Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle

Cells can maintain their functions despite fluctuations in intracellular parameters, such as protein activities and gene expression levels. This commonly observed biological property of cells is called robustness. On the other hand, these parameters have different limitations, each reflecting the property of the subsystem containing the parameter. The budding yeast cell cycle is quite fragile upon overexpression of CDC14, but is robust upon overexpression of ESP1. The gene products of both CDC14 and ESP1 are regulated by 1∶1 binding with their inhibitors (Net1 and Pds1), and a mathematical model predicts the extreme fragility of the cell cycle upon overexpression of CDC14 and ESP1 caused by dosage imbalance between these genes. However, it has not been experimentally shown that dosage imbalance causes fragility of the cell cycle. In this study, we measured the quantitative genetic interactions of these genes by performing combinatorial “genetic tug-of-war” experiments. We first showed experimental evidence that dosage imbalance between CDC14 and NET1 causes fragility. We also showed that fragility arising from dosage imbalance between ESP1 and PDS1 is masked by CDH1 and CLB2. The masking function of CLB2 was stabilization of Pds1 by its phosphorylation. We finally modified Chen's model according to our findings. We thus propose that dosage imbalance causes fragility in biological systems

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Dietary overlap among coral-feeding butterflyfishes (Chaetodontidae) at Lizard Island, northern Great Barrier Reef

This study documented the range of corals,\ud and other prey types, consumed by 20 species of but-\ud terflyfishes, which co-occur at Lizard Island, northern\ud Great Barrier Reef, Australia. Six species (Chaetodon\ud aureofasciatus, C. baronessa, C. lunulatus, C. plebius,\ud C. rainfordi and C. trifascialis) fed almost exclusively\ud on scleractinian corals, and a further eight species\ud (C. citrinellus, C. kleinii, C. lunula, C. melannotus,\ud C. rafflesi, C. speculum, C. ulietensis,and C. unima-\ud culatus) took a significant proportion of their bites\ud from corals. The other six species (C. auriga, C. ep-\ud hippium, C. lineolatus, C. semeion, C. vagabundus, and\ud Chelmon rostratus) rarely consumed coral, but fed on\ud small discrete prey items from non-coral substrates.\ud Coral-feeding butterflyfishes consumed a wide range of\ud corals. Chaetodon lunulatus, for example, consumed 51\ud coral species from 24 different genera. However, there\ud was up to 72% dietary overlap between coral-feeding\ud butterflyfishes, with 11/14 species feeding predomi-\ud nantly on Acropora hyacinthus or Pocillopora dami-\ud cornis. The most specialised corallivore, C. trifascialis,\ud took 88% of bites from A. hyacinthus. Chaetodon tri-\ud fascialis defend territories encompassing one or more\ud colonies of A. hyacinthus, and may have prevented\ud other species such as C. lunulatus from feeding even\ud more extensively on this coral. This study has shown\ud that coexistence of coral-feeding butterflyfishes occurs\ud despite an apparent lack of partitioning of prey\ud resources. While different coral-feeding butterflyfishes\ud were more or less selective in their use of different coral prey, virtually all species fed predominantly on\ud A. hyacinthus or P. damicornis

The Reproductive Ecology of Industrial Societies, Part I : Why Measuring Fertility Matters.

Is fertility relevant to evolutionary analyses conducted in modern industrial societies? This question has been the subject of a highly contentious debate, beginning in the late 1980s and continuing to this day. Researchers in both evolutionary and social sciences have argued that the measurement of fitness-related traits (e.g., fertility) offers little insight into evolutionary processes, on the grounds that modern industrial environments differ so greatly from those of our ancestral past that our behavior can no longer be expected to be adaptive. In contrast, we argue that fertility measurements in industrial society are essential for a complete evolutionary analysis: in particular, such data can provide evidence for any putative adaptive mismatch between ancestral environments and those of the present day, and they can provide insight into the selection pressures currently operating on contemporary populations. Having made this positive case, we then go on to discuss some challenges of fertility-related analyses among industrialized populations, particularly those that involve large-scale databases. These include "researcher degrees of freedom" (i.e., the choices made about which variables to analyze and how) and the different biases that may exist in such data. Despite these concerns, large datasets from multiple populations represent an excellent opportunity to test evolutionary hypotheses in great detail, enriching the evolutionary understanding of human behavior