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Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunitiesPI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.

Detailed computational and structural analysis of a large data set of non-peptidic macrocycles revealed particular functional groups, substituents and molecular properties that are critical for dictating cellular permeability. Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein–protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo –designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure–permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

We have discovered a class of PI3Kγ inhibitors exhibiting over 1,000-fold selectivity over PI3Kα and PI3Kβ. On the basis of X-ray crystallography, hydrogen-deuterium exchange–mass spectrometry and surface plasmon resonance experiments we propose that the cyclopropylethyl moiety displaces the DFG motif of the enzyme away from the adenosine tri-phosphate binding site, inducing a large conformational change in both the kinase- and helical domains of PI3Kγ. Site directed mutagenesis explained how the conformational changes occur. Our results suggest that these cyclopropylethyl substituted compounds selectively inhibit the active state of PI3Kγ, which is unique to these compounds and to the PI3Kγ isoform, explaining their excellent potency and unmatched isoform selectivity that were confirmed in cellular systems. This is the first example of a Class I PI3K inhibitor achieving its selectivity by affecting the DFG motif in a manner that bears similarity to DFG in/out for type II protein kinase inhibitors. Combining X-ray structures, surface plasmon resonance and hydrogen-deuterium exchange–mass spectrometry, a class of highly selective inhibitors was found to bind to an active state of PI3Kγ breaking a conformational ‘lock’ important for activation of PI3Kγ.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

Natural products (NPs) have played a vital role in human survival for millennia, particularly for their medicinal properties. Many traditional medicine practices continue to utilise crude plants and animal products for treating various diseases, including inflammation. In contrast, contemporary medicine focuses more on isolating drug-lead compounds from NPs to develop new and better treatment drugs for treating inflammatory disorders such as inflammatory bowel diseases. There is an ongoing search for new drug leads as there is still no cure for many inflammatory conditions. Various approaches and technologies are used in drug discoveries from NPs. This review comprehensively focuses on anti-inflammatory small molecules and describes the key strategies in identifying, extracting, fractionating and isolating small-molecule drug leads. This review also discusses the (i) most used approaches and recently available techniques, including artificial intelligence (AI), (ii) machine learning, and computational approaches in drug discovery; (iii) provides various animal models and cell lines used in in-vitro and in-vivo assessment of the anti-inflammatory potential of NPs.

Pressurized chemical looping combustion (PCLC) provides the benefit of simplifying the carbon capture process by generating a flue gas stream with high CO2 concentration. However, flue gas polishing is required to remove the residual impurities for pipeline transport. The intensified heat exchanger reactor (IHXR) is a promising method for flue gas polishing while maximizing useful heat recovery that incorporates alternating catalytic packed beds with interstage cooling via printed circuit heat exchangers (PCHE). This work offers a design process for an IHXR capable of polishing a flue gas stream from a 100 MWth natural gas-fired PCLC unit while recovering 1.6 MW of useful heat in the form of saturated steam at 180 °C. Simulation work performed in Aspen HYSYS was used to determine the polished flue gas outlet species concentrations as well as the required number and size of the packed bed sections. The PCHEs for interstage cooling were sized via a thermal circuit approach. The final IHXR consists of six packed beds at 0.06 m in length and five PCHEs at 0.265 m in length, combining to a total IHXR length of 1.685 m. The height and width of the IHXR is shared between the packed beds and PCHEs at 0.91 m and 0.45 m, respectively. The resulting IHXR is capable of recovering heat at a rate of approximately 2.3 MW/m3.

The management and conservation of the world's oceans require synthesis of spatial data on the distribution and intensity of human activities and the overlap of their impacts on marine ecosystems. We developed an ecosystem-specific, multiscale spatial model to synthesize 17 global data sets of anthropogenic drivers of ecological change for 20 marine ecosystems. Our analysis indicates that no area is unaffected by human influence and that a large fraction (41%) is strongly affected by multiple drivers. However, large areas of relatively little human impact remain, particularly near the poles. The analytical process and resulting maps provide flexible tools for regional and global efforts to allocate conservation resources; to implement ecosystem-based management; and to inform marine spatial planning, education, and basic research.

Past and future trends in the frequency of high-danger fire weather conditions have been analysed for the UK. An analysis of satellite-derived burned area data from the last 18 years has identified the seasonal cycle with a peak in spring and a secondary peak in summer, a high level of interannual variability, and a lack of a significant trend despite some large events occurring in the last few years. These results were confirmed with a longer series of fire weather indices back to 1979. The Initial Spread Index (ISI) has been used for spring, as this reflects the moisture of fine fuel surface vegetation, whereas conditions conducive to summer wildfires are hot, dry weather reflected in the moisture of deeper organic layers which is encompassed in the Fire Weather Index (FWI). Future projections are assessed using an ensemble of regional climate models from the UK Climate Projections, combining variables to derive the fire weather indices. The results show a large increase in hazardous fire weather conditions in summer. At 2 ∘C global warming relative to 1850–1900, the frequency of days with “very high” fire danger is projected to double compared to the recent historical period. This frequency increases by a factor of 5 at 4 ∘C of global warming. Smaller increases are projected for spring, with a 150 % increase for England at 2 ∘C of global warming and a doubling at 4 ∘C. A particularly large projected increase for late summer and early autumn suggests a possible extension of the wildfire season, depending on fuel availability. These results suggest that wildfire can be considered an “emergent risk” for the UK, as past events have not had widespread major impacts, but this could change in future, with adaptation actions being required to manage the future risk. The large increase in risk between the 2 and 4 ∘C levels of global warming highlights the importance of global efforts to keep warming below 2 ∘C.

Background Atrial fibrillation is the most common arrhythmia syndrome and causes significant morbidity and mortality. Current therapeutics, however, have limited efficacy. Notably, many therapeutics shown to be efficacious in animal models have not proved effective in humans. Thus, there is a need for a drug screening platform based on human tissue. The aim of this study was to develop a robust protocol for generating atrial cardiomyocytes from human-induced pluripotent stem cells. Methods A novel protocol for atrial differentiation, with optimized timing of retinoic acid during mesoderm formation, was compared to two previously published methods. Each differentiation method was assessed for successful formation of a contractile syncytium, electrical properties assayed by optical action potential recordings and multi-electrode array electrophysiology, and response to the G-protein-gated potassium channel activator, carbamylcholine. Atrial myocyte monolayers, derived using the new differentiation protocol, were further assessed for cardiomyocyte purity, gene expression, and the ability to form arrhythmic rotors in response to burst pacing. Results Application of retinoic acid at day 1 of mesoderm formation resulted in a robust differentiation of atrial myocytes with contractile syncytium forming in 16/18 differentiations across two cell lines. Atrial-like myocytes produced have shortened action potentials and field potentials, when compared to standard application of retinoic acid at the cardiac mesoderm stage. Day 1 retinoic acid produced atrial cardiomyocytes are also carbamylcholine sensitive, indicative of active I kach currents, which was distinct from ventricular myocytes and standard retinoic addition in matched differentiations. A current protocol utilizing reduced Activin A and BMP4 can produce atrial cardiomyocytes with equivalent functionality but with reduced robustness of differentiation; only 8/17 differentiations produced a contractile syncytium. The day 1 retinoic acid protocol was successfully applied to 6 iPSC lines (3 male and 3 female) without additional optimization or modification. Atrial myocytes produced could also generate syncytia with rapid conduction velocities, > 40 cm s −1 , and form rotor style arrhythmia in response to burst pacing. Conclusions This method combines an enhanced atrial-like phenotype with robustness of differentiation, which will facilitate further research in human atrial arrhythmia and myopathies, while being economically viable for larger anti-arrhythmic drug screens.