Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Characterization of the SNAG and SLUG Domains of Snail2 in the Repression of E-Cadherin and EMT Induction: Modulation by Serine 4 Phosphorylation

Snail1 and Snail2, two highly related members of the Snail superfamily, are direct transcriptional repressors of E-cadherin and EMT inducers. Previous comparative gene profiling analyses have revealed important differences in the gene expression pattern regulated by Snail1 and Snail2, indicating functional differences between both factors. The molecular mechanism of Snail1-mediated repression has been elucidated to some extent, but very little is presently known on the repression mediated by Snail2. In the present work, we report on the characterization of Snail2 repression of E-cadherin and its regulation by phosphorylation. Both the N-terminal SNAG and the central SLUG domains of Snail2 are required for efficient repression of the E-cadherin promoter. The co-repressor NCoR interacts with Snail2 through the SNAG domain, while CtBP1 is recruited through the SLUG domain. Interestingly, the SNAG domain is absolutely required for EMT induction while the SLUG domain plays a negative modulation of Snail2 mediated EMT. Additionally, we identify here novel in vivo phosphorylation sites at serine 4 and serine 88 of Snail2 and demonstrate the functional implication of serine 4 in the regulation of Snail2-mediated repressor activity of E-cadherin and in Snail2 induction of EMT

Massage Therapy for Osteoarthritis of the Knee: A Randomized Dose-Finding Trial

In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination.We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks.WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3-32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1-12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose.Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials.ClinicalTrials.gov NCT00970008

Partial versus general compulsory solidarity: an experimental analysis

We focus on ways and means of solidarity and their more or less voluntary and involuntary character. Alternative ways of redistribution are modeled by combining redistribution as emergent from a non-discriminatory voluntary contribution mechanism, VCM, with an outside option for a “super-rich”, R, participant to donate to VCM participants. The outsider may discriminate between participants of the VCM on the basis of information accessible at a cost to her. Inclusion in and exclusion from the VCM are involuntary while contributions in it are voluntary. How involuntary inclusion of R in VCM affects her discriminatory voluntary donations and contribution behavior is explored experimentally

Transcriptomic analysis of the late stages of grapevine (Vitis vinifera cv. Cabernet Sauvignon) berry ripening reveals significant induction of ethylene signaling and flavor pathways in the skin

Background: Grapevine berry, a nonclimacteric fruit, has three developmental stages; the last one is when berrycolor and sugar increase. Flavors derived from terpenoid and fatty acid metabolism develop at the very end of thisripening stage. The transcriptomic response of pulp and skin of Cabernet Sauvignon berries in the late stages ofripening between 22 and 37 \ub0Brix was assessed using whole-genome micorarrays.Results: The transcript abundance of approximately 18,000 genes changed with \ub0Brix and tissue type. There were alarge number of changes in many gene ontology (GO) categories involving metabolism, signaling and abioticstress. GO categories reflecting tissue differences were overrepresented in photosynthesis, isoprenoid metabolismand pigment biosynthesis. Detailed analysis of the interaction of the skin and pulp with \ub0Brix revealed that therewere statistically significantly higher abundances of transcripts changing with \ub0Brix in the skin that were involved inethylene signaling, isoprenoid and fatty acid metabolism. Many transcripts were peaking around known optimalfruit stages for flavor production. The transcript abundance of approximately two-thirds of the AP2/ERF superfamilyof transcription factors changed during these developmental stages. The transcript abundance of a unique clade ofERF6-type transcription factors had the largest changes in the skin and clustered with genes involved in ethylene,senescence, and fruit flavor production including ACC oxidase, terpene synthases, and lipoxygenases. The transcriptabundance of important transcription factors involved in fruit ripening was also higher in the skin.Conclusions: A detailed analysis of the transcriptome dynamics during late stages of ripening of grapevine berriesrevealed that these berries went through massive transcriptional changes in gene ontology categories involvingchemical signaling and metabolism in both the pulp and skin, particularly in the skin. Changes in the transcriptabundance of genes involved in the ethylene signaling pathway of this nonclimacteric fruit were statisticallysignificant in the late stages of ripening when the production of transcripts for important flavor and aroma compoundswere at their highest. Ethylene transcription factors known to play a role in leaf senescence also appear to play a role infruit senescence. Ethylene may play a bigger role than previously thought in this non-climacteric fruit