Sorting large libraries of cells for improved small molecule secretion is throughput limited. Here, we combine producer/secretor cell libraries with whole-cell biosensors using a microfluidic-based screening workflow. This approach enables a mix-and-match capability using off-the-shelf biosensors through either coencapsulation or pico-injection. We demonstrate the cell type and library agnostic nature of this workflow by utilizing single-guide RNA, transposon, and ethyl-methyl sulfonate mutagenesis libraries across three distinct microbes (, , and ), biosensors from two organisms ( and ), and three products (triacetic acid lactone, naringenin, and L-DOPA) to identify targets improving production/secretion.
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http://dx.doi.org/10.1073/pnas.2106818118 | DOI Listing |
Alzheimers Dement
December 2024
University of Exeter, Exeter, Devon, United Kingdom.
Background: Huntington's disease (HD) is an autosomal dominant condition causing severe neurodegeneration in the striatum and the entorhinal cortex (EC). An epigenome wide association study of DNA methylation in HD by our group, identified potential hypomethylation at the PTGDS gene in the striatum. We aimed to validate this result through pyrosequencing, examining the locus in fine detail, and to assess the signal specificity by profiling multiple neurodegenerative diseases.
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December 2024
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Background: SNX19 is a key player in endolysosomal and autophagy pathways, which have been extensively reported in neuronal dysfunction and neurodegenerative diseases. Although genetic and cellular evidence suggests SNX19 contributes to neuropathology, the underlying mechanisms remain unknown. Here, we propose to study the mechanism in aging postmortem brain tissue at single cell level and model SNX19 in human induced pluripotent stem cell (hiPSCs) derived brain organoids.
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December 2024
Denali Therapeutics Inc., South San Francisco, CA, USA.
Background: Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. We've previously described a high-affinity mouse TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), ATV:4D9. Single-cell RNA sequencing and morphometry revealed that ATV:4D9 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology.
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December 2024
Barrow Neurological Institute, Phoenix, AZ, USA; Arizona State University, Tempe, AZ, USA.
Background: TDP-43 is an RNA binding protein that is a pathological hallmark of multiple neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). The frequency of observed TDP-43 pathology is estimated at 97% in ALS, 45% in FTD and 40-57% in AD and is characterized by a mislocalization of TDP-43 from the nucleus to the cytoplasm. Indeed, TDP-43 is the third most common proteinopathy in AD, behind only Amyloid beta and Tau.
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December 2024
Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
Background: While social and medical debate about the efficacy and safety of anti-Aβ immunotherapy is ongoing, one thing that emerged is that we have little understanding of the working mechanisms of these antibodies and this lack of knowledge complicates the interpretation of the clinical results. Here, we aimed to establish if microglia are required for the efficacy of Lecanemab, one of the most promising FDA-approved disease-modifying therapy for AD (Van Dyck et al. N Engl J Med 2023).
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