Understanding the role of intermolecular interactions between lissoclimides and the eukaryotic ribosome.

Natural products that target the eukaryotic ribosome are promising therapeutics to treat a variety of cancers. It is therefore essential to determine their molecular mechanism of action to fully understand their mode of interaction with the target and to inform the development of new synthetic compounds with improved potency and reduced cytotoxicity. Toward this goal, we have previously established a short synthesis pathway that grants access to multiple congeners of the lissoclimide family. Here we present the X-ray co-crystal structure at 3.1 Å resolution of C45, a potent congener with two A-ring chlorine-bearing stereogenic centers with 'unnatural' configurations, with the yeast 80S ribosome, intermolecular interaction energies of the C45/ribosome complex, and single-molecule FRET data quantifying the impact of C45 on both human and yeast ribosomes. Together, these data provide new insights into the role of unusual non-covalent halogen bonding interactions involved in the binding of this synthetic compound to the 80S ribosome.

Toward Learned Chemical Perception of Force Field Typing Rules.

Molecular mechanics force fields define how the energy and forces in a molecular system are computed from its atomic positions, thus enabling the study of such systems through computational methods like molecular dynamics and Monte Carlo simulations. Despite progress toward automated force field parametrization, considerable human expertise is required to develop or extend force fields. In particular, human input has long been required to define atom types, which encode chemically unique environments that determine which parameters will be assigned. However, relying on humans to establish atom types is suboptimal. Human-created atom types are often developed without statistical justification, leading to over- or under-fitting of data. Human-created types are also difficult to extend in a systematic and consistent manner when new chemistries must be modeled or new data becomes available. Finally, human effort is not scalable when force fields must be generated for new (bio)polymers, compound classes, or materials. To remedy these deficiencies, our long-term goal is to replace human specification of atom types with an automated approach, based on rigorous statistics and driven by experimental and/or quantum chemical reference data. In this work, we describe novel methods that automate the discovery of appropriate chemical perception: SMARTY allows for the creation of atom types, while SMIRKY goes further by automating the creation of fragment (nonbonded, bonds, angles, and torsions) types. These approaches enable the creation of move sets in atom or fragment type space, which are used within a Monte Carlo optimization approach. We demonstrate the power of these new methods by automating the rediscovery of human defined atom types (SMARTY) or fragment types (SMIRKY) in existing small molecule force fields. We assess these approaches using several molecular data sets, including one which covers a diverse subset of the DrugBank database.

Is quality of life associated with compliance to pharmacoterapy in patients with chronic kidney disease undergoing maintenance hemodialysis?

Objective To analyzed the association of quality of life and compliance to drug treatment in chronic kidney disease patients. Methods The Short Form Health Survey was used to evaluate the quality of life of these patients, and the therapeutic complexity index was verified. The Morisky-Green test and the Brief Medication Questionnaire were applied to check compliance to drug therapy. Results A total of 197 patients were included. The Morisky-Green test and Brief Medication Questionnaire showed that most patients had low compliance to treatment (50.3% and 80.6%, respectively). Compliance was highly associated with gender (male) and slightly associated with complexity of therapy, mental health, and social aspects. Conclusion We observed a slight association between compliance to pharmacotherapy and quality of life and complexity of therapy, and a strong association with gender.

Is quality of life associated with compliance to pharmacoterapy in patients with chronic kidney disease undergoing maintenance hemodialysis? / Existe associação entre qualidade de vida e adesão à farmacoterapia em pacientes com doença renal crônica em hemodiálise?

ABSTRACT Objective To analyzed the association of quality of life and compliance to drug treatment in chronic kidney disease patients. Methods The Short Form Health Survey was used to evaluate the quality of life of these patients, and the therapeutic complexity index was verified. The Morisky-Green test and the Brief Medication Questionnaire were applied to check compliance to drug therapy. Results A total of 197 patients were included. The Morisky-Green test and Brief Medication Questionnaire showed that most patients had low compliance to treatment (50.3% and 80.6%, respectively). Compliance was highly associated with gender (male) and slightly associated with complexity of therapy, mental health, and social aspects. Conclusion We observed a slight association between compliance to pharmacotherapy and quality of life and complexity of therapy, and a strong association with gender.

RESUMO Objetivo Analisar a associação entre a qualidade de vida e a adesão ao tratamento farmacológico de pacientes com doença renal crônica. Métodos Utilizou-se o Short Form Health Survey para avaliar a qualidade de vida destes pacientes. O índice de complexidade terapêutico foi avaliado. O teste de Morisky-Green e o Brief Medication Questionnaire foram aplicados para avaliar a adesão a farmacoterapia. Resultados Nos 197 pacientes que participaram do estudo, o teste de Morisky-Green e o Brief Medication Questionnaire mostraram que a maioria deles apresentava baixa adesão ao tratamento (50,3% e 80,6%, respectivamente). A adesão esteve altamente associada ao sexo (masculino) e ligeiramente associada à complexidade da terapia, à saúde mental e aos aspectos sociais. Conclusão Observaram-se ligeira associação da adesão farmacoterapêutica com qualidade de vida e complexidade terapêutica, e forte associação com o sexo.

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides.

The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.

Performance of chronotypes on memory tests during the morning and the evening shifts.

Memory consists of several phases or processes that can be influenced by many factors, including the individual's circadian rhythm and the time of day at which tests are performed. The present objective was to evaluate the performance on memory tests of different chronotypes during the morning and the evening shifts. Subjects (21 men and 26 women, between the ages of 20 and 35 yr.) were evaluated for memory and metamemory differences in the morning and in the afternoon, using a battery of neuropsychological tests composed of the Word List with Emotional Content, Visual Memory, Scale-Semantic Memory, Digit Span, Word-Pairs Associated, Verbal Fluency Test, and Metamemory questionnaire. In the evening shift, there was a statistical difference among chronotypes on the Word List with Neutral Content and on the Verbal Fluency Test. In the morning, there were no statistically significant differences; however, the morning-type subjects had higher scores on the metamemory tests (p<.01), while the evening-type subjects had higher scores in the afternoon (p<.01). In spite of their perception, on Word-Pairs Associated and Word List with Emotional Content, the subjects, independently of their chronotype, showed better performance by the evening than by the morning shift. These results highlight the importance of controlling the shift of day and chronotype in studies with the objective of exploration of human performance.

Association of daytime sleepiness and the morningness/eveningness dimension in young adult subjects in Brazil.

Sleepiness is a major public health problem associated with motor vehicle crashes, occupational accidents, decreased productivity, and interpersonal problems. It can be influenced by many factors, including the individual's circadian rhythm. The objective of this study is to assess the correlation between the morningness/eveningness dimension and daytime sleepiness in medical school students. This is a cross-sectional study; 310 subjects (123 women and 187 men, M age 20.5 +/- 1.9 yr.) completed a questionnaire on use of drugs, diagnostic diseases, sleeping habits, the Morningness/Eveningness Questionnaire and the Epworth Sleepiness Scale. The only variable related to daytime sleepiness was the morningness/eveningness dimension (r = -.18, p=.002). Questions with higher coefficients of discrimination between the morning and the evening chronotype were "Lying down to rest in the afternoon when circumstances permit" (.61), "Sitting and reading" (.53), and "As a passenger in a car for an hour without a break" (.53). The implications of the findings are discussed.

Association between mental health screening by self-report questionnaire and insomnia in medical students

Epidemiological research points to the high prevalence of psychiatric disorders among insomniacs. We carried out a cross-sectional study with medical students with the aim of evaluating the association between insomnia and suspicion of psychiatric disorder; 302 medical students were included (184 males and 118 females; mean age = 20.47Ý1.89 years). The main association was tested by logistic regression analysis. The overall prevalence of positivity in a screening test for psychiatric disorder was 22.19 percent; and of insomnia, 28.15 percent. Difficulty initiating sleep (OR=3.45), difficulty maintaining sleep (OR=7.61), falling asleep later (OR=1.99) and waking up earlier (OR=1.91) were associated with suspicion of psychiatric disorder. As a group, the variables difficulty initiating sleep, difficulty maintaining sleep, falling asleep after 11 pm, and waking up before 6 am presented an odds ratio of 5.96 for positivity in the screening for psychiatric disorder. Furthermore, difficulty maintaining sleep (OR=2.24) was associated with "being female," and falling asleep later (OR=0.43) was associated with "being male". These results underscore the importance of determining in what cases difficulty sleeping may have severe clinical repercussions or affect performance