Chromatin signatures of pluripotent cell lines

Epigenetic genome modifications are thought to be important for specifying the lineage and developmental stage of cells within a multicellular organism. Here, we show that the epigenetic profile of pluripotent embryonic stem cells (ES) is distinct from that of embryonic carcinoma cells, haematopoietic stem cells (HSC) and their differentiated progeny. Silent, lineage-specific genes replicated earlier in pluripotent cells than in tissue-specific stem cells or differentiated cells and had unexpectedly high levels of acetylated H3K9 and methylated H3K4. Unusually, in ES cells these markers of open chromatin were also combined with H3K27 trimethylation at some non-expressed genes. Thus, pluripotency of ES cells is characterized by a specific epigenetic profile where lineage-specific genes may be accessible but, if so, carry repressive H3K27 trimethylation modifications. H3K27 methylation is functionally important for preventing expression of these genes in ES cells as premature expression occurs in embryonic ectoderm development (Eed)-deficient ES cells. Our data suggest that lineage-specific genes are primed for expression in ES cells but are held in check by opposing chromatin modifications.     

Privileged structure based ligands for melanocortin receptors--4,4-disubstituted piperidine derivatives

Homologation and cyclization back to the chiral methine of compound 3 yields achiral 4,4-disubstituted piperidine privileged structures (e.g., 8a) useful in the construction of melanocortin 4 receptor (MC4R) ligands. The piperidine nitrogen was replaced with carbon, oxygen, sulfur, and sulfone with minor erosion of binding. The methyl cyclohexane substituent was the most potent while significant affinity was still seen for smaller lipophilic groups such as ethyl.     

Phosphorylation of the major Drosophila lamin in vivo: site identification during both M-phase (meiosis) and interphase by electrospray ionization tandem mass spectrometry

Phosphorylation can have profound effects on the properties of nuclear lamins. For instance, phosphorylation of specific sites on mammalian lamins drastically alters their propensity to polymerize. Relatively little is known about the effects of phosphorylation during interphase and about phosphorylation of invertebrate nuclear lamins. Here, using electrospray ionization tandem mass spectrometry, we determined the phosphorylation sites of both interphase and M-phase isoforms of nuclear lamin Dm from Drosophila melanogaster. Interphase lamins are phosphorylated at three sites: two of these sites (Ser25 and a site located between residues 430 and 438) flank the alpha-helical rod domain, whereas the third site (Ser595) is located close to the C-terminus. The M-phase lamin isoform is phosphorylated predominantly at Ser45, a residue contained within a sequence matching the consensus site for phosphorylation by cdc2 kinase. Our study confirms the important role in vivo for cdc2 kinase in M-phase disassembly of nuclear lamins and provides the basis for understanding Drosophila lamin phosphorylation during interphase.     

A comparison of hydrocortisone and triamcinolone inhibition of scale and feather development

Hydrocortisone (30-40 micrograms on day 10) and triamcinolone (10-20 ng on day 7-8) both inhibit or alter morphogenesis of scales and feathers. However, there are marked temporal and region-specific differences in the effects induced by these two glucocorticoids. Triamcinolone (TAC) is most teratogenic on day 7 or 8, inhibiting formation of spurs and feathers and inducing club feather formation. Hydrocortisone is most teratogenic later in development, on day 10. Unique hydrocortisone-induced responses are complete inhibition of scutellate scale formation, bent feathers, and apteria around the external auditory meatus. Altered synthesis of keratin polypeptides follows inhibition of scale morphogenesis by hydrocortisone and TAC. These in vivo data suggest that heterogeneity of glucocorticoid binding occurs in embryonic chick metatarsal skin. Survival data indicate that TAC is 2,000 times more embryotoxic than hydrocortisone.     

Pneumocystis Pneumonia: Epidemiology and Options for Prophylaxis in Non-HIV Immunocompromised Pediatric Patients

The pediatric population of non-HIV immunocompromised patients at risk for Pneumocystis pneumonia (PCP) continues to increase. While prophylactic therapy can be highly effective in preventing this opportunistic pathogen, identifying the at-risk populations appropriate for use of prophylaxis and navigating the risks and benefits of each therapeutic option can be challenging. In this article, the available epidemiology for baseline rates of PCP is presented for a variety of non-HIV immunocompromised pediatric populations. Additionally, the comparative effectiveness and side effect profiles for trimethoprim/sulfamethoxazole, dapsone, atovaquone, and pentamidine are discussed. Institutions are encouraged to review the data and to establish and implement a local practice guideline for PCP prophylaxis that can be monitored for effectiveness over time. An example of a standardized practice guideline is suggested.     

Lipid oxidation in fit young adults during postexercise recovery.

To evaluate the hypothesis that lipid oxidation predominates in postexercise recovery, we examined healthy men (n = 6; age = 21.2 +/- 0.6 yr) and women (n = 6; age = 22.8 +/- 2.1 yr) during and after two exercise tasks [89 min at 45% and 60 min at 65% of peak rate of oxygen consumption (V(O2 peak))] as well as a time-matched resting control trial (Con). Exercise bouts were matched for energy expenditure. Respiratory exchange ratios (RER) during exercise at 65% V(O2 peak) for both men and women (0.95 +/- 0.01 and 0.93 +/- 0.02) were significantly higher than 45% V(O2 peak) (0.89 +/- 0.01 and 0.86 +/- 0.02) and Con trials (0.86 +/- 0.01 and 0.86 +/- 0.02, respectively). During recovery, for men RER values were 0.78 +/- 0.01 and 0.76 +/- 0.01 after 45% and 65% exercise, respectively. For women, values were 0.79 +/- 0.01 and 0.78 +/- 0.01. These were significantly lower than during both the preexercise resting period and the corresponding no-exercise Con period (0.82 +/- 0.01 and 0.83 +/- 0.01, mean RER for men and women, respectively). Hence, the contribution of lipid oxidation to energy supply increased significantly during recovery compared with preexercise levels, and it was greater after exercise than during the time-matched, no-exercise Con period. It is concluded that, although carbohydrate is the major fuel source during moderate- to high-intensity exercise, 1) there is substantial postexercise lipid oxidation; and 2) lipid oxidation is the same during postexercise recovery whether the relative power output is 45% or 65% of V(O2 peak) when energy expenditure of exercise is matched.     

Features of the fundal glands of the mammalian stomach and their relation to type of diet (morphometric analysis)

According to a standartized technique, a morphometrical investigation of the stomach tunica mucosa (STM) has been performed in 11 practically healthy persons and 69 animals representing 4 orders and 9 femilies of Mammalia. In Mammalia, together with a principle similarity in the stomach microscopical structure, there is a great variety of main morphometrical parameters of the STM. The whole complex of these parameters is species-specific. It is determined by the systemic position of the given species and reflects the filogenetically-dependent nutritional specialization. The main mechanism and the filogenetically-dependent characteristic of adaptation to protein nutrition is an increase in the number of the main, but not the parietal glandulocytes. The dependence revealed gives a new interpretation to the problem concerning the relation between the structure and function of the STM in animals with different nutrition type; this dependence makes it possible to consider the problem of ulcerogenesis and its biological prerequisites in the man from new positions.