A Systematic Review on Participant Diversity in Clinical Trials-Have We Made Progress for the Management of Obesity and Its Metabolic Sequelae in Diet, Drug, and Surgical Trials.

OBJECTIVE: Individuals from Black and Hispanic backgrounds represent a minority of the overall US population, yet are the populations most affected by the disease of obesity and its comorbid conditions. Black and Hispanic individuals remain underrepresented among participants in obesity clinical trials, despite the mandate by the National Institutes of Health (NIH) Revitalization Act of 1993. This systematic review evaluates the racial, ethnic, and gender diversity of clinical trials focused on obesity at a national level. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of clinicaltrials.gov, PubMed, Cochrane Central, and Web of Science was undertaken to locate phase 3 and phase 4 clinical trials on the topic of obesity that met associated inclusion/exclusion criteria. Ultimately, 18 studies were included for review. RESULTS: White non-Hispanic individuals represented the majority of clinical trial participants, as did females. No study classified participants by gender identity. Reporting of race/ethnicity was not uniform, with noted variability among racial/ethnic subgroups. CONCLUSIONS: Our findings suggest that disparities remain in the diverse racial, ethnic, and gender representation of participants engaged in clinical trials on obesity relative to the prevalence of obesity in underrepresented populations. Commitment to inclusive and intentional recruiting practices is needed to increase the representation of underrepresented groups, thus increasing the generalizability of future research.

Domestic cat embryos reveal unique transcriptomes of developing incisor, canine, and premolar teeth.

Division of the dentition into morphologically distinct classes of teeth (incisors, canines, premolars, and molars) and the acquisition of tribosphenic molars facilitated precise occlusion between the teeth early in mammal evolution. Despite the evolutionary and ecological importance of distinct classes of teeth with unique cusp, crest, and basin morphologies, relatively little is known about the genetic basis for the development of different tooth classes within the embryo. Here we investigated genetic differences between developing deciduous incisor, canine, and premolar teeth in the domestic cat (Felis catus), which we propose to be a new model for tooth development. We examined differences in both developmental timing and crown morphology between the three tooth classes. Using RNA sequencing of early bell stage tooth germs, we showed that each of the three deciduous tooth classes possess a unique transcriptional profile. Three notable groups of genes emerged from our differential expression analysis; genes involved in the extracellular matrix (ECM), Wnt pathway signaling, and members of multiple homeobox gene families (Lhx, Dlx, Alx, and Nkx). Our results suggest that ECM genes may play a previously under-appreciated role in shaping the surface of the tooth crown during development. Differential regulation of these genes likely underlies differences in tooth crown shape and size, although subtle temporal differences in development between the tooth germs could also be responsible. This study provides foundational data for future experiments to examine the function of these candidate genes in tooth development to directly test their potential effects on crown morphology.

Single cell transcriptomic analysis of external genitalia reveals complex and sexually dimorphic cell populations in the early genital tubercle.

External genital organs are among the most recognizable sexually dimorphic characters. The penis and clitoris develop from the embryonic genital tubercle, an outgrowth at the anterior margin of the cloaca that undergoes an extensive period of development in male and female embryos prior to the onset of sexual differentiation. In mice, differentiation into the penis and clitoris begins around embryonic day (E)15.5. Current knowledge of cell types that comprise the genital tubercle is limited to a few studies that have fate mapped derivatives of endoderm, mesoderm, and ectoderm. Here we use single cell transcriptomics to characterize the cell populations in the genital tubercles of male and female mouse embryos at E14.5, approximately 24 â€‹h before the onset of sexual differentiation, and we present the first comprehensive atlas of single-cell gene expression during external genital development. Clustering analyses and annotation using marker genes shows 19 distinct cell populations in E14.5 genital tubercles. Mapping of cell clusters to anatomical locations using in situ gene expression patterns revealed granularity of cellular specializations and positional identities. Although E14.5 precedes sexually dimorphic morphogenesis of the genital tubercle, comparative analysis of males and females identified sexual dimorphisms at the single cell level, including male-specific cell clusters with transcriptional signatures of smooth muscle and bone progenitors, both of which are known to be sexually dimorphic in adult genitalia, as well as immune cells. These results provide a new resource for classification of external genital cell types based on gene expression profiles and reveal sex-specific cellular specializations in the early genital tubercle.

Review and experimental evaluation of the embryonic development and evolutionary history of flipper development and hyperphalangy in dolphins (Cetacea: Mammalia).

Cetaceans are the only mammals to have evolved hyperphalangy, an increase in the number of phalanges beyond the mammalian plesiomorphic condition of three phalanges per digit. In this study, cetaceans were used as a novel model to review previous studies of mammalian hyperphalangy and contribute new experimental evidence as to the molecular origins of this phenotype in embryos of the pantropical spotted dolphin (Stenella attenuata). Results show embryos of dolphins, mice, and pigs share similar spatiotemporal patterns of signaling proteins known to shape limbs of mammals (e.g., FGF8, BMP2/4, WNT, GREM). However, fetal dolphins differ in that their interdigital tissues are retained, instead of undergoing apoptosis, and that multiple waves of interdigital signals likely contribute to the patterning of supernumerary joints and phalanges in adjacent digits. Integration of fossil and experimental evidence suggests that the presence of interdigital webbing within the fossils of semi-aquatic cetaceans, recovered from the Eocene Epoch (49Ma), was probably the result of BMP-antagonists counteracting interdigital apoptosis during embryonic limb development. Modifications to signals originating in these interdigital tissues likely contributed to the origin of an incipient form of hyperphalangy in obligatorily aquatic cetaceans about 35Ma. Finally, an extreme form of hyperphalangy, with six or more phalanges per digit, evolved independently in rorqual whales (Balaenopteridae) and delphinids, and was probably associated with a wave of signaling within the interdigital tissues.

Molecular Characterization of the Genital Organizer: Gene Expression Profile of the Mouse Urethral Plate Epithelium.

PURPOSE: Lower urinary tract malformations are among the most common congenital anomalies in humans. Molecular genetic studies of mouse external genital development have begun to identify mechanisms that pattern the genital tubercle and orchestrate urethral tubulogenesis. The urethral plate epithelium is an endodermal signaling region that has an essential role in external genital development. However, little is known about the molecular identity of this cell population or the genes that regulate its activity. MATERIALS AND METHODS: We used microarray analysis to characterize differences in gene expression between urethral plate epithelium and surrounding tissue in mouse genital tubercles. In situ hybridizations were performed to map gene expression patterns and ToppCluster (https://toppcluster.cchmc.org/) was used to analyze gene associations. RESULTS: A total of 84 genes were enriched at least 20-fold in urethral plate epithelium relative to surrounding tissue. The majority of these genes were expressed throughout the urethral plate in males and females at embryonic day 12.5 when the urethral plate is known to signal. Functional analysis using ToppCluster revealed genetic pathways with known functions in other organ systems but unknown roles in external genital development. Additionally, a 3-dimensional molecular atlas of genes enriched in urethral plate epithelium was generated and deposited at the GUDMAP (GenitoUrinary Development Molecular Anatomy Project) website (http://gudmap.org/). CONCLUSIONS: We identified dozens of genes previously unknown to be expressed in urethral plate epithelium at a crucial developmental period. It provides a novel panel of genes for analysis in animal models and in humans with external genital anomalies.

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies.

Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor α (ERα) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERα have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA.

Development and evolution of the unique cetacean dentition.

The evolutionary success of mammals is rooted in their high metabolic rate. A high metabolic rate is sustainable thanks to efficient food processing and that in turn is facilitated by precise occlusion of the teeth and the acquisition of rhythmic mastication. These major evolutionary innovations characterize most members of the Class Mammalia. Cetaceans are one of the few groups of mammals in which precise occlusion has been secondarily lost. Most toothed whales have an increased number of simple crowned teeth that are similar along the tooth row. Evolution toward these specializations began immediately after the time cetaceans transitioned from terrestrial-to-marine environments. The fossil record documents the critical aspects of occlusal evolution of cetaceans, and allows us to pinpoint the evolutionary timing of the macroevolutionary events leading to their unusual dental morphology among mammals. The developmental controls of tooth differentiation and tooth number have been studied in a few mammalian clades, but nothing is known about how these controls differ between cetaceans and mammals that retain functional occlusion. Here we show that pigs, a cetacean relative with regionalized tooth morphology and complex tooth crowns, retain the typical mammalian gene expression patterns that control early tooth differentiation, expressing Bmp4 in the rostral (mesial, anterior) domain of the jaw, and Fgf8 caudally (distal, posterior). By contrast, dolphins have lost these regional differences in dental morphology and the Bmp4 domain is extended into the caudal region of the developing jaw. We hypothesize that the functional constraints underlying mammalian occlusion have been released in cetaceans, facilitating changes in the genetic control of early dental development. Such major developmental changes drive morphological evolution and are correlated with major shifts in diet and food processing during cetacean evolution.

An interspecific analysis of relative jaw-joint height in primates.

Jaw-joint height (JJH) above the occlusal plane is thought to be influenced by cranial base angle (CBA) and facial angulation during growth. To better understand how JJH relates to midline craniofacial form, we test the hypothesis that relative increases in JJH are correlated with increasing CBA flexion and facial kyphosis (i.e., ventral bending) across primates. We compared JJH above the occlusal plane to CBA and the angle of facial kyphosis (AFK) across adults from 82 species. JJH scales with positive allometry relative to a skull geometric mean in anthropoids and most likely strepsirrhines. Anthropoid regressions for JJH are elevated above strepsirrhines, whereas catarrhines exhibit a higher slope than platyrrhines. Semipartial correlations between relative JJH and both CBA and AFK show no association across a small strepsirrhine sample, limited associations among catarrhines and anthropoids, but strong correlations in platyrrhines. Contrary to our hypothesis, however, increases in relative JJH are correlated with relatively less flexed basicrania and more airorhynch faces (i.e., reduced ventral bending) in platyrrhines. The mosaic pattern of relationships involving JJH across primate clades points to multiple influences on JJH across primates. In clades showing little association with basicranial and facial angles, such as strepsirrhines, the potential morphological independence of JJH may facilitate a relative freedom for evolutionary changes related to masticatory function. Finally, failure to associate relative JJH and basicranial flexion in most clades suggests that the relatively taller JJH and more flexed basicrania of anthropoids compared to strepsirrhines may have evolved as an isolated event during the origin of anthropoids.