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Amyloid-beta (Aβ) peptide accumulation on blood vessels in the brain is a hallmark of neurodegeneration. While Aβ peptides constrict cerebral arteries and arterioles, their impact on capillaries is less understood. Aβ was recently shown to constrict brain capillaries through pericyte contraction, but whether—and if so how—Aβ affects endothelial cells (ECs) remains unknown. ECs represent the predominant vascular cell type in the cerebral circulation, and we recently showed that the mechanosensitive ion channel Piezo1 is functionally expressed in the plasma membrane of ECs.

Advanced deep learning and statistical methods can predict structural models for RNA molecules. However, RNAs are flexible, and it remains difficult to describe their macromolecular conformations in solutions where varying conditions can induce conformational changes. Small-angle X-ray scattering (SAXS) in solution is an efficient technique to validate structural predictions by comparing the experimental SAXS profile with those calculated from predicted structures. There are two main challenges in comparing SAXS profiles to RNA structures: the absence of cations essential for stability and charge neutralization in predicted structures and the inadequacy of a single structure to represent RNA's conformational plasticity.

Synaptotagmin-1 (Syt1) is a major calcium sensor for rapid neurotransmitter release in neurons and hormone release in many neuroendocrine cells. It possesses two tandem cytosolic C2 domains that bind calcium, negatively charged phospholipids, and the neuronal SNARE complex. Calcium binding to Syt1 triggers exocytosis, but how this occurs is not well understood. Syt1 has additional roles in docking dense core vesicles (DCV) and synaptic vesicles (SV) to the plasma membrane (PM) and in regulating fusion pore dynamics.

Intrinsically disordered proteins (IDPs) show structural changes stimulated by changes in external conditions. This study aims to reveal the temperature dependence of the structure and dynamics of the intrinsically disordered region of Hef, one of the typical IDPs, using an integrative approach. Small-angle X-ray scattering (SAXS) and circular dichroism (CD) studies revealed that the radius of gyration and ellipticity at 222 nm remained constant up to 313-323 K, followed by a decline above this temperature range.

In the circulatory system, the microenvironment surrounding cancer cells is complex and involves multiple coupled factors. We selected two core physical factors, shear stress and hydraulic resistance, and constructed a microfluidic device with dual negative inputs to study the trade-off movement behavior of cancer cells when facing coupled factors. We detected significant shear stress escape phenomena in the MDA-MB-231 cell line and qualitatively explained this behavior using a cellular force model.

Cholesterol-enriched plasma membrane domains are known to serve as signaling platforms in a diverse array of cellular processes. However, the link between cholesterol homeostasis and mutant APC-KRas-associated colorectal tumorigenesis remains to be established. Thus, we investigated the impact of Apc-Kras on (i) colonocyte plasma membrane cholesterol homeostasis, order, and receptor nanoclustering, (ii) colonocyte cell proliferation, and (iii) whether these effects are modulated by select membrane active dietaries (MADs).

Despite their large functional diversity and poor sequence similarity, tetrameric and pseudo-tetrameric potassium, sodium, calcium and cyclic-nucleotide gated channels, as well as two-pore channels, transient receptor potential channels and ionotropic glutamate receptors share a common folding pattern of the transmembrane (TM) helices in the pore-forming domain. In each subunit or repeat, the pore domain has two TM helices connected by a membrane-reentering P-loop. The P-loop includes a membrane-descending helix, P1, which is structurally the most conserved element of these channels, and residues that contribute to the selectivity-filter region at the constriction of the ion-permeating pathway.

G-Protein coupled receptors (GPCRs) represent one of the largest classes of therapeutic targets. However, developing successful therapeutics to target GPCRs is a challenging endeavor with many molecules failing during in vivo clinical trials due to a lack of efficacy. The in vitro identification of drug targeted residence time (1/koff) has been suggested to improve prediction of in vivo success. Here, a ligand binding assay using fluorescence anisotropy was implemented to successfully determine on-rates (kon) and off-rates (koff) of labeled and unlabeled ligands binding to the adenosine A2A receptor (A2AR) purified into nanodiscs (A2AR-NDs).

Statement of significance: The HIV-1 capsid plays a complex role in infection of a host cell; the capsid must remain intact to carry its cargo into the cell’s nucleus but break apart to deliver the viral genome. This makes capsid an important target for therapy, but the mechanisms by which small molecules affect its integrity remain elusive. To elucidate these mechanisms, we systematically interrogated the impact of two small molecules known to alter capsid stability on the interface between capsid subunits. Our all-atom simulations suggest the charged sugar IP6 stabilizes flatter sections of the capsid, while PF74 partially locks interfaces into narrow ranges of curvature. These findings highlight modulation of curvature as a mechanism by which small molecules affect capsid stability.

SIGNIFICANCE Breast-tumor cells experience viscoelasticity, varying spatially in ECM, and these cells respond to localized cues of viscoelasticity and its spatial changes. Such ECM viscoelasticity in breast-tumor 3D cell cultures for modeling breast-tumor progression in biomedical applications has yet to be precisely detected. We present a probabilistic modeling method to advance magnetic microrheometry, the only current technique that can measure cell-scale viscoelasticity from inside of cancer 3D cell cultures up to stiffness as found in breast-tumor biopsies. Our method uses inherently sparse data by measurement probes of the microrheometry, and can—for the first time—quantify probabilistic spatial variability of cell-scale viscoelasticity in each microscopy field of view based on Bayesian modeling using raw measurement signals.

Under standard physiological conditions, budding relies on asymmetries, including differences in leaflet composition, area, and osmotic conditions, and involves large curvature changes in nanoscale lipid vesicles. So far, the combined impact of asymmetry and high curvatures on budding has remained unknown. Here, using continuum elastic theory, the budding pathway is detailed under realistic conditions. The model enables a quantitative description of the budding process and the budded state of both ideally and non-ideally mixed lipid nanoscale vesicles.