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The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because the blood-brain barrier (BBB) leakage is a well-known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum-exposed brain organoids are able to recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3α/β) levels, respectively. In addition, single-cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid-based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.

Pendulum equation with a phase shift, parametric and external excitations is investigated in detail. By applying Melnikov's method, we prove the criteria of existence of chaos under periodic perturbation. Numerical simulations, including bifurcation diagrams of fixed points, bifurcation diagrams of the system in three- and two-dimensional spaces, homoclinic and heteroclinic bifurcation surfaces, Maximum Lyapunov exponents (ML), Fractal Dimension (FD), phase portraits, Poincaré maps are plotted to illustrate the theoretical analysis, and to expose the complex dynamical behaviors including the onset of chaos, sudden conversion of chaos to period orbits, interior crisis, periodic orbits, the symmetry-breaking of periodic orbits, jumping behaviors of periodic orbits, new chaotic attractors including two-three-four-five-six-eight-band chaotic attractors, nonchaotic attractors, period-doubling bifurcations from period-1, 2, 3 and 5 to chaos, reverse period-doubling bifurcations from period-3 and 5 to chaos, and so on. By applying the second-order averaging method and Melnikov's method, we obtain the criteria of existence of chaos in an averaged system under quasi-periodic perturbation for Ω = nω + ϵν, n = 1, 2, 4, but cannot prove the criteria of existence of chaos in the averaged system under quasi-periodic perturbation for Ω = nω + ϵν, n = 3, 5 - 15, by Melnikov's method, where ν is not rational to ω. By using numerical simulation, we have verified our theoretical analysis and studied the effect of parameters of the original system on the dynamical behaviors generated under quasi-periodic perturbations, such as the onset of chaos, jumping behaviors of quasi-periodic orbits, interleaving occurrence of chaotic behaviors and nonchaotic behaviors, interior crisis, quasi-periodic orbits to chaotic attractors, sudden conversion of chaos to quasi-periodic behaviors, nonchaotic attractors, and so on. However, we did not find period-doubling and reverse period-doubling bifurcations. We found that the dynamical behaviors under quasi-periodic perturbations are different from that under periodic perturbations, and the dynamics with a phase shift are different from the dynamics without phase shift. [ABSTRACT FROM AUTHOR]

Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2 is specifically expressed in vertebrate striated muscles. By gene knockdown in zebrafish or genetic knockout in mice, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with Styxl2 being deleted in mature myofibers to assess its role in sarcomere maintenance, and the other in adult muscle satellite cells (MuSCs) to assess its role in de novo sarcomere assembly. We find that Styxl2 is not required for sarcomere maintenance but functions in de novo sarcomere assembly during injury-induced muscle regeneration. Mechanistically, Styxl2 interacts with non-muscle myosin IIs, enhances their ubiquitination, and targets them for autophagy-dependent degradation. Without Styxl2, the degradation of non-muscle myosin IIs is delayed, which leads to defective sarcomere assembly and force generation. Thus, Styxl2 promotes de novo sarcomere assembly by interacting with non-muscle myosin IIs and facilitating their autophagic degradation., Competing Interests: XC, YL, JX, YC, QW, HY, YL, CG, LJ, HW, ZW, ZY, ZW No competing interests declared, (© 2023, Chen, Li et al.)

Background: The stemness characteristics of cancer cells, such as self-renewal and tumorigenicity, are considered to be responsible, in part, for tumor metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in promoting both stemness and tumor metastasis. Although the traditional medicine juglone is thought to play an anticancer role by affecting cell cycle arrest, induction of apoptosis, and immune regulation, a potential function of juglone in regulating cancer cell stemness characteristics remains unknown., Methods: In the present study, tumor sphere formation assay and limiting dilution cell transplantation assays were performed to assess the function of juglone in regulating maintenance of cancer cell stemness characteristics. EMT of cancer cells was assessed by western blot and transwell assay in vitro , and a liver metastasis model was also performed to demonstrate the effect of juglone on colorectal cancer cells in vivo ., Results: Data gathered indicates juglone inhibits stemness characteristics and EMT in cancer cells. Furthermore, we verified that metastasis was suppressed by juglone treatment. We also observed that these effects were, in part, achieved by inhibiting Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1)., Conclusions: These results indicate that juglone inhibits maintenance of stemness characteristics and metastasis in cancer cells., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)