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Focuses on isiko lentambo, a sacrificial ceremony for the enhancement and renewal of the powers of healing and divination of an indigenous healer of Xhosa speaking people in South Africa. Reasons for the performance of the ceremony; Overview of the ceremony; Analysis of the ceremony.

Focuses on the association of the songs sung at a particular intlombe with the life events of the participant in the healing ceremony of Xhosa healers in Africa. Belief of Xhosa on death; Attitude of their ancestors; Expression of the ancestors displeasure to their living kin.

Examines the healing ceremony of Xhosa healers in South Africa. Aim of the ceremony; Clarification of dreams and disturbing events; Meaning of the ritual.

Comments on the article 'Numinous experiences: frequent or rare?,' by Daniel Hoy published in the January 1983 issue of 'Journal of Analytical Psychology.' Difference between rituals in Western society and rituals in African society; Ritual therapeutic procedures of the healers aim at stimulating numinous experiences; Integration of the experiences of a previous ceremony.

Fragment-based drug discovery has played an important role in medicinal chemistry and pharmaceutical research. Despite numerous demonstrated successes, the limited diversity and overrepresentation of planar, sp 2 -rich structures in commercial libraries often hamper the full potential of this approach. Hence, the thorough design of screening libraries inevitably determines the probability for meaningful hits and subsequent structural elaboration. Against this background, we present the generation of an exclusive fragment library based on iterative entry nomination by a specifically designed computational workflow: "Fragtory". Following a pharmacophore diversity-driven approach, we used Fragtory in an interdisciplinary academic setting to guide both tailored synthesis efforts and the implementation of in-house compounds to build a curated 288-member library of sp 3 -enriched fragments. Subsequent NMR screens against a model protein and hit validation by protein crystallography led to the identification of structurally novel ligands that were further characterized by isothermal titration calorimetry, demonstrating the applicability of our experimental approach.

High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide-alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them via the high-throughput In-Cell Western assay. Select inhibitors were resynthesized, validated via conventional biological and biochemical methods such as western blots and liquid chromatography-mass spectrometry (LC-MS) labeling, and successfully co-crystallized. Two of these compounds showed over 20-fold increased inhibitory activity compared to the parental compound. This study demonstrates that high-throughput LSF of covalent inhibitors at the nanomole-scale level can be an auspicious approach in improving the properties of lead chemical matter.

p38α mitogen-activated protein kinase (MAPK) is an attracting pharmacological target in inflammatory diseases and cancer. Searching for new and more efficient p38-MAPK inhibitors, two recently developed pyrazolobenzothiazine-based (COXP4M12 and COXH11) compounds were investigated in this study using a cellular model of p38 activation. This consisted of HT29 human colorectal adenocarcinoma cells exposed to H 2 O 2 or lipopolysaccharide (LPS). Immunoblot data confirmed the inhibitory effect of COXP4M12 and COXH11 on p38 substrate phosphorylation (MAPK-APK2 and ATF2 transcription factor). Compound cytotoxicity was very low and apparent efficacy of these inhibitors was comparable with that of SB203580, a commercially available type I inhibitor of p38. All these compounds also inhibit upstream kinases that promote p38-MAPK phosphorylation and co-activate the stress-activated protein kinase JNK, while ERK1/2 MAPK phosphorylation was unaffected. Compound-target kinase interaction was investigated by means of co-crystallization experiments that provided further structural and molecular insight on the inhibitory mechanism and optimization strategy of this new class of p38-MAPK inhibitors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A chemical genetic approach is presented to covalently target a unique lipid binding pocket in the protein kinase p38α, whose function is not yet known. Based on a series of cocrystal structures, a library of 2-arylquinazolines that were decorated with electrophiles were designed and synthesized to covalently target tailored p38α mutants containing artificially introduced cysteine residues. Matching protein-ligand pairs were identified by MS analysis and further validated by MS/MS studies and protein crystallography. The covalent ligands that emerged from this approach showed excellent selectivity towards a single p38α mutant and will be applicable as suitable probes in future studies of biological systems to dissect the function of the lipid pocket by means of pharmacological perturbations., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I 1 / 2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.

In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography.

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET -rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET -rearranged cells, we identify the CCDC6-RET I788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Skepinone-L was recently reported to be a p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, this class of compounds still act as fully ATP-competitive Type I binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first Type I1/2 binders for p38α MAP kinase. Type I1/2 inhibitors interfere with the R-spine, inducing a glycine flip and occupying both hydrophobic regions I and II. This design approach leads to prolonged target residence time, binding to both the active and inactive states of the kinase, excellent selectivity, excellent potency on the enzyme level, and low nanomolar activity in a human whole blood assay. This promising binding mode is proven by X-ray crystallography., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC 50 CK1δ = 4 nM, IC 50 CK1ε = 25 nM), 12a (IC 50 CK1δ = 19 nM, IC 50 CK1ε = 227 nM), and 16b (IC 50 CK1δ = 8 nM, IC 50 CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b , displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC 50 = 3.5 µM) and Panc89 (EC 50 = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α.

Psychiatrists and psychologists are often requested by the legal fraternity to report on the mental state of Black people accused of an alleged crime. The question raised in this paper is whether personnel trained in the Western tradition, applying Western categories of mental states, are able to overcome their ethnocentricity. When the interviewer and the person interviewed are from widely different cultural groups, the former should make every effort to enter the inner world of the latter.

This article is primarily concerned with the early recognition of infantile autism. Since this syndrome is always a manifestation of disturbed interpersonal relationships, the normal development of an early mother-infant interaction is described. It should thus be easy to observe distorted interaction and to investigate the cause. Autism is one of several manifestations of impaired interaction.

The difficulties of the Western-trained psychiatrist in dealing with Xhosa patients are threefold; the language and intricacies of its usage, the cultural beliefs, customs and rituals and the inapplicability of the Western psychiatric model to people of a different culture. To a lesser extent, all White medical staff experience the same problems.

The limitations and validity of psychiatric diagnosis, especially as it pertains to medicolegal cases, are discussed. Two clinical cases are used to demonstrate some of the problems. Two young black men were facing charges of murdering a woman; in one case the victim was not a relation and in the other she was the subject's mother. During the period of observation no hard signs of psychosis could be demonstrated, yet the second subject later became overtly psychotic, while the first was and remained normal. Suggestions about diagnostic procedures are made.

Two mental states occurring in black people, thwasa and bewitchment, are differentiated from schizophrenia and catatonic schizophrenia. The aetiology is seen as arising from the relationship of the afflicted individual to his ancestors, i.e. either positive or negative. An important concept of analytical psychology is that the attitude of the ego can constellate positive or negative complexes form the unconscious. This concept is useful for a better understanding of thwasa and bewitchment.