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PubMed2003

Reflective critique and collaborative practice in evaluation: promoting change in medical education.

The School of Medicine at the University of Tasmania has recently begun to implement a process of curriculum evaluation,which aims to reflect contemporary best practice in evaluation in tertiary pedagogy and medical education. Best practice must accommodate a broadening interest in cooperative and collaborative evaluation strategies among stakeholders, advances in applied qualitative educational research and recognition that critical reflection on practice is the cornerstone of professional education. This paper reports a recent evaluation strategy in a specific year-long unit in the second year of a six-year undergraduate medical degree. The paper begins by presenting the context; it then discusses and rationalises the evaluation strategy and presents findings. The paper concludes by arguing that curriculum evaluation as best practice must be reflective, informed by the scholarship of medical education, and internalized as a dynamic process that can promote sustainable change and improvement in medical curricula. Such an approach will contribute to an undergraduate medical curriculum that prepares students for the demands and complexities of medical practice.

Cooperative Behavior↗

PubMedDate not supplied

Education Now and Babies Later (ENABL): life history of a campaign to Postpone Sexual Involvement.

Education Now and Babies Later (ENABL), a statewide adolescent pregnancy prevention initiative, was inaugurated in California in June 1992. Developed by the state's Office of Family Planning, ENABL utilized a five-session intervention curriculum, Postponing Sexual Involvement (PSI), targeted at delaying the onset of sexual activity among youths aged 12-14. Schoolwide and community-based activities, along with a statewide media and public relations campaign, reinforced the intervention's message. Data collected from nearly 9,000 surveys, 75 individual interviews and 50 focus groups indicated that youths, parents and community representatives supported the initiative and endorsed its message, although most recommended changes to the curriculum. However, because no impact on sexual behavior could be demonstrated, the campaign was abruptly terminated in February 1996, despite recommendations that the program be retained and improved.

Adolescent↗

PubMed1999

Stable formation of a pyrimidine-rich loop hairpin in a cruciform promoter.

We have determined the solution structure of a TCC-loop hairpin in the cruciform promoter for the bacteriophage N4 virion RNA polymerase (N4 vRNAP). This hairpin and its complementary GGA-loop hairpin are extruded at physiological superhelical density and are required for vRNAP recognition. Contrary to its complementary GGA-loop, the three pyrimidines in the TCC-loop are all unpaired. However, with the help of two juxtaposed stem Watson-Crick G.C base-pairs, each nucleotide in the loop employs a special method to stabilize the hairpin structure. The resulting structures display extensive loop base-stacking rearrangement yet minor backbone distortion, which is largely accomplished through some loop zeta and alpha torsional angle changes. Consistent with the structural studies, UV melting of the GAAGCTCCGCTTC hairpin revealed a higher melting temperature (66 degrees C) than that of the GAACGTCCCGTTC hairpin (58 degrees C) with reversed stem G.C base-pairs, indicating significant contribution from the extra three loop-stem H-bonds. Thermodynamic parameters DeltaG degrees 25of the GAAGCTCCGCTTC hairpin and its complementary GAAGCGGAGCTTC hairpin are -4.1 and -4. 3 kcal/mol respectively, indicating approximately equal contribution of each hairpin to the cruciform formation of the N4 virion RNA polymerase promoter. No significant loop dynamics in the microsecond to millisecond NMR time-scale was observed, and the abundant well-defined exchangeable and non-exchangeable proton NOEs allowed us to efficiently determine a well-converged family for the final structures of the TCC-loop hairpin.

Base Pairing↗

PubMedDate not supplied

Breastfeeding practices in Indonesia.

UNLABELLED: Breastfeeding promotion program was started by the paediatricians and others in 1977, and is becoming a strong activity since 1990 it was declared by the President of the Republic of Indonesia as a National Movement. One year later the First Lady stated the importance of every Indonesian mother to breast-feed her baby, and thereafter many hospitals created the so called "Baby Friendly Hospital". In this occasion we only limit with eminent topics, i.e., "Exclusive Breast-feeding" in Indonesia, and "Breastfeeding amongst Working Mothers." In fact, until now the percentage of mothers who breastfeed exclusively is very low. Although the ever breastfed babies in Indonesia is 97% (Kodyat, 1996) but the data of the "Exclusive Breastfeeding" of Indonesia is just like Pakistan and Thailand, i.e. nearly 2 months, whereas the Philippines and Ceylon showed a figure of 4 months, and India 5 months. The Home Health Survey (SKRT) data in 1992 showed that 63.7% of the babies were exclusively breast-fed until 3 months. Three quarter of the quality of the exclusive breastmilk is quite good, enough or excellent, whereas the other one quarter is poor and this should be interfered by increasing the quality of the breastmilk and/or adding other formula, to prevent the baby of getting "failure to thrive" (Suharyono, 1996). Working mothers use to do "Early Weaning Practices" with very high mixed feeding practices (Matulessy et al, 1996). Mothers have to go to work because they have to support their family income, but unfortunately most of them ignore their main task of care their children. IN CONCLUSION: the experience in Indonesia proves that a very hard work should still be continued on the effort of promoting breastfeeding, especially regarding the two issues, i.e. "Exclusive breastfeeding" (we do hope at least until 4 months) and the other issue is regarding the "Working Mothers".

Breast Feeding↗

PubMed2004

Regulation of checkpoint kinases through dynamic interaction with Crb2.

ATR/Rad3-like kinases promote the DNA damage checkpoint through regulating Chk1 that restrains the activation of cyclin-dependent kinases. In fission yeast, Crb2, a BRCT-domain protein that is similar to vertebrate 53BP1, plays a crucial role in establishing this checkpoint. We report here that Crb2 regulates DNA damage checkpoint through temporal and dynamic interactions with Rad3, Chk1 and replication factor Cut5. The active complex formation between Chk1 and Crb2 is regulated by Rad3 and became maximal during the checkpoint arrest. Chk1 activation seems to need two steps of interaction changes: the loss of Rad3-Chk1 and Rad3-Crb2 interactions, and the association between hyperphosphorylated forms of Chk1 and Crb2. Chk1 is the major checkpoint kinase for the arrest of DNA polymerase mutants. The in vitro assay of Chk1 showed that its activation requires the presence of Crb2 BRCT. Hyperphosphorylation of Crb2 is also dependent on its intact BRCT. Finally, we show direct interaction between Rad3 and Crb2, which is inhibitory to Rad3 activity. Hence, Crb2 is the first to interact with both Rad3 and Chk1 kinases.

Cell Cycle↗

PubMed1986

The self in society: effects of social contexts on the sense of self.

It is assumed here that even as intimate and individualistic an experience as one's sense of self is affected by the social context in which the self-thoughts arise. As regards two major social worlds of childhood, family and school, it is postulated that the family's nurturent atmosphere fosters a more passive self-concept in contrast to a more dynamic sense of self promoted by the school's press toward achievement. Six predictions were derived that self-thoughts in the two contexts will differ in basic psycholinguistic characteristics, the types of verbs used to describe the self. To test these predictions children's three-minute descriptions of their family and of their school were content analysed into successive subject/verb/complement thought segments, from among which we selected out self-thoughts (segments with self as subject). An analysis of the types of verbs used in self-thoughts evoked by family versus school probes supported the six predicted differences in verb types derived from our postulate of a more passive self-concept in the family context. Specifically, in family more than in school contexts the self is perceived passively in terms of state rather than action verbs (of what one is rather than what one does); in terms of static states of being rather than dynamic states of becoming; in terms of overt actions rather than covert reactions; in terms of physical actions rather than social interactions; in terms of cold cognitions rather than hot affects; and in terms of simple affirmations rather than reflexive negations. These six manifestations of a more passive self in family than school social contexts are robust across age, gender and response modality.

Child↗

PubMed1990

An exogenous albumin promoter can become silent in dedifferentiated hepatoma variants as well as intertypic hybrids.

In order to evaluate the ability of an exogenous tissue-specific promoter to undergo the same dynamic changes in activity as the endogenous one, a 400-base pair fragment of the rat albumin proximal promoter, upstream of the bacterial gpt gene, has been introduced into rat hepatoma cells. Four clones containing a single integrated copy of the construct and producing substantial amounts of albumin and of xanthine phosphoribosyltransferase were isolated. These clones were subjected to two treatments known to result in silencing of the albumin gene: selection for dedifferentiated variants, and fusion with L-cell fibroblasts. In most cases, the albumin-negative progeny obtained no longer expressed the gpt gene: the exogenous promoter of 400 base pairs must contain the sequences required to respond to the mechanisms that block activity of the endogenous gene. However, exceptions were observed: the albumin-deficient variants of one clone remained xanthine phosphoribosyltransferase positive, and some of the albumin-negative hybrids from a different clone continued to produce xanthine phosphoribosyltransferase. These cases of dissociation in expression of the endogenous and the exogenous genes indicate that the site of integration of the alb-gpt construct in one clone renders the sequences insensitive to the mechanisms responsible for albumin gene silencing in dedifferentiated variants, and in the other clone to the mechanism of extinction. Consequently, the mechanisms causing gene silencing in variants and in intertypic hybrids must be different.

Aflatoxin B1↗

PubMed2026

Kinetic model of E-P condensates dynamics reveals transcriptional speed, noise, and energy trade-offs.

Gene regulation emerges from the interplay between chromatin architecture and the molecular interactions that connect enhancers to promoters. To study how these interactions shape transcriptional dynamics, we developed a kinetic model that incorporates multivalent enhancer-promoter binding, transcription factor competition, steric constraints, and chromatin accessibility. The model shows that competition among regulatory factors can generate bistable promoter states at the expense of increased transcriptional noise, revealing a direct relationship between bistability and noise levels. It further predicts that promoter response times are fastest in parameter regimes where bistability appears, suggesting that regulatory dynamics supporting two promoter states may intrinsically enable rapid activation. Extending this analysis, we find that intermediate chromatin accessibility and competition between activators and repressors both promote bistable enhancer-bound promoter clusters and fast switching at the cost of higher noise, whereas very high or low accessibility and noncompetitive transcription factors result in monostable expression states. The model also offers a quantitative framework to compare the energetic costs of different regulatory strategies, indicating that, under energy constraints, cells may favor adjusting transcription factor concentrations rather than altering chromatin accessibility, thereby linking energy expenditure to regulatory flexibility and robustness.

Kinetics↗

PubMed2000

Mature mRNAs accumulated in the nucleus are neither the molecules in transit to the cytoplasm nor constitute a stockpile for gene expression.

In higher eukaryotes, the regulation of pre-mRNA processing is still poorly known. The accumulation of various mature mRNAs, which can be observed in the nuclei of mammalian cells, is suggestive of a regulatory role of transport. However, the significance of these nuclear mRNA is presently unknown. We have used a tetracycline-regulated promoter to investigate the dynamics of these pools of mRNAs upon arrest of transcription. We observed, for beta-globin and LT-alpha genes, a slow disappearance of these mRNA from the nucleus, with an apparent half-life that is similar to their cytoplasmic half-life. In view of these dynamics, these mRNA cannot simply be mature mRNAs in transit to the cytoplasm. They could be mRNAs retained in the nucleus, provided that the regulation of mRNA stability is comparable in the nucleus and the cytoplasm. But, because of their limited stability, these nuclear mRNAs cannot constitute a significant stock for gene expression. Alternatively, they could reflect a bidirectional transport of mRNA, that is, to and from the cytoplasm, which would provide a direct explanation for the similarity in both compartments of their half-life and poly(A) tail shortening over time.

3T3 Cells↗

PubMed2001

Differential phosphorylation of tau proteins during kitten brain development and Alzheimer's disease.

Differential distribution and phosphorylation of tau proteins were studied in developing kitten brain by using several antibodies, and was compared to phosphorylation in Alzheimer's disease. Several antibodies demonstrated the presence of phosphorylated tau proteins during kitten brain development and identified pathological structures in human brain tissue. Antibody AD2, recognized tau in kittens and adult cats, but reacted in Alzheimer's tissue only with a pathological tau form. Antibody AT8 was prominent in developing kitten neurons and was found in axons and dendrites. After the first postnatal month this phosphorylation type disappeared from axons. Furthermore, dephosphorylation of kitten tau with alkaline phosphatase abolished immunoreactivity of AT8, but not that of AD2, pointing to a protection of the AD2 epitope in cats. Tau proteins during early cat brain development are phosphorylated at several sites that are also phosphorylated in paired helical filaments during Alzheimer's disease. In either event, phosphorylation of tau may play a crucial role to modulate microtubule dynamics, contributing to increased microtubule instability and promoting growth of processes during neuronal development or changing dynamic properties of the cytoskeleton and contributing to the formation of pathological structures in neurodegenerative diseases.

Aged↗

PubMed2006

Ndj1, a telomere-associated protein, promotes meiotic recombination in budding yeast.

Dynamic telomere repositioning is a prominent feature of meiosis. Deletion of a telomere-associated protein, Ndj1, results in the failure of both attachment and clustering of telomeres at the nuclear envelope and delays several landmarks of meiosis I, such as pairing, synaptonemal complex formation, and timing of the meiosis I division. We explored the role of Ndj1 in meiotic recombination, which occurs through the formation and repair of programmed double-strand breaks. The ndj1delta mutation allows for the formation of the first detectable strand invasion intermediate (i.e., single-end invasion) with wild-type kinetics; however, it confers a delay in the formation of the double-Holliday junction intermediate and both crossover and noncrossover products. These results challenge the widely held notion that clustering of telomeres in meiosis promotes the ability of homologous chromosomes to find one another in budding Saccharomyces cerevisiae. We propose that an Ndj1-dependent function is critical for stabilizing analogous strand invasion intermediates that exist in two separate branches of the bifurcated pathway, leading to either noncrossover or crossover formation. These findings provide a link between telomere dynamics and a distinct mechanistic step of meiotic recombination that follows the homology search.

Cell Cycle Proteins↗

PubMed2005

Differential Trk expression in explant and dissociated trigeminal ganglion cell cultures.

During embryonic development, expression of neurotrophin receptor tyrosine kinases (Trks) by sensory ganglia is continuously and dynamically regulated. Neurotrophin signaling promotes selective survival and axonal differentiation of sensory neurons. In embryonic day (E) 15 rat trigeminal ganglion (TG), NGF receptor TrkA is expressed by small diameter neurons, NT-3 receptor TrkC and BDNF receptor TrkB are expressed by large diameter neurons. Organotypic explant and dissociated cell cultures of the TG (and dorsal root ganglia) are commonly used to assay neurotrophin effects on developing sensory neurons. In this study, we compared Trk expression in E15 rat TG explant and dissociated cell cultures with or without neurotrophin treatment. Only a subset of TG cells express each of the three Trk receptors in wholemount explant cultures as in vivo conditions. In contrast, all TG neurons co-express all three Trk receptors upon dissociation, regardless of neurotrophin treatment. Neurons cultured in low concentrations of one neurotrophin first, and switched to higher concentrations of another after 1 day, survive and display morphological characteristics of neurons cultured in a mixture of both neurotrophins for 3 days. Our results indicate that wholemount explant cultures of sensory ganglia represent in vivo conditions in terms of Trk expression patterns; whereas dissociation dramatically alters Trk expression by primary sensory neurons.

Animals↗

PubMedDate not supplied

Ventricular pressure-volume relations as the primary basis for evaluation of cardiac mechanics. Return to Frank's diagram.

Considering ventricular function from the vantage point of the pressure-volume (P-V) diagram permits not only quantification of ventricular working capacity under normal and pathophysiological conditions but also promotes understanding of cardiac dynamics including prediction of the effects of mechanical and pharmacological interventions. Therefore it seems appropriate, at least intellectually, to classify all measured volume and pressure data into the scheme of the P-V diagram. The use of so-called contractility indices and also the restriction to the end-systolic P-V relation alone means deliberate renunciation of important information. In principle, Frank's original concept can be confirmed which, under afterloaded conditions, implies the existence of distinct end-systolic P-V curves each related to a particular end-diastolic volume. As an approximation, however, the assumption of one common end-systolic P-V relation seems tolerable. Based on Frank's diagram, a concept for assessment of ventricular and myocardial function is presented following a discussion of the determinants of the diastolic and end-systolic P-V relations, as well as the methodological difficulties and different notions with regard to the end-systolic P-V curve. The P-V area between the curves of systolic maxima and diastolic minima, up to a defined end-diastolic pressure, is recommended as a measure for quantitative evaluation of ventricular working capacity. Transformation into stress-length (sigma-l) relations is indispensable for assessment of myocardial function under the conditions of changed ventricular geometry. The normalized sigma-l area yields a measure for interindividual evaluation of myocardial working capacity. This concept of evaluation does not mean acknowledgement of the visco-elastic theory of muscle contraction nor of the Emax concept. The P-V and sigma-l relations must, however, be complemented by time related parameters in order to estimate ventricular and myocardial power capacity. After a long-lasting search through international literature for "contractility indices" of general applicability and significance it seems appropriate to return to Frank's diagram as the primary basis for evaluating cardiac mechanics.

Animals↗

PubMed1995

Differences in peptide binding of DR11 and DR13 microvariants demonstrate the power of minor variation in generating DR functional diversity.

The influence of subtle HLA diversification on antigen binding was explored using murine L-cell transfectants expressing alleles in the DR11/DR13 family and a panel of peptides. The levels of binding among this family of DR microvariants were as diverse as the levels of binding among distantly related DR molecules. Even a single amino acid difference between allelic products had a profound effect on peptide binding. Specific amino acid substitutions, generated using site-directed mutagenesis to alter polymorphic residues at DR beta 32, 37, 57, 58, 67, 71, 86, demonstrated that a specific change within the context of a single DR molecule differed in its effect on the binding of specific peptides. In addition, a specific amino acid substitution had a differential effect on the binding level of a peptide to different DR molecules. Each polymorphic amino acid appeared to play a role in the binding of some peptide. Studies using the amino-terminal portion of the invariant chain CLIP peptide suggested that this peptide may offer varying degrees of competition in the binding of the cellular peptide pool in cells expressing different DR molecules. Finally, the results obtained with two strain-specific peptides from an immunodominant region of a malarial parasite show differential binding to two DR13 molecules, suggesting that immune pressure may promote parasite diversity. A dynamic interaction may exist between pathogens and the immune system shaping the HLA profile in a population. Thus even subtle diversification of the HLA molecules, possibly pathogen driven, can have a substantial effect on peptide binding and immune recognition.

Alleles↗

PubMed2006

HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse.

HS1, the leukocyte-specific homolog of cortactin, regulates F-actin in vitro and is phosphorylated in response to TCR ligation, but its role in lymphocyte activation has not been addressed. We demonstrate that HS1-deficient T cells fail to accumulate F-actin at the immune synapse (IS) and, upon TCR ligation, form actin-rich structures that are disordered and unstable. Early TCR activation events are intact in these cells, but Ca2+ influx and IL-2 gene transcription are defective. Importantly, HS1 tyrosine phosphorylation is required for its targeting to the IS and for its function in regulating actin dynamics and IL-2 promoter activity. Phosphorylation also links HS1 to multiple signaling proteins, including Lck, PLCgamma1, and Vav1, and is essential for the stable recruitment of Vav1 to the IS. Taken together, our studies show that HS1 is indispensable for signaling events leading to actin assembly and IL-2 production during T cell activation.

Actins↗

PubMed2005

Multi-Monte Carlo method for coagulation and condensation/evaporation in dispersed systems.

A new multi-Monte Carlo (MMC) method is promoted to consider general dynamic equation (GDE) for particle coagulation and condensation/evaporation. MMC method introduces the concept of a "weighted fictitious particle" and is based on time-driven Monte Carlo technique, constant number of fictitious particles technique, and constant volume technique. MMC method for independent coagulation, for independent condensation/evaporation, and for simultaneous coagulation and condensation/evaporation are validated by some special cases in which analytical solutions exist, in which numerical results agree with corresponding analytical solutions well. Furthermore, the computation cost of MMC method is low enough to be applied in engineering computation and general scientific quantitative analysis.

Journal Article↗

PubMed2005

Effect of hsp70 chaperone on the folding and misfolding of polypeptides modeling an elongating protein chain.

Virtually nothing is known about the interaction of co-translationally active chaperones with nascent polypeptides and the resulting effects on peptide conformation and folding. We have explored this issue by NMR analysis of apomyoglobin N-terminal fragments of increasing length, taken as models for different stages of protein biosynthesis, in the absence and presence of the substrate binding domain of Escherichia coli Hsp70, DnaK-beta. The incomplete polypeptides misfold and self-associate under refolding conditions. In the presence of DnaK-beta, however, formation of the original self-associated species is completely or partially prevented. Chaperone interaction with incomplete protein chains promotes a globally unfolded dynamic DnaK-beta-bound state, which becomes folding-competent only upon incorporation of the residues corresponding to the C-terminal H helix. The chaperone does not bind the full-length protein at equilibrium. However, its presence strongly disfavors the kinetic accessibility of misfolding side-routes available to the full-length chain. This work supports the role of DnaK as a "holder" for incomplete N-terminal polypeptides. However, as the chain approaches its full-length status, the tendency to intramolecularly bury non-polar surface efficiently outcompetes chaperone binding. Under these conditions, DnaK serves as a "folding enhancer" by supporting folding of a population of otherwise folding-incompetent full-length protein chains.

Apoproteins↗

PubMed2006

Cantilever dynamics and quality factor control in AC mode AFM height measurements.

We show that inconsistent-imaging dynamics, in which the cantilever oscillates in the attractive regime on substrate background but in the repulsive regime on sample, leads to artifacts in apparent height in AC mode Atomic force microscopy. Active Q control can be used to effectively tune the imaging dynamics. Increased effective Q promotes the attractive regime, improves imaging sensitivity, and results in less invasive imaging of soft biological molecules.

DNA↗