Cytoskeletal Components of an Invasion Machine—The Apical Complex of Toxoplasma gondii

The apical complex of Toxoplasma gondii is widely believed to serve essential functions in both invasion of its host cells (including human cells), and in replication of the parasite. The understanding of apical complex function, the basis for its novel structure, and the mechanism for its motility are greatly impeded by lack of knowledge of its molecular composition. We have partially purified the conoid/apical complex, identified ~200 proteins that represent 70% of its cytoskeletal protein components, characterized seven novel proteins, and determined the sequence of recruitment of five of these proteins into the cytoskeleton during cell division. Our results provide new markers for the different subcompartments within the apical complex, and revealed previously unknown cellular compartments, which facilitate our understanding of how the invasion machinery is built. Surprisingly, the extreme apical and extreme basal structures of this highly polarized cell originate in the same location and at the same time very early during parasite replication

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Learners of a New Generation

To identify educational practices that will best facilitate the development of expertise, we must first understand the learner. Student cohorts in post K-12 education are generally composed of learners from multiple generations. Learning cohorts from previous generations who were accustomed to a limited range of educational resources acclimated to learning through primarily aural and read/write modalities. The educational environment for millennial generation learners has been dominated by technology. As a result a variety of learning styles, not apparent in previous generations, have become common. These learning styles are incidental to novel resources to which learners now have access. Strategies designed to promote successful knowledge acquisition for learners of any style should incorporate a variety of the ever-increasing array of available innovative educational paradigms and digital resources. In addition to resources, other factors that should be considered in the design of strategies which can influence the success of next generation learning include their (1) tendency to learn via real-world applications, (2) unfamiliarity with educational technology, (3) weakness in information literacy, (4) need for frequent feedback, and (5) predilection to work in teams. A multifactorial approach to facilitate the development of expertise will best support individual scholarly effort and preparation for lifelong learning

A Novel Way to Engage Medical Students in Learning Gross Anatomy at the Philadelphia College of Osteopathic Medicine

There is no abstract for this article

Evidence for a conserved myogenic program

An invariant, temporal sequence in the accumulation of muscle specific proteins is described, based on studies of nascent, postmitotic, mononucleated myoblasts from three chick skeletal muscle systems; (1) cultured breast muscle, (2) in vivo myotome and (3) in vivo limb. Desmin was the first muscle specific protein found, followed by titin and shortly thereafter, coordinately, by a cohort of myofibrillar proteins. The myofibrillar proteins were first detected in the form of small, irregularly shaped aggregates. Although titin appeared just prior to the other myofibrillar proteins, in this aggregate form, it was not detected as organized filaments earlier than the others. It is therefore unlikely that titin can act as a scaffold in sarcomere formation. If titin acted in this capacity, it would be expected to be exist as a filament earlier than the other myofibrillar proteins, in order that they could assemble upon it. The accumulation and assembly of these proteins was also found to be independent of fusion. In all three of the systems examined, unfused myoblasts were found which contained sarcomeres, identical to those found in adult muscle, already assembled into myofibril. Mononucleated cells were able to synthesize and assemble myofibrillar proteins without the prerequisite of fusion. Although newly born in vivo myoblasts in both myotome and limb displayed the muscle specific protein sequence already described, the source of the precursors of these cells has been a question of considerable interest. Are these precursor cells already postmitotic myoblasts or are they still replicating cells? The myotome proper was found to contain cells that were desmin +/myofibrillar protein +. However, a region identical in each somite--the dorsalmost portion of the somite--displayed cells that were desmin +/myofibrillar protein $-$. These desmin +/myofibrillar protein--cells suggest a local pool of replicating myoblasts. Limb stained for desmin, indicated the cells that invest the limb are not as yet differentiated myoblasts. At no stage at which somitic cells have been found to invest the limb were cells that were desmin + found to extend from the ventral aspect of the somite to the limb