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Efficient identification of drug mechanisms of action remains a challenge. Computational docking approaches have been widely used to predict drug binding targets; yet, such approaches depend on existing protein structures, and accurate structural predictions have only recently become available from AlphaFold2. Here, we combine AlphaFold2 with molecular docking simulations to predict protein‐ligand interactions between 296 proteins spanning Escherichia coli's essential proteome, and 218 active antibacterial compounds and 100 inactive compounds, respectively, pointing to widespread compound and protein promiscuity. We benchmark model performance by measuring enzymatic activity for 12 essential proteins treated with each antibacterial compound. We confirm extensive promiscuity, but find that the average area under the receiver operating characteristic curve (auROC) is 0.48, indicating weak model performance. We demonstrate that rescoring of docking poses using machine learning‐based approaches improves model performance, resulting in average auROCs as large as 0.63, and that ensembles of rescoring functions improve prediction accuracy and the ratio of true‐positive rate to false‐positive rate. This work indicates that advances in modeling protein‐ligand interactions, particularly using machine learning‐based approaches, are needed to better harness AlphaFold2 for drug discovery. Synopsis: Assessing molecular docking simulations based on AlphaFold2‐predicted structures with high‐throughput measurements of protein‐ligand interactions reveals weak model performance. Machine learning‐based approaches improve performance and better harness AlphaFold2 for drug discovery. AlphaFold2‐based molecular docking predictions for 296 Escherichia coli proteins, 218 active antibacterial compounds and 100 inactive compounds predict widespread promiscuity and similar distributions of binding affinities between active and inactive compounds.Quantitative enzymatic inhibition assays for 12 essential E. coli proteins treated with each of the 218 antibacterial compounds confirm extensive promiscuity.The enzymatic inhibition dataset reveals that the performance of the molecular docking model is weak.Rescoring of docking poses using machine learning‐based scoring functions improves model performance. [ABSTRACT FROM AUTHOR]

Background and Purpose: Stimuli that predict rewarding events can control choice between future actions, and this control could be mediated by δ-opioid receptors in the nucleus accumbens shell (NAc-S). Stimuli predicting the absence of important events can also guide choice, although it remains unknown whether they do so via changes in an accumbal δ-opioid receptor-related process.Experimental Approach: δ-opioid receptor-eGFP mice were trained to perform two instrumental actions that delivered different food outcomes. Choice between the two actions was then tested in the presence of stimuli paired with either the delivery or the non-delivery of each of the two outcomes. Bilateral infusions of the δ-opioid receptor antagonist naltrindole into the NAc-S were used to determine the role of these receptors at the time of choice and δ-opioid receptor expression in the NAc-S used to assess functional activity.Key Results: A stimulus predicting a specific outcome biased choice performance towards the action previously earning that same outcome. In contrast, a stimulus signalling the absence of that outcome biased performance away from the action that delivered that outcome towards actions associated with the absence of that outcome. Both effects were associated with increased δ-opioid receptor expression on the membrane of cholinergic interneurons within the NAc-S. Furthermore, both effects were blocked by naltrindole infused into the NAc-S.Conclusions and Implications: These findings suggest that δ-opioid receptors in the NAc-S were involved in the effects of predictive learning on choice between actions, whether those predictions involve the presence or absence of specific rewarding events.Linked Articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. [ABSTRACT FROM AUTHOR]

Relatively few international comparisons of the incidence of influenza related to climate parameters have been performed, particularly in the Eastern hemisphere. In this study, the incidence of influenza and climate data such as temperature, relative humidity, and rainfall, from cities at different latitudes with contrasting climates: Singapore, Hong Kong (China), Ulaanbaatar (Mongolia), Vancouver (Canada), and three Australian cities (Brisbane, Melbourne and Sydney) were examined to determine whether there was any overall relationship between the incidence of influenza and climate. Applying time-series analyses to the more comprehensive datasets, it was found that relative humidity was associated with the incidence of influenza A in Singapore, Hong Kong, Brisbane, and Vancouver. In the case of influenza B, the mean temperature was the key climate variable associated with the incidence of influenza in Hong Kong, Brisbane, Melbourne, and Vancouver. Rainfall was not significantly correlated with the incidence of influenza A or B in any of these cities. J. Med. Virol. 82:1958-1965, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Aim: To explore and compare the features of menstruation, perception and management of menstrual pain between two cohorts of Australian and Chinese women. Methods: A pilot comparison study was carried out using modified valid menstrual questionnaires. The study included 120 Australian women and 122 Chinese women aged from 18 to 45 years with primary dysmenorrhea. Results: Australian women rated menstrual pain as more intense than Chinese women (8.5 ± 1.5 on a 10-point pain scale vs 7.3 ± 1.8, P < 0.001), duration of pain was 36% longer (3.0 ± 2.5 vs 2.2 ± 0.9 days, P = 0.002) and menarche commenced earlier (12.7 ± 1.5 vs 14.2 ± 1.4 years, P < 0.001). The mean reported menstrual interval was also shorter (29.2 ± 5.3 vs 30.52 ± 3.7, P = 0.020) with heavier overall menstrual flow ( P = 0.002) and fewer clots in menstrual blood (83% vs 95.8%, P = 0.001). There was no significant difference in duration of menstruation (5.2 ± 1.3 vs 5.4 ± 1.1 days; P = 0.180). Correlations were found between earlier menarche and increased intensity of menstrual pain ( r = −0.16, P = 0.011), and between heavier menstrual flow and increased intensity of menstrual pain ( r = 0.19, P = 0.003). Conclusion: Evidence from this pilot study suggested that the clinical menstrual presentations in the cohorts of Australian and Chinese women were different. Although the findings are preliminary, evaluating ethnic differences in menstruation and experimental menstrual pain models may not only provide some information about underlying mechanisms but may also predict or explain group differences. [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence and risk factors for mixed urinary incontinence (MUI) among Chinese women.Method: In this cross-sectional survey study we analyzed the answers to a modified Bristol Female Lower Urinary Tract Symptoms questionnaire provided by 19024 women older than 20 years and from 6 regions in China.Results: The overall prevalence of MUI was 9.4%. The prevalence of MUI increased with age and reached 24.1% among women older than 70 years. Multivariable logistic regression analysis revealed that age, vaginal delivery, chronic constipation, pelvic organ prolapse, chronic pelvic pain, respiratory system disease, menstrual disorder, urinary system disease, alcohol consumption, pelvic surgery, obesity, and a low educational level were independent risk factors for MUI.Conclusion: We found age, vaginal delivery, and chronic constipation to be the main risk factors for MUI among adult women in China. [ABSTRACT FROM AUTHOR]

Objectives: To determine the role of neuropeptide Y (NPY) in anterior and posterior vaginal epithelium in the etiologic development of pelvic organ prolapse (POP) and stress urinary incontinence (SUI).Methods: Forty biopsy specimens from anterior and posterior vaginal epithelium were obtained from 40 POP/SUI patients and controls. The specimens were stained using hematoxylin and eosin and NPY immunohistochemical staining. NPY was measured semiquantitatively and NPY mRNA expression was assessed using DNA hybridization in situ.Results: There were no significant differences in NPY between anterior and posterior vaginal epithelium. NPY profiles in posterior vaginal epithelium in the SUI group were significantly lower than in the POP (P<0.05) and control (P<0.05) groups. In the POP group, the NPY profile correlated negatively with advancing age and years post menopause.Conclusion: The reduction in NPY in the anterior and posterior vaginal wall epithelium might be related to nerve damage or degeneration, resulting in a change in blood flow, atrophy, and pelvic floor laxity in patients with POP and SUI, especially post menopause and with advancing age. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy and safety of the tension-free vaginal tape (TVT) and transobturator suburethral tape (TVT-O) procedures for the treatment of mild and moderate stress urinary incontinence (SUI).Methods: A total of 56 women were randomly selected to undergo the TVT-O or the TVT procedure. In some patients, vaginal repair or vaginal hysterectomy was done simultaneously for associated indications.Results: Mean blood loss and hospital stay duration were the same for the 2 groups, but mean +/- SD operative time was significantly shorter in the TVT-O than in the TVT group (16+/-4 min vs 27+/-6 min; P<0.001). On the second day following surgery a residual urine volume less than 100 mL was noted in 86% and 89% of the patients in the TVT-O and TVT groups, respectively; cure was achieved in 92.9% and 92.6% of the patients. No serious complications occurred in either group. Outcome was subjectively assessed, with the patients followed-up for a mean of 27.6 months.Conclusion: No significant differences in rates of cure, postoperative urine retention, or operative complications were found following the TVT-O or the TVT procedure. [ABSTRACT FROM AUTHOR]

Fluorescence excitation can result in the formation of reactive oxygen species and free radicals damaging to live cells. In the case of erythrocytes, reaction of these reactive oxygen species with membrane components causes large-scale morphological changes followed by cell haemolysis. In an effort to understand the origin of these morphological changes, we have studied the consequences of localized photodamage on the erythrocyte membrane. For this, we irradiated a small area of the cell membrane using a focused laser beam in the presence of an external photosensitizer. We observed the rapid formation of an invagination (approximately 1 μm deep) at the laser focus, long before photohaemolysis occurred. We measured the rate of invagination formation and the rate of cell haemolysis, using a combination of fluorescence contrast imaging (to detect the membrane position) with fluorescence correlation spectroscopy (to measure photosensitizer concentration). We found that the kinetics of both processes depend in a similar manner on light energy flux, fluorophore concentration and the presence of oxygen scavenger. This leads us to the conclusion that the observed invagination is due to the photooxidation of membrane-associated proteins, representing a precursor of cellular photohaemolysis. We then discuss two different molecular mechanisms (conformational change of the protein band 3 and detachment of the spectrin cytoskeleton from the lipid membrane) that may explain how the photodamage of membrane-associated proteins can lead to a deformation of the lipid bilayer. [ABSTRACT FROM AUTHOR]

A value chain is defined as an end-to-end solution to a problem, with the beneficiary constituting one end of the chain and the enabling technologies (or parties) making up the rest of the chain. In this context, enabling technologies such as health monitoring, damage detection, and reliability are viewed as sequential components in a chain, with each continuing the chain while adding value to it, so that the aggregate value of the chain can be delivered to the ownership. This holistic view is taken to expose a current imbalance in technology development, and the weak link corresponds to a lack of information that relares technology-investment costs to financial benefits for the owner. Structural reliability, useful life expectancy, and other information of this genre are seen to be keeping the full value of the chain from being realized and appreciated by the ownership. An example of what the desired linkage may be comes from aerospace and mechanical engineering. In the form of so-called symptom-based reliability technology, reliability is quantified for existing structures based on actual usage instead of natural age and measured symptoms instead of idealized model prediction. Hence it is also compatible with current health-monitoring and damagedetection developments (enabling technologies of the value chain). Since the value of the chain is only as (in)effective as its weakest link, it is argued that future research effort should stress balanced development throughout the chain. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical presentation of perineal endometriosis and evaluate its treatment.Methods: Clinical data were analyzed from the records of 36 patients with perineal endometriosis who were operated on between 1983 and 2007 at Peking Union Medical College Hospital, and followed up for 0.5 to 14 years.Results: The incidence of perineal endometriosis was 0.31% among the women with endometriosis treated surgically at the hospital. The latent period was between 4 months and 13 years. All patients had cyclical and painful lesions. Of the 36 patients, 5 (13.9%) also suffered from pelvic endometriosis. All patients without anal sphincter involvement were cured after complete surgical excision. In 7 patients who had anal sphincter involvement, disease recurred because of incomplete excision.Conclusion: Perineal endometriosis can be diagnosed on the basis of clinical features and surgical excision is the treatment of choice. The recurrence rate of perineal endometriosis is related to sphincter involvement making preoperative evaluation of anal sphincter important. [ABSTRACT FROM AUTHOR]

ObjectiveTo report a case of laparoscopic ilioinguinal nerve damage due to direct trauma from a secondary trocar placed in the right iliac fossa. DesignCase report and literature review. SettingTertiary referral hospital in an Australian city. ConclusionPatients with ilioinguinal neuralgia present significant diagnostic and management problems. This report highlights the need for gynaecologists to have a knowledge of the anatomical relations of the inguinal nerves in the lower abdominal wall, so that iatrogenic injury can be avoided. [ABSTRACT FROM AUTHOR]

ObjectiveTo assess the usefulness of workshops in basic laparoscopic skills in promoting the use of laparoscopy in gynaecological surgery. DesignProspective observational survey. SettingDepartment of Obstetrics and Gynaecology, Liverpool Hospital, Sydney, New South Wales and Department of Obstetrics and Gynaecology, Mercy Hospital, Melbourne, Victoria, Australia. ResultsBetween 1993 and 1996 12 laparoscopic workshops have been conducted, with eight participants in each course. Of the participants, 82.5% were male, and 72.3% were over the age of 45 years. Out of 62 respondents to a questionnaire, 60 (96.8%) were performing more laparoscopic procedures after the course, with 38/62 (61.3%) performing more complex procedures. ConclusionsLaparoscopic surgery does have a place in gynaecological practice, and laparoscopic workshops are useful for the introduction of laparoscopic techniques to the gynaecologist. [ABSTRACT FROM AUTHOR]