Hedgehog signaling is required for endometrial remodeling and myometrial homeostasis in the cycling mouse uterus.

Decades of work demonstrate that the mammalian estrous cycle is controlled by cycling steroid hormones. However, the signaling mechanisms that act downstream, linking hormonal action to the physical remodeling of the cycling uterus, remain unclear. To address this issue, we analyzed gene expression at all stages of the mouse estrous cycle. Strikingly, we found that several genetic programs well-known to control tissue morphogenesis in developing embryos displayed cyclical patterns of expression. We find that most of the genetic architectures of Hedgehog signaling (ligands, receptors, effectors, and transcription factors) are transcribed cyclically in the uterus, and that conditional disruption of the Hedgehog receptor smoothened not only elicits a failure of normal cyclical thickening of the endometrial lining but also induces aberrant deformation of the uterine smooth muscle. Together, our data shed light on the mechanisms underlying normal uterine remodeling specifically and cyclical gene expression generally.

UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon 'paternally expressed gene 10 (PEG10)' in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated 'nucleocapsid' fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through the regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

Assessing pharmacists' readiness to prescribe oral antibiotics for limited infections using a case-vignette technique.

Background Pharmacist's skills are underutilized whilst they are directly involved with antibiotic supply to the community. Addressing this issue could lead to better use of antibiotics and hence decreased resistance. Objective Explore how pharmacists can prescribe oral antibiotics to treat a limited range of infections whilst focusing on their confidence and appropriateness of prescribing. Setting Community pharmacies, Western Australia. Method Data were collected using a self-administered questionnaire also containing case vignettes. These were distributed to a random sample of metropolitan and rural community pharmacies in Western Australia. A Generalised Estimating Equation was used to compare respondents' level of confidence in treating various infections and to assess appropriateness of prescribing. Main outcome measure Appropriateness and confidence of antibiotic prescribing. Results A response rate of 34.2% (i.e. 425 responses to case vignettes) was achieved from 240 pharmacies. There were high levels of confidence to treat simple infections such as uncomplicated UTIs (n = 73; 89.0%), impetigo (n = 65; 79.3%), mild bacterial skin infections (n = 62; 75.6%) and moderate acne (n = 61; 72.4%). Over 80% of respondents were confident to prescribe amoxicillin (n = 73; 89%), trimethoprim (n = 72; 87.8%), amoxicillin and clavulanic acid (n = 70; 85.4%), flucloxacillin (n = 70; 85.4%) and cephalexin (n = 68; 82.9%). High levels of appropriate antibiotic prescribing were shown for uncomplicated UTI (97.2%), cellulitis (98.2%) and adolescent acne (100.0%). Conclusion This study identified key limited infections and antibiotics for which pharmacists were supportive and confident to prescribe. This role could lead to better use of antibiotics in the community and minimisation of resistance.