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Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

Biologists have replaced the metaphor of “genetic transmission” with a detailed account of the molecular mechanisms underlying the phenomenon which Darwin referred to as “like produces like.” Cultural evolution theorists, in contrast, continue to appeal to “imitation” or “copying.” The notion of ritual and instrumental stances does not resolve this issue, and ignores the institutions in which people live.

Knowledge of free ligand conformational preferences (energy minima) and conformational dynamics (rotational energy barriers) of small molecules in solution can guide drug design hypotheses and help rank ideas to bias syntheses towards more active compounds. Visualization of conformational exchange dynamics around torsion angles, by replica exchange with solute tempering molecular dynamics (REST-MD), gives results in agreement with high-resolution 1H nuclear magnetic resonance (NMR) spectra and complements free ligand conformational analyses. Rotational energy barriers around individual bonds are comparable between calculated and experimental values, making the in-silico method relevant to ranking prospective design ideas in drug discovery programs, particularly across a series of analogs. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the “right molecules” for effective medicines.

A global phenomenon is the reorganization of care for very young children. Institutions are replacing the context of family and community. Increasingly in Colombia young children spend hours each day in institutions directed by public policy and administrative guidelines. We explore, first, how research on this phenomenon adopts a reductionist perspective, a focus on “quality” and “outcomes” measured in ways that assume a Western axiology. Second, we consider how the institutionalization of childhood amounts to a “government” that imposes Western individualism. Third, we illustrate the tension created for childcare professionals and for Indigenous communities as their rights to make decisions about the best ways to care for children are threatened.

In this study, we present a fully automatic platform based on our Monte Carlo algorithm, the Protein Energy Landscape Exploration method (PELE), for the estimation of absolute protein-ligand binding free energies, one of the most significant challenges in computer aided drug design. Based on a ligand pathway approach, an initial short enhanced sampling simulation is performed to identify reasonable starting positions for more extended sampling. This stepwise approach allows for a significant faster convergence of the free energy estimation using the Markov State Model (MSM) technique. PELE-MSM was applied on four diverse protein and ligand systems, successfully ranking compounds for two systems. Based on the results, current limitations and challenges with physics-based methods in computational structural biology are discussed. Overall, PELE-MSM constitutes a promising step toward computing absolute binding free energies and in their application into drug discovery projects.

The three-dimensional conformations adopted by a free ligand in solution impact bioactivity and physicochemical properties. Solution 1D NMR spectra inherently contain information on ligand conformational flexibility and three-dimensional shape, as well as the propensity of the free ligand to fully preorganize into the bioactive conformation. Herein we discuss some key learnings, distilled from our experience developing potent and selective synthetic macrocyclic inhibitors, including Mcl-1 clinical candidate AZD5991. Case studies have been selected from recent oncology research projects, demonstrating how 1D NMR conformational signatures can complement X-ray protein-ligand structural information to guide medicinal chemistry optimization. Learning to extract free ligand conformational information from routinely available 1D NMR signatures has proven to be fast enough to guide medicinal chemistry decisions within design cycles for compound optimization.

We explore contemporary evolutionary perspectives on children’s psychological development, questioning the view that high-fidelity, inter-individual transmission of information explains the cumulative character of human cultures, and children’s ontogenesis within these cultures. We argue that humans construct an environmental niche that is unique in being composed of institutions, which function to coordinate activity over multiple time scales. Institutions involve not simply customs or conventions but a deontology of future-binding rights, responsibilities, duties, and obligations. The origins of institutions can be traced in hominin evolution to Paleolithic hunter-gatherers, where kinship, the first institution, made possible community support of an extended and demanding form of ontogenesis. Since the human environmental niche is an institutional reality, children today need to acquire the ability to understand and act effectively within institutions. We propose that this ability emerges not as an adaptation solely to past conditions but through differentiation and reintegration of an “extended ontogenetic system” of which the child is a constituent, leading to a quality of self-consciousness on the part of the child that makes possible the ability to live in an institutional reality.

The current clinically approved PARP inhibitors have limited subtype selectivity and are to some degree restricted in their ability to penetrate the central nervous system (CNS) due to efflux transporters, potentially limiting their efficacy in treating metastatic disease or primary tumors in the brain. The current study evaluated the potential of AZD9574, a next generation, PARP1 selective inhibitor/trapper, to penetrate the CNS in cynomolgus monkey, and its occupancy of the PARP1 enzyme, using positron emission tomography (PET). In vitro bidirectional efflux assay data suggested AZD9574 showed minimal substrate potential compared to the clinically approved PARP inhibitors. This was reflected in an increased ratio of unbound brain to unbound plasma concentration (Kpuu) in the rat of ~0.31. Therefore AZD9574 was taken forward into cynomolgus monkey PET studies. Firstly, the Kpuu was determined following dosing of [11C]AZD9574, co-administered with unlabeled drug to minimize the impact of specific binding. The high specific signal observed lead to the development of [11C]AZ3391, a PARP1 selective, CNS penetrant PET tracer, which was subsequently used to directly assess the PARP1 target engagement of AZD9574 in the brain. AZD9574 was found to show a Kpuu in cynomolgus monkeys of 0.79, close to unity with unbound plasma concentrations suggesting minimal CNS restriction. Furthermore, an i.v. infusion dose response study with AZD9574, conducted to examine its ability to block target occupancy by the PET tracer [11C]AZ3391, demonstrated a reduction in [11C]AZ3391 accumulation in whole brain. The resulting calculated occupancy of AZD9574 ranged from 17% for the lowest dose (0.003 mg/kg) to 95% for the highest dose tested (0.05 mg/kg). Comparable reduction in occupancy was seen for peripheral tissue, such as bone marrow, supporting the conclusion that AZD9574 shows minimal CNS restriction. These data show that AZD9574 is the first PARP inhibitor to reach the clinic which combines PARP1 selectivity, trapping and high CNS penetration in a single molecule and supports its development as a potential therapy for the treatment of metastatic disease and primary brain tumors. Citation Format: Andy Pike, Amber Balazs, Zsolt Cselényi, Sébastien L. Degorce, Avipsa Ghosh, Sudhir M. Hande, Jeffrey Johannes, Peter Johnström, Martin J. Packer, Magnus Schou, XiaoLan Zheng. Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5076.

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683)., High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

Knowledge of free ligand conformational preferences (energy minima) and conformational dynamics (rotational energy barriers) of small molecules in solution can guide drug design hypotheses and help rank ideas to bias syntheses towards more active compounds. Visualization of conformational exchange dynamics around torsion angles, by replica-exchange with solute tempering molecular dynamics (REST-MD), gives results in agreement with high resolution 1H NMR spectra and complements free ligand conformational analyses. Rotational energy barriers around individual bonds are comparable between calculated and experimental values, making the in silico method relevant to ranking prospective design ideas in drug discovery programs, particularly across a series of analogues. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the right molecules for effective medicines.

Resumen Este artículo proporciona una introducción y una visión general de la psicología cultural. Comienza con la introducción de las tres figuras principales del Círculo Vygotskiano en los años veinte y treinta: Lev Vygotsky, Alexander Luria y Alekséi Leontiev, ya que la colaboración entre ellos es importante porque demuestra que el estudio de la cultura y de la neurobiología no son líneas de investigación opuestas, sino complementarias. Seguido a esto, se bosqueja brevemente la historia de la psicología cultural en el mundo de habla inglesa y se presentan algunas de sus principales figuras. Después, se hace énfasis en el proyecto de Vygotsky, explicando su diagnóstico de la crisis en la psicología y su solución para evitar el dualismo. Luego, se hace foco en las características clave del relato de Vygotsky sobre el desarrollo de los niños, describiendo su reconstrucción de las etapas y transiciones de la ontogénesis y ofreciendo una interpretación del proceso de internalización. Concluye con una discusión de la metodología de la investigación en psicología cultural, explicando en qué se diferencia de los diseños cuasi experimentales típicos de la psicología transcultural. Abstract The article provides an introduction to and overview of cultural psychology. It begins by introducing the three major figures of the Vygotsky Circle in the 1920s and 30s: Lev Vygotsky, Alexander Luria, and Aleksei Leontiev. Their collaboration is important not least because it demonstrates that study of culture and of neurobiology are not opposed lines of investigation but complementary. It also provides context to the founding of the International Society for Cultural and Activity Research (ISCAR) in 2002 through merger of the International Society for Cultural Research and Activity Theory (ISCRAT) and the Conference for Sociocultural Research. The article then briefly sketches the history of cultural psychology in the English-speaking world and introduces some of the major figures. It turns to consider Vygotsky's project in more detail, explaining his diagnosis of the crisis in the psychology of his time and his solution for avoiding dualism. It then focuses on the key features of Vygotsky's account of children's development, outlining his reconstruction of the stages and transitions of ontogenesis and offering an interpretation of the process of internalization. It concludes with a discussion of research methodology in cultural psychology, explaining how it differs from the quasi-experimental designs that are typical in cross-cultural psychology. Resumo O artigo proporciona uma introdução e uma visão geral da psicologia cultural. Começa com a introdução das três figuras principais do "Círculo Vygotskiano" nos anos 20 e 30: Lev Vygotsky, Alexander Luria e Alekséi Leontiev. A colaboração entre eles é importante, não só porque demostra que o estudo da cultura e da neurobiologia não são linhas de pesquisa opostas, mas complementárias. O artigo logo esboça brevemente a história da psicologia cultural no mundo de língua inglesa e apresenta algumas de suas principais figuras. Depois passa a considerar o projeto de Vygotskycom mais detalhe, explicando seu diagnóstico da crise na psicologia e sua solução para evitar o dualismo. Após, enfoca-se nas características chave do relate de Vygotsky sobre o desenvolvimento das crianças, descrevendo sua reconstrução das etapas e transições da ontogênese e oferecendo uma interpretação do processo de internalização. Conclui com uma discussão da metodologia da pesquisa em psicologia cultural, explicando em que se diferencia dos desenhos quase experimentais típicos da psicologia transcultural.

There is growing appreciation of the role of culture in children’s psychological development (also called human ontogenesis). However, there are several distinct approaches to research on this matter. Cross-cultural psychology explores the causal influence of culture on differences in children’s development, treated as dependent variables. Researchers interested in the role of cultural learning in human evolution view culture as beliefs and values that are transferred from the mind of one individual to that of another. By contrast, “cultural psychology” views culture not as a cause, but a constituent of human psychological functioning. It invites us to pay attention to the fact that humans live in societies filled with material artifacts, tools, and signs that mediate human activity; that is to say, they provide the means with which people interact with the world around them and with one another. From this perspective, culture provides constituents that are essential to human development: it has a constitutive role in development. Although there continues to be much debate over how to define culture, it is generally agreed that different human social groups have distinct cultures, and it is common to assume that cultural differences lead to differences in the trajectories of children’s development. This is true, but it is also the case that culture is a universal requirement for development. Every child is born into a family and community with a language, customs, and conventions, and in which people occupy institutional roles with rights and responsibilities. These facts define universal requisites of human psychological development and include the acquisition of language, the development of a social identity, the understanding of community obligations, and the ability to contribute to the reproduction of the community. The interdependence of human communities—which probably had its origins in collaborative foraging and cooperative childrearing—seems to have placed species-specific demands on children’s development, selecting for the capacity to acquire a sensitivity not only to people’s goals and intentions but also to rights and responsibilities.

Developmental scientists increasingly agree that children’s psychological development and learning should be considered in their evolutionary and cultural context. In this chapter we suggest an evolutionary perspective that focuses on three key aspects: the centrality of generational reproduction; the ways organisms extend into an environment that often they have constructed; and the constitutive character of ontogenesis. We emphasize the fact that the varied niches into which children are born are highly structured social worlds—institutional realities—which underpin the interactions in which children are involved by defining future-binding obligations. This aspect of human community life appears to have begun with hunter-gatherers, for whom kinship was the first institution: it included not simply family connections but a way of relating to the cosmos. Kinship made possible a specifically human mode of reproduction which continues, in a modified form, to the present day. In this mode, ontogenesis is marked by its long duration, plasticity, and communal character. Today, as in the distant past, it is crucial that children learn about the institutional reality into which they are born as an essential concomitant of the process of acquiring culturally essential skills and knowledge. Learning is achieved in many contexts, both historically and synchronically, but today the learning that is dominant in the lives of most of the world’s children has been institutionalized. Becoming literate in school is a particularly clear example of the three components of evolution, and of the interweaving of ontogenesis, societal change, and evolutionary change.

While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

Since the approval of olaparib in 2014 for BRCA mutated (BRCAm) ovarian cancer, many PARP inhibitors have been developed and have seen widespread success. However, as a class, these drugs are not without adverse events which have limited their ability to be combined with chemotherapy. Most first generation PARP inhibitors were developed and optimized before the concept of PARP1-DNA trapping was discovered as the mechanism by which PARP inhibitors exert their synthetic lethal effects on BRCAm cells. Moreover, the first generation PARP inhibitors were not optimized for selectivity across the PARP family potentially driving undesirable side effects, including intestinal toxicity from tankyrase inhibition or hematological toxicity from PARP2 inhibition. With this in mind, we set out to discover a best-in-class, second generation PARP inhibitor that was highly selective for PARP1 over the other 16 members of the PARP family, as well as a highly potent PARP1-DNA trapper. PARP1 and PARP2 have a highly similar amino acid sequence, and most of the residues around the nicotinamide binding site are identical. However, there are some key residue differences in the helical domain which serves a regulator of the nicotinamide binding pocket. The publication of NMS-P118 in 2015 by Nerviano Medical Sciences showed that a highly selective PARP1 inhibitor could be found. This work inspired us to screen an extensive list of previously reported PARP inhibitors for selectivity against PARP2 and we found that FR257516 met the selectivity criteria as previously reported, but lacked the ability to trap PARP1 to DNA and hence lacked any activity in a cell colony formation assay in DLD-1 BRCA2-/- cells. Using parallel chemistry to generate diverse analogs, X-ray crystallography to enable structure-based design, and exploration of multiple nicotinamide mimetic cores, we were able to generate lead compound AZ4554, which was a PARP1 selective PARP1-DNA trapper with potent activity in BRCAm cells. Using concepts of property-based drug design, we were able to optimize lead compound AZ4554 into candidate drug AZD5305, making key improvements in secondary pharmacology, including reducing hERG activity, and intrinsic clearance in human microsomes through the introduction of polar atoms to lower logD without compromising permeability or oral bioavailability. AZD5305 is a highly selective binder of PARP1 over PARP2 and other PARP enzymes by fluorescence polarization, surface plasmon resonance, and single molecule spectroscopy. It is highly potent against DLD-1 BRCA2-/- cells, while sparing isogenic BRCA WT cells. The secondary pharmacology of AZD5305 is remarkably clean, with hERG activity >40 µM. AZD5305 has a very favorable pre-clinical PK profile, low predicted human dose, and has shown efficacy in an MDA-MB-436 mouse xenograft model. Citation Format: Sudhir Hande, Amber Balazs, Sébastien L. Degorce, Kevin Embrey, Avipsa Ghosh, Sonja J. Gill, Anders Gunnarsson, Giuditta Illuzzi, Jordan Lane, Carrie Larner, Elisabetta Leo, Andrew Madin, Lisa McWilliams, Mark J. O'Connor, Jonathan Orme, Fiona Pachl, Martin Packer, Andy Pike, Philip Rawlins, Marianne Schimpl, Anna D. Staniszewska, Andrew Zhang, Xiaolan Zheng, Jeffrey W. Johannes. Structure-based and property-based drug design of AZD5305, a highly selective PARP1 inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 296.

Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein–ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is ...

[Image: see text] The concepts behind targeting waters for potency and selectivity gains have been well documented and explored, although maximizing such potential gains can prove to be challenging. This problem is exacerbated in cases where there are multiple interacting waters, wherein perturbation of one water can affect the free energy landscape of the remaining waters. Knowing the right modification a priori is challenging, and computational approaches are ideally suited to help answer the key question of which substitution is best to try. Here, we use Grand Canonical Monte Carlo and the recent Grand Canonical Alchemical Perturbation methods to both understand and predict the effect of ligand-mediated water displacement when more than one water molecule is involved, as well as to understand how exploiting water networks can help govern selectivity.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor α (PDGFRα). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFRα mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Patients with GIST have an unmet need for a well-tolerated drug that robustly inhibits a range of KIT/PDGFRα mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFRα designed to inhibit a broad range of primary and imatinib-resistant secondary mutations seen in GIST. In engineered and GIST-derived cell lines, AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents-imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST.

The IMPRESSION machine learning system can predict NMR parameters for 3D structures with similar results to DFT but in seconds rather than hours., The IMPRESSION (Intelligent Machine PREdiction of Shift and Scalar information Of Nuclei) machine learning system provides an efficient and accurate method for the prediction of NMR parameters from 3-dimensional molecular structures. Here we demonstrate that machine learning predictions of NMR parameters, trained on quantum chemical computed values, can be as accurate as, but computationally much more efficient (tens of milliseconds per molecular structure) than, quantum chemical calculations (hours/days per molecular structure) starting from the same 3-dimensional structure. Training the machine learning system on quantum chemical predictions, rather than experimental data, circumvents the need for the existence of large, structurally diverse, error-free experimental databases and makes IMPRESSION applicable to solving 3-dimensional problems such as molecular conformation and stereoisomerism.

This article uses a variety of principles of cultural-historical activity theory to extend Herbert Simon’s (1996) insight into the inherent linkage between the creation of artifacts and design. We argue that design research must grapple with the doubly artificial, as the classrooms in which many educational designs are implemented are themselves already artificial and contingent—the products of design—and the learning that is the focus of investigation is already an adaptation to the classroom environment and so artificial. Focusing our discussion on the mesogenetic character of the temporal characteristics of typical educational design-based intervention research, we present an example of an 18-year-long life span of an intervention that was initially expected to last 3 or 4 years. Crises late in the life of the system, 1 of which rescued the system, 1 of which terminated it, documented through field notes written by undergraduate participants, provide evidence for the dynamics of the system’s internal f...

Michael Tomasello, codirector of the Max Planck Institute for Evolutionary Biology, is now James F. Bonk Professor of Psychology and Neuroscience at Duke University. In his latest book, A Natural H...

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound

This updated and expanded edition is a unique examination of qualitative research in the social sciences, raising and answering the question of why we do this kind of investigation. Rather than providing instructions on how to conduct qualitative research, The Science of Qualitative Research explores the multiple roots of qualitative research - including phenomenology, hermeneutics, and critical theory - in order to diagnose the current state of the field and recommend an alternative. The author argues that much qualitative research today uses the mind-world dualism that is typical of traditional experimental investigation, and recommends that instead we focus on constitution: the relationship of mutual formation between a form of life and its members. Michel Foucault's program for 'a history ontology of ourselves' provides the basis for this fresh approach. The new edition features updated chapters, and a brand new chapter which offers a discussion on how to put into practice Foucault's concept.

Having an entire research institute at one’s disposal must present challenges, but it certainly provides benefits. During his tenure as codirector of the Max Planck Institute for Evolutionary Anthr...

3,3-Di-methyl-azetidin-2-ones were identified as potent and selective 11β-HSD1 inhibitors against the human and mouse forms of the enzyme. Structure guided optimisation of LLE was conducted, utilising a key polar interaction and identifying stereochemical preference for the 4S isomer. Metabolic stability was improved to afford oral exposure, providing tool compounds suitable for pre-clinical evaluation.