Oligonucleotide therapeutics hold transformative potential, yet their clinical translation is hindered by delivery barriers, including rapid renal/hepatic clearance and poor organ specificity. Bottlebrush polymers conjugates have emerged as a promising vector to address these limitations, but conventional architectures with uniform backbones can only achieve an unmodifiable, rigid biodistribution profile. Here, we report a library of sequence-defined "digital" bottlebrush polymers, precisely engineered with controlled placements of chemical motifs that modify physiochemical properties - including lipids, cholesterol, and cationic groups - along a polyphosphodiester backbone. Systematic evaluation of the digital bottlebrush polymer library reveals distinct structure-property relationships and enables organ-biased systemic delivery to several traditionally difficult-to-reach tissues, including muscle and skin. In a mouse model of rheumatoid arthritis, a single dose of a spleen-homing polymer-conjugated antisense oligonucleotide targeting TNF-α achieves potent knockdown and drives full functional recovery. These findings establish a versatile design framework for tailoring bottlebrush polymers to specific therapeutic applications.

The overexpression of receptor tyrosine kinase AXL receptor tyrosine kinase (AXL) is linked to acquired drug resistance in cancer treatments. Aptamers, acting as antibody surrogates, have been envisioned as potential inhibitors for AXL. However, aptamers face difficult pharmacological challenges including rapid degradation and clearance. Herein, a phosphodiester-backboned bottlebrush polymer is reported as a carrier for conjugated aptamers. Termed polymer-augmented conjugates of DNA (pacDNA), the conjugate improves aptamer specificity in vivo, prolongs blood retention, and enhances overall aptamer bioactivity. Treatment with pacDNA in AXL-overexpressing cell lines significantly inhibits AXL phosphorylation, resulting in reduced cancer cell migration and invasion. In a non-small cell lung cancer xenograft model (NCI-H1299), pacDNA treatment leads to single-agent reduction in tumor growth. These results highlight the potential of bottlebrush polymers in the field of aptamer therapeutics.

This study investigates the effect of TiC particles regarding the properties of aluminium-lithium alloys under high-temperature conditions, focusing on the reinforcing effect of TiC and TiB2 particles in the aluminium matrix and the effect on the coarsening process of T1 precipitates. Aluminium-lithium alloys are widely used in aerospace applications, especially as skin materials for fast vehicles, due to their excellent high specific strength and corrosion resistance. However, conventional aluminium alloys are inadequate in meeting the elevated temperature service requirements associated with supersonic flight. Consequently, there is a significant scientific imperative to investigate the heat resistance of novel aluminium-lithium alloys. The inclusion of TiC and TiB2 nanoparticles has been demonstrated to enhance the mechanical properties of the alloys, particularly at high temperatures of 200 °C. These particles have been shown to enhance the strength and toughness of the alloy through mechanisms such as grain refinement and increased dislocation density. Concurrently, this study determined that the coarsening phenomenon of T1 precipitates occurs at elevated temperatures. The inclusion of TiC particles, however, has been shown to inhibit the coarsening process, delay the coarsening of the T1 phase, and enhance the mechanical properties of the material. This outcome is of considerable significance for the composition design of aluminium-lithium alloys and their performance optimisation in high-temperature applications.

The poor prognosis of hepatocellular carcinoma (HCC) is mainly due to its high metastatic properties. Hence, metastasis inhibition might provide a reliable strategy for HCC treatment. As its pivotal role in the tumor cell proliferation, survival and metastasis, a disintegrin and metalloproteinase 17 (ADAM17) has become an attractive target for cancer therapy. Nevertheless, the role of ADAM17 in HCC metastasis and its underlying mechanisms remain enigmatic. In the present study, we discovered a novel ADAM17 inhibitor FLF-15, with an IC50 value of 10.43 nM. Further mechanistic studies showed that FLF-15 inhibits HCC migration and invasion in vitro and in vivo mainly by reducing interleukin-6 receptor (IL-6R) shedding, which inhibits IL-6 trans-signaling, while also leading to a reduction in IL-6 levels and downregulation of IL-6 classic-signaling. Furthermore, we revealed an overlapping but distinct biological effects of IL-6 classic and trans-signaling in HCC. Specifically, JAK2/STAT3 and ERK1/2 signaling can be stimulated by both IL-6 classic and trans-signaling pathway. However, AKT appears to be only activated by IL-6 trans-signaling pathway, suggesting its essential role for FLF-15 induced metastasis suppression in HCC. Taken together, our study identified FLF-15 as a novel ADAM17 inhibitor and elucidated its underlying mechanism of HCC metastasis suppression. These findings indicated FLF-15 might be a promising candidate for the development of HCC therapeutic agents.

The clinical translation of oligonucleotide-based therapeutics continues to encounter challenges in delivery. In this study, we introduce a novel class of delivery vehicles for oligonucleotides that are based on poly(ethylene glycol) (PEG) bottlebrush polymers with sequence-defined backbones. Using solid-phase synthesis and bespoke phosphoramidites, the oligonucleotide and the polymer backbone can be assembled on the solid support. The synthesis allows chemical modifiers such as carbon 18 (C18) units to be incorporated into the backbone in specific patterns to modulate the cell-material interactions. Subsequently, PEG side chains were grafted onto the polymer segment of the resulting polymer-oligonucleotide conjugate, yielding bottlebrush polymers. We report an optimal pattern of the C18 modifier that leads to improved cellular uptake, plasma pharmacokinetics, biodistribution, and antisense activity in vivo. Our results provide valuable insights into the structure-property relationship of polymer-oligonucleotide conjugates and suggest the possibility of tuning the polymer backbone to meet the specific delivery requirements of various diseases.

The overexpression of receptor tyrosine kinase AXL is linked to acquired drug resistance in cancer treatments. Aptamers, acting as antibody surrogates, have been envisioned as potential inhibitors for AXL. However, aptamers face difficult pharmacological challenges including rapid degradation and clearance. Herein, we report a phosphodiester-backboned bottlebrush polymer as a carrier for conjugated aptamers. Termed pacDNA, the conjugate improves aptamer specificity in vivo, prolongs blood retention, and enhances overall aptamer bioactivity. Treatment with pacDNA in AXL-overexpressing cell lines significantly inhibits AXL phosphorylation, resulting in reduced cancer cell migration and invasion. In a non-small cell lung cancer xenograft model (NCI-H1299), pacDNA treatment leads to single-agent reduction in tumor growth. These results highlight the potential of bottlebrush polymers in the field of aptamer therapeutics. ### Competing Interest Statement The authors have declared no competing interest.

Spinal cord injury (SCI) can lead to serious functional disorders, which have serious impacts on patients and society. The current traditional treatments of SCI are not effective the injured spinal cord is difficult to repair and regenerate. In recent years, stem cell transplantation for the treatment of SCI has been a hot research topic. Dental pulp stem cells have strong abilities of self-renewal and multi-directional differentiation, and have been applied for tissue engineering and regenerative medicine. And dental pulp stem cells have certain advantages in neuro-regenetation, bringing new hope to biotherapy for SCI. This article reviews the characteristics of dental pulp stem cells and their research progress in the treatment of SCI.

Oligonucleotide therapeutics have the unique ability to address traditionally undruggable targets through various target engagement pathways. However, despite advances in chemically modified oligonucleotides and carrier-assisted delivery systems such as lipid nanoparticles and protein/peptide conjugates, the development of oligonucleotide drugs is still plagued with lackluster potency, narrow therapeutic window, poor delivery to non-liver target sites, and/or high potential for toxicity and unwanted immune system activation. In this perspective, we discuss an unconventional delivery solution based upon bottlebrush polymers, which overcomes many key challenges in oligonucleotide drug development. We address the molecular basis of the polymer's ability to enhance tissue bioavailability and drug potency, reduce side effects, and suppress anti-carrier immunity. Furthermore, we discuss the potential of the technology in advancing oligonucleotide-based therapies for non-liver targets.

Aptamers face challenges for use outside the ideal conditions in which they are developed. These difficulties are most palpable in vivo due to nuclease activities, rapid clearance, and off-target binding. Herein, we demonstrate that a polyphosphodiester-backboned molecular brush can suppress enzymatic digestion, reduce non-specific cell uptake, enable long blood circulation, and rescue the bioactivity of a conjugated aptamer in vivo. The backbone along with the aptamer is assembled via solid-phase synthesis, followed by installation of poly(ethylene glycol) (PEG) side chains using a two-step process with near-quantitative efficiency. The synthesis allows for precise control over polymer size and architecture. Consisting entirely of building blocks that are generally recognized as safe for therapeutics, this novel molecular brush is expected to provide a highly translatable route for aptamer-based therapeutics.

Journal of Dental EducationVolume 86, Issue S1 p. 808-811 ADVANCING THROUGH INNOVATION Student perspectives and feedback on dental licensure by nonpatient-based alternative examination Natalie Inoue DDS, Natalie Inoue DDS orcid.org/0000-0002-2917-7593 Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USASearch for more papers by this authorJiachen Lin DMD, Jiachen Lin DMD orcid.org/0000-0002-5911-4235 Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USASearch for more papers by this authorEmily Chen DMD, Emily Chen DMD University of North Carolina at Chapel Hill Adams School of DentistrySearch for more papers by this authorHiroe Ohyama DDS, MMSc, PhD, DMD, Corresponding Author Hiroe Ohyama DDS, MMSc, PhD, DMD [email protected] orcid.org/0000-0002-3599-1671 Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USA Correspondence Hiroe Ohyama, DDS, MMSc, PhD, DMD, Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. Email: [email protected]Search for more papers by this author Natalie Inoue DDS, Natalie Inoue DDS orcid.org/0000-0002-2917-7593 Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USASearch for more papers by this authorJiachen Lin DMD, Jiachen Lin DMD orcid.org/0000-0002-5911-4235 Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USASearch for more papers by this authorEmily Chen DMD, Emily Chen DMD University of North Carolina at Chapel Hill Adams School of DentistrySearch for more papers by this authorHiroe Ohyama DDS, MMSc, PhD, DMD, Corresponding Author Hiroe Ohyama DDS, MMSc, PhD, DMD [email protected] orcid.org/0000-0002-3599-1671 Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USA Correspondence Hiroe Ohyama, DDS, MMSc, PhD, DMD, Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. Email: [email protected]Search for more papers by this author First published: 17 December 2021 https://doi.org/10.1002/jdd.12851Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1Iyer P, Aziz K, Ojcius DM. Impact of COVID-19 on dental education in the United States. J Dent Educ. 2020; 84(6): 718-722. https://doi.org/10.1002/jdd.12163 2The Commission on Dental Competency Assessments. ADEX approves CompeDontTM non-patient based exam alternative. 2020. Accessed August 31, 2021. https://www.cdcaexams.org/adex-approves-compedont/ 3 American Board of Dental Examiners (ADEX). 2021 ADEX acceptance maps. Accessed August 31, 2021. https://www.cdcaexams.org/adex-acceptance-map/ 4Chu TG, Makhoul NM, Silva DR, Gonzales TS, Letra A, Mays KA. Should live patient licensing examinations in dentistry be discontinued? Two viewpoints: viewpoint 1: alternative assessment models are not yet viable replacements for live patients in clinical licensure exams and viewpoint 2: ethical and patient care concerns about live patient exams require full acceptance of justifiable alternatives. J Dent Educ. 2018; 82(3): 246-251. https://doi.org/10.21815/JDE.018.023 5Scarbrough AR. Ethics of using live patients for licensing board examinations. J Am Dent Assoc. 2018; 149(2): 163-164. https://doi.org/10.1016/j.adaj.2017.11.028 Volume86, IssueS1Supplement: Advancing Through InnovationJune 2022Pages 808-811 ReferencesRelatedInformation

Journal of Dental EducationVolume 86, Issue S1 p. 769-771 ISSUE INFORMATIONFree Access Journal of Dental Education Volume 86 Number S1/June 2022 First published: 24 June 2022 https://doi.org/10.1002/jdd.12690AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Volume86, IssueS1Supplement: Advancing Through InnovationJune 2022Pages 769-771 RelatedInformation

Purpose: To determine the wait time for dental treatment under general anesthesia (GA) and its impact on clinical outcomes in a pediatric population at federally qualified health centers in the United States. Methods: Data were collected from 566 pediatric subjects who underwent dental rehabilitation under GA between July 1, 2013, and June 30, 2014. One-way analysis of variance and linear regression analyses were performed. Results: Patients waited 110.6 days (±standard deviation: 103.9 days) between the initial and treatment visits. Regression analysis demonstrated that prolonged wait time was a significant predictor for an increased number of preoperative visits and more teeth treated than planned. Among the 25.1 percent of patients who returned for follow-up after surgery, 18.6 percent presented with pain, swelling, or broken/ displaced restorations. The Canadian diagnostic code system was associated with the American Society of Anesthesiologists classification system (P <0.001) and was not coincident with wait time. Conclusion: Longer wait time was associated with continuous pain, more teeth treated than planned, and more frequent pre- and post-operative visits. Wait time was predictive of a higher number of preoperative visits. Initial visit pain, and extra- and intra-oral swelling were associated with the Canadian diagnostic system.

Front Cover: The cover image is based on the Research Article TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease by Weisheng Chen et al., https://doi.org/10.1002/humu.23907. Cover image © Nan Wu Images.

Objective The aim of this study is to isolate and identify the pancreatic stem cells from the pancreas of neonatal rats.Methods The pancreatic tissue was collected from neonatal rats in aseptic environment,and then digested with 5.5 mg/ml collagenase Ⅳ.The organoid cultured in RPMI 1640 medium supplemented with 10％fetal bovine serum (FBS).Differential centrifugation method was carried out to isolate the epithelial cell and fibroblast.The epithelial cells were purified for several times.The 4th-generation cells were then induced to differentiate into β islet cells,and stained with immunofluorescent signal.High concentration of glucose was applied to induce insulin secretion.Results The pancreatic stem cells in the pancreas of the neonatal rats possessed high proliferative rate and can be applied for continuous passage.Immunofluorescence staining of the4th-generation cells showed positive Pancreatic duodenal homeobox-1 (PDX-1),Nestin,neurogenin3 (NGN3),Vimentin,insulin and C-peptide which were pancreatic stem/progenitor cell specific proteins;after inducing to differentiation,the cells displayed positive with Dithizone staining,while immunohistochemistry test showed cells were PDX-1 and C-peptide positive;for glucose stimulation assay,insulin secretion of induced ICCs [(30.0 ± 11.5) pIU/ml] was significantly higher than that of non-induced ICCs [(5.3 ± 1.5) pIU/ml,P =0.035).Conclusion The isolated pancreas cells were pancreas stem cells.

骨骼发育不良(SD)是一组以全身骨骼生长发育障碍为特征的遗传性骨骼系统疾病,其临床表型具有多样性和复杂性.分子诊断技术可帮助临床医师明确疾病的类型、病因和转归.全外显子组测序(WES)目前作为基因组学中被广泛应用的技术,在SD的致病突变和发病机制研究中取得了显著成果.本文就近3年来应用WES在SD领域的分子遗传学研究进展进行综述.

The present study examined dispositional hope as a potential mediator of the association between sexual assault and negative affective conditions, namely, depressive and anxious symptoms in a sample of 223 female college students. Results from conducting bootstrapped mediation analyses indicated that hope agency, but not hope pathways, mediated the link between sexual assault victimization and negative affective conditions in females. Importantly, the associations of sexual assault with both depressive and anxious symptoms remained highly significant independent of hope. Some implications of the present findings are discussed.

In the present study, we examined the relations between perfectionism and spirituality in a sample of college students. Results of correlational analyses were generally consistent with the notion that adaptive perfectionism dimensions (e.g., personal standards 82 organization) were positively associated with spirituality, whereas maladaptive perfectionism dimensions (e.g., concern over mistakes, parental criticism) were negatively associated with spirituality. Furthermore, results of conducting regression analyses provided support for perfectionism dimensions as unique predictors of different dimensions of spirituality. Interestingly, we found parental expectations to be a positive and unique predictor for all three dimensions of spirituality. Some implications on the importance of the present findings for future research on perfectionism and spirituality in adults are discussed. (c) 2015 Elsevier Ltd. All rights reserved.

This study examined the role of hope in understanding the link between loneliness and negative affective conditions (viz., anxiety and depressive symptoms) in a sample of 318 adults. As expected, loneliness was found to be a significant predictor of both anxiety and depressive symptoms. Noteworthy, hope was found to significantly augment the prediction of depressive symptoms, even after accounting for loneliness. Furthermore, we found evidence for a significant Loneliness × Hope interaction effect in predicting anxiety. A plot of the interaction confirmed that the association between loneliness and anxiety was weaker among high, compared to low, hope adults. Some implications of the present findings are discussed.