Organogenesis in deep time: A problem in genomics,development, and paleontology

The fossil record is a unique repository of information on major morphological transitions. Increasingly, developmental, embryological, and functional genomic approaches have also conspired to reveal evolutionary trajectory of phenotypic shifts. Here, we use the vertebrate appendage to demonstrate how these disciplines can mutually reinforce each other to facilitate the generation and testing of hypotheses of morphological evolution. We discuss classical theories on the origins of paired fins, recent data on regulatory modulations of fish fins and tetrapod limbs, and case studies exploring the mechanisms of digit loss in tetrapods. We envision an era of research in which the deep history of morphological evolution can be revealed by integrating fossils of transitional forms with direct experimentation in the laboratory via genome manipulation, thereby shedding light on the relationship between genes, developmental processes, and the evolving phenotype.Paleontologists in recent decades have discovered a host of new taxa that reveal transitional stages in the evolution of birds, whales, mammals, tetrapods, frogs, salamanders, and arthropods (1–9). This pulse of discovery is not an accident, but the result of an elaboration of our ability to identify likely sites for fossil recovery by using increasingly refined phylogenies, stratigraphic maps, and geological records. Likewise, imaging techniques, such as high-energy CT, have opened up old and understudied fossil collections as new vehicles for discovery. With advances in both fieldwork and imaging, the discovery of the phenotypic basis for morphological innovation is at a critical moment in its long history: Novel perspectives on classical questions of anatomical evolution are within our reach.Fossils, when placed in a phylogenetic context, can reveal taxa with novel combinations of characters that could not be predicted by studying extant creatures alone. If we lacked fossil evidence of mammal-like reptiles, for example, then the physiological and morphological similarities of birds and mammals would likely be interpreted as homologies rather than examples of parallel evolution (e.g., the discredited “Haemothermia” clade) (10, 11). In addition to identifying solid taxonomic groupings, these same fossils reveal transitional series in the origin of the mammalian dentition, ear, and cranium (3). Our understanding of numerous other transformations, from the origin of birds to the origin of tetrapods, is seriously limited without the knowledge of extinct stem taxa.A rich fossil record permits us to document robustly supported transformation series in the evolution of an anatomical feature, organ system, or body plan. However, to understand the pattern and process of evolutionary transitions, paleontologists have increasingly turned their attention to development. In recent years, the combination of technologies from developmental biology and abundant genomic resources for a multitude of model and nonmodel organisms has greatly enriched our understanding of the genetic and developmental processes underlying organogenesis. This broad set of tools provides a new framework for testing hypotheses derived from paleontological findings, thereby forming an interdisciplinary research program with comparative genomics as well as genetic manipulation of embryonic development (12–15).Here, we use the evolution and diversification of the vertebrate limb as an exemplar to reveal how discoveries in paleontology can leverage experimental and comparative work in molecular biology, genomics, and embryology. First, we review how fossil analyses of early gnathostomes, coupled with embryological studies, offer the foundation for hypotheses on the origin of paired appendages. Then, we discuss current research on model and nonmodel species that shed light on the origin of digits by comparing gene expression and regulatory mechanisms underlying fin and limb development. Next, we examine recent studies that identify the genetic and developmental basis for digit reduction in tetrapods. Finally, we highlight novel technologies that are enabling biologists to solve century-old evolutionary puzzles with state-of-the-art molecular approaches. The synthesis of modern technology with paleontological findings has been an ongoing topic of interest (16–18). Continued advances in technology now give morphologists an ever-expanding toolkit to test genome function and, ultimately, manipulate genomes in a phylogenetic framework. When these new technologies are coupled with paleontological discovery, new insights into classical questions in evolutionary morphology lie in the offing.     

Evaluating the validity of model for end‐stage liver disease exception points for hepatocellular carcinoma patients with multiple nodules <2 cm

Liver transplant allocation policy does not give model for end‐stage liver disease (MELD) exception points for patients with a single hepatocellular carcinoma (HCC) <2 cm in size, but does give points to patients with multiple small nodules. Because standard‐of‐care imaging for HCC struggles to differentiate HCC from other nodules, it is possible that a subset of patients receiving liver transplant for multiple nodules <2 cm in size does not have HCC. We evaluate risk of post‐transplant HCC recurrence and wait‐list dropout for patients with multiple small nodules using competing risks regression based on the Fine and Gray model. We identified 5002 adult HCC patients in the OPTN/UNOS dataset diagnosed and transplanted between January 2006 and September 2010. Compared to patients with >1 tumor <2 cm, risk of developing recurrence was significantly higher in patients with one or more tumors with only one tumor ≥2 cm (SHR 1.63, p = 0.009), as well as in patients with 2–3 tumors ≥2 cm (SHR 1.84, p = 0.02). Dropout risk was not significantly different among size categories. HCC recurrence risk was significantly lower in patients with multiple nodules <2 cm in size than in those with larger tumors, supporting the possibility that some patients received unnecessary transplants. The priority given to these patients must be re‐examined.     

Autistic Adults May Be Erroneously Perceived as Deceptive and Lacking Credibility

Journal of Autism and Developmental Disorders - We hypothesized that autistic adults may be erroneously judged as deceptive or lacking credibility due to demonstrating unexpected and atypical...     

Navigated robotic assistance results in improved screw accuracy and positive clinical outcomes: an evaluation of the first 54 cases

Computer-aided navigation and robotic guidance systems have become widespread in their utilization for spine surgery. A recent innovation combines these tw     

Association of pretreatment body mass index with risk of head and neck cancer: a large single-center study

Smoking and alcohol exposure continue to be the dominant risk factors for the development of head and neck squamous cell carcinoma (SCCHN) worldwide. Moreover, human papillomavirus (HPV) is associated with SCCHN, particularly SCC of the oropharynx (SCCOP). Body mass index (BMI) has been reported as a possible risk factor for SCCHN, yet the data available so far about the relationship between BMI and SCCHN risk have been mixed. We sought to clarify this relationship. BMI and demographic, clinical, and epidemiological information at diagnosis were collected from 2310 SCCHN cases and 1915 controls (who were cancer-free) from October 2001 through May 2013. The odds ratios (ORs) and 95 percent confidence intervals (95% CI) were determined using the logistic regression process. Multivariable models were used to evaluate the strength of the relation between BMI and SCCHN risk. At diagnosis, 64 (2.8%) of the cases were underweight (BMI <18.5 kg/m²), 661 (28.6%) were normal weight (BMI 18.5<25 kg/m²), 833 (36.1%) were overweight (BMI 25<30 kg/m²), and 752 (32.6%) were obese (BMI ≥30 kg/m²). Comparatively, the ORs (95% CIs) for SCCHN associated with being underweight, overweight, and obese were 2.6 (1.54.7), 0.7 (0.6-0.8), and 0.8 (0.7-0.9), respectively, after adjusting for age, gender, race/ethnicity, smoking, and alcohol consumption. On analysis stratified by tumor sites, the risk of SCCOP among patients seropositive for HPVE6 and/or HPVE7 was higher among the overweight (OR, 5.4, 95% CI, 1.3-23.1) and obese patients (OR, 2.4, 95% CI, 1.1-7.6) compared to the normal weight patients. These findings suggest that pretreatment BMI could be a major risk factor for SCCHN, and the association between BMI and HPV may increase the risk of SCCOP.