Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold

Host Transcription Factors in the Immediate Pro-Inflammatory Response to the Parasitic Mite Psoroptes ovis

BACKGROUND: Sheep scab, caused by infestation with the ectoparasitic mite Psoroptes ovis, results in the rapid development of cutaneous inflammation and leads to the crusted skin lesions characteristic of the disease. We described previously the global host transcriptional response to infestation with P. ovis, elucidating elements of the inflammatory processes which lead to the development of a rapid and profound immune response. However, the mechanisms by which this response is instigated remain unclear. To identify novel methods of intervention a better understanding of the early events involved in triggering the immune response is essential. The objective of this study was to gain a clearer understanding of the mechanisms and signaling pathways involved in the instigation of the immediate pro-inflammatory response. RESULTS: Through a combination of transcription factor binding site enrichment and pathway analysis we identified key roles for a number of transcription factors in the instigation of cutaneous inflammation. In particular, defined roles were elucidated for the transcription factors NF-kB and AP-1 in the orchestration of the early pro-inflammatory response, with these factors being implicated in the activation of a suite of inflammatory mediators. CONCLUSIONS: Interrogation of the host temporal response to P. ovis infestation has enabled the further identification of the mechanisms underlying the development of the immediate host pro-inflammatory response. This response involves key regulatory roles for the transcription factors NF-kB and AP-1. Pathway analysis demonstrated that the activation of these transcription factors may be triggered following a host LPS-type response, potentially involving TLR4-signalling and also lead to the intriguing possibility that this could be triggered by a P. ovis allergen

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe

Northern Eurasia Future Initiative (NEFI): facing the challenges and pathways of global change in the 21st century

During the past several decades, the Earth system has changed significantly, especially across Northern Eurasia. Changes in the socio-economic conditions of the larger countries in the region have also resulted in a variety of regional environmental changes that can have global consequences. The Northern Eurasia Future Initiative (NEFI) has been designed as an essential continuation of the Northern Eurasia Earth Science Partnership Initiative (NEESPI), which was launched in 2004. NEESPI sought to elucidate all aspects of ongoing environmental change, to inform societies and, thus, to better prepare societies for future developments. A key principle of NEFI is that these developments must now be secured through science-based strategies co-designed with regional decision makers to lead their societies to prosperity in the face of environmental and institutional challenges. NEESPI scientific research, data, and models have created a solid knowledge base to support the NEFI program. This paper presents the NEFI research vision consensus based on that knowledge. It provides the reader with samples of recent accomplishments in regional studies and formulates new NEFI science questions. To address these questions, nine research foci are identified and their selections are briefly justified. These foci include: warming of the Arctic; changing frequency, pattern, and intensity of extreme and inclement environmental conditions; retreat of the cryosphere; changes in terrestrial water cycles; changes in the biosphere; pressures on land-use; changes in infrastructure; societal actions in response to environmental change; and quantification of Northern Eurasia's role in the global Earth system. Powerful feedbacks between the Earth and human systems in Northern Eurasia (e.g., mega-fires, droughts, depletion of the cryosphere essential for water supply, retreat of sea ice) result from past and current human activities (e.g., large scale water withdrawals, land use and governance change) and potentially restrict or provide new opportunities for future human activities. Therefore, we propose that Integrated Assessment Models are needed as the final stage of global change assessment. The overarching goal of this NEFI modeling effort will enable evaluation of economic decisions in response to changing environmental conditions and justification of mitigation and adaptation efforts

The Geomechanics of CO2 Storage in Deep Sedimentary Formations

This paper provides a review of the geomechanics and modeling of geomechanics associated with geologic carbon storage (GCS), focusing on storage in deep sedimentary formations, in particular saline aquifers. The paper first introduces the concept of storage in deep sedimentary formations, the geomechanical processes and issues related with such an operation, and the relevant geomechanical modeling tools. This is followed by a more detailed review of geomechanical aspects, including reservoir stress-strain and microseismicity, well integrity, caprock sealing performance, and the potential for fault reactivation and notable (felt) seismic events. Geomechanical observations at current GCS field deployments, mainly at the In Salah CO2 storage project in Algeria, are also integrated into the review. The In Salah project, with its injection into a relatively thin, low-permeability sandstone is an excellent analogue to the saline aquifers that might be used for large scale GCS in parts of Northwest Europe, the U.S. Midwest, and China. Some of the lessons learned at In Salah related to geomechanics are discussed, including how monitoring of geomechanical responses is used for detecting subsurface geomechanical changes and tracking fluid movements, and how such monitoring and geomechanical analyses have led to preventative changes in the injection parameters. Recently, the importance of geomechanics has become more widely recognized among GCS stakeholders, especially with respect to the potential for triggering notable (felt) seismic events and how such events could impact the long-term integrity of a CO{sub 2} repository (as well as how it could impact the public perception of GCS). As described in the paper, to date, no notable seismic event has been reported from any of the current CO{sub 2} storage projects, although some unfelt microseismic activities have been detected by geophones. However, potential future commercial GCS operations from large power plants will require injection at a much larger scale. For such largescale injections, a staged, learn-as-you-go approach is recommended, involving a gradual increase of injection rates combined with continuous monitoring of geomechanical changes, as well as siting beneath a multiple layered overburden for multiple flow barrier protection, should an unexpected deep fault reactivation occur

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development

The UK10K project identifies rare variants in health and disease

M. Kivimäki työryhmäjäsen.The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.Peer reviewe

Characterisation of side-chain conformational preferences in a biologically active but unfolded protein.

A combination of experimental NMR 3J alpha beta coupling constant measurements and theoretical predictions from a statistical model for a random coil have been used to characterise the conformations of amino acid side-chains in an unfolded fibronectin binding protein. The statistical model uses the distribution of torsion angles in a data base of native folded protein structures to provide a description of the torsion angle populations of each residue in a random coil. For all but three of the residues studied a close agreement is observed between the experimental 3J alpha beta data and the model predictions (correlation coefficient 0.90; RMSD 0.70 Hz). In these cases the populations about the chi 1 torsion angles in the conformational ensemble defining the fibronectin binding protein are well described by those present in the protein data base. For Phe 69, Asp 92 and Asp 105 however significant deviations are observed between the predictions and experimental data. Each of these side-chains is found to be involved in persistent non-random structural features arising from clustering of hydrophobic groups or interactions between charged side-chains. The analysis demonstrates the detailed insight that can be provided into conformationally disordered states by combining experimental and theoretical approaches