http://www.cell.com/article/S1934590923001297/pdf

Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Objective: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution. Method: Profiling of 32 DLPFC samples from 11 individuals with PTSD, 10 with MDD, and 11 control subjects was conducted (∼415K nuclei; >13K cells per sample). A replication sample included 15 DLPFC samples (∼160K nuclei; >11K cells per sample). Results: Differential gene expression analyses identified significant single-nucleus RNA-seq differentially expressed genes (snDEGs) in excitatory (EX) and inhibitory (IN) neurons and astrocytes, but not in other cell types or bulk tissue. MDD samples had more false discovery rate–corrected significant snDEGs, and PTSD samples had a greater replication rate. In EX and IN neurons, biological pathways that were differentially enriched in PTSD compared with MDD included glucocorticoid signaling. Furthermore, glucocorticoid signaling in induced pluripotent stem cell (iPSC)–derived cortical neurons demonstrated greater relevance in PTSD and opposite direction of regulation compared with MDD, especially in EX neurons. Many snDEGs were from the 17q21.31 locus and are particularly interesting given causal roles in disease pathogenesis and DLPFC-based neuroimaging (PTSD: ARL17B, LINC02210-CRHR1, and LRRC37A2; MDD: LRRC37A and LRP4), while others were regulated by glucocorticoids in iPSC-derived neurons (PTSD: SLC16A6, TAF1C; MDD: CDH3). Conclusions: The study findings point to cell-type-specific mechanisms of brain stress response in PTSD and MDD, highlighting the importance of examining cell-type-specific gene expression and indicating promising novel biomarkers and therapeutic targets. 

Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response.

In vitro modeling of the neurobiological effects of glucocorticoids: A review

Genotype × environment interactions in gene regulation and complex traits

Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n = 19 hiPSC and n = 20 PBMC donors) and controls (n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics. 

/pdf/modeling-gene-x-environment-interactions-in-ptsd-using-human-17aea5mm.pdf

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

/pdf/mennonite-and-metis-adjacent-histories-adjacent-truths-2mukomcbj8.pdf

Mennonite and Métis: Adjacent Histories, Adjacent Truths?

In 1977 a Canadian teaching at Messiah College in the United States published a ground-breaking book, Rich Christians in an Age of Hunger, in which he argued that North American Christians were failing to discern or attend to the offensive proclamation of the gospel on the dangers of wealth.1 Ronald Sider, the author, bluntly asserted: “The ever more affluent standard of living is the god of 20th century North America and the adman is its prophet” (46). Affluent Christians, he went on to argue at the heart of the book – “A Biblical Perspective on the Poor and Possessions”– have allowed economic self-interest to distort their interpretation of Scripture (77). In contrast to certain liberation theologians who talked about God’s preferential option for the poor, Sider made the interesting argument that God is not partial; it only appears that way to those seduced by the God of affluence and success:

/pdf/rich-mennonites-in-an-age-of-mammon-is-a-messianic-political-4nyth7bf7u.pdf

Rich Mennonites in an Age of Mammon: Is a Messianic Political Economy Possible?

Anyone who reads Postsecular History: Political Theology and the Politics of Time will know that Maxwell Kennel is an exciting scholar to think with! I’m grateful to have been able to spend five years with him at McMaster University. The intellectual liveliness, curiosity, careful close reading, and collegial affection that he brought was a delight, and this book puts all of these gifts on display. There’s obviously far too much to respond to, and given that he first drafted a couple of his chapters as essays in graduate seminars (on Nietzsche and Augustine, and on Melville), I’m going to continue the conversation here by returning to what he rightly identifies as a primary interest of mine: namely,messianic political theology from an apocalyptic, figural perspective. I think Kennel and I agree that a messianic political theology and a postsecular one differ significantly, though both of us aim to trouble periodization when it comes to religion, secularity, and politics. As he suggests in Postsecular History, the prefix “‘post’ better serves to name mediations, entanglements, and figural reconfigurations of the tensions and terms it purports to move beyond.” These latter terms consistently frame his narration of the historiographical project between conflicting normative orders, especially those rooted in narrow identitarian agendas that seek to “possess, instrumentalize and manage’ these terms. Such agendas include the enforcement of binaries between religion and the secular in exclusivist and increasingly violent directions. I worry, however, that these framing considerations—despite all the engaged close readings of a remarkable range of sources—remain overly abstract. “Postsecular,” like “posthistorical,” in the literal Augustinian sense, would suggest that we’d be “out of time,” just as “posthuman” or even worse “transhuman” might suggest that we’re “out of nature” too! Perhaps this is also found in the figurative sense intended in Francis Fukuyama’s provocative The End of History, paired nicely in his title with Nietzsche’s nightmare of the Last Man. This might help prove just how prophetic Fredric Jameson was when he said that “someone said” it’s easier for us now to imagine the end of the world than the end of capitalism. We should rightly be nervous about all this “post” language! It seems we

Postsecular History or Figural Messianism?

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Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

Mennonite and Métis: Adjacent Histories, Adjacent Truths?

Rich Mennonites in an Age of Mammon: Is a Messianic Political Economy Possible?

Postsecular History or Figural Messianism?