The Teaching Relationship: A Hypothesized Mental Model and Its Consequences

It is proposed that people share a "mental model" of the student-teacher relationship, out of which develop unexamined expectations and attitudes that may be responsible for some long-standing problems of higher education. The model assumes that 1) a knowledge-differential is central to the relationship; 2) the relationship is voluntary, so that both participants must find it rewarding; and 3) both participants are able to play their roles successfully. The first assumption leads to an emphasis on the teacher's expertise and accounts for the importance of research as the chief measure of academic virture. The second allows either participant to assume that the other has initiated the relationship, often leading to frustrated expectations. The third complements the first, implying that "anybody who knows something can teach it," and accounts for both teachers' dissatisfaction with under-prepared students and the widespread failure to recognize differences in teaching skills. Surverydata arepresented on teachers' opinions ofwhat makes students satisfying to teach, providing evidence for the reality of the model's second assumption

Antagonism of the Azoles to Olorofim and Cross-Resistance Are Governed by Linked Transcriptional Networks in Aspergillus fumigatus

Aspergillosis, in its various manifestations, is a major cause of morbidity and mortality. Very few classes of antifungal drugs have been approved for clinical use to treat these diseases and resistance to the first-line therapeutic class, the triazoles are increasing. A new class of antifungals that target pyrimidine biosynthesis, the orotomides, are currently in development with the first compound in this class, olorofim in late-stage clinical trials. In this study, we identified an antagonistic action of the triazoles on the action of olorofim. We showed that this antagonism was the result of an azole-induced upregulation of the pyrimidine biosynthesis pathway. Intriguingly, we showed that loss of function in the higher order transcription factor, HapB a member of the heterotrimeric HapB/C/E (CBC) complex or the regulator of nitrogen metabolic genes AreA, led to cross-resistance to both the azoles and olorofim, indicating that factors that govern resistance were under common regulatory control. However, the loss of azole-induced antagonism required decoupling of the pyrimidine biosynthetic pathway in a manner independent of the action of a single transcription factor. Our study provided evidence for complex transcriptional crosstalk between the pyrimidine and ergosterol biosynthetic pathways. IMPORTANCE: Aspergillosis is a spectrum of diseases and a major cause of morbidity and mortality. To treat these diseases, there are a few classes of antifungal drugs approved for clinical use. Resistance to the first line treatment, the azoles, is increasing. The first antifungal, olorofim, which is in the novel class of orotomides, is currently in development. Here, we showed an antagonistic effect between the azoles and olorofim, which was a result of dysregulation of the pyrimidine pathway, the target of olorofim, and the ergosterol biosynthesis pathway, the target of the azoles.This work was supported by the Wellcome Trust grant number 219551/Z/19/Z and 208396/Z/17/Z to M.J.B. C.V. was funded by a postdoctoral fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-BEPE 2020/01131-5).S

Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation

Context. Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial's Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant's perception of change. Methods. Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. Results. Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. Conclusions. Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this populatio

Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17

Sex hormones influence the susceptibility of inbred mice to liver cancer. C57BR/cdJ (BR) females are extremely susceptible to spontaneous and chemically induced liver tumors, in part due to a lack of protection against hepatocarcinogenesis normally offered by ovarian hormones. BR males are also moderately susceptible, and the susceptibility of both sexes of BR mice to liver tumors induced with N,N-diethylnitrosamine relative to the resistant C57BL/6J (B6) strain is caused by two loci designated Hcf1 and Hcf2 (hepatocarcinogenesis in females) located on chromosomes 17 and 1, respectively. The Hcf1 locus on chromosome 17 is the predominant modifier of liver cancer in BR mice. To validate the existence of this locus and investigate its potential interaction with Hcf2, congenic mice for each region were generated. Homozygosity for the B6.BR(D17Mit164-D17Mit2) region resulted in a 4-fold increase in liver tumor multiplicity in females and a 4.5-fold increase in males compared with B6 controls. A series of 16 recombinants covering the entire congenic region was developed to further narrow the area containing Hcf1. Susceptible heterozygous recombinants demonstrated a 3- to 7-fold effect in females and a 1.5- to 2-fold effect in males compared with B6 siblings. The effect in susceptible lines completely recapitulated the susceptibility of heterozygous full-length chromosome 17 congenics and furthermore narrowed the location of the Hcf1 locus to a single region of the chromosome from 30.05 to 35.83 Mb

Anaerobic Energy Expenditure and Mechanical Efficiency during Exhaustive Leg Press Exercise

Information about anaerobic energy production and mechanical efficiency that occurs over time during short-lasting maximal exercise is scarce and controversial. Bilateral leg press is an interesting muscle contraction model to estimate anaerobic energy production and mechanical efficiency during maximal exercise because it largely differs from the models used until now. This study examined the changes in muscle metabolite concentration and power output production during the first and the second half of a set of 10 repetitions to failure (10RM) of bilateral leg press exercise. On two separate days, muscle biopsies were obtained from vastus lateralis prior and immediately after a set of 5 or a set of 10 repetitions. During the second set of 5 repetitions, mean power production decreased by 19% and the average ATP utilisation accounted for by phosphagen decreased from 54% to 19%, whereas ATP utilisation from anaerobic glycolysis increased from 46 to 81%. Changes in contraction time and power output were correlated to the changes in muscle Phosphocreatine (PCr; r = −0.76; P<0.01) and lactate (r = −0.91; P<0.01), respectively, and were accompanied by parallel decreases (P<0.01-0.05) in muscle energy charge (0.6%), muscle ATP/ADP (8%) and ATP/AMP (19%) ratios, as well as by increases in ADP content (7%). The estimated average rate of ATP utilisation from anaerobic sources during the final 5 repetitions fell to 83% whereas total anaerobic ATP production increased by 9% due to a 30% longer average duration of exercise (18.4±4.0 vs 14.2±2.1 s). These data indicate that during a set of 10RM of bilateral leg press exercise there is a decrease in power output which is associated with a decrease in the contribution of PCr and/or an increase in muscle lactate. The higher energy cost per repetition during the second 5 repetitions is suggestive of decreased mechanical efficiency

Aspergillus fumigatus strains that evolve resistance to the agrochemical fungicide ipflufenoquin in vitro are also resistant to olorofim

Widespread use of azole antifungals in agriculture has been linked to resistance in the pathogenic fungus Aspergillus fumigatus. We show that exposure of A. fumigatus to the agrochemical fungicide, ipflufenoquin, in vitro can select for strains that are resistant to olorofim, a first-in-class clinical antifungal with the same mechanism of action. Resistance is caused by non-synonymous mutations within the target of ipflufenoquin/olorofim activity, dihydroorotate dehydrogenase (DHODH), and these variants have no overt growth defects.</p