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Documenting the magnitude of finite strain within ductile shear zones is critical for understanding lithospheric deformation. However, pervasive recrystallization within shear zones often destroys the deformed markers from which strain can be measured. Intensity parameters calculated from quartz crystallographic preferred orientation (CPO) distributions have been interpreted as proxies for the relative strain magnitude within shear zones, but thus far have not been calibrated to absolute strain magnitude. Here, we present equations that quantify the relationship between CPO intensity parameters (cylindricity and density norm) and finite strain magnitude, which we calculate by integrating quartz CPO analyses (n = 87) with strain ellipsoids from stretched detrital quartz clasts (n = 49) and macro‐scale ductile thinning measurements (n = 7) from the footwall of the Northern Snake Range décollement (NSRD) in Nevada. The NSRD footwall exhibits a strain gradient, with Rs(XZ) values increasing from 5.4 ± 1.4 to 282 ± 122 eastward across the range. Cylindricity increases from 0.52 to 0.83 as Rs increases from 5.4 to 23.5, and increases gradually to 0.92 at Rs values between 160 and 404. Density norm increases from 1.68 to 2.97 as Rs increases from 5.4 to 23.5, but stays approximately constant until Rs values between 160 and 404. We present equations that express average finite strain as a function of average cylindricity and density norm, which provide a broadly applicable tool for estimating the first‐order finite strain magnitude within any shear zone from which quartz CPO intensity can be measured. To demonstrate their utility, we apply our equations to published data from Himalayan shear zones and a Cordilleran core complex. Key Point: Quantifying the relationship between crystallographic preferred orientation distribution intensity parameters and finite strain magnitude [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disorder that is a major global health concern, affecting millions of people worldwide. Past molecular studies of AUD used underpowered single cell analysis or bulk homogenates of postmortem brain tissue, which obscures gene expression changes in specific cell types. Here we performed single nuclei RNA-sequencing analysis of 73 post-mortem samples from individuals with AUD (N=36, N nuclei = 248,873) and neurotypical controls (N=37, N nuclei = 210,573) in both sexes across two institutional sites. We identified 32 clusters and found widespread cell type-specific transcriptomic changes across the cortex in AUD, particularly affecting glia. We found the greatest dysregulation in novel microglial and astrocytic subtypes that accounted for the majority of differential gene expression and co-expression modules linked to AUD. Analysis for cell type-specific enrichment of aggregate genetic risk for AUD identified subtypes of microglia and astrocytes as potential key players not only affected by but causally linked to the progression of AUD. These results highlight the importance of cell-type specific molecular changes in AUD and offer opportunities to identify novel targets for treatment.

Alcohol use disorder (AUD) is likely associated with complex transcriptional alterations in addiction-relevant brain regions. We characterize AUD-associated differences in cell type-specific gene expression and chromatin accessibility in the caudate nucleus by conducting a single-nucleus RNA-seq assay and a single-nucleus RNA-seq + ATAC-seq (multiome) assay on caudate tissue from 143 human postmortem brains (74 with AUD). We identified 17 cell types. AUD was associated with a higher proportion of microglia in an activated state and more astrocytes in a reactive state. There was widespread evidence for differentially expressed genes across cell types with the most identified in oligodendrocytes and astrocytes, including genes involved in immune response and synaptic regulation, many of which appeared to be regulated in part by JUND and OLIG2 . Microglia-astrocyte communication via interleukin-1 beta, and microglia-astrocyte-oligodendrocyte interaction via transforming growth factor beta 1 were increased in individuals with AUD. Expression quantitative trait loci analysis revealed potential driver genes of AUD, including ADAL, that may protect against AUD in medium spiny neurons and interneurons. This work provides a thorough profile of the effects of AUD in the human brain and identifies several promising genes for further study.

Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed Aβ localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) Aβ pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal Aβ. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with Aβ 1-42 , and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of Aβ in neuronal lysosomes to drive AD amyloid pathology., Competing Interests: Competing interests: The first and senior author are inventors on patent 5470.946.WO entitled: Targeting lysosomal lipid in Alzheimer’s disease. The first and senior author are inventors on patent 5470.946PR entitled: Targeting lysosomal lipid in Alzheimer’s disease.

Postmortem brain donation for medical research is a little-known form of organ donation. While most brain research is carried out using animal models, many neurological diseases are uniquely human. Greater availability of human postmortem brain tissue from diseased individuals and controls would therefore improve the development of treatments for neurological and neuropsychiatric diseases. Globally, organ donation for medical research is dwarfed by organ donation for transplantation. In 2021, 36% of Australians were registered organ donors for transplantation, with public "in-principle" support even higher, at 76%. In contrast, there are little data on Australian or international brain donation rates for research. A 30-item online survey was conducted to ascertain knowledge of, and attitudes toward, brain donation in Australia. Of the respondents, 12/237 (5%) were current brain donors and excluded from further analysis. Of the remaining 225, 75% were registered organ donors for transplant. The vast majority ( n  = 189/225, 84%) of respondents supported or strongly supported the principle of brain donation. However, of those registered for transplantation or whole-body donors, 93/170 (55%) were not aware that brain donation was possible, while 50%, alternatively or also, thought that registering as an organ donor for transplantation rendered them a brain donor by default. Only 9/225 (4%) respondents indicated that they would definitely not donate their brain in the future, while 27 remained unsure. There is prominent public support for brain donation in Australia, with 84% of respondents willing to donate their brain. Yet, the extent of public misconceptions on brain donation for research suggests the need for further education on all types of organ donation, so individuals may make informed decisions.