Spatial Multi-omics Reveals the Role of the Wnt Modulator, Dkk2, in Palatogenesis'.

Multiple genetic and environmental etiologies contribute to the pathogenesis of cleft palate, which is the most common of the inherited disorders of the craniofacial complex. Insights into the molecular mechanisms regulating osteogenic differentiation and patterning in the palate during embryogenesis are limited and needed for the development of innovative diagnostics and cures. This study used the Pax9-/- mouse model with a consistent phenotype of cleft secondary palate to investigate the role of Pax9 in the process of palatal osteogenesis. Although prior research has identified the upregulation of Wnt pathway modulators Dkk1 and Dkk2 in Pax9-/- palate mesenchyme, limitations of spatial resolution and technology restricted a more robust analysis. Here, data from single-nucleus transcriptomics and chromatin accessibility assays validated by in situ highly multiplex targeted single-cell spatial profiling technology suggest a distinct relationship between Pax9+ and osteogenic populations. Loss of Pax9 results in spatially restricted osteogenic domains bounded by Dkk2, which normally interfaces with Pax9 in the mesenchyme. Moreover, the loss of Pax9 leads to a disruption in the normal osteodifferentiaion of palatal osteogenic mesenchymal cells. These results suggest that Pax9-dependent Wnt signaling modulators influence osteogenic programming during palate formation, potentially contributing to the observed cleft palate phenotype.

Harold C. Slavkin: A Transformative Leader of Our Times.

Harold (Hal) C. Slavkin, DDS, the 22nd president of the American Association for Dental, Oral, and Craniofacial Research (1993 to 1994), died on December 22, 2023. During a career that spanned almost 6 decades, Hal distinguished himself as an international authority on craniofacial biology and an advocate for oral health equity. He served as dean of the University of Southern California's dental school, founded the school's Center for Craniofacial Molecular Biology, created the nation's first PhD program in craniofacial biology, and served as the sixth director of the National Institute of Dental and Craniofacial Research. Hal's studies of the molecular and cellular underpinnings of craniofacial malformations prepared him to champion translational research later in his career, when his work with patient advocates revealed the importance of applying new discoveries to clinical practice. A visionary thinker, skilled administrator, progressive educator, compelling communicator, researcher, scholar, and mentor, Hal was known as a Renaissance leader. He rejoiced in fostering collaborative synergies among people and organizations. Throughout his life, family was his central grounding force. He and his wife, Lois, advanced a wide range of social and community initiatives and took great pride in their children, grandchildren, and great-grandchildren. We remember Hal for his indelible spirit, unflappable enthusiasm for science, fierce advocacy for social justice, and infectious zest for life. Here, we outline his multidimensional accomplishments through the lenses of academia, government, and nonprofit organizations. Although it is with heavy hearts that we bid goodbye to this remarkable man, our spirits are lightened by the many gifts he left behind.

Geroscience: Aging and Oral Health Research.

Research in aging has significantly advanced; scientists are now able to identify interventions that slow the biologic aging processes (i.e., the "hallmarks of aging"), thus delaying the onset and progression of multiple diseases, including oral conditions. Presentations given during the 3-part session "Geroscience: Aging and Oral Health Research," held during the 2023 American Association for Dental, Oral, and Craniofacial Research meeting, are summarized in this publication. Speakers' topics spanned the translational research spectrum. Session 1 provided an overview of the geroscience and health span (disease-free and functional health throughout life) concepts. The common molecular mechanisms between oral cancer and aging were discussed, and research was presented that showed periodontal microflora as a potential factor in Alzheimer's disease progression. Session 2 focused on behavioral and social science aspects of aging and their oral health significance. The keynote provided evidence that loneliness and isolation can have major health effects. These social conditions, along with poor oral health, tooth loss, and cognitive decline, could potentially affect healthy eating ability and systemic health in older adults. Research could help elucidate the directions and pathways connecting these seemingly disparate conditions. Session 3 focused on the delivery of oral care in different settings and the many barriers to access care faced by older adults. Research is needed to identify and implement effective technology and strategies to improve access to dental care, including new delivery and financing mechanisms, workforce models, interprofessional provider education and practice, and use of big data from medical-dental integration of electronic health records. Research to improve the "oral health span," reduce oral health disparities, and increase health equity must be tackled at all levels from biologic pathways to social determinants of health and health policies.

The Influence of the Synthesis Method on the Characteristics of BaTiO3.

In this work, barium titanate powders were produced by sol-gel and sol-precipitation methods from metal alkoxides. In the sol-gel method, tetraisopropyl orthotitanate was mixed with 2-propanol, acetic acid and barium acetate, and the gel samples obtained were calcined at 600 °C, 800 °C and 1000 °C. Through the sol-precipitation method, tetraisopropyl orthotitanate was mixed with acetic acid and deionized water and precipitated by the addition of a concentrated solution of KOH. The products were calcined at various temperatures, and the microstructural and dielectric properties of the BaTiO3 prepared for the two processes were analyzed and compared. The results of these analyses allowed us to observe an increase in the tetragonal phase and the dielectric constant (15-50 at 20 kHz) with increasing temperatures in the samples produced by the sol-gel method, while the sample obtained by sol precipitation was cubic. The presence of BaCO3 is more evident in the sample produced by sol-precipitation, and the band gap of the products obtained did not show significant variation, changing the synthesis method (3.363-3.594 eV).

Translating Science into Improved Health for All.

Our world is at a turning point with biological and social pathogens wreaking havoc at the same time that science and technology are exploding with new discoveries. It is a pivotal time for the new report Oral Health in America: Advances and Challenges to be released and a pivotal time for our profession to take action and lead. The art, science, and practice of dentistry is very different from 20 y ago when the original Surgeon General's report was released. We are on the precipice of individualized health care where providers will collaborate to deliver diagnostics and therapeutics that are data driven and inclusive of the social determinants of health. To move forward with alacrity requires a strong scientific foundation, effective educational approaches, an understanding of the upstream determinants of health, and partnerships across the health professions and beyond. Oral health has never been more important, and now is the time for our profession to further develop, elevate, and translate the science into practice and policy to improve the nation's health.

Molecular Diagnostics and In Utero Therapeutics for Orofacial Clefts.

Orofacial clefts and their management impose a substantial burden on patients, on their families, and on the health system. Under the current standard of care, affected patients are subjected to a lifelong journey of corrective surgeries and multidisciplinary management to replace bone and soft tissues, as well as restore esthetics and physiologic functions while restoring self-esteem and psychological health. Hence, a better understanding of the dynamic interplay of molecular signaling pathways at critical phases of palate development is necessary to pioneer novel prenatal interventions. Such pathways include transforming growth factor-ß (Tgfß), sonic hedgehog (Shh), wingless-integrated site (Wnt)/ß-catenin, bone morphogenetic protein (Bmp), and fibroblast growth factor (Fgf) and its associated receptors, among others. Here, we summarize commonly used surgical methods used to correct cleft defects postnatally. We also review the advances made in prenatal diagnostics of clefts through imaging and genomics and the various in utero surgical corrections that have been attempted thus far. An overview of how key mediators of signaling that drive palatogenesis are emphasized in the context of the framework and rationale for the development and testing of therapeutics in animal model systems and in humans is provided. The pros and cons of in utero therapies that can potentially restore molecular homeostasis needed for the proper growth and fusion of palatal shelves are presented. The theme advanced throughout this review is the need to develop preclinical molecular therapies that could ultimately be translated into human trials that can correct orofacial clefts at earlier stages of development.

Gender Inequalities in the Dental Workforce: Global Perspectives.

The aim of this review is to investigate the growth of diversity and inclusion in global academic dental research with a focus on gender equality. A diverse range of research methodologies were used to conduct this review, including an extensive review of the literature, engagement of key informants in dental academic leadership positions around the world, and review of current data from a variety of national and international organizations. Results provide evidence of gender inequalities that currently persist in dental academics and research. Although the gender gap among graduating dental students in North America and the two most populous countries in Europe (the United Kingdom and France) has been narrowed, women make up 30% to 40% of registered dentists in countries throughout Europe, Oceania, Asia, and Africa. In academic dentistry around the globe, greater gender inequality was found to correlate with higher ranking academic and leadership positions in the United States, United Kingdom, several countries in European Union, Japan, and Saudi Arabia. Further disparities are noted in the dental research sector, where women make up 33% of dental researchers in the European Union, 35% in North America, 55% in Brazil, and 25% in Japan. Family and societal pressures, limited access to research funding, and lack of mentoring and leadership training opportunities are reported as also contributing to gender inequalities. To continue advancing gender equality in dental academia and research, efforts should be geared toward the collection and public dissemination of data on gender-specific distributions. Such evidence-driven information will guide the selection of future strategies and best practices for promoting gender equity in the dental workforce, which provides a major pipeline of researchers and scholars for the dental profession.

Empowering Women Researchers in the New Century: IADR's Strategic Direction.

Gender inequality in science, medicine, and dentistry remains a central concern for the biomedical research workforce today. Although progress in areas of inclusivity and gender diversity was reported, growth has been slow. Women still face multiple challenges in reaching higher ranks and leadership positions while maintaining holistic success in these fields. Within dental research and academia, we might observe trends toward a more balanced pipeline. However, women continue to face barriers in seeking leadership roles and achieving economic equity and scholarship recognition. In an effort to evaluate the status of women in dental research and academia, the authors examined the role of the International Association for Dental Research (IADR), a global research organization, which has improved awareness on gender inequality. The goal of this article is to review five crucial issues of gender inequality in oral health research and academics-workforce pipeline, economic inequality, workplace harassment, gender bias in scholarly productivity, and work-life balance-and to discuss proactive steps that the IADR has taken to promote gender equality. Providing networking and training opportunities through effective mentoring and coaching for women researchers, the IADR has developed a robust pipeline of women leaders while promoting gender equality for women in dental academia through a culture shift. As knowledge gaps remained on the levels of conscious and unconscious bias and sexist culture affecting women advancement in academics, as well as the intersectionality of gender with race, gender identity, ability status, sexual orientation, and cultural backgrounds, the IADR has recognized that further research is warranted.

Bioactive injectable aggregates with nanofibrous microspheres and human dental pulp stem cells: A translational strategy in dental endodontics.

Regeneration of the pulp-dentin complex with stem cells is a potential alternative to conventional root canal treatments. Human dental pulp stem cells (hDPSCs) have been extensively studied because of their ability to proliferate and differentiate into mineralized dental and non-dental tissues. Here we combined hDPSCs with two types of injectable poly-l-lactic acid (PLLA) microsphere with a nanofibrous or smooth surface to form bioactive injectable aggregates, and examined their ability to promote pulp regeneration in the root canal in an in vivo model. We investigated the biocompatibility, biosafety and odontogenic potential of fibrous (F-BIM) and smooth bioactive injectable microspheres (S-BIM) in vitro and in vivo. Our results demonstrated that PLLA microspheres and hDPSCs were able to form bioactive injectable aggregates that promoted dentin regeneration in both in vitro and in vivo models. Our results suggest that F-BIM and S-BIM may induce dentinogenesis upon in vivo grafting, and propose that the potential usefulness of the microsphere-hDPSC aggregates described here should be evaluated in clinical settings. Copyright © 2017 John Wiley & Sons, Ltd.

Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice.

To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9-/- mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9-/- embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/Edar pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and Edar-related genes are expressed in normal palatal tissues and that the Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/Edar signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex.

Our Essential and Endangered Dentist-Scientist Workforce.

Future advances in dental medicine rely on a robust and stable pipeline of dentist-scientists who are dedicated to research inspired by the patients' condition. The biomedical research community faces external and internal pressures that have been building over years. This is now threatening the current and future status of basic, translational and patient-oriented research by dentist-scientists who study dental, oral and craniofacial diseases, population sciences, and prevention. The dental academic, research and practicing communities can no longer ignore the warning signs of a system that is under considerable stress. Here, the authors report findings of the Physician-Scientist Workforce Working Group, charged by the National Institutes of Health (NIH) Director, to perform quantitative and qualitative analyses on dentist-scientists by addressing the size, composition and activities of the group, relative to other health professions. From 1999 to 2012, trends in the numbers of grant applications and awards to dentist-scientists point to an overall decline. Disturbing are the low numbers of new investigators who apply for Early Career NIH Programs. While more seasoned dentist researchers enjoy greater success, the average age of first-time funded dentists is 52.7 y for females and 54.6 y for males, with a relatively low number of applications submitted and funded. These new data led the panel to stress the need to expand the capacity of the dentist-scientist workforce to leverage technologies and research opportunities that benefit the profession at-large. Suggestions were made to invest in developing clinical research faculty, including those with foreign degrees, through new training mechanisms. The creation of new alliances between national organizations like the American Association for Dental Research, the American Dental Education Association and the American Dental Association will undoubtedly lead to bold and concerted actions that must be pursued with a sense of urgency. A more supportive culture within dental schools and universities for dentist-scientists is needed, as their success is critical to the future career choices of their mentees. Knowledge Transfer Statement: Advances in dental medicine rely on a pipeline of dentist-scientists who are dedicated to research inspired by the patients' condition. Despite the recent advancement in technology and innovation, the dental community can no longer ignore the various pressures that threaten the future of the dentist-scientist profession. Here, the authors report findings of the Physician-Scientist Workforce Working Group of NIH that were published in 2014, and draw attention to the key issues threatening the NIH-funded pool of dentist-scientists.

Ex Vivo Modeling of Multidomain Peptide Hydrogels with Intact Dental Pulp.

Preservation of a vital dental pulp is a central goal of restorative dentistry. Currently, there is significant interest in the development of tissue engineering scaffolds that can serve as biocompatible and bioactive pulp-capping materials, driving dentin bridge formation without causing cytotoxic effects. Our earlier in vitro studies described the biocompatibility of multidomain peptide (MDP) hydrogel scaffolds with dental pulp-derived cells but were limited in their ability to model contact with intact 3-dimensional pulp tissues. Here, we utilize an established ex vivo mandible organ culture model to model these complex interactions. MDP hydrogel scaffolds were injected either at the interface of the odontoblasts and the dentin or into the pulp core of mandible slices and subsequently cultured for up to 10 d. Histology reveals minimal disruption of tissue architecture adjacent to MDP scaffolds injected into the pulp core or odontoblast space. Additionally, the odontoblast layer is structurally preserved in apposition to the MDP scaffold, despite being separated from the dentin. Alizarin red staining suggests mineralization at the periphery of MDP scaffolds injected into the odontoblast space. Immunohistochemistry reveals deposition of dentin sialophosphoprotein by odontoblasts into the adjacent MDP hydrogel, indicating continued functionality. In contrast, no mineralization or dentin sialophosphoprotein deposition is evident around MDP scaffolds injected into the pulp core. Collagen III expression is seen in apposition to gels at all experimental time points. Matrix metalloproteinase 2 expression is observed associated with centrally injected MDP scaffolds at early time points, indicating proteolytic digestion of scaffolds. Thus, MDP scaffolds delivered centrally and peripherally within whole dental pulp tissue are shown to be biocompatible, preserving local tissue architecture. Additionally, odontoblast function and pulp vitality are sustained when MDP scaffolds are intercalated between dentin and the odontoblast region, a finding that has significant implications when considering these materials as pulp-capping agents.