Introducing original methods for integrating sociocultural and discourse studies into science and engineering education, this book provides a much-needed framework for how to conduct qualitative ...research in this field. The three dimensions of learning identified in the Next Generation Science Standards (NGSS) create a need for research methods that examine the sociocultural components of science education. With cutting-edge studies and examples consistent with the NGSS, this book offers comprehensive research methods for integrating discourse and sociocultural practices in science and engineering education and provides key tools for applying this framework for students, pre-service teachers, scholars, and researchers.
The asexual blood stages of Plasmodium falciparum cause the most lethal form of human malaria. During growth within an infected red blood cell, parasite multiplication and formation of invasive ...merozoites is called schizogony. Here, we present a detailed analysis of the phosphoproteome of P. falciparum schizonts revealing 2541 unique phosphorylation sites, including 871 novel sites. Prominent roles for cAMP-dependent protein kinase A- and phosphatidylinositol-signaling were identified following analysis by functional enrichment, phosphoprotein interaction network clustering and phospho-motif identification tools. We observed that most key enzymes in the inositol pathway are phosphorylated, which strongly suggests additional levels of regulation and crosstalk with other protein kinases that coregulate different biological processes. A distinct pattern of phosphorylation of proteins involved in merozoite egress and red blood cell invasion was noted. The analyses also revealed that cAMP-PKA signaling is implicated in a wide variety of processes including motility. We verified this finding experimentally using an in vitro kinase assay and identified three novel PKA substrates associated with the glideosome motor complex: myosin A, GAP45 and CDPK1. Therefore, in addition to an established role for CDPK1 in the motor complex, this study reveals the coinvolvement of PKA, further implicating cAMP as an important regulator of host cell invasion.
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IJS, KILJ, NUK, PNG, UL, UM
Ubiquitylation is a common post translational modification of eukaryotic proteins and in the human malaria parasite, Plasmodium falciparum (Pf) overall ubiquitylation increases in the transition from ...intracellular schizont to extracellular merozoite stages in the asexual blood stage cycle. Here, we identify specific ubiquitylation sites of protein substrates in three intraerythrocytic parasite stages and extracellular merozoites; a total of 1464 sites in 546 proteins were identified (data available via ProteomeXchange with identifier PXD014998). 469 ubiquitylated proteins were identified in merozoites compared with only 160 in the preceding intracellular schizont stage, suggesting a large increase in protein ubiquitylation associated with merozoite maturation. Following merozoite invasion of erythrocytes, few ubiquitylated proteins were detected in the first intracellular ring stage but as parasites matured through trophozoite to schizont stages the apparent extent of ubiquitylation increased. We identified commonly used ubiquitylation motifs and groups of ubiquitylated proteins in specific areas of cellular function, for example merozoite pellicle proteins involved in erythrocyte invasion, exported proteins, and histones. To investigate the importance of ubiquitylation we screened ubiquitin pathway inhibitors in a parasite growth assay and identified the ubiquitin activating enzyme (UBA1 or E1) inhibitor MLN7243 (TAK-243) to be particularly effective. This small molecule was shown to be a potent inhibitor of recombinant PfUBA1, and a structural homology model of MLN7243 bound to the parasite enzyme highlights avenues for the development of P. falciparum specific inhibitors. We created a genetically modified parasite with a rapamycin-inducible functional deletion of uba1; addition of either MLN7243 or rapamycin to the recombinant parasite line resulted in the same phenotype, with parasite development blocked at the schizont stage. Nuclear division and formation of intracellular structures was interrupted. These results indicate that the intracellular target of MLN7243 is UBA1, and this activity is essential for the final differentiation of schizonts to merozoites.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
INTRODUCTION
The U.S. faces a critical gap between residency training and clinical practice that affects the recruitment and preparation of internal medicine residents for primary care ...careers. The patient-centered medical home (PCMH) represents a new clinical microsystem that is being widely promoted and implemented to improve access, quality, and sustainability in primary care practice.
AIM
We address two key questions regarding the training of internal medicine residents for practice in PCMHs. First, what are the educational implications of practice transformations to primary care home models? Second, what must we do differently to prepare internal medicine residents for their futures in PCMHs?
PROGRAM DESCRIPTION
The 2011 Society of General Internal Medicine (SGIM) PCMH Education Summit established seven work groups to address the following topics: resident workplace competencies, teamwork, continuity of care, assessment, faculty development, ‘medical home builder’ tools, and policy. The output from the competency work group was foundational for the work of other groups. The work group considered several educational frameworks, including developmental milestones, competencies, and entrustable professional activities (EPAs).
RESULTS
The competency work group defined 25 internal medicine resident PCMH EPAs. The 2011 National Committee for Quality Assurance (NCQA) PCMH standards served as an organizing framework for EPAs.
DISCUSSION
The list of PCMH EPAs has the potential to begin to transform the education of internal medicine residents for practice and leadership in the PCMH. It will guide curriculum development, learner assessment, and clinical practice redesign for academic health centers.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents
resulting in improved antitumor activity and a wider therapeutic margin. ...The theory relies on the observation that the majority
of tumors are deficient in the G 1 -DNA damage checkpoint pathway resulting in reliance on S and G 2 checkpoints for DNA repair and cell survival. The S and G 2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage;
thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however,
have a functioning G 1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762,
a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition
of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor
activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models
with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy
of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. Mol Cancer
Ther 2008;7(9):2955–66
Abstract
Background
The resistance of
Plasmodium falciparum
to artemisinin-based (ART) drugs, the front-line drug family used in artemisinin-based combination therapy (ACT) for treatment of malaria, ...is of great concern. Mutations in the
kelch13
(
k13
) gene (for example, those resulting in the Cys580Tyr C580Y variant) were identified as genetic markers for ART-resistant parasites, which suggests they are associated with resistance mechanisms. However, not all resistant parasites contain a
k13
mutation, and clearly greater understanding of resistance mechanisms is required. A genome-wide association study (GWAS) found single nucleotide polymorphisms associated with ART-resistance in
fd
(ferredoxin),
arps10
(apicoplast ribosomal protein S10),
mdr2
(multidrug resistance protein 2), and
crt
(chloroquine resistance transporter), in addition to
k13
gene mutations, suggesting that these alleles contribute to the resistance phenotype. The importance of the FD and ARPS10 variants in ART resistance was then studied since both proteins likely function in the apicoplast, which is a location distinct from that of K13.
Methods
The reported mutations were introduced, together with a mutation to produce the
k13
-C580Y variant into the ART-sensitive 3D7 parasite line and the effect on ART-susceptibility using the 0−3 h ring survival assay (RSA
0−3 h
) was investigated.
Results and conclusion
Introducing both
fd
-D193Y and
arps10
-V127M into a
k13
-C580Y-containing parasite, but not a wild-type
k13
parasite, increased survival of the parasite in the RSA
0−3 h
. The results suggest epistasis of
arps10
and
k13
, with
arps10
-V127M a modifier of ART susceptibility in different
k13
allele backgrounds.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The inducible Di-Cre system was used to delete the putative ubiquitin-conjugating enzyme 13 gene (ubc13) of Plasmodium falciparum to study its role in ubiquitylation and the functional consequence ...during the parasite asexual blood stage. Deletion resulted in a significant reduction of parasite growth in vitro, reduced ubiquitylation of the Lys63 residue of ubiquitin attached to protein substrates, and an increased sensitivity of the parasite to both the mutagen, methyl methanesulfonate and the antimalarial drug dihydroartemisinin (DHA), but not chloroquine. The parasite was also sensitive to the UBC13 inhibitor NSC697923. The data suggest that this gene does code for an ubiquitin conjugating enzyme responsible for K63 ubiquitylation, which is important in DNA repair pathways as was previously demonstrated in other organisms. The increased parasite sensitivity to DHA in the absence of ubc13 function indicates that DHA may act primarily through this pathway and that inhibitors of UBC13 may both enhance the efficacy of this antimalarial drug and directly inhibit parasite growth.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Age‐related changes in resting‐state (RS) neural rhythms in typically developing children (TDC) but not children with autism spectrum disorder (ASD) suggest that RS measures may be of clinical use in ...ASD only for certain ages. The study examined this issue via assessing RS peak alpha frequency (PAF), a measure previous studies, have indicated as abnormal in ASD. RS magnetoencephalographic (MEG) data were obtained from 141 TDC (6.13–17.70 years) and 204 ASD (6.07–17.93 years). A source model with 15 regional sources projected the raw MEG surface data into brain source space. PAF was identified in each participant from the source showing the largest amplitude alpha activity (7‐13 Hz). Given sex differences in PAF in TDC (females > males) and relatively few females in both groups, group comparisons were conducted examining only male TDC (N = 121) and ASD (N = 183). Regressions showed significant group slope differences, with an age‐related increase in PAF in TDC (R2 = 0.32) but not ASD (R2 = 0.01). Analyses examining male children below or above 10‐years‐old (median split) indicated group effects only in the younger TDC (8.90 Hz) and ASD (9.84 Hz; Cohen's d = 1.05). In the older ASD, a higher nonverbal IQ was associated with a higher PAF. In the younger TDC, a faster speed of processing was associated with a higher PAF. PAF as a marker for ASD depends on age, with a RS alpha marker of more interest in younger versus older children with ASD. Associations between PAF and cognitive ability were also found to be age and group specific.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Apicomplexan parasites constitute one of the most significant groups of pathogens infecting humans and animals. The liver stage sporozoites of Plasmodium spp. and tachyzoites of Toxoplasma gondii, ...the causative agents of malaria and toxoplasmosis, respectively, use a unique mode of locomotion termed gliding motility to invade host cells and cross cell substrates. This amoeboid-like movement uses a parasite adhesin from the thrombospondin-related anonymous protein (TRAP) family and a set of proteins linking the extracellular adhesin, via an actin-myosin motor, to the inner membrane complex. The Plasmodium blood stage merozoite, however, does not exhibit gliding motility. Here we show that homologues of the key proteins that make up the motor complex, including the recently identified glideosome-associated proteins 45 and 50 (GAP40 and GAP50), are present in P. falciparum merozoites and appear to function in erythrocyte invasion. Furthermore, we identify a merozoite TRAP homologue, termed MTRAP, a micronemal protein that shares key features with TRAP, including a thrombospondin repeat domain, a putative rhomboid-protease cleavage site, and a cytoplasmic tail that, in vitro, binds the actin-binding protein aldolase. Analysis of other parasite genomes shows that the components of this motor complex are conserved across diverse Apicomplexan genera. Conservation of the motor complex suggests that a common molecular mechanism underlies all Apicomplexan motility, which, given its unique properties, highlights a number of novel targets for drug intervention to treat major diseases of humans and livestock.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Turner syndrome (TS), a common neurogenetic disorder caused by complete or partial absence of an X chromosome in females, is characterized by distinct physical, cognitive, and social-emotional ...features. Girls with TS typically display average overall intellectual functioning with relative strength in verbal abilities and weaknesses in visuospatial processing, executive function (EF), and social cognition. This study was designed to better understand longitudinal trajectories of cognitive and social-emotional domains commonly affected in TS. Participants included 57 girls with monosomic 45,X TS and 55 age- and verbal-IQ matched girls who completed behavioral, child-report, and parent-report measures across four timepoints. Group differences in visuospatial processing, EF, social cognition, and anxiety were assessed longitudinally. Potential effects of estrogen replacement therapy (ERT) were assessed cross-sectionally on an exploratory basis. The TS group showed poorer performance on measures of visuospatial processing, EF, and social cognition, but not anxiety, compared to controls throughout childhood and adolescence. There were no significant group differences in the trajectory of skill development over time. Exploratory analyses within the TS group revealed that girls who were receiving ERT showed better performance on measures of overall IQ, expressive vocabulary, and visuospatial processing compared to those not receiving ERT. Consistent with existing literature, weaknesses in visuospatial processing, EF, and social competence among girls with TS persisted throughout childhood and adolescence. Exploratory analyses suggest that ERT may help improve some aspects of cognitive function in TS, although other pre-existing, nonhormonal differences between the two TS subgroups may alternatively explain these findings, given our study design. Future studies are needed to examine potential impacts of ERT on cognitive and social-emotional development in TS.
•TS group showed poorer visuospatial processing, EF, and social cognition.•Cognitive weaknesses among girls with TS persisted throughout pubertal transition.•No significant group differences in trajectory of skill development over time•ERT may help improve some aspects of cognitive function in TS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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