Interspecies transcriptomics identify genes that underlie disproportionate foot growth in jerboas.

Despite the great diversity of vertebrate limb proportion and our deep understanding of the genetic mechanisms that drive skeletal elongation, little is known about how individual bones reach different lengths in any species. Here, we directly compare the transcriptomes of homologous growth cartilages of the mouse (Mus musculus) and bipedal jerboa (Jaculus jaculus), the latter of which has "mouse-like" arms but extremely long metatarsals of the feet. Intersecting gene-expression differences in metatarsals and forearms of the two species revealed that about 10% of orthologous genes are associated with the disproportionately rapid elongation of neonatal jerboa feet. These include genes and enriched pathways not previously associated with endochondral elongation as well as those that might diversify skeletal proportion in addition to their known requirements for bone growth throughout the skeleton. We also identified transcription regulators that might act as "nodes" for sweeping differences in genome expression between species. Among these, Shox2, which is necessary for proximal limb elongation, has gained expression in jerboa metatarsals where it has not been detected in other vertebrates. We show that Shox2 is sufficient to increase mouse distal limb length, and a nearby putative cis-regulatory region is preferentially accessible in jerboa metatarsals. In addition to mechanisms that might directly promote growth, we found evidence that jerboa foot elongation may occur in part by de-repressing latent growth potential. The genes and pathways that we identified here provide a framework to understand the modular genetic control of skeletal growth and the remarkable malleability of vertebrate limb proportion.

Augmented seizure susceptibility and hippocampal epileptogenesis in a translational mouse model of febrile status epilepticus.

OBJECTIVE: Prolonged fever-induced seizures (febrile status epilepticus [FSE]) during early childhood increase the risk for later epilepsy, but the underlying mechanisms are incompletely understood. Experimental FSE (eFSE) in rats successfully models human FSE, recapitulating the resulting epileptogenesis in a subset of affected individuals. However, the powerful viral and genetic tools that may enhance mechanistic insights into epileptogenesis and associated comorbidities, are better-developed for mice. Therefore, we aimed to determine if eFSE could be generated in mice and if it provoked enduring changes in hippocampal-network excitability and the development of spontaneous seizures. METHODS: We employed C57BL/6J male mice, the strain used most commonly in transgenic manipulations, and examined if early life eFSE could be sustained and if it led to hyperexcitability of hippocampal networks and to epilepsy. Outcome measures included vulnerability to the subsequent administration of the limbic convulsant kainic acid (KA) and the development of spontaneous seizures. In the first mouse cohort, adult naive and eFSE-experiencing mice were exposed to KA. A second cohort of control and eFSE-experiencing young adult mice was implanted with bilateral hippocampal electrodes and recorded using continuous video-electroencephalography (EEG) for 2 to 3 months to examine for spontaneous seizures (epileptogenesis). RESULTS: Induction of eFSE was feasible and eFSE increased the susceptibility of adult C57BL/6J mice to KA, thereby reducing latency to seizure onset and increasing seizure severity. Of 24 chronically recorded eFSE mice, 4 (16.5%) developed hippocampal epilepsy with a latent period of ~3 months, significantly different from the expectation by chance (P = .04). The limbic epilepsy that followed eFSE was progressive. SIGNIFICANCE: eFSE promotes pro-epileptogenic network changes in a majority of C57BL/6J male mice and frank "temporal lobe-like" epilepsy in one sixth of the cohort. Mouse eFSE may thus provide a useful tool for investigating molecular, cellular, and circuit changes during the development of temporal lobe epilepsy and its comorbidities.

Evolutionary loss of foot muscle during development with characteristics of atrophy and no evidence of cell death.

Many species that run or leap across sparsely vegetated habitats, including horses and deer, evolved the severe reduction or complete loss of foot muscles as skeletal elements elongated and digits were lost, and yet the developmental mechanisms remain unknown. Here, we report the natural loss of foot muscles in the bipedal jerboa, Jaculus jaculus. Although adults have no muscles in their feet, newborn animals have muscles that rapidly disappear soon after birth. We were surprised to find no evidence of apoptotic or necrotic cell death during stages of peak myofiber loss, countering well-supported assumptions of developmental tissue remodeling. We instead see hallmarks of muscle atrophy, including an ordered disassembly of the sarcomere associated with upregulation of the E3 ubiquitin ligases, MuRF1 and Atrogin-1. We propose that the natural loss of muscle, which remodeled foot anatomy during evolution and development, involves cellular mechanisms that are typically associated with disease or injury.

Comparing medical, dental, and nursing students' preparedness to address lesbian, gay, bisexual, transgender, and queer health.

BACKGROUND: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) populations face multiple health disparities including barriers to healthcare. Few studies have examined healthcare trainees' perceptions of their preparedness to care for LGBTQ populations and none have compared perceptions of training across medicine, dental medicine, and nursing. We aimed to understand variations across disciplines in LGBTQ health by assessing medical, dental, and nursing students' perceptions of preparedness across three domains: comfort levels, attitudes, and formal training. METHODS: We developed a 12-item survey with an interprofessional panel of LGBTQ students from the schools of medicine, dental medicine, and nursing at a top-tier private university in the United States. Any student enrolled full time in any of the three schools were eligible to respond. We performed descriptive statistical analyses and examined patterns in responses using Kruskal-Wallis tests and an ordered logistic regression model. RESULTS: 1,010 students from the Schools of Medicine, Dental Medicine, and Nursing responded to the survey for an overall response rate of 43%. While 70-74% of all student respondents felt comfortable treating LGBTQ patients, fewer than 50% agreed that their formal training had prepared them to do so. Overall, 71-81% of students reported interest in receiving formal LGBTQ health education, though dental students were significantly less likely than medical students to report this interest (OR 0.53, p<0.01). Respondents who identified as LGBQ were significantly less likely than heterosexual students to agree that training was effective (OR 0.55, p<0.01) and that their instructors were competent in LGBTQ health (OR 0.56, p<0.01). CONCLUSION: Despite high comfort levels and positive attitudes towards LGBTQ health, most student respondents did not report adequate formal preparation. There were some significant differences between disciplines, but significant gaps in training exist across disciplines. Health professional schools should develop formal content on LGBTQ health and utilize this content as an opportunity for interprofessional training.