New classes of Gram-positive selective antibacterials: inhibitors of MRSA and surrogates of the causative agents of anthrax and tuberculosis

An antimicrobial phenolic stilbene, (E)-3-hydroxy-5-methoxystilbene, 1 was recently isolated from the leaves of Comptonia peregrina (L.) Coulter and shown to possess inhibitory activity against several Gram-positive bacteria, including isolates of methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium bovis BCG, and avirulent Bacillusanthracis (Sterne strain), among others. These results prompted the design and synthesis of two new classes of compounds, phenoxystyrenes and phenothiostyrenes, as analogs of the natural antimicrobial stilbene. These and additional stilbenoid analogs were synthesized using new, efficient, copper-mediated coupling strategies. Minimum inhibitory concentration (MIC) antimicrobial assays were performed on all compounds prepared. These preliminary structure-activity relationship studies indicated that both new classes of synthetic analogs, as well as the stilbenes, show promising activity against Gram-positive bacteria when at least one phenolic moiety is present, but not when absent. The potencies of the phenolic phenoxystyrenes and phenothiostyrenes were found to be comparable to those of the phenolic stilbenes tested.     

Combined deficiency of the Cnr1 and Cnr2 receptors protects against age‐related bone loss by osteoclast inhibition

The endocannabinoid system plays a role in regulating bone mass and bone cell activity and inactivation of the type 1 (Cnr1) or type 2 (Cnr2) cannabinoid receptors influences peak bone mass and age‐related bone loss. As the Cnr1 and Cnr2 receptors have limited homology and are activated by different ligands, we have evaluated the effects of combined deficiency of Cnr1 and 2 receptors (Cnr1/2^?/?) on bone development from birth to old age and studied ovariectomy induced bone loss in female mice. The Cnr1/2^?/? mice had accelerated bone accrual at birth when compared with wild type littermates, and by 3 months of age, they had higher trabecular bone mass. They were also significantly protected against ovariectomy‐induced bone loss due to a reduction in osteoclast number. The Cnr1/2^?/? mice had reduced age‐related bone loss when compared with wild‐type due to a reduction in osteoclast number. Although bone formation was reduced and bone marrow adiposity increased in Cnr1/2^?/? mice, the osteoclast defect outweighed the reduction in bone formation causing preservation of bone mass with aging. This contrasts with the situation previously reported in mice with inactivation of the Cnr1 or Cnr2 receptors individually where aged‐related bone loss was greater than in wild‐type. We conclude that the Cnr1 and Cnr2 receptors have overlapping but nonredundant roles in regulating osteoclast and osteoblast activities. These observations indicate that combined inhibition of Cnr1 and Cnr2 receptors may be beneficial in preventing age‐related bone loss, whereas blockade of individual receptors may be detrimental.     

Genetic diversity of Salmonella Paratyphi A isolated from enteric fever patients in Bangladesh from 2008 to 2018

BackgroundThe proportion of enteric fever cases caused by Salmonella Paratyphi A is increasing and may increase further as we begin to introduce typhoid conjugate vaccines (TCVs). While numerous epidemiological and genomic studies have been conducted for S. Typhi, there are limited data describing the genomic epidemiology of S. Paratyphi A in especially in endemic settings, such as Bangladesh.Principal findingsWe conducted whole genome sequencing (WGS) of 67 S. Paratyphi A isolated between 2008 and 2018 from eight enteric disease surveillance sites across Bangladesh. We performed a detailed phylogenetic analysis of these sequence data incorporating sequences from 242 previously sequenced S. Paratyphi A isolates from a global collection and provided evidence of lineage migration from neighboring countries in South Asia. The data revealed that the majority of the Bangladeshi S. Paratyphi A isolates belonged to the dominant global lineage A (67.2%), while the remainder were either lineage C (19.4%) or F (13.4%). The population structure was relatively homogenous across the country as we did not find any significant lineage distributions between study sites inside or outside Dhaka. Our genomic data showed presence of single point mutations in gyrA gene either at codon 83 or 87 associated with decreased fluoroquinolone susceptibility in all Bangladeshi S. Paratyphi A isolates. Notably, we identified the pHCM2- like cryptic plasmid which was highly similar to S. Typhi plasmids circulating in Bangladesh and has not been previously identified in S. Paratyphi A organisms.SignificanceThis study demonstrates the utility of WGS to monitor the ongoing evolution of this emerging enteric pathogen. Novel insights into the genetic structure of S. Paratyphi A will aid the understanding of both regional and global circulation patterns of this emerging pathogen and provide a framework for future genomic surveillance studies.     

Canonical Correlation Analysis of Infant's Size at Birth and Maternal Factors: A Study in Rural Northwest Bangladesh

This analysis was conducted to explore the association between 5 birth size measurements (weight, length and head, chest and mid-upper arm [MUAC] circumferences) as dependent variables and 10 maternal factors as independent variables using canonical correlation analysis (CCA). CCA considers simultaneously sets of dependent and independent variables and, thus, generates a substantially reduced type 1 error. Data were from women delivering a singleton live birth (n = 14506) while participating in a double-masked, cluster-randomized, placebo-controlled maternal vitamin A or β-carotene supplementation trial in rural Bangladesh. The first canonical correlation was 0.42 (P<0.001), demonstrating a moderate positive correlation mainly between the 5 birth size measurements and 5 maternal factors (preterm delivery, early pregnancy MUAC, infant sex, age and parity). A significant interaction between infant sex and preterm delivery on birth size was also revealed from the score plot. Thirteen percent of birth size variability was explained by the composite score of the maternal factors (Redundancy, R_Y/X = 0.131). Given an ability to accommodate numerous relationships and reduce complexities of multiple comparisons, CCA identified the 5 maternal variables able to predict birth size in this rural Bangladesh setting. CCA may offer an efficient, practical and inclusive approach to assessing the association between two sets of variables, addressing the innate complexity of interactions.     

Niche modelling predicts that soil fungi occupy a precarious climate in boreal forests

Aim

Efforts to predict the responses of soil fungal communities to climate change are hindered by limited information on how fungal niches are distributed across environmental hyperspace. We predict the climate sensitivity of North American soil fungal assemblage composition by modelling the ecological niches of several thousand fungal species.

Location

One hundred and thirteen sites in the United States and Canada spanning all biomes except tropical rain forest.

Major Taxa Studied

Fungi.

Time Period

2011–2018.

Methods

We combine internal transcribed spacer (ITS) sequences from two continental-scale sampling networks in North America and cluster them into operational taxonomic units (OTUs) at 97% similarity. Using climate and soil data, we fit ecological niche models (ENMs) based on logistic ridge regression for all OTUs present in at least 10 sites (n = 8597). To describe the compositional turnover of soil fungal assemblages over climatic gradients, we introduce a novel niche-based metric of climate sensitivity, the Sørensen climate sensitivity index. Finally, we map climate sensitivity across North America.

Results

ENMs have a mean out-of-sample predictive accuracy of 73.8%, with temperature variables being strong predictors of fungal distributions. Soil fungal climate niches clump together across environmental space, which suggests common physiological limits and predicts abrupt changes in composition with respect to changes in climate. Soil fungi in North American climates are more likely to be limited by cold and dry conditions than by warm and wet conditions, and ectomycorrhizal fungi generally tolerate colder temperatures than saprotrophic fungi. Sørensen climate sensitivity exhibits a multimodal distribution across environmental space, with a peak in climates corresponding to boreal forests.

Main Conclusions

The boreal forest occupies an especially precarious region of environmental space for the composition of soil fungal assemblages in North America, as even small degrees of warming could trigger large compositional changes characterized mainly by an influx of warm-adapted species.     

Single dose vitamin A treatment in acute shigellosis in Bangladesh children: randomised double blind controlled trial.

OBJECTIVE: To evaluate the efficacy of a single large oral dose of vitamin A in treating acute shigellosis in children in Bangladesh. DESIGN: Randomised double blind controlled clinical trial. SETTING: Dhaka Hospital, International Centre for Diarrhoeal Disease Research, Bangladesh. SUBJECTS: 83 children aged 1-7 years with bacteriologically proved shigellosis but no clinical signs of vitamin A deficiency; 42 were randomised to treatment with vitamin A and 41 formed a control group. INTERVENTION: Children were given a single oral dose of 200,000 IU of vitamin A plus 25 IU vitamin E or a control preparation of 25 IU vitamin E. MAIN OUTCOME MEASURES: Clinical cure on study day 5 and bacteriological cure. RESULTS: Baseline characteristics of the subjects in the two treatment groups were similar. Significantly more children in the vitamin A group than in the control group achieved clinical cure (19/42 (45%) v 8/14 (20%); chi 2 = 5.14, 1 df, P = 0.02; risk ratio = 0.68 (95% confidence interval; 0.50 to 0.93)). When cure was determined bacteriologically, the groups had similar rates (16/42 (38%) v 16/41 (39%); chi 2 = 0.02, 1 df, P = 0.89; risk ratio = 0.98 (0.70 to 1.39)). CONCLUSIONS: Vitamin A reduces the severity of acute shigellosis in children living in areas where vitamin A deficiency is a major public health problem.     

Goniothalamin – a potent mosquito larvicide from Bryonopsis laciniosa L.

Abstract: Goniothalamin isolated from the indigenous plant, Bryonopsis laciniosa L., was highly effective against the larvae of the mosquito, Culex quinquefasciatus Say, as a mosquitocide. This is the first report of goniothalamin. The structure of the bioactive compound isolated from the EtOAc (CH₃COOC₂H₅) fraction was established through spectroscopic methods using ¹H-NMR and ¹³C-NMR in CDCl₃. The mass spectrum was also recorded using VG micromass ZAB mass spectrometer.     

Serum T4, T3 and reverse T3 in ethanol fed rats.

To investigate the influence of chronic ethanol consumption on circulating thyroid hormone levels, male and female rats were given 20% ethanol as the only drinking solution daily for 8 weeks. Blood ethanol levels ranged 30–45 mg/L. In male rats serum T₄ decreased from the initial mean ± SD value of 5.2±1.4 to3.0 ±0.7 μg/dl; T₃ decreased from initial value of 97±14 to 66±11 ng/dl and rT₃ decreased from initial value of 19±9 to 10±1 ng/dl after 8 weeks of ethanol ingestion. Under similar experimental conditions, female rats showed a significant decrease in serum T₄ and rT₃ levels; however, T₃ levels decreased slightly but not significantly as compared to initial values. The results indicate adverse effect of chronic ethanol intake on serum thyroid hormone levels in rats.     

Spectroscopic studies of 1,2-diaminoanthraquinone (DAQ) as a fluorescent probe for the imaging of nitric oxide in living cells.

Spectroscopic analysis of the fluorescent probe 1,2-diaminoanthraquinone () provides information about the mechanism of nitric oxide imaging in living cells. Fluorescent aggregates of a reaction product of are thought to be responsible for the images obtained with confocal fluorescence microscopy.