Search PubMed⌕ Search

Biomedical subjects

J M Adams

Publications and source records attributed to J M Adams.

At least 19 recordsLinked to original sources
PubMed2006

Polycystic ovarian morphology in normal women does not predict the development of polycystic ovary syndrome.

CONTEXT: Polycystic ovarian morphology (PCOM) is present in 25% of normal women in the absence of polycystic ovary syndrome (PCOS); however, the natural history of PCOM is unknown. OBJECTIVE: We hypothesized that the presence of PCOM predisposes the development of PCOS. DESIGN: The study was a longitudinal follow-up study over 8.2 +/- 5.2 yr (mean +/- sd; range 1.7-17.5 yr). SETTING: The study took place in an outpatient setting. SUBJECTS: Women who took part in a previous study as a normal control and had an ultrasound examination (n = 40) participated. INTERVENTION: Subjects underwent an interval menstrual history, physical exam, blood sampling, and repeat ultrasound in the follicular phase. MAIN OUTCOME MEASURE: Development of PCOS was diagnosed by irregular menses and hyperandrogenism, in the absence of other disorders. Changes in ovarian morphology over time were evaluated. RESULTS: At the baseline visit, 23 women (57.5%) had PCOM and 17 (42.5%) had normal ovarian morphology. One subject with PCOM developed irregular menses and presumptive PCOS. Eleven subjects with PCOM no longer met the criteria for PCOM at follow-up. There was no factor that predicted the change to normal ovarian morphology at the follow-up visit. CONCLUSIONS: These data suggest that PCOM in women with regular ovulatory cycles does not commonly predispose the development of PCOS. Although it is unusual to develop PCOM if the ovaries are normal on first assessment, ovaries in women with PCOM no longer meet the criteria for PCOM in approximately half of cases over time.

Adult↗
PubMed2006

Spontaneous shears in smectic elastomers.

We model the spontaneous elastic shear deformations of smectic elastomers as they make the thermal transition between the A and C phases. Tilt of the director is accompanied by shear. Unlike nematic elastomers where spontaneous elongation is associated with changes in the magnitude of order, spontaneous distortion in smectics is instead shear and is associated with rotation of the director of the underlying nematic order. The effect of the multistage cross-linking associated with creating monodomain elastomers is taken into account. The angle of molecular tilt and the angle associated with spontaneous shear deformation are not simply related.

Journal Article↗
PubMed2005

Structural analysis of a set of proteins resulting from a bacterial genomics project.

The targets of the Structural GenomiX (SGX) bacterial genomics project were proteins conserved in multiple prokaryotic organisms with no obvious sequence homolog in the Protein Data Bank of known structures. The outcome of this work was 80 structures, covering 60 unique sequences and 49 different genes. Experimental phase determination from proteins incorporating Se-Met was carried out for 45 structures with most of the remainder solved by molecular replacement using members of the experimentally phased set as search models. An automated tool was developed to deposit these structures in the Protein Data Bank, along with the associated X-ray diffraction data (including refined experimental phases) and experimentally confirmed sequences. BLAST comparisons of the SGX structures with structures that had appeared in the Protein Data Bank over the intervening 3.5 years since the SGX target list had been compiled identified homologs for 49 of the 60 unique sequences represented by the SGX structures. This result indicates that, for bacterial structures that are relatively easy to express, purify, and crystallize, the structural coverage of gene space is proceeding rapidly. More distant sequence-structure relationships between the SGX and PDB structures were investigated using PDB-BLAST and Combinatorial Extension (CE). Only one structure, SufD, has a truly unique topology compared to all folds in the PDB.

Databases, Protein↗
PubMed2005

Soft elasticity in smectic elastomers.

We investigate the soft elastic modes of smectic elastomers, that is shape change without energy cost. We use a microscopic model for their nonlinear elasticity, similar to those used for nematic elastomers. We consider two different phases of smectic elastomer; the biaxial smectic A for a simple illustration, and smectic C phases which are of great practical significance. We show that only one nontrivial trajectory of the director gives soft deformations. We give a geometrical interpretation of this soft elastic mode and give an explicit example.

Journal Article↗
PubMed2005

Elasticity of smectic-A elastomers.

We present a fully nonlinear model of the elasticity smectic-A elastomers, and compare our results with a wide range of experimental observations: extreme Poisson ratios, the in-plane modulus, the modulus before and after threshold to layer rotation in response to stretches along the layer normal, the threshold strain, the characteristic, and singular rotation of layers after the threshold. We calculate the x-ray scattering from rotating layers and compare with available data. The model is derived in two ways: from geometrical constraints imposed by layers on a nematic elastomer, and from application of statistical mechanics to a microscopic model of the effect of crosslink points confined in a corrugated potential.

Journal Article↗
PubMed2005

Hairpin rubber elasticity.

We model the elastic properties of main chain liquid crystalline elastomers, formed by cross linking chains in a strongly nematic state, when they have hairpin defects. We study the response of the elastomer to imposed uniaxial extension along the nematic direction, and employ a microscopic model of how the deformation is distributed non-affinely amongst the hairpin and straight chain populations. The rubber shows a plateau in the stress as a function of the elongation imposed along the director. It is a consequence of the depletion of the actively stretching population of hairpin chains and should not be confused with soft elasticity effects associated with director rotation.

Computer Simulation↗
PubMed2005

Subversion of the Bcl-2 life/death switch in cancer development and therapy.

The Bcl-2 protein family, which largely determines commitment to apoptosis, has central roles in tumorigenesis and chemoresistance. Its three factions of interacting proteins include the BH3-only proteins (e.g., Bim, Puma, Bad, Noxa), which transduce diverse cytotoxic signals to the mammalian pro-survival proteins (Bcl-2, Bcl-x(L), Bcl-w, Mcl-1, A-1), whereas Bax and Bak, when freed from pro-survival constraint, provoke the mitochondrial permeabilization that triggers apoptosis. We have discovered unexpected specificity in their interactions. Only Bim and Puma, which mediate multiple cytotoxic signals, engage all the pro-survival proteins. Noxa and Bad instead bind subsets and cooperate in killing, indicating that apoptosis requires neutralization of different pro-survival subsets. Furthermore, Mcl-1 and Bcl-x(L), but not Bcl-2, directly sequester Bak in healthy cells, and Bak is freed only when BH3-only proteins neutralize both its guards. BH3-only proteins such as Bim are tumor suppressors and mediate many of the cytotoxic signals from anticancer agents. Hence, compounds mimicking them may prove valuable for therapy. Indeed, the recently described ABT-737 is a promising "BH3 mimetic" of Bad. We find that, like Bad, ABT-737 kills cells efficiently only if Mcl-1 is absent or down-regulated. Thus, manipulation of apoptosis by targeting the Bcl-2 family has exciting potential for cancer treatment.

Animals↗
PubMed2004

On the polarization of chiral main-chain liquid-crystalline elastomers.

A mechanism of developing a polarization in a chiral main-chain liquid-crystalline polymer by aligning the dipoles of the monomers is explored. It is shown that the polarization of a pure liquid crystal elastomer is zero in equilibrium due to rotation of the director in the elastomer. A constraint or specific non-ideality in the elastomer is required to prevent this relaxation of the director in order to realize a non-zero polarization. Three methods that circumvent this result are explored. We consider the effect of an oscillating shear, the pinning effect of the layers in a smectic-A composed of chiral smectogens and a binary mixture of chiral main chains and non-chiral side chains. Each of these methods is shown to produce a polarization, which is much larger than that produced in a piezoelectric alpha-quartz crystal per unit stress.

Journal Article↗
PubMed2003

Bfk: a novel weakly proapoptotic member of the Bcl-2 protein family with a BH3 and a BH2 region.

Proteins of the Bcl-2 family are critical regulators of apoptosis. Proapoptotic members, like Bax, contain three of the four Bcl-2 homology regions (BH1-3), while BH3-only proteins, like Bim, possess only the short BH3 motif. Database searches revealed Bfk, an unusual novel member of the Bcl-2 family that contains a BH2 and BH3 region but not BH1 or BH4. Bfk is thus most closely related to Bcl-G(L). It lacks a C-terminal membrane anchor and is cytosolic. Enforced expression of Bfk weakly promoted apoptosis and antagonized Bcl-2's prosurvival function. Like Bcl-G(L), Bfk did not bind to any Bcl-2 family members, even though its BH3 motif can mediate association with prosurvival proteins. Low amounts of Bfk were found in stomach, ovary, bone marrow and spleen, but its level in the mammary gland rose markedly during pregnancy, suggesting that Bfk may play a role in mammary development.

Amino Acid Sequence↗
PubMed2002

Uncertainties in the role of land vegetation in the carbon cycle.

Since the late 1950s the CO2 concentration of the atmosphere has been increasing by around 0.5-3 ppm per year. Understanding of carbon sinks is vital to understanding this trend and its future behaviour. Here we examine some of the factors which may affect the proportion of anthropogenic CO2 ending up in the atmosphere in the present and in the future, and variability in the CO2 increase from one year to another. We also examine the evidence for the potential of terrestrial ecosystem carbon sinks to take up or release CO2. In some cases, a careful re-examination of the research methods used to deduce present and future feedbacks may be necessary. The most advanced technology and the most complex models do not necessarily produce reliable results. They should be carefully checked against a general background knowledge of ecological processes before their results are accepted.

Agriculture↗
PubMed2001

Ceramide modulates nicotinic receptor-dependent Ca(2+) signaling in rat chromaffin cells.

Ceramide, which is an integral component of the sphingomyelin signaling pathway, can attenuate voltage-gated Ca(2+) channel (VGCC) activity in a number of cell types. The aim of the present study was to determine whether ceramide can also modulate VGCC activity, and as a consequence nicotinic receptor-dependent Ca(2+) signaling and catecholamine secretion, in rat adrenal chromaffin cells. Short-term C(6)-ceramide (CER) treatment dose-dependently inhibited nicotine (NIC)-induced peak intracellular Ca(2+) transients. Sphingomyelinase elicited similar responses, whereas the inactive ceramide analog C(2)-dihydroceramide had no effect on NIC-induced Ca(2+) transients. CER suppressed KCl- and NIC-induced Ca(2+) transients to a similar extent, suggesting that the voltage-gated Ca(2+) channel was a primary site of inhibition. In direct support of this concept, whole-cell patch-clamp analysis demonstrated that CER and sphingomyelinase significantly reduced peak Ca(2+) currents. Pretreatment with staurosporine significantly attenuated CER-dependent inhibition of both NIC-induced Ca(2+) transients and peak Ca(2+) current, suggesting that the effects of CER are mediated at least in part by protein kinase C. Consistent with suppressed Ca(2+) signaling, CER also significantly inhibited NIC-induced catecholamine secretion measured at the single-cell level by carbon fiber amperometry. This effect of CER was also significantly attenuated by pretreatment with staurosporine These data demonstrate that the sphingomyelin signaling pathway can modulate nicotinic receptor-dependent Ca(2+) signaling and catecholamine secretion in rat chromaffin cells.

Adrenal Medulla↗
PubMed2001

Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim.

Bim is a proapoptotic protein of the Bcl-2 family that shares only the short BH3 domain with other members. It has three isoforms, apparently produced by alternative splicing. The demonstration that Bim is essential for certain apoptotic responses and to prevent overproduction of hematopoietic cells suggests that it may be a tumor suppressor. We have, therefore, investigated the organization of the mouse Bim gene, delineating its promoter and splicing, and positioned the gene on both mouse and human chromosomes. Bim has six exons, but the third is a facultative intron that is spliced out in the mRNAs for the smaller isoforms (BimL and BimS), but not that encoding the largest isoform (BimEL). The 0.8-kb region 5' to exon 1, which contains a TATA-less promoter and binding sites for several transcription factors, can drive expression of a reporter gene. Mouse Bim localizes to the distal third of Chromosome (Chr) 2, near the F-G boundary, and its human counterpart to Chr 2q12 or q13. Deletions of these bands have been reported in ten tumors (eight hematopoietic), reinforcing the possibility that Bim is a tumor suppressor. These findings should help to clarify the regulation of Bim expression and to assess whether mutations involving Bim contribute to neoplastic and other diseases.

Alternative Splicing↗
PubMed2001

Life-or-death decisions by the Bcl-2 protein family.

In response to intracellular damage and certain physiological cues, cells enter the suicide program termed apoptosis, executed by proteases called caspases. Commitment to apoptosis is typically governed by opposing factions of the Bcl-2 family of cytoplasmic proteins. Initiation of the proteolytic cascade requires assembly of certain caspase precursors on a scaffold protein, and the Bcl-2 family determines whether this complex can form. Its pro-survival members can act by sequestering the scaffold protein and/or by preventing the release of apoptogenic molecules from organelles such as mitochondria. Pro-apoptotic family members act as sentinels for cellular damage: cytotoxic signals induce their translocation to the organelles where they bind to their pro-survival relatives, promote organelle damage and trigger apoptosis.

Animals↗
PubMed2001

A structural genomics approach to the study of quorum sensing: crystal structures of three LuxS orthologs.

BACKGROUND: Quorum sensing is the mechanism by which bacteria control gene expression in response to cell density. Two major quorum-sensing systems have been identified, system 1 and system 2, each with a characteristic signaling molecule (autoinducer-1, or AI-1, in the case of system 1, and AI-2 in system 2). The luxS gene is required for the AI-2 system of quorum sensing. LuxS and AI-2 have been described in both Gram-negative and Gram-positive bacterial species and have been shown to be involved in the expression of virulence genes in several pathogens. RESULTS: The structure of the LuxS protein from three different bacterial species with resolutions ranging from 1.8 A to 2.4 A has been solved using an X-ray crystallographic structural genomics approach. The structure of LuxS reported here is seen to have a new alpha-beta fold. In all structures, an equivalent homodimer is observed. A metal ion identified as zinc was seen bound to a Cys-His-His triad. Methionine was found bound to the protein near the metal and at the dimer interface. CONCLUSIONS: These structures provide support for a hypothesis that explains the in vivo action of LuxS. Specifically, acting as a homodimer, the protein binds a methionine analog, S-ribosylhomocysteine (SRH). The zinc atom is in position to cleave the ribose ring in a step along the synthesis pathway of AI-2.

Amino Acid Sequence↗
PubMed2001

Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim.

Apoptosis is triggered when proapoptotic members of the Bcl-2 protein family bearing only the BH3 association domain bind to Bcl-2 or its homologs and block their antiapoptotic activity. To test whether loss of the BH3-only protein Bim could prevent the cellular attrition caused by Bcl-2 deficiency, we generated mice lacking both genes. Mice without Bcl-2 have a fragile lymphoid system, become runted, turn gray, and succumb to polycystic kidney disease. Concomitant absence of Bim prevented all these disorders. Indeed, loss of even one bim allele restored normal kidney development, growth, and health. These results demonstrate that Bim levels set the threshold for initiation of apoptosis in several tissues and suggest that degenerative diseases might be alleviated by blocking BH3-only proteins.

Alleles↗
PubMed2001

Entry of gut lymph into the circulation primes rat neutrophil respiratory burst in hemorrhagic shock.

OBJECTIVE: Endothelial cell injury by polymorphonuclear neutrophil (neutrophil [PMN]) respiratory burst after trauma and hemorrhagic shock (T/HS) predisposes subjects to acute respiratory distress syndrome and multiple organ failure. T/HS mesenteric lymph injures endothelial cell and lymph duct ligation (LDL) before T/HS prevents pulmonary injury. We investigated the role of mesenteric lymph in PMN priming by T/HS. DESIGN: Prospective experiment in rats. SETTING: University hospital laboratory. SUBJECTS: Adult male rats. INTERVENTIONS: Mesenteric lymph was obtained from rats undergoing T/HS (30 mm Hg, 90 mins) or sham shock (T/SS). Plasma was harvested from uninstrumented control (UC), T/HS, T/SS, and T/HS+LDL rats. PMNs were isolated from UC, T/HS, and T/HS+LDL rats. MEASUREMENTS AND MAIN RESULTS: PMNs from UC rats were incubated in buffer, 1% T/HS lymph, and 1% T/SS lymph. PMNs from UC rats were incubated in UC, T/HS, T/SS, and T/HS+LDL plasma. PMN respiratory burst was initiated by using macrophage inflammatory protein (MIP)-2/platelet-aggregating factor (PAF) or phorbol myristate acetate. Cytosolic calcium ([Ca2+]i) responses to MIP-2/PAF were assayed in PMN from UC, T/HS, and T/HS+LDL rats. PMN preincubated in T/HS lymph showed significant elevations in MIP/PAF-elicited respiratory burst compared with T/HS lymph or buffer only (p <.05; analysis of variance/Tukey's test). T/HS lymph incubation also increased (p <.05) phorbol myristate acetate elicited respiratory burst compared with buffer or T/SS. Preincubation in T/HS plasma increased MIP-2/PAF-elicited respiratory burst (p <.05) compared with UC or T/SS plasma. LDL blocked T/HS priming of respiratory burst. Control PMN [Ca2+]i responses to MIP-2 and PAF were low. T/SS PMN were significantly more responsive, but the T/HS PMN showed still higher responses (p <.01). LDL reversed the priming of [Ca2+]i responses by T/HS (p <.01). CONCLUSIONS: PMNs are primed by T/HS lymph but not T/SS lymph and by T/HS plasma but not T/SS plasma. LDL before shock prevents T/HS plasma from priming PMN. The magnitude of respiratory burst found here paralleled the [Ca2+]i responses seen to receptor dependent initiating agonists. Mesenteric lymph is both necessary and sufficient to prime PMN after T/HS in the rat, and it primes PMN in part by enhancing [Ca2+]i responses to G-protein coupled chemoattractants. Mesenteric lymph mediates postshock PMN dysfunction.

Analysis of Variance↗
PubMed2001

The immunomodulatory effects of damage control abdominal packing on local and systemic neutrophil activity.

BACKGROUND: Damage control laparotomy (DCL) with abdominal packing has become commonplace after major trauma, but the immune consequences of DCL are unknown. METHODS: We collected 37 fluid samples from laparotomy pads (LPF) removed from 28 patients 1 hour to 7 days after DCL. Samples from eight patients who underwent serial packing were assayed for their mediator content and effects on neutrophil (PMN) function. Respiratory burst (RB) to N-formyl-methionyl-leucyl-phenylalanine and phorbol myristate acetate (PMA), as well as PMN calcium ([Ca2+]i) mobilization by GRO-alpha and platelet-activating factor were studied using dihydrorhodamine and fura-2-acetoxymethyl ester fluorescence. Brief exposure to 20% LPF (LPF20) modeled LPF acting on peritoneal PMNs and 2% LPF (LPF2) modeled the systemic effects on PMNs. Endotoxin (ETX), GRO-alpha, and leukotriene B4 were assayed by enzyme-linked immunosorbent assay. Data analysis was by analysis of variance with Dunn's comparisons or the Mann-Whitney test when indicated. RESULTS: LPF increased N-formyl- methionyl-leucyl-phenylalanine-induced RB from 0.4 +/- 0.1 x 103 counts per second (control) to 0.7 +/- 0.1 (LPF2) to 1.3 +/- 0.3 (LPF20) (p < 0.05), with LPF2 increasingly active at later times after injury. PMA-elicited RB was primed only by LPF2 from < 24 hours. Both LPF2 and LPF20 markedly suppressed GRO-alpha [Ca2+]i flux. Suppression by LPF2 was maximal at < 24 hours, abating after 48 hours. Suppression of GRO-alpha response was dose dependent: 150 +/- 8 nmol/L in control PMNs, 97 +/- 19 after LPF2, and 59 +/- 4 after LPF20 (all p < 0.05). [Ca2+]i flux after 1 nmol/L platelet-activating factor was only suppressed (from 181 +/- 14 nmol/L to 149 +/- 15 nmol/L, p < 0.05) by LPF20. LPF contained ETX, GRO-alpha, and leukotriene B4 at 10- to 20-fold plasma concentration in trauma patients. CONCLUSION: DCL results in peritoneal ETX and mediator accumulation even when cultures are sterile. LPF exposure primes PMN RB elicited by nonreceptor- (PMA) or receptor-coupled agonists that resist receptor desensitization. Conversely, LPF suppresses PMN responses to agonists that undergo receptor desensitization at high mediator concentrations. PMN dysfunction in such circumstances probably reflects a concomitant priming of some cell functions (e.g., RB) and desensitization of other (receptor-dependent) functions after an exposure to concentrated mediators. Peritoneal mediator production after DCL may be ETX driven, and may contribute to systemic inflammatory response syndrome. DCL trades early hemostasis for later inflammation. This should be considered in planning management strategies.

Abdominal Injuries↗