Project description:Theoretically, crystals with supercells exist at a unique crossroads where they can be considered as either a large unit cell with closely spaced reflections in reciprocal space or a higher dimensional superspace with a modulation that is commensurate with the supercell. In the latter case, the structure would be defined as an average structure with functions representing a modulation to determine the atomic location in 3D space. Here, a model protein structure and simulated diffraction data were used to investigate the possibility of solving a real incommensurately modulated protein crystal using a supercell approximation. In this way, the answer was known and the refinement method could be tested. Firstly, an average structure was solved by using the `main' reflections, which represent the subset of the reflections that belong to the subcell and in general are more intense than the `satellite' reflections. The average structure was then expanded to create a supercell and refined using all of the reflections. Surprisingly, the refined solution did not match the expected solution, even though the statistics were excellent. Interestingly, the corresponding superspace group had multiple 3D daughter supercell space groups as possibilities, and it was one of the alternate daughter space groups that the refinement locked in on. The lessons learned here will be applied to a real incommensurately modulated profilin-actin crystal that has the same superspace group.
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where the additional presence of pulmonary hypertension (PH) reduces survival. In particular, the presence of coexistent pulmonary vascular disease in patients with advanced lung parenchymal disease results in worse outcomes than either diagnosis alone. This is true with respect to the natural histories of these diseases, outcomes with medical therapies, and even outcomes following lung transplantation. Consequently, there is a striking need for improved treatments for PH in the setting of IPF. In this review, we summarize existing therapies from the perspective of molecular mechanisms underlying lung fibrosis and vasoconstriction/vascular remodelling and discuss potential future targets for pharmacotherapy. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.
Project description:A 54-year-old man with a history of atrial flutter presented with anterior ST-segment elevation myocardial infarction complicated by cardiogenic shock and underwent percutaneous coronary intervention of the left main coronary artery. He was placed on triple antithrombotic therapy and ultimately recovered. However, before discharge, he developed hypotension, confusion, and hemiplegia. (Level of Difficulty: Beginner.).
Project description:Prototheca spp. are environmental algae that may cause serious infection in the immunocompromised patient. Clinical manifestations may mimic other diseases. We present a case of fatal infection in a 78-year-old cardiac transplant recipient and discuss pitfalls in the clinical and laboratory diagnoses.
Project description:Florivory, or damage to flowers by herbivores, can make flowers less attractive to pollinators, potentially resulting in reduced plant fitness. However, not many studies have combined observations with experiments to assess the causal link between florivory and pollination. We conducted field observations at eight sites in northern California, combined with field experiments that involved artificial floral damage, to study the effect of florivory on pollination in the hummingbird-pollinated sticky monkeyflower, Mimulus aurantiacus We used two indicators of pollinator visitation, stigma closure and the presence of microorganisms in floral nectar. The field observations revealed that stigma closure was less frequent in damaged flowers than in intact flowers. In the experiments, however, floral damage did not decrease stigma closure or microbial detection in nectar. Instead, neighbouring flowers were similar for both indicators. These results suggest that the observed negative association between florivory and pollination is not causal and that the location of flowers is more important to pollinator visitation than florivory in these populations of M. aurantiacus.
Project description:FURIN is a pro-protein convertase previously shown to be important for placental syncytialisation (Zhou et al. [1]), a process of cell fusion whereby placental cytotrophoblast cells fuse to form a multinucleated syncytium. This finding has been broadly accepted however, we have evidence suggesting the contrary. Spontaneously syncytialising term primary human trophoblast cells and BeWo choriocarcinoma cells were treated with either FURIN siRNA or negative control siRNA or the protease inhibitor, DEC-RVKR-CMK, or vehicle. Cells were then left to either spontaneously syncytialise (primary trophoblasts) or were induced to syncytialise with forskolin (BeWo). Effects on syncytialisation were measured by determining human chorionic gonadotrophin secretion and E-cadherin protein levels. We showed that FURIN is not important for syncytialisation in either cell type. However, in primary trophoblasts another protease also inhibited by DEC-RVKR-CMK, may be involved. Our results directly contrast with those published by Zhou et al. Zhou et al. however, used first trimester villous explants to study syncytialisation, and we used term primary trophoblasts. Therefore, we suggest that FURIN may be involved in syncytialisation of first trimester trophoblasts, but not term trophoblasts. What is more concerning is that our results using BeWo cells do not agree with their results, even though for the most part, we used the same experimental design. It is unclear why these experiments yielded different results, however we wanted to draw attention to simple differences in measuring syncytialisation or flaws in method reporting (including omission of cell line source and passage numbers, siRNA concentration and protein molecular weights) and choice of immunoblot loading controls, that could impact on experimental outcomes. Our study shows that careful reporting of methods by authors and thorough scrutiny by referees are vital. Furthermore, a universal benchmark for measuring syncytialisation is required so that various studies of syncytialisation can be validated.
Project description:We present a case study to demonstrate how complex molecule synthesis can benefit from quantum mechanics (QM) calculations. Theory is applied in two contexts: testing the chemical intuition used in retrosynthetic planning, along with expediting the resolution of unexpected challenges encountered during the course of the synthesis. From a computational lens, we examine retrospectively the strategies employed and the decisions made during our synthetic efforts toward the diterpenoid natural product ineleganolide. Seemingly logical and robust hypotheses are found to be ill-fated after theoretical investigation. Prior knowledge of these issues may have potentially saved valuable time and resources during our synthetic efforts. This cautionary tale suggests that synthetic campaigns can benefit from computational evaluation of synthetic plans.
Project description:Little is known about the contribution of frailty in improving patient-level prediction beyond readily available clinical information. The objective of this study is to compare the predictive ability of 129 combinations of seven frailty markers (cognition, energy, mobility, mood, nutrition, physical activity, and strength) and quantify their contribution to predictive accuracy beyond age, sex, and number of chronic diseases.Two cohorts from the Established Populations for Epidemiologic Studies of the Elderly were used. The model with the best predictive fit in predicting 6-year incidence of disability was determined using the Akaike Information Criterion. Predictive accuracy was measured by the C statistic.Incident disability was 23% in one cohort and 20% in the other cohort. The "best model" in each cohort was found to be a model including between five and seven frailty markers including cognition, mobility, nutrition, physical activity, and strength. Predictive accuracy of the 129 models ranged from 0.73 to 0.77 across both cohorts. Adding frailty markers to age, sex, and chronic disease increased predictive accuracy by up to 3% in both cohorts (p < .001). The contribution of frailty increased up to 9% in the oldest age group.Adding frailty markers provided a modest increase in patient-level prediction of disability. Such a modest increase may still be worthwhile because while age, sex, and the number of chronic diseases are not modifiable, frailty may be. Further studies examining the contribution of frailty in improving prediction are needed before adopting frailty as a prognostic tool.
Project description:This paper advises caution in relation to the increasing interest in molecular-genetic association studies in developmental psychology based on a set of empirical examples from the NICHD Study of Early Child Care and Youth Development (SECCYD) that highlight the fragility of effects reported in the literature on the molecular-genetic correlates of infant attachment. Specifically, this paper updates and provides three extensions to results reported in Luijk et al. (2011), which recently failed to replicate evidence from smaller-sample studies that a set of dopaminergic, serotonergic, and oxytonergic markers are significantly associated with infant attachment security or disorganization. First, we report here that the average effect of "usual suspect" polymorphisms on infant attachment security and disorganization in the SECCYD is approximately zero. Second, because Luijk et al. (2011) reported data based exclusively on the White infants in the SECCYD, this paper reveals that the average effect of polymorphisms featured in this literature is also of trivial magnitude in the non-White sub-sample (cf. Chen, Barth, Johnson, Gotlib, & Johnson, 2011). Third, this paper attempts, but fails, to replicate a recent finding by Raby et al. (2012) suggesting that, although molecular-genetic polymorphisms might not be implicated in security versus insecurity, the serotonin transporter gene contributes to variation in emotional distress during the Strange Situation Procedure. Implications for future research on the genetics of developmental phenotypes in general and attachment in particular are discussed, with a focus on statistical power and model-based theory testing.
Project description:We found a startling correlation (Pearson ρ > 0.97) between a single event in daily sea surface temperatures each spring, and peak fish egg abundance measurements the following summer, in 7 years of approximately weekly fish egg abundance data collected at Scripps Pier in La Jolla California. Even more surprising was that this event-based result persisted despite the large and variable number of fish species involved (up to 46), and the large and variable time interval between trigger and response (up to ~3 months). To mitigate potential over-fitting, we made an out-of-sample prediction beyond the publication process for the peak summer egg abundance observed at Scripps Pier in 2020 (available on bioRxiv). During peer-review, the prediction failed, and while it would be tempting to explain this away as a result of the record-breaking toxic algal bloom that occurred during the spring (9x higher concentration of dinoflagellates than ever previously recorded), a re-examination of our methodology revealed a potential source of over-fitting that had not been evaluated for robustness. This cautionary tale highlights the importance of testable true out-of-sample predictions of future values that cannot (even accidentally) be used in model fitting, and that can therefore catch model assumptions that may otherwise escape notice. We believe that this example can benefit the current push towards ecology as a predictive science and support the notion that predictions should live and die in the public domain, along with the models that made them.