and optical properties have typically limited its clinical applications. Efforts to improve these properties have resulted in enhanced GICs. EQUIA Forte HT GIC offers enhanced mechanical and optical properties with potential applications in posterior and anterior restorative procedures.

Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

A new computational drug repurposing method using established disease-drug pair knowledge.

MOTIVATION: Drug repurposing is a potential alternative to the classical drug discovery pipeline. Repurposing involves finding novel indications for already approved drugs. In this work, we present a novel machine learning-based method for drug repurposing. This method explores the anti-similarity between drugs and a disease to uncover new uses for the drugs. More specifically, our proposed method takes into account three sources of information: (i) large-scale gene expression profiles corresponding to human cell lines treated with small molecules, (ii) gene expression profile of a human disease and (iii) the known relationship between Food and Drug Administration (FDA)-approved drugs and diseases. Using these data, our proposed method learns a similarity metric through a supervised machine learning-based algorithm such that a disease and its associated FDA-approved drugs have smaller distance than the other disease-drug pairs. RESULTS: We validated our framework by showing that the proposed method incorporating distance metric learning technique can retrieve FDA-approved drugs for their approved indications. Once validated, we used our approach to identify a few strong candidates for repurposing. AVAILABILITY AND IMPLEMENTATION: The R scripts are available on demand from the authors. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic assessment of the internal transcribed spacer region (ITS1.2) in Mangifera indica L. landraces.

Mango (Mangifera indica) is one of the most important tropical fruits in the world. Twenty-two genotypes of native mangoes from different regions of southern Iran (Hormozgan and Kerman) were collected and analyzed for the ribosomal genes. GC content was found to be 55.5%. Fu and Li's D* test statistic (0.437), Fu and Li's F* test statistic (0.500) and Tajima's D (1.801) were positive and nonsignificant. A total of 769 positions were identified (319 with insertion or deletion including 250 polymorphic and 69 monomorphic loci; 450 loci without any insertion or deletion including 35 Singletons and 22 haplotypes). Nucleotide diversity of 0.309 and a high genetic differentiation including Chi square of 79.8; P value of 0.3605 and df value of 76 was observed among mango genotypes studied. The numerical value of the ratio dN/dS (0.45) indicated a pure selection in the examined gene and the absence of any key changes. Cluster analysis differentiated the mango used in this research (M. indica L.) into two genotypes but could not differentiate their geographical locations. The results of this study indicated that a high genetic distance exists between HajiGholam (Manojan) and Arbabi (Rodan) genotypes and showed higher genetic diversity in mango of Rodan region. Results of present study suggested that for successful breeding, the genotypes of Rodan region mango especially Arbabi mango can be used as a gene donor and ITS can be a suitable tool for genetic evaluations of inter and intra species.

Comparative evaluation of the physical properties of a reinforced glass ionomer dental restorative material.

STATEMENT OF PROBLEM: While glass ionomer cements have many unique properties and advantages, they still lack favorable mechanical properties. EQUIA Forte Fil is a newly developed glass ionomer cement (GIC) with improved mechanical strength. However, research and data on the physical properties of EQUIA Forte Fil are lacking. PURPOSE: The purpose of this in vitro study was to evaluate and compare the compressive, diametral tensile, and flexural strengths of EQUIA Forte Fil with Fuji IX GP and ChemFil Rock, restorative GICs commonly used in dentistry. Moreover, fluoride-releasing properties and surface hardness of the GICs were also assessed. MATERIAL AND METHODS: Ten disk-shaped specimens of each GIC (EQUIA Forte Fil, Fuji IX GP, and ChemFil Rock) were fabricated for mechanical and surface hardness tests by using polydimethylsiloxane (PDMS) molds. The specimens were tested after 24 hours and 7 days of immersion in distilled water at 37 °C. By using a mechanical testing machine, the compressive, diametral tensile, and flexural strengths of each GIC were measured. Fluoride-releasing properties were also evaluated (10 specimens per group). A microhardness tester was used to measure the surface hardness. The mean data were analyzed by using 1- and 2-way ANOVA (α=.05). RESULTS: EQUIA Forte Fil glass ionomer cements exhibited significantly greater (P<.05) flexural strength and surface hardness than Fuji IX GIC specimens. However, no significant difference (P>.05) was observed between the compressive and diametral tensile strength of EQUIA Forte Fil and Fuji IX GIC specimens. ChemFil Rock exhibited higher flexural strength than EQUIA Forte Fil (P>.05) but significantly lower compressive strength and microhardness (P<.05). Tested GICs matured after 1 week of immersion in distilled water, demonstrating a significant improvement in their mechanical properties. All the examined glass ionomers exhibited comparable initial fluoride-releasing properties, whereas EQUIA Forte Fil exhibited significantly higher (P<.05) amounts of fluoride release from the bulk of the material after 4 weeks. CONCLUSIONS: EQUIA Forte Fil is a promising restorative material with superior flexural strength and surface hardness compared with its predecessor, Fuji IX GP, or other commercially available glass ionomers.

An approach to infer putative disease-specific mechanisms using neighboring gene networks.

MOTIVATION: The ultimate goal of any experiment is to understand the biological phenomena underlying the condition investigated. This process often results in genes network through which a certain biological mechanism is explained. Such networks have been proven to be extremely useful, for the prediction of mechanisms of action of drugs or the responses of an organism to a specific impact (e.g. a disease, a treatment, etc.). Here, we introduce an approach able to build a network that captures the putative mechanisms at play in the given condition, by using datasets from multiple experiments studying the same phenotype. This method takes advantage of known interactions extracted from multiple sources such as protein-protein interactions and curated biological pathways. Based on such prior knowledge, we overcome the drawbacks of snap-shot data by considering the possible effects of each gene on its neighbors. RESULTS: We show the effectiveness of this approach in three different case studies and validate the results in two ways considering the identified genes and interactions between them. We compare our findings with the results of two widely-used methods in the same category as well as the classical approach of selecting differentially expressed (DE) genes in an investigated condition. The results show that 'neighbor-net' analysis is able to report biological mechanisms that are significantly relevant to the given diseases in all the three case studies, and performs better compared to all reference methods using both validation approaches. AVAILABILITY AND IMPLEMENTATION: The proposed method is implemented as in R and will be available an a Bioconductor package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SPATIAL: A System-level PAThway Impact AnaLysis approach.

The goal of pathway analysis is to identify the pathways that are significantly impacted when a biological system is perturbed, e.g. by a disease or drug. Current methods treat pathways as independent entities. However, many signals are constantly sent from one pathway to another, essentially linking all pathways into a global, system-wide complex. In this work, we propose a set of three pathway analysis methods based on the impact analysis, that performs a system-level analysis by considering all signals between pathways, as well as their overlaps. Briefly, the global system is modeled in two ways: (i) considering the inter-pathway interaction exchange for each individual pathways, and (ii) combining all individual pathways to form a global, system-wide graph. The third analysis method is a hybrid of these two models. The new methods were compared with DAVID, GSEA, GSA, PathNet, Crosstalk and SPIA on 23 GEO data sets involving 19 tissues investigated in 12 conditions. The results show that both the ranking and the P-values of the target pathways are substantially improved when the analysis considers the system-wide dependencies and interactions between pathways.

Effects of an etching solution on the adhesive properties and surface microhardness of zirconia dental ceramics.

STATEMENT OF PROBLEM: Conventional approaches to adhesive bonding are not applicable to zirconia restorations. Recently, an etching solution, Zeta Etching Solution (ZES), has been introduced for etching the surface of zirconia. The effects of this etching solution on the bond strength and mechanical properties of zirconia are unknown. PURPOSE: The purpose of this in vitro study was to examine the effects of ZES on the bond strength and surface hardness of zirconia. MATERIAL AND METHODS: Two different types of partially stabilized tetragonal polycrystalline zirconia (TZP), Prettau zirconia (group P) and anterior Prettau (group AP), were evaluated with and without ZES etching. Each group was bonded to a zirconia substrate by using an adhesive resin cement. After 24 hours of storage in distilled water, the bond strength of the zirconia was analyzed. Vickers hardness was determined by using a microhardness tester. Scanning electron microscopy was used to analyze the surface microstructure and determine the mode of failure for each specimen. Results were analyzed and compared using 1-way ANOVA and Student t tests (α=.05). RESULTS: Scanning electron microscopy analysis showed that etching the surface of zirconia with ZES etching solution for 60 minutes changed the morphological characteristics and microstructure of zirconia, making the surface more irregular. The changes were more pronounced for AP specimens. Etching with ZES significantly increased the shear bond strength of zirconia (P<.05) in AP specimens. The bond strength of Prettau (P group) specimens after ZES etching did not increase significantly (P>.05). An adhesive failure mode was observed for P zirconia specimens, whereas zirconia specimens exhibited a cohesive mode of failure. No significant decrease (P>.05) was observed in the mean Vickers hardness numbers. CONCLUSIONS: Within the limitations of this in vitro study, it was concluded that etching in ZES for 30 minutes significantly enhanced the shear bond strength of highly translucent anterior Prettau (AP) zirconia restorations. Moreover, etching with ZES did not adversely affect the surface hardness of the zirconia specimens tested.

A novel pathway analysis approach based on the unexplained disregulation of genes.

A crucial step in the understanding of any phenotype is the correct identification of the signaling pathways that are significantly impacted in that phenotype. However, most current pathway analysis methods produce both false positives as well as false negatives in certain circumstances. We hypothesized that such incorrect results are due to the fact that the existing methods fail to distinguish between the primary dis-regulation of a given gene itself and the effects of signaling coming from upstream. Furthermore, a modern whole-genome experiment performed with a next-generation technology spends a great deal of effort to measure the entire set of 30,000-100,000 transcripts in the genome. This is followed by the selection of a few hundreds differentially expressed genes, step that literally discards more than 99% of the collected data. We also hypothesized that such a drastic filtering could discard many genes that play crucial roles in the phenotype. We propose a novel topology-based pathway analysis method that identifies significantly impacted pathways using the entire set of measurements, thus allowing the full use of the data provided by NGS techniques. The results obtained on 24 real data sets involving 12 different human diseases, as well as on 8 yeast knock-out data sets show that the proposed method yields significant improvements with respect to the state-of-the-art methods: SPIA, GSEA and GSA. AVAILABILITY: Primary dis-regulation analysis is implemented in R and included in ROntoTools Bioconductor package (versions ≥ 2.0.0). https://www.bioconductor.org/packages/release/bioc/html/ROntoTools.html.

Alginate/hyaluronic acid hydrogel delivery system characteristics regulate the differentiation of periodontal ligament stem cells toward chondrogenic lineage.

Cartilage tissue regeneration often presents a challenging clinical situation. Recently, it has been shown that Periodontal Ligament Stem Cells (PDLSCs) possess high chondrogenic differentiation capacity. In this study, we developed a stem cell delivery system based on alginate/hyaluronic acid (HA) loaded with TGF-ß1 ligand, encapsulating PDLSCs; and investigated the chondrogenic differentiation of encapsulated cells in alginate/HA hydrogel microspheres in vitro and in vivo. The results showed that PDLSCs, as well as human bone marrow mesenchymal stem cells (hBMMSCs), as the positive control, were stained positive for both toluidine blue and alcian blue staining, while exhibiting high levels of gene expression related to chondrogenesis (Col II, Aggrecan and Sox-9), as assessed via qPCR. The quantitative PCR analyses exhibited that the chondrogenic differentiation of encapsulated MSCs can be regulated by the modulus of elasticity of hydrogel delivery system, confirming the vital role of the microenvironment, and the presence of inductive signals for viability and differentiation of MSCs. In vivo, histological and immunofluorescence staining for chondrogenic specific protein markers confirmed ectopic cartilage-like tissue regeneration inside transplanted hydrogels. PDLSCs presented significantly greater capability for chondrogenic differentiation than hBMMSCs (P < 0.05). Altogether, our findings confirmed that alginate/HA hydrogels encapsulating PDLSCs are a promising candidate for cartilage regeneration.

Dental and orofacial mesenchymal stem cells in craniofacial regeneration: The prosthodontist's point of view.

Of the available regenerative treatment options, craniofacial tissue regeneration using mesenchymal stem cells (MSCs) shows promise. The ability of stem cells to produce multiple specialized cell types along with their extensive distribution in many adult tissues have made them an attractive target for applications in tissue engineering. MSCs reside in a wide spectrum of postnatal tissue types and have been successfully isolated from orofacial tissues. These dental- or orofacial-derived MSCs possess self-renewal and multilineage differentiation capacities. The craniofacial system is composed of complex hard and soft tissues derived from sophisticated processes starting with embryonic development. Because of the complexity of the craniofacial tissues, the application of stem cells presents challenges in terms of the size, shape, and form of the engineered structures, the specialized final developed cells, and the modulation of timely blood supply while limiting inflammatory and immunological responses. The cell delivery vehicle has an important role in the in vivo performance of stem cells and could dictate the success of the regenerative therapy. Among the available hydrogel biomaterials for cell encapsulation, alginate-based hydrogels have shown promising results in biomedical applications. Alginate scaffolds encapsulating MSCs can provide a suitable microenvironment for cell viability and differentiation for tissue regeneration applications. This review aims to summarize current applications of dental-derived stem cell therapy and highlight the use of alginate-based hydrogels for applications in craniofacial tissue engineering.

Gingival Mesenchymal Stem Cell (GMSC) Delivery System Based on RGD-Coupled Alginate Hydrogel with Antimicrobial Properties: A Novel Treatment Modality for Peri-Implantitis.

PURPOSE: Peri-implantitis is one of the most common inflammatory complications in dental implantology. Similar to periodontitis, in peri-implantitis, destructive inflammatory changes take place in the tissues surrounding a dental implant. Bacterial flora at the failing implant sites resemble the pathogens in periodontal disease and consist of Gram-negative anaerobic bacteria including Aggregatibacter actinomycetemcomitans (Aa). Here we demonstrate the effectiveness of a silver lactate (SL)-containing RGD-coupled alginate hydrogel scaffold as a promising stem cell delivery vehicle with antimicrobial properties. MATERIALS AND METHODS: Gingival mesenchymal stem cells (GMSCs) or human bone marrow mesenchymal stem cells (hBMMSCs) were encapsulated in SL-loaded alginate hydrogel microspheres. Stem cell viability, proliferation, and osteo-differentiation capacity were analyzed. RESULTS: Our results showed that SL exhibited antimicrobial properties against Aa in a dose-dependent manner, with 0.50 mg/ml showing the greatest antimicrobial properties while still maintaining cell viability. At this concentration, SL-containing alginate hydrogel was able to inhibit Aa growth on the surface of Ti discs and significantly reduce the bacterial load in Aa suspensions. Silver ions were effectively released from the SL-loaded alginate microspheres for up to 2 weeks. Osteogenic differentiation of GMSCs and hBMMSCs encapsulated in the SL-loaded alginate microspheres were confirmed by the intense mineral matrix deposition and high expression of osteogenesis-related genes. CONCLUSION: Taken together, our findings confirm that GMSCs encapsulated in RGD-modified alginate hydrogel containing SL show promise for bone tissue engineering with antimicrobial properties against Aa bacteria in vitro.

Regulation of the Stem Cell-Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti-Inflammatory Drug.

The host immune system is known to influence mesenchymal stem cell (MSC)-mediated bone tissue regeneration. However, the therapeutic capacity of hydrogel biomaterial to modulate the interplay between MSCs and T-lymphocytes is unknown. Here it is shown that encapsulating hydrogel affects this interplay when used to encapsulate MSCs for implantation by hindering the penetration of pro-inflammatory cells and/or cytokines, leading to improved viability of the encapsulated MSCs. This combats the effects of the host pro-inflammatory T-lymphocyte-induced nuclear factor kappaB pathway, which can reduce MSC viability through the CASPASE-3 and CAS-PASE-8 associated proapoptotic cascade, resulting in the apoptosis of MSCs. To corroborate rescue of engrafted MSCs from the insult of the host immune system, the incorporation of the anti-inflammatory drug indomethacin into the encapsulating alginate hydrogel further regulates the local microenvironment and prevents pro-inflammatory cytokine-induced apoptosis. These findings suggest that the encapsulating hydrogel can regulate the MSC-host immune cell interplay and direct the fate of the implanted MSCs, leading to enhanced tissue regeneration.

Pluronic F-127 hydrogel as a promising scaffold for encapsulation of dental-derived mesenchymal stem cells.

Dental-derived mesenchymal stem cells (MSCs) provide an advantageous therapeutic option for tissue engineering due to their high accessibility and bioavailability. However, delivering MSCs to defect sites while maintaining a high MSC survival rate is still a critical challenge in MSC-mediated tissue regeneration. Here, we tested the osteogenic and adipogenic differentiation capacity of dental pulp stem cells (DPSCs) in a thermoreversible Pluronic F127 hydrogel scaffold encapsulation system in vitro. DPSCs were encapsulated in Pluronic (®) F-127 hydrogel and stem cell viability, proliferation and differentiation into adipogenic and osteogenic tissues were evaluated. The degradation profile and swelling kinetics of the hydrogel were also analyzed. Our results confirmed that Pluronic F-127 is a promising and non-toxic scaffold for encapsulation of DPSCs as well as control human bone marrow MSCs (hBMMSCs), yielding high stem cell viability and proliferation. Moreover, after 2 weeks of differentiation in vitro, DPSCs as well as hBMMSCs exhibited high levels of mRNA expression for osteogenic and adipogenic gene markers via PCR analysis. Our histochemical staining further confirmed the ability of Pluronic F-127 to direct the differentiation of these stem cells into osteogenic and adipogenic tissues. Furthermore, our results revealed that Pluronic F-127 has a dense tubular and reticular network morphology, which contributes to its high permeability and solubility, consistent with its high degradability in the tested conditions. Altogether, our findings demonstrate that Pluronic F-127 is a promising scaffold for encapsulation of DPSCs and can be considered for cell delivery purposes in tissue engineering.

Dental-derived stem cells in tissue engineering: the role of biomaterials and host response.

Dental-derived stem cells (DSCs) are attractive cell sources due to their easy access, superior growth capacity and low immunogenicity. They can respond to multiple extracellular matrix signals, which provide biophysical and biochemical cues to regulate the fate of residing cells. However, the direct transplantation of DSCs suffers from poor proliferation and differentiation toward functional cells and low survival rates due to local inflammation. Recently, elegant advances in the design of novel biomaterials have been made to give promise to the use of biomimetic biomaterials to regulate various cell behaviors, including proliferation, differentiation and migration. Biomaterials could be tailored with multiple functionalities, e.g., stimuli-responsiveness. There is an emerging need to summarize recent advances in engineered biomaterials-mediated delivery and therapy of DSCs and their potential applications. Herein, we outlined the design of biomaterials for supporting DSCs and the host response to the transplantation.

Effects of routine repetitive transcranial magnetic stimulation on the sleep duration of patients with treatment-resistant depression: A prospective cohort study.

Aim: The aim of this study was to evaluate the short-term and long-term effects of routine repetitive transcranial magnetic stimulation (rTMS) on the sleep duration, depressive symptoms, and quality of life of patients with treatment-resistant depression (TRD). Methods: In this prospective cohort study, 25 participants with TRD were assessed using the Insomnia Severity Index (ISI) and four sleep duration components of the Pittsburgh Sleep Quality Index (PSQI). Depression severity was measured with Hamilton's Depression Rating Scale (HDRS) and Beck's Depression Inventory (BDI-II), and patient-perceived quality of life with the 36-Item Short-Form Survey (SF-36). All of these measures were evaluated at baseline (T0), and immediately (T1), 6 weeks (T2), and 12 weeks (T3) after the end of intervention. Results: At T1 endpoint, HDRS, BDI, SF-36, ISI, and three PSQI items (time to wake up, time taken to fall asleep, and Real Sleep Time) significantly improved, though these gains were reduced at follow-up endpoints (T2 and T3). Adjusting for confounders (age, sex, occupational status, BMI, and hypnotic medication) revealed that only improvements in HDRS, BDI, and time taken to fall asleep at T1 remained statistically significant. Linear regression analyses showed no significant association between reduced time taken to fall asleep and depression symptoms, suggesting rTMS can independently enhance this parameter, irrespective of depression resolution. Conclusion: Routine rTMS therapy can potentially enhance sleep duration in TRD individuals, alongside improved depressive symptoms and quality of life. However, these benefits tend to decrease over long-term follow-up, emphasizing a more pronounced short-term efficacy of rTMS.

Precise Engineering of Growth Factor Presentation Using Extracellular Microenvironment-Mimicking Microfluidic Microparticles.

One of the main challenges in tissue engineering is finding a way to deliver specific growth factors (GFs) with precise spatiotemporal control over their presentation. Here, we report a novel strategy for generating microscale carriers with enhanced affinity for high content loading suitable for the sustained and localized delivery of GFs. Our developed microparticles can be injected locally and sustainably release encapsulated growth factors for up to 28 days. Fine-tuning of particles' size, affinity, microstructures, and release kinetics is achieved using a microfluidic system along with bioconjugation techniques. We also describe an innovative 3D micromixer platform to control the formation of core-shell particles based on superaffinity using a polymer-peptide conjugate for further tuning of release kinetics and delayed degradation. Chitosan shells block the burst release of encapsulated GFs and enable their sustained delivery for up to 10 days. The matched release profiles and degradation provide the local tissues with biomimetic, developmental-biologic-compatible signals to maximize regenerative effects. The versatility of this approach is verified using three different therapeutic proteins, including human bone morphogenetic protein-2 (rhBMP-2), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1α). As in vivo morphogenesis is typically driven by the combined action of several growth factors, the proposed technique can be developed to generate a library of GF-loaded particles with designated release profiles.

Properties of a proline-containing glass ionomer dental cement.

STATEMENT OF PROBLEM: Proline-containing glass ionomers are promising fast-set dental restorative materials with superior mechanical properties; however, little information is available on other physical properties of this type of glass ionomer. PURPOSE: The objectives of this study were to synthesize and characterize a polyacrylic acid terpolymer containing proline derivative (PD) and to investigate the physical properties of this glass ionomer cement (GIC) and its cytotoxicity in vitro. MATERIAL AND METHODS: A terpolymer of AA (acrylic acid), IA (itaconic acid), and proline derivative (MP) with an 8:1:1 molar ratio was synthesized and characterized. Experimental GIC specimens were made from the synthetized terpolymer with Fuji IX (GC America, Alsip, Ill) commercial glass ionomer powder as recommended by the manufacturer. Specimens were mixed and fabricated at room temperature and were conditioned in distilled water at 37°C for 1 day and 1 week. Vickers hardness was determined with a microhardness tester. The water sorption characteristics and fluoride releasing properties of the specimens were investigated. The in vitro cytotoxicity of the experimental glass ionomer was assessed by evaluating the C2C12 cell metabolism with methyltetrazolium (MTT) assay. Commercial Fuji IX was used as a control for comparison. The data obtained for the experimental GIC (PD) were compared with the control group by using 1- and 2-way ANOVA and the Tukey multiple range test at α=.05. RESULTS: Proline-modified GIC (PD) exhibited significantly higher surface hardness values (Vickers hardness number [VHN] 58 ±6.1) in comparison to Fuji IX GIC (VHN 47 ±5.3) after 1 week of maturation. Statistical analysis of data showed that the water sorption properties of the experimental cement (PD) were significantly greater than those of the control group (P<.05). The experimental GIC showed a significant increase in the amounts of initial fluoride release (P<.05) with continued fluoride release from the bulk of the material. The experimental group showed slightly reduced cell metabolism and cell number in comparison to the control group. However, the results were not statistically different (P>.05). CONCLUSIONS: An amino acid-containing GIC had better surface hardness properties than commercial Fuji IX GIC. This formulation of fast-set glass ionomer showed increased water sorption without adversely affecting the amount of fluoride release. Considering its biocompatibility, this material shows promise not only as a dental restorative material but also as a bone cement with low cytotoxicity.