The crystal structure of Pneumolysin at 2.0 Å resolution reveals the molecular packing of the pre-pore complex

Pneumolysin is a cholesterol-dependent cytolysin (CDC) and virulence factor of Streptococcus pneumoniae. It kills cells by forming pores assembled from oligomeric rings in cholesterol-containing membranes. Cryo-EM has revealed the structures of the membrane-surface bound pre-pore and inserted-pore oligomers, however the molecular contacts that mediate these oligomers are unknown because high-resolution information is not available. Here we have determined the crystal structure of full-length pneumolysin at 1.98 Å resolution. In the structure, crystal contacts demonstrate the likely interactions that enable polymerisation on the cell membrane and the molecular packing of the pre-pore complex. The hemolytic activity is abrogated in mutants that disrupt these intermolecular contacts, highlighting their importance during pore formation. An additional crystal structure of the membrane-binding domain alone suggests that changes in the conformation of a tryptophan rich-loop at the base of the toxin promote monomer-monomer interactions upon membrane binding by creating new contacts. Notably, residues at the interface are conserved in other members of the CDC family, suggesting a common mechanism for pore and pre-pore assembly

Evaluation of certain Nitrogen-Fixing Bacteria against Fusarium spp. infected peanut

In this study, the inhibition of soil borne pathogenic fungi Fusarium spp. that cause root and pod rot diseases in peanut (Arachis hypogaea) was investigated by using  soil-isolated Plant Growth Promoting Rhizobacteria (PGPR), (Azotobacter and Azospirillum) and root-nodule Brady- Rhizobium as biological agents. Twenty seven isolates of  Azotobacter  and  26 isolates of  Azospirillum obtained from rhizosphere of peanut plants, The efficiency of the nitrogenase activity was estimated and the best four  Azotobacter isolates including (A3, A7, A11, and A20) and three Azospirillum isolates including (AZ2, AZ14 and AZ18) were selected as the most efficient in  nitrogenase activity. These isolates were subjected to test their ability in solubilizing zinc and phosphate and their strength in direct antagonism. The isolates A7 and Az18 were more efficient in solubilizing Phosphate and zinc. Azospirillum sp. AZ18, Azotobacter sp. A7 and Brady-Rhizobium sp. B-Rh1 achieved the highest reduction percentage in mycelia linear growth of pathogenic fungi in vitro. Under greenhouse conditions, Azotobacter sp. A7 recorded the highest disease reduction percentage of peanut root rot (44.38 %). Furthermore, Brady-Rhizobium sp. B-Rh1 recorded the highest disease reduction of peanut pod rot (50.6%) followed by Azotobacter sp. A7 (47.62%). In addition, our results showed that inoculation with the tested nitrogen fixing bacteria gave remarkable increase in the yield parameters of peanut plants such as number and weight of pods and  increased the vegetative biomass overall

New GMM Estimators for Dynamic Panel Data Models

In dynamic panel data (DPD) models, the generalized method of moments (GMM) estimation gives efficient estimators. However, this efficiency is affected by the choice of the initial weighting matrix. In practice, the inverse of the moment matrix of the instruments has been used as an initial weighting matrix which led to a loss of efficiency. Therefore, we will present new GMM estimators based on optimal or suboptimal weighting matrices in GMM estimation. Monte Carlo study indicates that the potential efficiency gain by using these matrices. Moreover, the bias and efficiency of the new GMM estimators are more reliable than any other conventional GMM estimators

Improving the Efficiency of GMM Estimators for Dynamic Panel Models

In dynamic panel models, the generalized method of moments (GMM) has been used in many applications since it gives efficient estimators. This efficiency is affected by the choice of the initial weighted matrix. It is common practice to use the inverse of the moment matrix of the instruments as an initial weighted matrix. However, an initial optimal weighted matrix is not known, especially in the system GMM estimation procedure. Therefore, we present the optimal weighted matrix for level GMM estimator, and suboptimal weighted matrices for system GMM estimator, and use these matrices to increase the efficiency of GMM estimator. By using the Kantorovich inequality (KI), we find that the potential efficiency gain becomes large when the variance of individual effects increases compared with the variance of the errors

Improving the Efficiency of GMM Estimators for Dynamic Panel Models

In dynamic panel models, the generalized method of moments (GMM) has been used in many applications since it gives efficient estimators. This efficiency is affected by the choice of the initial weighted matrix. It is common practice to use the inverse of the moment matrix of the instruments as an initial weighted matrix. However, an initial optimal weighted matrix is not known, especially in the system GMM estimation procedure. Therefore, we present the optimal weighted matrix for level GMM estimator, and suboptimal weighted matrices for system GMM estimator, and use these matrices to increase the efficiency of GMM estimator. By using the Kantorovich inequality (KI), we find that the potential efficiency gain becomes large when the variance of individual effects increases compared with the variance of the errors

Photodynamic Therapy in Primary Breast Cancer

Photodynamic therapy (PDT) is a technique for producing localized necrosis with light after prior administration of a photosensitizing agent. This study investigates the nature, safety, and efficacy of PDT for image-guided treatment of primary breast cancer. We performed a phase I/IIa dose escalation study in 12 female patients with a new diagnosis of invasive ductal breast cancer and scheduled to undergo mastectomy as a first treatment. The photosensitizer verteporfin (0.4 mg/kg) was administered intravenously followed by exposure to escalating light doses (20, 30, 40, 50 J; 3 patients per dose) delivered via a laser fiber positioned interstitially under ultrasound guidance. MRI (magnetic resonance imaging) scans were performed prior to and 4 days after PDT. Histological examination of the excised tissue was performed. PDT was well tolerated, with no adverse events. PDT effects were detected by MRI in 7 patients and histology in 8 patients, increasing in extent with the delivered light dose, with good correlation between the 2 modalities. Histologically, there were distinctive features of PDT necrosis, in contrast to spontaneous necrosis. Apoptosis was detected in adjacent normal tissue. Median follow-up of 50 months revealed no adverse effects and outcomes no worse than a comparable control population. This study confirms a potential role for PDT in the management of early breast cancer

Callous-unemotional traits, low cortisol reactivity and physical aggression in children: findings from the Wirral Child Health and Development Study

Callous-unemotional (CU) traits are thought to confer risk for aggression via reduced amygdala responsivity to distress cues in others. Low cortisol reactivity is thought to confer risk for aggression via reduced arousal and this effect may be confined to boys. We tested the hypothesis that the association between childhood CU traits and aggression would be greatest in the absence of the inhibitory effects of cortisol reactivity, and that this effect would be sex dependent. Participants were 283 members of a stratified subsample within an epidemiological longitudinal cohort (WCHADS). Cortisol reactivity to a social stressor was assessed at 5 years. CU traits were reported by mothers at 5 years, and physical aggression by mothers and teachers at age 7. Results showed that CU traits were associated with elevated aggression at 7 years controlling for earlier aggression. There was no main effect of cortisol reactivity on regression. The association between CU traits and aggression was moderated by cortisol reactivity (p = .011) with a strong association between CU traits and aggression in the presence of low reactivity, and a small and non-significant association in the presence of high reactivity. This association was further moderated by child sex (p = .041) with the joint effect of high CU traits and low cortisol reactivity seen only in boys (p = .016). We report first evidence that a combined deficit in inhibitory processes associated with CU traits and low cortisol reactivity increases risk for childhood aggression, in a sex-dependent manner

A role for Rad5 in ribonucleoside monophosphate (rNMP) tolerance

YesRibonucleoside monophosphate (rNMP) incorporation in genomic DNA poses a significant threat to genomic integrity. In addition to repair, DNA damage tolerance mechanisms ensure replication progression upon encountering unrepaired lesions. One player in the tolerance mechanism is Rad5, which is an E3 ubiquitin ligase and helicase. Here, we report a new role for yeast Rad5 in tolerating rNMP incorporation, in the absence of the bona fide ribonucleotide excision repair pathway via RNase H2. This role of Rad5 is further highlighted after replication stress induced by hydroxyurea or by increasing rNMP genomic burden using a mutant DNA polymerase (Pol ε - Pol2-M644G). We further demonstrate the importance of the ATPase and ubiquitin ligase domains of Rad5 in rNMP tolerance. These findings suggest a similar role for the human Rad5 homologues helicase-like transcription factor (HLTF) and SNF2 Histone Linker PHD RING Helicase (SHPRH) in rNMP tolerance, which may impact the response of cancer cells to replication stress-inducing therapeutics

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries.

BACKGROUND: Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. METHODS: The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. RESULTS: Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55-3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. CONCLUSIONS: Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure