Comparative study of the binding mode between cytochrome P450 17A1 and prostate cancer drugs in the absence of haem iron

Abstract

According to the X-ray crystal structures of CYP17A1 (including its complexes with inhibitors), it is shown that a hydrogen bond exists between CYP17A1 and its inhibitors (such as abiraterone and TOK-001). Previous short MD simulations (50?ns) suggested that the binding of abiraterone to CYP17A1 is stronger than that of TOK-001. In this work, by carrying out long atomistic MD simulations (200?ns) of CYP17A1 and its complexes with abiraterone and TOK-001, we observed a binding mode between CYP17A1 and abiraterone, which is different from the binding mode between CYP17A1 and TOK-001. In the case of abiraterone binding, the unfilled volume in the active site cavity increases the freedom of movement of abiraterone within CYP17A1, leading to the collective motions of the helices G and B′ as well as the breaking of hydrogen bond existing between the 3β-OH group of abiraterone and N202 of CYP17A1. However, the unfilled volume in the active site cavity can be occupied by the benzimidazole ring of TOK-001, restraining the motion of TOK-001. By pulling the two inhibitors (abiraterone and TOK-001) out of the binding pocket in CYP17A1, we discovered that abiraterone and TOK-001 were moved from their binding sites to the surface of protein similarly through the channels formed by the helices G and B′. In addition, based on the free energy calculations, one can see that it is energetically favorable for the two inhibitors (abiraterone and TOK-001) to enter into the binding pocket in CYP17A1.     

Binding orientation and specificity of calmodulin to rat olfactory cyclic nucleotide-gated ion channel

Calmodulin (CaM), the primary intracellular Ca²⁺ receptor, regulates a large number of key enzymes and controls a wide spectrum of important biological responses. Recognition between CaM and its target sequence in rat olfactory cyclic nucleotide-gated ion channel (OLFp) was investigated by circular dichroism (CD), fluorescence, and NMR spectroscopy. Fluorescence data showed the OLFp tightly bound to CaM with a dissociation constant of 12?nM in a 1:1 stoichiometry. Far-UV CD data showed that approximately 60% of OLFp residues formed α-helical structures when associated with CaM. NMR data showed that most of the ¹⁵N–¹H HSQC cross-peaks of the ¹⁵N-labeled CaM not only shifted but also split into two sets of peaks upon association with the OLFp. Our data indicated that the two distinct CaM/OLFp complexes existed simultaneously with stable structures that were not interexchangeable within the NMR time scale. In light of the palindromic sequence of OLFp (FQRIVRLVGVIRDW) for CaM targeting, we proposed that the helical OLFp with C₂ symmetry may bind to CaM in two orientations. This hypothesis is supported by the observation that only one set of ¹⁵N–¹H HSQC cross-peaks of the ¹⁵N-labeled CaM was detected upon association with OLFp-M13 chimeric peptide (OLFMp), a mutated OLFp lacking the palindromic feature. The binding specificity of OLFMp to CaM was restored when the palindromic feature was destroyed. Binding modes of CaM/OLFp and CaM/OLFMp simulated by molecular docking were in accord with their distinct patterns observed in HSQC spectra. Our studies suggest that the palindromic residues in OLFp are crucial for the orientation-specific recognition by CaM.     

Resveratrol Binding to Human Serum Albumin

Abstract

Resveratrol (Res), a polyphenolic compound found largely in the skin of red grape and wine, exhibits a wide range of pharmaceutical properties and plays a role in prevention of human cardiovascular diseases [Pendurthi et al., Arterioscler. Thromb. Vasc. Biol. 19, 419–426 (1999)]. It shows a strong affinity towards protein binding and used as inhibitor for cyclo- oxygenase and ribonuclease reductase. The aim of this study was to examine the interaction of resveratrol with human serum albumin (HSA) in aqueous solution at physiological conditions, using a constant protein concentration (0.3 mM) and various pigment contents μM to mM). FTIR, UV-Visible, CD, and fluorescence spectroscopic methods were used to determine the resveratrol binding mode, the binding constant and the effects of pigment complexation on protein secondary structure.

Structural analysis showed that resveratrol bind non-specifically (H-bonding) via polypeptide polar groups with overall binding constant of K_Res = 2.56× 10⁵ M^?1. The protein secondary structure, analysed by CD spectroscopy, showed no major alterations at low resveratrol concentrations (0.125 mM), whereas at high pigment content (1 mM), major increase of α-helix from 57% (free HSA) to 62% and a decrease of β-sheet from 10% (free HSA) to 7% occurred in the resveratrol-HSA complexes. The results indicate a partial stabilization of protein secondary structure at high resveratrol content.     

Effects of Age,Sex, Index Admission,and Predominant Polarity on the Seasonality of Acute Admissions For Bipolar Disorder: A Population-Based Study

Bipolar disorder seasonality has been documented previously, though information on the effect of demographic and clinical variables on seasonal patterns is scant. This study examined effects of age, sex, index admission, and predominant polarity on bipolar disorder seasonality in a nationwide population. An inpatient cohort admitted to hospital exclusively for mental illness was derived from the Taiwan National Health Insurance Research Database for 2002–2007. The authors identified 9619 inpatients with bipolar disorder, who had generated 15 078 acute admission records. An empirical mode decomposition method was used to identify seasonal oscillations in bipolar admission data, and regression and cross-correlation analyses were used to quantify the degree and timing of bipolar admission seasonality. Results for seasonality timing found that manic or mixed episodes peak in spring or summer, and depressive episodes peak in winter. Analysis for degree of seasonality revealed that (1) the polarity of patients' index admission predicted the seasonality of relapse admissions; (2) seasonality was significant in female admissions for depressive episodes and in male admissions for manic episodes; (3) young adults displayed a higher degree of seasonality for acute admissions than middle-aged adults; and (4) patients with predominantly depressive admissions displayed a higher degree of seasonality than patients with predominantly manic admissions. Demographic and clinical variables were found to affect the seasonality of acute admissions for bipolar disorders. These findings highlight the need for research on identification and management of seasonal features in bipolar patients. (Author correspondence: ccyang@physionet.org)     

Thermotactile thresholds at the fingertip: Effect of contact area and contact location

Thresholds for the detection of changes in temperature are used to indicate neuropathy, but a variety of different contact areas and contact locations are used. This study was designed to determine the effects of variations in contact area and contact location on both warm and cool thresholds at the fingertip. With 20 healthy subjects (10 females and 10 males aged 20–30 years), warm thresholds and cool thresholds were determined in two separate sessions using the method of limits. In the first part of each session, thresholds were determined around the centre of the whorl using circular contactors with five different diameters (3, 6, 9, 12, and 55 mm). In the second part of each session, thresholds were determined using two contactors (6- and 12-mm diameter) at three locations along the fingertip: (i) distal (5 mm from the nail), (ii) middle (centre of whorl), and (iii) proximal (3 mm from the distal interphalangeal joint). With increasing contact area, the warm thresholds decreased, the cool thresholds increased, and the inter-subject variability in both warm and cool thresholds decreased. Using the 6-mm diameter contactor, warm thresholds were independent of location but cool thresholds increased from distal to proximal locations. It is concluded that temperature sensitivity at the fingertip increases with increasing area of contact, with the variability in thresholds consistent with the existence of warm and cool “insensitive fields”. The findings show that the influence of contact area and contact location should be considered when assessing thermotactile thresholds at the fingertip.     

The limitations of ‘inter-racial contact’: stories from young South Africa

This paper argues that, while the demise of apartheid has led to many situations in which South Africans now come into closer contact with one another, this increased ‘contact’ does not amount to greater racial integration. Contact occurs within a context of unequal power relations in which ‘whiteness’ continues to be privileged over ‘blackness’. The result is that white people tend to benefit more from contact with the racial ‘other’ than black people, who often experience this contact as reinforcing their expectations of continued white dominance and privilege. While contact may undermine blatantly racist practices and overt racial conflict, racialized patterns of reasoning continue to exist, often unnoticed and unchallenged. These include the assumption that race is an incontrovertible fact of experience, the privileging of whiteness, the assumption that there exist different (biological) races which evince different forms of social behaviour and that these are essential properties of people rather than being historically or socially contingent.     

PATERNITY PROTECTION CAN PROVIDE A KICK‐START FOR THE EVOLUTION OF MALE‐ONLY PARENTAL CARE

Sperm competition and uncertainty of paternity hamper the evolution of male parental care. Thus, maternal care predominates in most taxa. What if males can, however, limit cuckoldry by guarding the eggs postmating? Here, we show that this provides a reason to reconsider an old and nowadays rather discredited hypothesis: that external fertilization is associated with male care because the parent who releases its gametes first can depart leaving the other in a “cruel bind,” having to care for the offspring. In our model, protection of paternity provides an additional incentive for the male to stay associated with its young. When we then assume that offspring survive better if guarded, paternity protection proves enough to kick‐start the evolution of male‐only parental care from a scenario with no care. This fits with data from fishes, where male‐only care is associated with external fertilization, whereas female‐only care almost always evolves after an initial transition to internal fertilization. Our model unifies disparate hypotheses regarding parental care roles and provides support for the idea that care roles can be influenced by sex differences in selection to be physically close to the offspring, including selection that is initially not based on offspring survival.     

Social encounter networks: characterizing Great Britain

A major goal of infectious disease epidemiology is to understand and predict the spread of infections within human populations, with the intention of better informing decisions regarding control and intervention. However, the development of fully mechanistic models of transmission requires a quantitative understanding of social interactions and collective properties of social networks. We performed a cross-sectional study of the social contacts on given days for more than 5000 respondents in England, Scotland and Wales, through postal and online survey methods. The survey was designed to elicit detailed and previously unreported measures of the immediate social network of participants relevant to infection spread. Here, we describe individual-level contact patterns, focusing on the range of heterogeneity observed and discuss the correlations between contact patterns and other socio-demographic factors. We find that the distribution of the number of contacts approximates a power-law distribution, but postulate that total contact time (which has a shorter-tailed distribution) is more epidemiologically relevant. We observe that children, public-sector and healthcare workers have the highest number of total contact hours and are therefore most likely to catch and transmit infectious disease. Our study also quantifies the transitive connections made between an individual''s contacts (or clustering); this is a key structural characteristic of social networks with important implications for disease transmission and control efficacy. Respondents'' networks exhibit high levels of clustering, which varies across social settings and increases with duration, frequency of contact and distance from home. Finally, we discuss the implications of these findings for the transmission and control of pathogens spread through close contact.     

基于FMEA和POSSUM评分的手术风险评估研究

??????? 目的 研究建立手术风险评估的架构,以正确决策手术时机。方法 采用用于计数死亡率和并发症发生率的生理学和手术严重性（POSSUM）评分原理进行分层计分,同时引用失效模式与效应分析方法对手术可能发生故障模式的严重度及发生可能性及风险因素的影响度3个维度进行评估。结果 建立了手术前风险预警机制及手术评估架构,利用评估架构对某综合医院2010年200例80岁高龄的手术病人进行了术前评估,结果手术后并发症的发生率较2009年同年龄的手术病人的并发症下降了10.45%。结论 在手术前对手术相关因素进行评估,可以为手术时机的选择提供参考。     

基于FMEA的C形臂X线机的使用风险分析与控制

??????? 目的 基于失效模式与效应分析（FMEA）方法分析控制C形臂X线机的使用风险。方法 成立FMEA 5人小组,运用现场观察和访谈的方法,识别C形臂X线机使用的潜在失效模式,并对其发生的严重度、发生概率及检测的难易度进行评价打分,计算失效原因的风险优先指数。结果 FMEA小组找出了必须优先解决的C臂机使用的失效模式,制定并实施了改进措施,在不增加管理成本的基础上,取得了良好的管理效果。结论 FMEA可以评估医疗设备使用过程的失效,并能排序优先解决的问题,不增加管理成本就能预防问题的发生,是有效的过程管理工具。