Let’s not forget tautomers

A compound exhibits tautomerism if it can be represented by two structures that are related by an intramolecular movement of hydrogen from one atom to another. The different tautomers of a molecule usually have different molecular fingerprints, hydrophobicities and pKa’s as well as different 3D shape and electrostatic properties; additionally, proteins frequently preferentially bind a tautomer that is present in low abundance in water. As a result, the proper treatment of molecules that can tautomerize, ~25% of a database, is a challenge for every aspect of computer-aided molecular design. Library design that focuses on molecular similarity or diversity might inadvertently include similar molecules that happen to be encoded as different tautomers. Physical property measurements might not establish the properties of individual tautomers with the result that algorithms based on these measurements may be less accurate for molecules that can tautomerize—this problem influences the accuracy of filtering for library design and also traditional QSAR. Any 2D or 3D QSAR analysis must involve the decision of if or how to adjust the observed Ki or IC50 for the tautomerization equilibria. QSARs and recursive partitioning methods also involve the decision as to which tautomer(s) to use to calculate the molecular descriptors. Docking virtual screening must involve the decision as to which tautomers to include in the docking and how to account for tautomerization in the scoring. All of these decisions are more difficult because there is no extensive database of measured tautomeric ratios in both water and non-aqueous solvents and there is no consensus as to the best computational method to calculate tautomeric ratios in different environments

A Forward-Genetic Screen and Dynamic Analysis of Lambda Phage Host-Dependencies Reveals an Extensive Interaction Network and a New Anti-Viral Strategy

Latently infecting viruses are an important class of virus that plays a key role in viral evolution and human health. Here we report a genome-scale forward-genetics screen for host-dependencies of the latently-infecting bacteriophage lambda. This screen identified 57 Escherichia coli (E. coli) genes—over half of which have not been previously associated with infection—that when knocked out inhibited lambda phage's ability to replicate. Our results demonstrate a highly integrated network between lambda and its host, in striking contrast to the results from a similar screen using the lytic-only infecting T7 virus. We then measured the growth of E. coli under normal and infected conditions, using wild-type and knockout strains deficient in one of the identified host genes, and found that genes from the same pathway often exhibited similar growth dynamics. This observation, combined with further computational and experimental analysis, led us to identify a previously unannotated gene, yneJ, as a novel regulator of lamB gene expression. A surprising result of this work was the identification of two highly conserved pathways involved in tRNA thiolation—one pathway is required for efficient lambda replication, while the other has anti-viral properties inhibiting lambda replication. Based on our data, it appears that 2-thiouridine modification of tRNAGlu, tRNAGln, and tRNALys is particularly important for the efficient production of infectious lambda phage particles

Progression of the first stage of spontaneous labour: A prospective cohort study in two sub-Saharan African countries.

BACKGROUND: Escalation in the global rates of labour interventions, particularly cesarean section and oxytocin augmentation, has renewed interest in a better understanding of natural labour progression. Methodological advancements in statistical and computational techniques addressing the limitations of pioneer studies have led to novel findings and triggered a re-evaluation of current labour practices. As part of the World Health Organization's Better Outcomes in Labour Difficulty (BOLD) project, which aimed to develop a new labour monitoring-to-action tool, we examined the patterns of labour progression as depicted by cervical dilatation over time in a cohort of women in Nigeria and Uganda who gave birth vaginally following a spontaneous labour onset. METHODS AND FINDINGS: This was a prospective, multicentre, cohort study of 5,606 women with singleton, vertex, term gestation who presented at ≤ 6 cm of cervical dilatation following a spontaneous labour onset that resulted in a vaginal birth with no adverse birth outcomes in 13 hospitals across Nigeria and Uganda. We independently applied survival analysis and multistate Markov models to estimate the duration of labour centimetre by centimetre until 10 cm and the cumulative duration of labour from the cervical dilatation at admission through 10 cm. Multistate Markov and nonlinear mixed models were separately used to construct average labour curves. All analyses were conducted according to three parity groups: parity = 0 (n = 2,166), parity = 1 (n = 1,488), and parity = 2+ (n = 1,952). We performed sensitivity analyses to assess the impact of oxytocin augmentation on labour progression by re-examining the progression patterns after excluding women with augmented labours. Labour was augmented with oxytocin in 40% of nulliparous and 28% of multiparous women. The median time to advance by 1 cm exceeded 1 hour until 5 cm was reached in both nulliparous and multiparous women. Based on a 95th percentile threshold, nulliparous women may take up to 7 hours to progress from 4 to 5 cm and over 3 hours to progress from 5 to 6 cm. Median cumulative duration of labour indicates that nulliparous women admitted at 4 cm, 5 cm, and 6 cm reached 10 cm within an expected time frame if the dilatation rate was ≥ 1 cm/hour, but their corresponding 95th percentiles show that labour could last up to 14, 11, and 9 hours, respectively. Substantial differences exist between actual plots of labour progression of individual women and the 'average labour curves' derived from study population-level data. Exclusion of women with augmented labours from the study population resulted in slightly faster labour progression patterns. CONCLUSIONS: Cervical dilatation during labour in the slowest-yet-normal women can progress more slowly than the widely accepted benchmark of 1 cm/hour, irrespective of parity. Interventions to expedite labour to conform to a cervical dilatation threshold of 1 cm/hour may be inappropriate, especially when applied before 5 cm in nulliparous and multiparous women. Averaged labour curves may not truly reflect the variability associated with labour progression, and their use for decision-making in labour management should be de-emphasized

ICAR: endoscopic skull‐base surgery

n/

Oral misoprostol for preventing postpartum haemorrhage in home births in rural Bangladesh : how effective is it?

AIMS: Evidence exists about prevention of postpartum haemorrhage (PPH) by oral administration of misoprostol in low-income countries, but effectiveness of prevention by lay community health workers (CHW) is not sufficient. This study aimed to investigate whether a single dose (400 µg) of oral misoprostol could prevent PPH in a community home-birth setting and to assess its acceptability and feasibility among rural Bangladeshi women. METHODS: This quasi-experimental trial was conducted among 2,017 rural women who had home deliveries between November 2009 and February 2010 in two rural districts of northern Bangladesh. In the intervention district 1,009 women received 400 µg of misoprostol immediately after giving birth by the lay CHWs, and in the control district 1,008 women were followed after giving birth with no specific intervention against PPH. Primary PPH (within 24 hours) was measured by women's self-reported subjective measures of the normality of blood loss using the 'cultural consensus model.' Baseline data provided socio-economic, reproductive, obstetric, and bleeding disorder information. FINDINGS: The incidence of primary PPH was found to be lower in the intervention group (1.6%) than the control group (6.2%) (p<0.001). Misoprostol provided 81% protection (RR: 0.19; 95% CI: 0.08-0.48) against developing primary PPH. The proportion of retained and manually removed placentae was found to be higher in the control group compared to the intervention group. Women in the control group were more likely to need an emergency referral to a higher level facility and blood transfusion than the intervention group. Unexpectedly few women experienced transient side effects of misoprostol. Eighty-seven percent of the women were willing to use the drug in future pregnancy and would recommend to other pregnant women. CONCLUSION: Community-based distribution of oral misoprostol (400 µg) by CHW appeared to be effective, safe, acceptable, and feasible in reducing the incidence of PPH in rural areas of Bangladesh. This strategy should be scaled up across the country where access to skilled attendance is limited

Semiconducting polymer nanoparticles as photoacoustic molecular imaging probes in living mice

Photoacoustic (PA) imaging holds great promise for the visualization of physiology and pathology at the molecular level with deep tissue penetration and fine spatial resolution. To fully utilize this potential, PA molecular imaging probes have to be developed. Herein we introduce near infrared (NIR) light absorbing semiconducting polymer nanoparticles (SPNs) as a new class of contrast agents for PA molecular imaging. SPNs can produce stronger signal than commonly used single-wall carbon nanotubes and gold nanorods on a per mass basis, permitting whole-body lymph node PA mapping in living mice at a low systematic injection mass. Furthermore, SPNs possess high structural flexibility, narrow PA spectral profiles, and strong resistance to photodegradation and oxidation, which enables development of the first NIR ratiometric PA probe for in vivo real-time imaging of reactive oxygen species—vital chemical mediators of many diseases. These results demonstrate SPNs an ideal nanoplatform for developing PA molecular probes