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Objective Genetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis. Methods In this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. We characterized the metabolic and behavioral phenotype of obese mutant mice and examined changes in hypothalamic gene expression. In humans, we examined genetic data from people with severe early onset obesity. Results We identified an obese mouse heterozygous for a missense mutation (pR108W) in orthopedia homeobox (Otp), a homeodomain containing transcription factor required for the development of neuroendocrine cell lineages in the hypothalamus, a region of the brain important in the regulation of energy homeostasis. OtpR108W/+ mice exhibit increased food intake, weight gain, and anxiety when in novel environments or singly housed, phenotypes that may be partially explained by reduced hypothalamic expression of oxytocin and arginine vasopressin. R108W affects the highly conserved homeodomain, impairs DNA binding, and alters transcriptional activity in cells. We sequenced OTP in 2548 people with severe early-onset obesity and found a rare heterozygous loss of function variant in the homeodomain (Q153R) in a patient who also had features of attention deficit disorder. Conclusions OTP is involved in mammalian energy homeostasis and behavior and appears to be necessary for the development of hypothalamic neural circuits. Further studies will be needed to investigate the contribution of rare variants in OTP to human energy homeostasis., Highlights • A mouse Otp mutation alters hypothalamic neuropeptide expression leading to increased food intake, obesity and anxiety. • In severe early onset obesity, we found a heterozygous LOF variant in a patient with attention deficit disorder features. • These studies show for the first time that mutations in the Otp/OTP gene cause obesity.

Acrylic bone cements, although successful in the field of orthopedics, suffer from a lack of bioactivity, not truly integrating with surrounding bone. Bioactive fixation is expected to enhance cement performance because of the natural interlocking and bonding with bone, which can improve the augmentative potential of the material in applications such as vertebroplasty (VP). In a recent study, two composite cements (PMMA-hydroxyapatite and PMMA-brushite) showed promising results demonstrating no deterioration in rheological and mechanical properties after CaP filler addition. In this study, the dynamic properties of the cements were investigated in vitro and in vivo. The hypothesis was that these composite cements will provide osseointegration around the implanted cement and increase new bone formation, thus decreasing the risk of bone structural failure. The effects of CaP elution were thus analyzed in vitro using these cements. Mass-loss, pore formation, and mechanical changes were tracked after cement immersion in Hank's salt solution. PMMA-brushite was the only cement with a significant mass loss; however it showed low bulk porosity. Surface porosity increases were observed in both composite cements. Mechanical properties were maintained after cement immersion. In vitro culture studies tested preosteoblast cell viability and differentiation on the cement surface. Cell viability was demonstrated with MTT assay and confirmed on the cement surface. ALP assays showed no inhibition of osteoblast differentiation on the cement surface. In vivo experiments were performed using a rat tibiae model to demonstrate bone ingrowth around the implanted cements. Critical size defects were created and then filled with the cements. The animal studies showed no loss in mechanical strength after implantation and increased bone ingrowth around the composite cements. In summary, the composite cements provided bioactivity without sacrificing mechanical strength.

Objective A previous genome‐wide association study linked overexpression of an ATP‐binding cassette transporter, ABCC5, in humans with a susceptibility to developing type 2 diabetes with age. Specifically, ABCC5 gene overexpression was shown to be strongly associated with increased visceral fat mass and reduced peripheral insulin sensitivity. Currently, the role of ABCC5 in diabetes and obesity is unknown. This study reports the metabolic phenotyping of a global Abcc5 knockout mouse. Methods A global Abcc5‐/‐ mouse was generated by CRISPR/Cas9. Fat mass was determined by weekly EchoMRI and fat pads were dissected and weighed at week 18. Glucose homeostasis was ascertained by an oral glucose tolerance test, intraperitoneal glucose tolerance test, and intraperitoneal insulin tolerance test. Energy expenditure and locomotor activity were measured using PhenoMaster cages. Glucagon‐like peptide 1 (GLP‐1) levels in plasma, primary gut cell cultures, and GLUTag cells were determined by enzyme‐linked immunosorbent assay. Results Abcc5‐/‐ mice had decreased fat mass and increased plasma levels of GLP‐1, and they were more insulin sensitive and more active. Recombinant overexpression of ABCC5 protein in GLUTag cells decreased GLP‐1 release. Conclusions ABCC5 protein expression levels are inversely related to fat mass and appear to play a role in the regulation of GLP‐1 secretion from enteroendocrine cells.

The surge of popular interest in virtual reality (VR), largely driven by recent advances making the hardware and software for VR development and use accessible to average consumers, is showing all the signs of a durable trend. One of those signs is active uptake in the academy, both for research (where it was pioneered) and in the classroom (where its footing is less certain). To be sure, VR offers exciting and relatively underdeveloped pedagogical terrain for teachers looking to enhance their curricula by deploying technologies that might optimize the learning process. This article offers a critical reflection on one such effort, specifically, our academic team’s grant-funded digital humanities research project called Focused Associational Thinking-Virtual Reality (FAT-VR). The main premise of the project was to create a virtual reality environment where students could cultivate creative fluency in divergent thinking. Such competencies are thought to afford students with a means of “thinking things together” in the service of transdisciplinary inquiry and problem solving. This essay recounts how, as we attempted to “move forward” by harnessing VR, we often found ourselves going “backward” and “in circles” due to technological glitches and challenging student feedback. Putting our digital pedagogy project in conversation with phenomenological philosophy and critical theory, we offer a provocation on how forward motion can sometimes set us back pedagogically, and how disorienting experiences—even failure—can become productive.

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects(1). Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse(2), which has been associated with mutations in at least five loci including bl(3). As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.