Patrik K. Johansson

. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.

and in complex biological samples.

Protein fibers play a crucial role in many disease related phenomena and biological systems. A structural analysis of fibrous proteins often requires labeling approaches or disruptive sample preparation while it lacks chemical specificity. Here we demonstrate that the technique of vibrational sum-frequency scattering (SFS) provides a label-free pathway for the chemical and structural analysis of protein fibers in solution. By examining collagen, the most abundant protein in mammals, we demonstrate that the SFS signal of fibers can be detected in the NH, CH stretching and bending, and amide I regions. SFS spectra were found to depend on the scattering angle, which implies the possibility to selectively probe various features of the fibers. The fitting of the data and maximum entropy method analysis revealed a different phase for side-chains and carbonyl contributions, which helps to identify these otherwise overlapping spectral peaks and provides the possibility to perform orientational analysis. Our findings suggest that SFS allows for the greater understanding of protein fibers in solution, which is important when, for example, designing scaffolds in tissue engineering or developing cures for diseases associated with protein fibers.

For the first time on nanoparticle-based Si electrodes, we monitor electrochemical reduction products of ethylene carbonate (EC) and fluoroethylene carbonate (FEC) using interface-sensitive operando spectroelectrochemical sum-frequency generation (SFG). We observe SFG signatures that suggest carbon monoxide (CO) evolution on nano-Si proceeds at distinct lithiation potentials for different electrolyte solvents. EC reduction to yield CO-associated species occurs at potentials associated with silicon’s most highly lithiated state (10 mV), whereas FEC is reduced to CO-associated species at 10 mV and 500 mV (vs Li/Li+). These results suggest that EC reduction is more sensitive than FEC to the lithiation state, validating previous computational predictions describing the reduction of both solvents. Our results suggest that low molecular weight oligomers that readily diffuse from the interface are formed during cycling, leading to SEI instability and an absence of SFG signal. Only upon prolonged EC reduction at 10 mV do we observe SFG signatures for poly(EC), which we hypothesize are due to the formation of higher molecular weight chains that remain on the electrode surface during SFG acquisition. Potential-dependent FEC reduction to Li2CO3, LiF, and CF-containing moieties evidently induces the predominant stabilizing effects to the interface, irrespective of the lithiation time scale. These results provide new, precise insight on the stability of high-capacity anodes.