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"Hatcher, John"
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The black death : a personal history
Recreating everyday life in a mid-fourteenth century rural English village, the author focuses on the experiences of ordinary villagers as they lived and died during the Black Death (1345-50). Hatcher describes the day-to-day existence of people struggling with the tragic effects of the plague.
Book
Crystal structure of human IRAK1
Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating innate immune responses against foreign pathogens and other types of dangers through their role in Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) mediated signaling pathways. Upon ligand binding, TLRs and IL-1Rs recruit adaptor proteins, such as myeloid differentiation primary response gene 88 (MyD88), to the membrane, which in turn recruit IRAKs via the death domains in these proteins to form the Myddosome complex, leading to IRAK kinase activation. Despite their biological and clinical significance, only the IRAK4 kinase domain structure has been determined among the four IRAK family members. Here, we report the crystal structure of the human IRAK1 kinase domain in complex with a small molecule inhibitor. The structure reveals both similarities and differences between IRAK1 and IRAK4 and is suggestive of approaches to develop IRAK1- or IRAK4-specific inhibitors for potential therapeutic applications. While the IRAK4 kinase domain is capable of homodimerization in the unphosphorylated state, we found that the IRAK1 kinase domain is constitutively monomeric regardless of its phosphorylation state. Additionally, the IRAK1 kinase domain forms heterodimers with the phosphorylated, but not unphosphorylated, IRAK4 kinase domain. Collectively, these data indicate a two-step kinase activation process in which the IRAK4 kinase domain first homodimerizes in the Myddosome, leading to its trans-autophosphorylation and activation. The phosphorylated IRAK4 kinase domain then forms heterodimers with the IRAK1 kinase domain within the Myddosome, leading to its subsequent phosphorylation and activation.
Journal Article
Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth
The paracaspase MALT1 plays an essential role in activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) downstream of B cell and TLR pathway genes mutated in these tumors. Although MALT1 is considered a compelling therapeutic target, the development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Here, we developed a target engagement assay that provides a quantitative readout for specific MALT1-inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable, irreversible substrate-mimetic compounds that bind the MALT1 active site. We confirmed that MALT1 targeting with compound 3 is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that a reduction in serum IL-10 levels exquisitely correlates with the drug pharmacokinetics and degree of MALT1 inhibition in vitro and in vivo and could constitute a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells.
Journal Article
A kinase-independent role for CDK8 in BCR-ABL1+ leukemia
Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. We provide evidence that CDK8 has a key role in B-ALL. Loss of CDK8 in leukemia mouse models significantly enhances disease latency and prevents disease maintenance. Loss of CDK8 is associated with pronounced transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects. Gene set enrichment analysis suggests that the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are highly sensitive to mTOR inhibitors. Analysis of large cohorts of human ALL and AML patients reveals a significant correlation between the level of CDK8 and of mTOR pathway members. We have synthesized a small molecule YKL-06-101 that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a potential therapeutic strategy for the treatment of ALL patients.
Cyclin-dependent kinases are deregulated in blood cancers. Here, the authors show that CDK8, independent of its kinase activity, regulates mTOR signalling for the maintenance of BCR-ABL1
+
leukemia, and that the dual inhibition of CDK8 and mTOR signalling induces apoptosis in these cells.
Journal Article
Passing the Torch
At the inception of the Five Year Plan of 1974 to 1979, the Universal House of Justice specifically called upon the Canadian Bahá'í community to \"cultivate opportunities for formal presentations, courses and lectureships on the Bahá'í Faith in Canadian universities and other institutions of higher learning\" (21 March 1974). For the past two decades, this model of education and action for community building on a global scale has been at the forefront of massive community development and enrollment, most prominently in some of the most remote regions of the world. In some of these places, the progress in the Administrative Order of the Bahá'í Faith now provides glimpses of the vision set forth by Shoghi Effendi of the rise, in the fullness of time, of \"the Bahá'í Commonwealth of the future, of which this vast Administrative Order is the sole framework,\" and which \"is, both in theory and practice, not only unique in the entire history of political institutions, but can find no parallel in the annals of any of the world's recognized religious systems\" (World Order 151). In the context of the passing of these giants on whose shoulders we stand, it is now my privilege, after seven years of editing the journal which they founded, to pass the torch of editorship to another generation of scholars. [...]it is with utmost pleasure that with this issue we introduce you to the new Editor for the journal, Michael Sabet, who, over the course of the past six months, has already proven himself extremely capable and an inspired appointment by our beloved
Journal Article
Louis Gregory
[...]he initiated a more extensive trip that lasted from 1919 to 1921, often accompanied by Roy Williams, an African-American Bahá'í from New York City. [...]in 1944 and 1945, Gregory, now in his seventies, traveled through five southern states where articles about him received public and press attention. IX, No. 14, November 23, 1918, before being presented again at the Ridván meeting of 1919. Because of the difficulty in communication during World War I, These tablets were sent incrementally, contained in fourteen letters written and sent between March of 1916 and March of 1917 by 'Abdu'l-Bahá to Bahá'ís to the United States and Canada. [...]as cited above, there is significant discussion of Gregory's work in South Carolina in Louis Venters' history No Jim Crow Church: The Origins of South Carolina's Bahá'í Community (University Press of Florida, 2015).
Journal Article
Helen Elsie Austin
Helen Elsie Austin was born May 10, 1908, to Mary Louise Austin and George J. Austin, both of whom worked at the Tuskegee Institute and were friends with Booker T. and Margaret Washington at the same university.1 The family moved several times because George Austin (a veteran of the Spanish-American War) served as \"Commander of Men\"2 at schools in Alabama, in Texas, and-with America's involvement in World War I-at the Fort Des Moines, Iowa, Provisional Army Officer Training School. [...]there were no black faculty; black students could not live in the dormitories, had limited access to the university pool, and were cautioned by the college administrator to be inconspicuous and to have low expectations. [...]she was honored as an invited speaker at a symposium in Cleveland.
Journal Article
Bahá’u’lláh’s Symbolic Use of the Veiled Ḥúríyyih
“Ḥúríyyih,” a term whose roots can be found in the Qur’án (44–54, 52:20, 56–22, and 55:72), refers to angelic female figures that reside in paradise and accompany the believers. In the Bahá’í Writings, the word has often been translated as “the Maid of Heaven,” a symbolic personifi cation of the divine reality of Bahá’u’lláh. In this article we explore how Bahá’u’lláh employs this figurative device to portray the forces at work in the context of His appearance as a Manifestation of God. In particular, we wish to examine the crucial symbolic role the unveiling of the Ḥúríyyih plays in relation to Bahá’u’lláh’s gradual unfolding of His mission. While some readers might believe the portrayal of this figure to be a literal depiction of the Holy Spirit appearing to Bahá’u’lláh, we hope to demonstrate that Bahá’u’lláh has, instead, created a figurative or symbolic portrayal of how He gradually reveals His guidance for this long-awaited era in human history—the “Day of Days,” the culmination of all previous revelations. Put simply, we feel that the image of the Ḥúríyyih does not represent a force separate from Bahá’u’lláh, but rather an expression of the Holy Spirit operating through the inherent spiritual capacity unique to a Manifestation of God.
Journal Article
Mizán of Affect in Material v. Metaphysical Models of Human Consciousness
From the viewpoint of the description of the human reality in the Bahá’í authoritative texts, the essence of a human being is the soul, a metaphysical reality from which emanate all our distinctively human capacities. Unlike materialist views of the human reality, the Bahá’í teachings assert that our essence—the spiritual “self”—takes its beginning during the process of conception, whereupon it associates with the body so long as the physical temple remains capable of manifesting the reality and powers of the soul. Once the body/brain deceases, the soul dissociates from this relationship and exists and functions and progresses eternally. This hypothesis in no way diminishes the importance of a healthy brain as essential to our physical, intellectual, and spiritual development; indeed, it posits the brain as a transceiver by means of which the self manifests the soul’s condition and development in action, speech, and comportment. Therefore, when the brain becomes dysfunctional, whether through trauma or mental illness, the transparency of the soul’s relation to reality ceases. This paper explores the implications of this relationship for our understanding of emotion and presents a model for understanding the function of emotion as providing us essential feedback on, and guidance for, our lives, feedback whose ultimate purpose is to help us better calibrate our approach to spiritual growth. Given the brain-as-transceiver model, this emotional feedback is reliable only so long as the brain remains transparent in this systematic relationship. The paper suggests ways in which the model could inform approaches to treatment for affective disorders.
Journal Article