Production costs in many shale-gas plays exceed current gas prices, and maintaining production requires ever-increasing drilling and the capital input to support it. SHALE GAS Two technologies - ...horizontal drilling coupled with large-scale, multi-stage hydraulic fracturing (fracking) - have made it possible to extract hydrocarbons trapped in impermeable rocks (see Nature 477, 271-275; 2011). Existing production histories are a few years at best, and thus are insufficient to substantiate such long lifetimes for wells. Because production declines more steeply than these models typically suggest, the method often overestimates ultimate recoveries and economic performance (see go.nature.com/kiamlk).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Molecular glues and bivalent inducers of protein degradation (also known as PROTACs) represent a fascinating new modality in pharmacotherapeutics: the potential to knockdown previously thought ...'undruggable' targets at sub-stoichiometric concentrations in ways not possible using conventional inhibitors. Mounting evidence suggests these chemical agents, in concert with their target proteins, can be modelled as three-body binding equilibria that can exhibit significant cooperativity as a result of specific ligand-induced molecular recognition. Despite this, many existing drug design and optimization regimens still fixate on binary target engagement, in part due to limited structural data on ternary complexes. Recent crystal structures of protein complexes mediated by degrader molecules, including the first PROTAC ternary complex, underscore the importance of protein-protein interactions and intramolecular contacts to the mode of action of this class of compounds. These discoveries have opened the door to a new paradigm for structure-guided drug design: borrowing surface area and molecular recognition from nature to elicit cellular signalling.
Principles of early drug discovery Hughes, JP; Rees, S; Kalindjian, SB ...
British journal of pharmacology,
March 2011, Letnik:
162, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12–15 years and cost in excess of $1 billion. The idea for a target can come from a ...variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development.
Recent advances in the technology available for culture-independent methods for identification and enumeration of environmental bacteria have invigorated interest in the study of the role of chicken ...intestinal microbiota in health and productivity. Chickens harbour unique and diverse bacterial communities that include human and animal pathogens. Increasing public concern about the use of antibiotics in the poultry industry has influenced the ways in which poultry producers are working towards improving birds’ intestinal health. Effective means of antibiotic-independent pathogen control through competitive exclusion and promotion of good protective microbiota are being actively investigated. With the realisation that just about any change in environment influences the highly responsive microbial communities and with the abandonment of the notion that we can isolate and investigate a single species of interest outside of the community, came a flood of studies that have attempted to profile the intestinal microbiota of chickens under numerous conditions. This review aims to address the main issues in investigating chicken microbiota and to summarise the data acquired to date.
Structure‐Based Design of a Macrocyclic PROTAC Testa, Andrea; Hughes, Scott J.; Lucas, Xavier ...
Angewandte Chemie (International ed.),
January 20, 2020, Letnik:
59, Številka:
4
Journal Article
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Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to ...enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Herein, we report the design and synthesis of a macrocyclic PROTAC by adding a cyclizing linker to the BET degrader MZ1. A co‐crystal structure of macroPROTAC‐1 bound in a ternary complex with VHL and the second bromodomain of Brd4 validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12‐fold loss of binary binding affinity for Brd4, macroPROTAC‐1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.
Closing the circle: A macrocyclic PROTAC has been designed and synthesized by adding a cyclizing linker to MZ1, a PROTAC targeting the bromodomain of the BET protein, Brd4. A co‐crystal structure of macroPROTAC‐1 bound in a ternary complex with E3 ligase VHL and the second bromodomain of Brd4 validated the rational design. This macrocyclization strategy enhanced the target specificity and cellular activity of the PROTAC.
Introduction
Prehabilitation prior to major surgery has increased in popularity over recent years and aims to improve pre-operative conditioning of patients to improve post-operative outcomes. The ...beneficial effect of such protocols is not well established with conflicting results reported. This review aimed to assess the effect of prehabilitation on post-operative outcome after major abdominal surgery.
Methods
EMBASE, Medline, PubMed and the Cochrane database were searched in August 2018 for trials comparing outcomes of patients undergoing prehabilitation involving prescribed respiratory and exercise interventions prior to abdominal surgery. Study characteristics, overall and pulmonary morbidity, length of stay (LOS), maximum inspiratory pressure and change in six-minute walking test (6MWT) distance were obtained. The primary outcome was post-operative overall morbidity within 30 days. Dichotomous data were analysed by fixed or random effects odds ratio. Continuous data were analysed with weighted mean difference.
Results
Fifteen RCTs were included in the analysis with 457 prehabilitation patients and 450 control group patients. A significant reduction in overall (OR 0.63 95% CI 0.46–0.87
I
2
34%,
p
= 0.005) and pulmonary morbidity (OR 0.4 95% CI 0.23–0.68,
I
2
= 0%,
p
= 0.0007) was observed in the prehabilitation group. No significant difference in LOS (WMD −2.39 95% CI −4.86 to 0.08
I
2
= 0%,
p
= 0.06) or change in 6MWT distance (WMD 9.06 95% CI −35.68, 53.81
I
2
= 88%,
p
= 0.69) was observed.
Conclusions
Prehabilitation can reduce overall and pulmonary morbidity following surgery and could be utilised routinely. The precise protocol of prehabilitation has not been completely established. Further work is required to tailor optimal prehabilitation protocols for specific operative procedures.
Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether ...any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase–target pair deemed unsuitable: the von Hippel–Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure–activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target–ligase combinations.
The porcine model has contributed significantly to biomedical research over many decades. The similar size and anatomy of pig and human organs make this model particularly beneficial for ...translational research in areas such as medical device development, therapeutics and xenotransplantation. In recent years, a major limitation with the porcine model was overcome with the successful generation of gene-targeted pigs and the publication of the pig genome. As a result, the role of this model is likely to become even more important. For the respiratory medicine field, the similarities between pig and human lungs give the porcine model particular potential for advancing translational medicine. An increasing number of lung conditions are being studied and modeled in the pig. Genetically modified porcine models of cystic fibrosis have been generated that, unlike mouse models, develop lung disease similar to human cystic fibrosis. However, the scientific literature relating specifically to porcine lung anatomy and airway histology is limited and is largely restricted to veterinary literature and textbooks. Furthermore, methods for in vivo lung procedures in the pig are rarely described. The aims of this review are to collate the disparate literature on porcine lung anatomy, histology, and microbiology; to provide a comparison with the human lung; and to describe appropriate bronchoscopy procedures for the pig lungs to aid clinical researchers working in the area of translational respiratory medicine using the porcine model.
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