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PubMed2004

Transition path sampling study of classical rate-promoting vibrations.

It is now widely accepted that there is a class of enzymatic proton transfer reactions, which proceed through quantum tunneling. In a series of papers we have argued that some experimental features of these reactions can be explained by assuming the presence of a "rate-promoting" vibration which brings donor and acceptor closer together, thus leading to rate enhancement. There has never been a study of this effect for classical systems. We used transition path sampling to study the equivalent classical problem and found a complicated dynamical behavior that cannot be captured by transition state theory. Slow promoting vibrations lead to reactive trajectories that overshoot the saddle point, but on the other hand the short period of fast oscillations allows the reactants to stay only briefly in a low-barrier regime. There is a competition between these effects, which results to an intermediate value for the frequency of the rate-promoting vibration that is optimal for enhancing the rate.

Algorithms↗

PubMed2005

Stalling HIV through social marketing: prospects in Pakistan.

Over the last two decades HIV/AIDS has evolved from a series of interesting case-reports to a growing epidemic that threatens the entire world. It is feared to cause devastation among large pockets of populations and may roll back more than thirty years of public health achievements. This killer disease has been more amenable to behavioral change than by provision of curative services and attempts are being made to educate the public about this threat. Various techniques of promotion have been tried through out the world including television dramas/soaps, mass media and school curricula. Social marketing is an evolving strategy used to influence human behavior and choices. By using the principles of marketing and promoting behavior as a product, social marketers attempt to understand the dynamics of human behaviour and devise messages and products to change, modify, accept or reject unsafe behaviors or practices. Thus, social marketers provide an effective force to combat the spread of HIV and may serve to be invaluable allies in health promotion efforts. In a complex and diversified cultural milieu of Pakistan, social marketing can have a significant impact on health determinants and the conditions that will facilitate the adoption of health-oriented behaviors and practices. This paper gives an account of the elements needed for the success of a health promotion strategy adopted in a developing country and makes a case for social marketing to be adopted as the lead strategy for stalling HIV/AIDS in Pakistan.

HIV Infections↗

PubMed2005

The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation.

Deciphering regulatory events that drive malignant transformation represents a major challenge for systems biology. Here, we analyzed genome-wide transcription profiling of an in vitro cancerous transformation process. We focused on a cluster of genes whose expression levels increased as a function of p53 and p16(INK4A) tumor suppressors inactivation. This cluster predominantly consists of cell cycle genes and constitutes a signature of a diversity of cancers. By linking expression profiles of the genes in the cluster with the dynamic behavior of p53 and p16(INK4A), we identified a promoter architecture that integrates signals from the two tumor suppressive channels and that maps their activity onto distinct levels of expression of the cell cycle genes, which, in turn, correspond to different cellular proliferation rates. Taking components of the mitotic spindle as an example, we experimentally verified our predictions that p53-mediated transcriptional repression of several of these novel targets is dependent on the activities of p21, NFY, and E2F. Our study demonstrates how a well-controlled transformation process allows linking between gene expression, promoter architecture, and activity of upstream signaling molecules.

Animals↗

PubMed2004

Dynamic targeting of microtubules by TPPP/p25 affects cell survival.

Recently we identified TPPP/p25 (tubulin polymerization promoting protein/p25) as a brain-specific unstructured protein that induced aberrant microtubule assemblies and ultrastructure in vitro and as a new marker for Parkinson's disease and other synucleopathies. In this paper the structural and functional consequences of TPPP/p25 are characterized to elucidate the relationship between the in vitro and the pathological phenomena. We show that at low expression levels EGFP-TPPP/p25 specifically colocalizes with the microtubule network of HeLa and NRK cells. We found that the colocalization was dynamic (tg=5 seconds by fluorescence recovery after photobleaching) and changed during the phases of mitosis. Time-lapse and immunofluorescence experiments revealed that high levels of EGFP-TPPP/p25 inhibited cell division and promoted cell death. At high expression levels or in the presence of proteosome inhibitor, green fusion protein accumulated around centrosomes forming an aggresome-like structure protruding into the nucleus or a filamentous cage of microtubules surrounding the nucleus. These structures showed high resistance to vinblastin. We propose that a potential function of TPPP/p25 is the stabilization of physiological microtubular ultrastructures, however, its upregulation may directly or indirectly initiate the formation of aberrant protein aggregates such as pathological inclusions.

Animals↗

PubMed1992

A small effect of weight bearing in promoting fracture healing.

We treated 66 consecutive type IV comminuted femoral shaft fractures with static Grosse-Kempf interlocking nails and followed them up for at least 1 year (median 27 months). Although the effect of weight bearing was completely lost, 60 fractures healed primarily without dynamization. We conclude that weight bearing contributes only an auxiliary role in promoting fracture healing, and that the most decisive role is adequate mechanical stability with sufficient nutrition.

Adolescent↗

PubMed2006

Highly sensitive determination of transient generation of biophotons during hypersensitive response to cucumber mosaic virus in cowpea.

The hypersensitive response (HR) is one mechanism of the resistance of plants to pathogen infection. It involves the generation of reactive oxygen species (ROS) which have crucial roles in signal transduction or as toxic agents leading to cell death. Often, ROS generation is accompanied by an ultraweak photon emission resulting from radical reactions that are initiated by ROS through the oxidation of living materials such as lipids, proteins, and DNA. This photon emission, referred to as 'biophotons', is extremely weak, but, based on the technique of photon counting imaging, a system has been developed to analyse the spatiotemporal properties of photon emission. Using this system, the dynamics of photon emission which might be associated with the oxidative burst, which promotes the HR, have been determined. Here, the transient generation of biophotons is demonstrated during the HR process in cowpea elicited by cucumber mosaic virus. The distinctive dynamics in spatiotemporal properties of biophoton emission during the HR expression on macroscopic and microscopic levels are also described. This study reveals the involvement of ROS generation in biophoton emission in the process of HR through the determination of the inhibitory effect of an antioxidant (Tiron) on biophoton emission.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗

PubMed2000

Caffeine during sleep deprivation: sleep tendency and dynamics of recovery sleep in rats.

The adenosine antagonist caffeine disrupts sleep, but whether caffeine promotes wakefulness by interfering with the expression of sleep or by attenuating sleepiness is unknown. The ability of caffeine to reduce sleep tendency in rats was directly tested by quantifying the number of stimuli needed to maintain wakefulness during sleep deprivation for 6 h after systemic caffeine treatment. In addition, the influence of caffeine on the dynamics between nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep was investigated by comparing the magnitude and time course of the compensatory sleep responses for 42 h postsleep deprivation. Caffeine significantly reduced the attempts to sleep during sleep deprivation, F(1,9) 8.83, p = 0.0157; 44.9% of vehicle), but did not change compensatory slow-wave activity during recovery sleep. During the initial recovery phase, caffeine suppressed compensatory REM sleep and reduced, but did not block, compensatory NREM sleep duration and continuity. By 42 h postsleep deprivation, the amount of NREM recovered (70.0% of deficit) did not differ from vehicle. In contrast, the REM sleep deficit recovered after caffeine (100%) was more than after vehicle (43.9%). Thus, caffeine slowed the rate of compensatory sleep after sleep deprivation, as indexed by the duration of sleep states and sleep continuity.

Animals↗

PubMed2002

Minor alteration of microtubule dynamics causes loss of tension across kinetochore pairs and activates the spindle checkpoint.

We have previously identified the opium alkaloid noscapine as a microtubule interacting agent that binds stoichiometrically to tubulin and alters its conformation. Here we show that, unlike many other microtubule inhibitors, noscapine does not significantly promote or inhibit microtubule polymerization. Instead, it alters the steady-state dynamics of microtubule assembly, primarily by increasing the amount of time that the microtubules spend in an attenuated (pause) state. Further studies reveal that even at high concentrations, noscapine does not alter the tubulin polymer/monomer ratio in HeLa cells. Cells treated with noscapine arrest at mitosis with nearly normal bipolar spindles. Strikingly, although most of the chromosomes in these cells are aligned at the metaphase plate, the rest remain near the spindle poles, both of which exhibit loss of tension across kinetochore pairs. Furthermore, levels of the spindle checkpoint proteins Mad2, Bub1, and BubR1 decrease by 138-, 3.7-, and 3.9-fold, respectively, at the kinetochore region upon chromosome alignment. Our results thus suggest that an exquisite control of microtubule dynamics is required for kinetochore tension generation and chromosome alignment during mitosis. Our data also support the idea that Mad2 and Bub1/BubR1 respond to kinetochore-microtubule attachment and/or tension to different degrees.

Animals↗

PubMed2006

Rho GTPase activity modulates paramyxovirus fusion protein-mediated cell-cell fusion.

The paramyxovirus fusion protein (F) promotes fusion of the viral envelope with the plasma membrane of target cells as well as cell-cell fusion. The plasma membrane is closely associated with the actin cytoskeleton, but the role of actin dynamics in paramyxovirus F-mediated membrane fusion is unclear. We examined cell-cell fusion promoted by two different paramyxovirus F proteins in three cell types in the presence of constitutively active Rho family GTPases, major cellular coordinators of actin dynamics. Reporter gene and syncytia assays demonstrated that expression of either Rac1(V12) or Cdc42(V12) could increase cell-cell fusion promoted by the Hendra or SV5 glycoproteins, though the effect was dependent on the cell type expressing the viral glycoproteins. In contrast, RhoA(L63) decreased cell-cell fusion promoted by Hendra glycoproteins but had little affect on SV5 F-mediated fusion. Also, data suggested that GTPase activation in the viral glycoprotein-containing cell was primarily responsible for changes in fusion. Additionally, we found that activated Cdc42 promoted nuclear rearrangement in syncytia.

Animals↗

PubMed2006

2-color photobleaching experiments reveal distinct intracellular dynamics of two components of the Hsp90 complex.

The abundant molecular chaperone Hsp90 functions in association with co-chaperones including p23 to promote the folding and maturation of a subset of cytosolic proteins. "Fluorescence recovery after photobleaching" (FRAP) experiments showed that the dynamics of p23 in live cells is dictated by Hsp90. Since Hsp90 is present in large excess over p23, the mobility of Hsp90 could conceivably be quite different. To facilitate the analysis and to allow a direct comparison with p23, we developed a 2-color FRAP technique. Two test proteins are expressed as fusion proteins with the two spectrally separable fluorescent proteins mCherry and enhanced green fluorescent protein (EGFP). The 2-color FRAP technique is powerful for the concomitant recording of two proteins located in the same area of a cell, two components of the same protein complex, or mutant and wild-type versions of the same protein under identical experimental conditions. 2-color FRAP of Hsp90 and p23 is virtually indistinguishable, consistent with the notion that they are both engaged in a multitude of large protein complexes. However, when Hsp90-p23 complexes are disrupted by the Hsp90 inhibitor geldanamycin, p23 moves by free diffusion while Hsp90 maintains its low mobility because it remains bound in remodeled multicomponent complexes.

Cytosol↗

PubMed2004

Dynamics and compartmentation of the nucleolar processing machinery.

In active nucleoli, machineries involved in the biogenesis of ribosomal RNAs (rRNAs) are compartmentalized. The late rRNA processing proteins are localized in the granular component (GC). Here we investigate the behavior of these proteins when production of 28S is impaired and when this blockage is reversed. The 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) provokes dispersion of rDNA clusters and we demonstrate that DRB induces disconnection of the late rRNA processing proteins from the transcription sites. These processing proteins are still associated in independent masses without detectable 28S rRNA, indicating that compartmentation of the late rRNA processing machinery is not necessarily linked to processing activity. Removing DRB reverses this disconnection and promotes rRNA processing. Nucleolar reformation occurs in two successive steps, dynamic recruitment to transcription sites of the processing proteins, followed by rDNA compaction. We demonstrate that both steps are sensitive to temperature, suggesting an energy-dependent process. Traffic of processing proteins analyzed by fluorescence recovery after photobleaching is similar in masses disconnected from transcription sites and in the granular component of the active nucleolus. This suggests that protein dynamics and interactions, and not only their processing activity, determine compartmentation of the nucleolar machineries.

Active Transport, Cell Nucleus↗

PubMed2002

bcl-2 overexpression promotes myocyte proliferation.

To determine the influence of Bcl-2 on the developmental biology of myocytes, we analyzed the population dynamics of this cell type in the heart of transgenic (TG) mice overexpressing Bcl-2 under the control of the alpha-myosin heavy chain promoter. TG mice and non-TG (wild type, WT) mice were studied at 24 days, 2 months, and 4 months after birth. Bcl-2 overexpression produced a significant increase in the percentage of cycling myocytes and their mitotic index. These effects were strictly connected to the expression of the transgene, as demonstrated in isolated myocytes. The formation of mitotic spindle and contractile ring was identified in replicating cells. These typical aspects of mitosis were complemented with the demonstration of karyokinesis and cytokinesis to provide structural evidence of cell division. Apoptosis was low at all ages and was not affected by Bcl-2. The higher cell replication rate in TG was conditioned by a decrease in the expression of the cell-cycle inhibitors, p21(WAF1) and p16(INK4a), and by an increase in Mdm2-p53 complexes. In comparison with WT, TG had 0.4 x 10(6), 0.74 x 10(6), and 1.2 x 10(6) more myocytes in the left ventricle at 24 days, 2 months, and 4 months, respectively. Binucleated myocytes were 12% and 25% larger in WT than in TG mice at 2 and 4 months of age. Taken together, these observations reveal a previously uncharacterized replication-enhancing function of Bcl-2 in myocytes in vivo in the absence of stressful conditions.

Animals↗

PubMed2006

Active PHO5 chromatin encompasses variable numbers of nucleosomes at individual promoters.

Transcriptional activation is often associated with chromatin remodeling. However, little is known about the dynamics of remodeling of nucleosome arrays in vivo. Upon induction of Saccharomyces cerevisiae PHO5, a novel kinetic assay of DNA methyltransferase accessibility showed that nucleosomes adjacent to the histone-free upstream activating sequence (UASp1) are disrupted earlier and at higher frequency in the cell population than are those more distal. Individually cloned molecules, each representing the chromatin state of a full promoter from a single cell, revealed multiple promoter classes with either no remodeling or variable numbers of disrupted nucleosomes. Individual promoters in the remodeled fraction were highly enriched for contiguous blocks of disrupted nucleosomes, the majority of which overlapped the UAS region. These results support a probabilistic model in which chromatin remodeling at PHO5 spreads from sites of transactivator association with DNA and attenuates with distance.

Acid Phosphatase↗

PubMed2006

Nitric oxide and synaptic dynamics in the adult brain: physiopathological aspects.

The adult brain retains the capacity to rewire mature neural circuits in response to environmental changes, brain damage or sensory and motor experiences. Two plastic processes, synaptic remodeling and neurogenesis, have been the subject of numerous studies due to their involvement in the maturation of the nervous system, their prevalence and re-activation in adulthood, and therapeutic relevance. However, most of the research looking for the mechanistic and molecular events underlying synaptogenic phenomena has been focused on the extensive synaptic reorganization occurring in the developing brain. In this stage, a vast number of synapses are initially established, which subsequently undergo a process of activity-dependent refinement guided by target-derived signals that act as synaptotoxins or synaptotrophins, promoting either loss or consolidation of pre-existing synaptic contacts, respectively. Nitric oxide (NO), an autocrine and/or paracrine-acting gaseous molecule synthesized in an activity-dependent manner, has ambivalent actions. It can act by mediating synapse formation, segregation of afferent inputs, or growth cone collapse and retraction in immature neural systems. Nevertheless, little information exists about the role of this ambiguous molecule in synaptic plasticity processes occurring in the adult brain. Suitable conditions for elucidating the role of NO in adult synaptic rearrangement include physiopathological conditions, such as peripheral nerve injury. We have recently developed a crush lesion model of the XIIth nerve that induces a pronounced stripping of excitatory synaptic boutons from the cell bodies of hypoglossal motoneurons. The decline in synaptic coverage was concomitant with de novo expression of the neuronal isoform of NO synthase in motoneurons. We have demonstrated a synaptotoxic action of NO mediating synaptic withdrawal and preventing synapse formation by cyclic GMP (cGMP)-dependent and, probably, S-nitrosylation-mediated mechanisms, respectively. This action possibly involves the participation of other signaling molecules working together with NO. Brain-derived neurotrophic factor (BDNF), a target-derived synaptotrophin synthesized and released postsynaptically in an activity-dependent form, is a potential candidate for effecting such a concerted action. Several items of evidence support an interrelationship between NO and BDNF in the regulation of synaptic remodeling processes in adulthood: i) BDNF and its receptor TrkB are expressed by motoneurons and upregulated by axonal injury; ii) they promote axon arborization and synaptic formation, and modulate the structural dynamics of excitatory synapses; iii) NO and BDNF each control the production and activity of the other at the level of individual synapses; iv) the NO/cGMP pathway inhibits BDNF secretion; and finally, v) BDNF protects F-actin from depolymerization by NO, thus preventing the collapsing and retracting effects of NO on growth cones. Therefore, we propose a mechanism of action in which the NO/BDNF ratio regulates synapse dynamics after peripheral nerve lesion. This hypothesis also raises the possibility that variations in this NO/BDNF balance constitute a common hallmark leading to synapse loss in the progression of diverse neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases.

Animals↗

PubMed2000

Biomimetic copper(I)--CO complexes: a structural and dynamic study of a cali.

Four novel calix[6]arene-based cuprous complexes are described. They present a biomimetic tris(imidazole) coordination core associated with a hydrophobic cavity that wraps the apical binding site. Each differs from the other by the methyl or ethyl substituents present on the phenoxyl groups (OR1) and on the imidazole arms (NR2) of the calix[6]arene structure. In solution, stable CO complexes were obtained. We have investigated their geometrical and dynamic properties with respect to the steric demand. IR and NMR studies revealed that, in solution, these complexes adopted two distinct conformations. The preferred conformation was dictated only by the size of the OR1 group. When R1 was an ethyl group, the complex preferentially adopted a flattened C3-symmetrical structure. The corresponding helical enantiomers were in conformational equilibrium, which, however, was slow on the 1H NMR time scale at -80 degrees C. When R1 was a methyl group, the low-temperature NMR spectra revealed the partial inclusion of one tBu group. The complex wobbled between three dissymmetric but equivalent conformations. Hence, small differences in the steric demand of the calixarene's skeleton changed the geometry and dynamics of the system. Indeed, this supramolecular control was promoted by the strong conformational coupling between the metal center and the host structure. Interestingly, this was not only the result of a covalent preorganization, but also stemmed from weak interactions within the hydrophobic pocket. The vibrational spectra of the bound CO were revealed to be a sensitive gauge of this supramolecular behavior, similar to copper proteins in which allosteric effects are common.

Carbon Monoxide↗

PubMed1997

Actin and tropomyosin isoforms in morphogenesis.

The major components of the actin microfilament system, actin and tropomyosin (Tm), are encoded by multigene families. There are at least 6 actin and over 20 Tm isoforms in mammals. The observation that isoforms are expressed in a tissue-specific manner has encouraged the hypothesis that they contribute to the formation of cell type-specific structures. Recent studies have indicated that certain specific isoforms do play unique structural roles. One nonmuscle actin isoform, beta, is implicated in the regulation of cell spreading and membrane organisation. The intracellular location of beta-actin mRNA has been shown to be regulated by growth factor stimulation of signal transduction pathways. Actin isoforms have also been shown to differ in their contractile properties in both muscle and non-muscle cells. Tropomyosins have been found to show isoform specific regulation in response to cell transformation. This has correlated with the view that some isoforms of tropomyosin promote filament stability whereas others are associated with more dynamic structures. Neuronal development and maturation are accompanied by dynamic spatial sorting of tropomyosin isoforms into different cellular compartments. It is now apparent that isoforms of these proteins perform different structural tasks. The challenge is now to link the significance of spatial sorting to the different physicochemical properties of these isoforms.

Actin Cytoskeleton↗

PubMed2005

Extracellular nucleotides activate Runx2 in the osteoblast-like HOBIT cell line: a possible molecular link between mechanical stress and osteoblasts' response.

Dynamic mechanical loading increases bone density and strength and promotes osteoblast proliferation, differentiation and matrix production, by acting at the gene expression level. Molecular mechanisms through which mechanical forces are conversed into biochemical signalling in bone are still poorly understood. A growing body of evidence point to extracellular nucleotides (i.e., ATP and UTP) as soluble factors released in response to mechanical stimulation in different cell systems. Runx2, a fundamental transcription factor involved in controlling osteoblasts differentiation, has been recently identified as a target of mechanical signals in osteoblastic cells. We tested the hypothesis that these extracellular nucleotides could be able to activate Runx2 in the human osteoblastic HOBIT cell line. We found that ATP and UTP treatments, as well as hypotonic stress, promote a significant stimulation of Runx2 DNA-binding activity via a mechanism involving PKC and distinct mitogen-activated protein kinase cascades. In fact, by using the specific inhibitors SB203580 (specific for p38 MAPK) and PD98059 (specific for ERK-1/2 MAPK), we found that ERK-1/2, but not p38, play a major role in Runx2 activation. On the contrary, another important transcription factor, i.e., Egr-1, that we previously demonstrated being activated by extracellular released nucleotides in this osteoblastic cell line, demonstrated to be susceptible to both ERK-1/2 and p38 kinases. These data suggest a possible differential involvement of these two transcription factors in response to extracellularly released nucleotides. The biological relevance of our data is strengthened by the finding that a target gene of Runx2, i.e., Galectin-3, is up-regulated by ATP stimulation of HOBIT cells with a comparable kinetic of that found for Runx2. Since it is known that osteocytes are the primary mechanosensory cells of the bone, we hypothesize that they may signal mechanical loading to osteoblasts through release of extracellular nucleotides. Altogether, these data suggest a molecular mechanism explaining the purinoreceptors-mediated activation of specific gene expression in osteoblasts and could be of help in setting up new pharmacological strategies for the intervention in bone loss pathologies.

Adenosine Triphosphate↗

PubMed2005

Vascular calcification in patients with renal failure: culprit or innocent bystander?

The mortality from cardiovascular events in CKD and dialysis patients is substantially higher than in the general population. VC is ubiquitous and progresses rapidly in this patient population. Although there has been progress in the understanding of the pathogenesis and correlates of VC, much work needs to be done in this area. The role of calcium and, probably, phosphate (obligatory participants) is unquestionable, but the understanding of the paracrine and molecular determinants of VC in renal failure is continuously evolving. VC is probably a dynamic process resulting from the imbalance between molecules that promote and those that inhibit VC. The understanding of latter area has recently evolved with identification of new signaling pathways with molecules such as osteoprotegerin, fetuin-A, and MPG. From a clinical perspective, new modalities such as EBCT and MDCT allow noninvasive detection and quantification of VC. VC may represent a potential useful index for prognostic stratification and treatment planning in patients who have renal failure. At present, however, the data on the prognostic value of VC are available only in populations of patients who have normal renal function. Large-scale, prospective, observational studies should be designed to identify the determinants of VC and to define the prognostic role of calcium scoring in cohorts of patients who have predialysis CKD and with ESRD.

Atherosclerosis↗