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BACKGROUND: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimers disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. METHODS: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

Understanding the microscopic origin of the superior electromechanical response in relaxor ferroelectrics requires knowledge not only of the atomic-scale formation of polar nanodomains (PNDs) but also the rules governing the arrangements and stimulated response of PNDs over longer distances. Using x-ray coherent nanodiffraction, we show the staggered self-assembly of PNDs into unidirectional mesostructures that we refer to as polar laminates in the relaxor ferroelectric 0.68PbMg1/3Nb2/3O3-0.32PbTiO3 (PMN-0.32PT). We reveal the highly heterogeneous electric-field-driven responses of intra- and interlaminate PNDs and establish their correlation with the local strain and the nature of the PND walls. Our observations highlight the critical role of hierarchical lattice organizations on macroscopic material properties and provide guiding principles for the understanding and design of relaxors and a wide range of quantum and functional materials.

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis.

[BaTiO_{3}]_{m}/[BaZrO_{3}]_{n} (m, n=4-12) superlattices are used to demonstrate the fabrication and deterministic control of an artificial relaxor. X-ray diffraction and atomic-resolution imaging studies confirm the production of high-quality heterostructures. With decreasing BaTiO_{3} layer thickness, dielectric measurements reveal systematically lower dielectric-maximum temperatures, while hysteresis loops and third-harmonic nonlinearity studies suggest a transition from ferroelectriclike to relaxorlike behavior driven by tuning the random-field strength. This system provides a novel platform for studying the size effect and interaction length scale of the nanoscale-polar structures in relaxors.

Hyaluronan (HA), also known as hyaluronic acid, is a glycosaminoglycan that is a critical component of the extracellular matrix (ECM). Production and deposition of ECM is a wound-healing response that occurs during chronic liver disease, such as cirrhosis. ECM production is a sign of the disease progression of fibrosis. Indeed, the accumulation of HA in the liver and elevated serum HA levels are used as biomarkers of cirrhosis. However, recent studies also suggest that the ECM, and HA in particular, as a functional signaling molecule, facilitates disease progression and regulation. The systemic and local levels of HA are regulated by de novo synthesis, cleavage, endocytosis, and degradation of HA, and the molecular mass of HA influences its pathophysiological effects. However, the regulatory mechanisms of HA synthesis and catabolism and the functional role of HA are still poorly understood in liver fibrosis. This review summarizes the role of HA in liver fibrosis at molecular levels as well as its clinical implications and discusses the potential therapeutic uses of targeting HA in liver fibrosis.

Relaxor ferroelectrics have been intensely studied for decades based on their unique electromechanical responses which arise from local structural heterogeneity involving polar nanoregions or domains. Here, we report first studies of the ultrafast dynamics and reconfigurability of the polarization in freestanding films of the prototypical relaxor 0.68PbMg1/3Nb2/3O3-0.32PbTiO3 (PMN-0.32PT) by probing its atomic-scale response via femtosecond-resolution, electron-scattering approaches. By combining these structural measurements with dynamic phase-field simulations, we show that femtosecond light pulses drive a change in both the magnitude and direction of the polarization vector within polar nanodomains on few-picosecond time scales. This study defines new opportunities for dynamic reconfigurable control of the polarization in nanoscale relaxor ferroelectrics.

Understanding the evolution and role of nanoscale polar structures during polarization rotation in relaxor ferroelectrics is a long-standing challenge in materials science and condensed-matter physics. These nanoscale polar structures are characterized by polar nanodomains, which are believed to play a key role in enabling the large susceptibilities of relaxors. Using epitaxial strain, we stabilize the intermediate step during polarization rotation in epitaxial films of a prototypical relaxor and study the co-evolution of polarization and polar nanodomains. Our multimodal approach allows for a detailed examination of correlations between polarization and polar nanodomains; illuminates the effect of local chemistry, strain and electric field on their co-evolution; and reveals the underappreciated role of strain in enabling the large electromechanical coupling in relaxors. As the strain increases, the competition between chemistry-driven disorder and strain-driven order of the polar units intensifies, which is manifested in the coexistence of inclined and elongated polar nanodomains in the intermediate step of polarization rotation. Our findings establish that structural transitions between polar nanodomain configurations underpins the polarization rotation and large electromechanical coupling of relaxors.

The TAROGE-M observatory is an autonomous antenna array on the top of Mt. Melbourne (∼2700 m altitude) in Antarctica, designed to detect radio pulses from ultra-high energy (over 1017 eV) air showers coming from near-horizon directions. The targeted sources include cosmic rays, Earth-skimming tau neutrinos, and most of all, the anomalous near-horizon upward-going events of yet unknown origin discovered by ANITA experiments. The detection concept follows that of ANITA: monitoring large area of ice from high-altitude and taking advantage of strong geomagnetic field and quiet radio background in Antarctica, whereas having significantly greater livetime and scalability. The TAROGE-M station, upgraded from its prototype built in 2019, was deployed in January 2020, and consists of 6 log-periodic dipole antennas pointing horizontally with bandwidth of 180-450 MHz. The station is then calibrated with drone-borne transmitter, with which the event reconstruction obtained ∼0.3° angular resolution. The station was then smoothly operating in the following month, with the live time of ∼ 30 days, before interrupted by a power problem, and its online filtering has identified several candidate cosmic-ray events and sent out via satellite communication. In this paper, the instrumentation of the station for polar and high-altitude environment, its radio-locating performance, the preliminary result on cosmic-ray detection, and the future extension plan are presented.

While teachers value cultural and linguistic diversity, they see the benefits of speaking different languages "in the future tense," feeling it hard to specify how language differences positively impact students' learning in the present. This study explores teachers' temporal perceptions of language differences, specifically focusing on how teacher perceptions of language differences as "future assets" are intertwined with native speakerism in the present. It draws on multi-year interviews that unveil how teachers prioritise monolingualism as the norm of classroom discourse and juxtaposes teachers' accounts with an immigrant child's navigation of cultural-linguistic assets to speak Korean and English in non-school contexts. Through this, we argue that, whereas teachers see the potential benefits of speaking different languages that seek to pluralise the educational futures, they continue to hold the normative view on language differences by not being offered the epistemic tools to question "whose future" and "whose language" are imagined as the desired endpoints of language education. Approaching teachers' statements as the outcome of the limited epistemic principles of normative futurity, this study calls for disrupting the continuity of native speakerism to support culturally and linguistically diverse students through the non-linear, reparative, and multiple relations to the futures in language education.

TAROGE-M is a self-triggered radio antenna array atop the 2700 m high Mt.Melbourne in Antarctica, designed to detect impulsive geomagnetic emission fromextensive air showers induced by ultra-high energy (UHE) particles beyond 0.1EeV, including cosmic rays (CRs), Earth-skimming tau neutrinos, andparticularly, the "ANITA anomalous events" (AAEs) from near and below thehorizon, which origin remains uncertain and requires more experimental inputsfor clarification. The detection concept of TAROGE-M takes advantage of a high altitude withsynoptic view toward the horizon as an efficient signal collector, and theradio quietness as well as strong and near vertical geomagnetic field inAntarctica. This approach has a low energy threshold, high duty cycle, and iseasy to extend for quickly enlarging statistics. Here we report experimentalresults from the first TAROGE-M station deployed in 2020, corresponding to$25.3$-days of livetime. The station consists of six receiving antennasoperating at 180-450 MHz, and can reconstruct source directions with$\sim0.3^\circ$ angular resolution. To demonstrate its ability to detect UHEair showers, a search for CR signals in the data was conducted, resulting inseven identified events. These events have a mean reconstructed energy of$0.95_{-0.31}^{+0.46}$ EeV and zenith angles between $25^\circ-82^\circ$, withboth distributions agreeing with simulations. The estimated CR flux is alsoconsistent with results of other experiments. The TAROGE-M sensitivity to AAEsis approximated by the tau neutrino exposure with simulations, suggestingcomparable sensitivity as ANITA's at $~1$ EeV energy with a few station-yearsof operation. These first results verified the station design and performancein a polar and high-altitude environment, and are promising for furtherdiscovery of tau neutrinos and AAEs after an extension in the near future.