Occupancy of specific receptors on neutrophils by adenosine or its analogues diminishes the stimulated release of toxic oxygen metabolites from neutrophils, while paradoxically promoting chemotaxis. We now report evidence that two distinct adenosine receptors are found on neutrophils (presumably the Al and A2 receptors of other cell types). These adenosine receptors modulate chemotaxis and 02 generation, respectively. N6-Cyclopentyladenosine (CPA), a selective A, agonist, promoted neutrophil chemotaxis to the chemoattractant FMLP as well as or better than 5'N-ethylcarboxamidoadenosine (NECA). In contrast, CPA did not inhibit O2 generation stimulated by FMLP. Pertussis toxin completely abolished promotion of chemotaxis by CPA but enhanced inhibition by NECA of 02 generation. Disruption of microtubules by colchicine or vinblastine also abrogated the enhancement by NECA of chemotaxis whereas these agents did not markedly interfere with inhibition by NECA of°2 generation. FMLP receptors, once they have bound ligand, shift to a high affinity state and become associated with the cytoskeleton. NECA significantly increased association of I3HIFMLP with cytoskeletal preparations as it inhibited 2.-Disruption of microtubules did not prevent NECA from increasing association of PHIFMLP with cytoskeletal preparations. Additionally, CPA (Al agonist) did not increase binding of IHIFMLP to the cytoskeleton as well as NECA (A2 agonist). These studies indicate that occupancy of one class of adenosine receptors (Al) promotes chemotaxis by a mechanism requiring intact microtubules and G proteins whereas engagement of a second class of receptors (A2) inhibits 0-generation. Signalling via A2 receptors is independent of microtubules, insensitive to pertussis toxin and is associated with binding of [HjFMLP to cytoskeletal preparations.

Activation of transforming potential of the cellular raf gene has uniformly been associated with the deletion of amino-terminal coding sequences. In order to determine whether 5' truncation alone could activate cellular raf, we constructed 21 human c-raf-l cDNAs with variable BAL 31-generated deletions distal to a Moloney murine sarcoma virus long terminal repeat and a consensus translation initiation sequence. The deletions ranged from 136 to 1,399 nucleotides of coding sequence and shortened the 648-amino-acid raf protein by 44 to 465 amino acids. The full-length c-raf-1 cDNA was nontransforming upon transfection of NIH 3T3 cells, as were four mutants with deletions of 142 or fewer amino acids. Seven of nine mutants with deletions of 154 to 273 amino acids induced transformation with efficiencies ranging from 0.25 to 70 foci per ,ug of DNA. Mutants with deletions of 303 to 324 amino acids displayed high transforming activities (comparable with that of v-rat), with a peak activity of 2,400 foci per ,ug of DNA when 305 amino acids were deleted. Deletions of >383 amino acids, extending into the raf kinase domain, lacked transforming activity. Northern (RNA) blotting and immunoprecipitation assays indicated that transfected NIH cells expressed raf RNAs and proteins of the expected sizes. Thus, 5' truncation alone can activate raf transforming potential, with a sharp peak of activation around amino acid 300. Analysis of three raf genes previously detected by transfection of tumor DNAs indicated that these genes were activated by recombination in raf intron 7 and encoded fusion proteins containing amino-terminal non-raf sequences. The extent of deletion of raf sequences in these recombinant genes corresponded to BAL 31 mutants which did not display high transforming activity, suggesting that the fused non-raf coding sequences may also contribute to biological activity.

Down syndrome (DS) is a genetic condition characterized by having three copies of chromosome 21 and has typically associated phenotypic and physiologic manifestations. Individuals with DS are at risk for a variety of medical conditions throughout their lifespan (Smith, 2001). Currently, there are an estimated 212,000 people with DS living in the United States (De Graaf, Buckley, & Skotko, 2017). The overall prevalence of DS continues to increase as lifespan improves due to advances in medical and psychosocial care, with many individuals with DS living well into their 60s (Bittles & Glasson 2004). As a result, individuals with DS are now reaching the age where chronic diseases impacted by decades of lifestyle habits often begin to present with complications. Physical activity is an important modifiable health behaviour that holds promise to mitigate several debilitating conditions that can co-occur with DS. For example, adults with DS are at increased risk for developing obesity and osteoporosis, both conditions known to improve with increased physical activity within the neurotypical population (Carfì et al., 2017; Rubin, Rimmer, Chicoine, Braddock, & McGuire, 1998). Adults with DS also have a substantially increased risk for dementia over time, and recent research has shown promise in using physical activity as a tool for preventing cognitive decline and progression of Alzheimer's type disease in this high-risk population (Ptomey et al., 2018). Despite the potential benefits of physical activity in DS, previous studies have indicated that individuals with DS have low levels of physical activity compared to the general population (Esposito,

Youth with Down syndrome (DS) have a higher prevalence of overweight and obesity compared to the general youth population. Due to physiological and cognitive differences observed in youth with DS, weight management recommendations developed for the general population, may not be suitable for youth with DS. However, there are no recent recommendations for weight management in youth with DS. A workgroup of clinicians and researchers with extensive experience working with youth with DS came together to give clinicians and families guidance for weight management in youth with DS. Recommendations were developed by the workgroup via a methodical, deliberative process. After the initial development of the recommendations, they were shared with an expert review panel and caregivers who rated the strength of the recommendation and strength of the evidence. The workgroup moved forward the recommendations which the review panels rated as strong. Eight recommendations were developed which focused on screening for overweight and obesity, screening for health conditions that may impact dietary intake and physical activity, screening for feeding difficulties, setting appropriate recommendations for dietary intake and physical activity, and well as prevention and treatment of overweight and obesity using evidence-based strategies. These recommendations can be implemented by clinicians working with youth with Down syndrome as well as the family, school, and other relevant entities.