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When making decisions, how people allocate their attention influences their choices. One empirical finding is that people are more likely to choose the option that they have looked at more. This relation has been formalized with the attentional drift-diffusion model (aDDM; Krajbich et al., 2010). However, options often have multiple attributes, and attention is also thought to govern the relative weighting of those attributes (Roe et al., 2001). Little is known about how these two distinct features of the choice process interact; we still lack a model (and tests of that model) that incorporate both option- and attribute-wise attention. Here, we propose a multi-attribute attentional drift-diffusion model (maaDDM) to account for attentional discount factors on both options and attributes. We then use five eye-tracking datasets (two-alternative, two-attribute preferential tasks) from different choice domains to test the model. We find very stable option-level and attribute-level attentional discount factors across datasets, though nonfixated options are consistently discounted more than nonfixated attributes. Additionally, we find that people generally discount the nonfixated attribute of the nonfixated option in a multiplicative way, and so that feature is consistently discounted the most. Finally, we also find that gaze allocation reflects attribute weights, with more gaze to higher-weighted attributes. In summary, our work uncovers an intricate interplay between attribute weights, gaze processes, and preferential choice. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

High conductivity anomalies in the shallow mantle are frequently attributed to minor partial melt (basalt or carbonatite) in the olivine-dominated peridotites. Conductivity of a melt-mineral mixture depends on the configuration of melt that could be affected by grain size of the constitutive mineral(s), but this has rarely been explored. Here, we provide experimental evidence using a conductive carbonatite analog and olivine that the bulk conductivity decreases systematically with increasing olivine grain size. The required amount of melt for producing the geophysically resolved high conductivities in the asthenosphere is much greater than previously assumed. We suggest that the effect of partial melt on many conductive regions in the asthenosphere is small. Instead, the electrical anomalies (especially those away from mid-ocean ridges) originate more likely from subsolidus solid assemblages in the upper mantle. This reconciles well the geochemical and petrological constraints of the shallow mantle with its geophysically determined electrical properties.

Omphacite is a diagnostic mineral of high- and ultrahigh-pressure rocks, and its association with garnet is characteristic of eclogites from subduction-related massifs and volcano-entrained xenoliths. Omphacite can accommodate significant amounts of water as structurally bound hydroxyl (OH) groups, and is able to convey water into Earth's interior. We show, for the first time, experimental evidence that the infrared absorption patterns of water in omphacite are temperature sensitive. This provides a new framework for discriminating water in natural omphacite equilibrated at different temperatures. We also demonstrate that in low-temperature omphacite, the integral absorbance ratio between the infrared OH absorption bands at 3620 cm−1 and 3450 cm−1 is linearly related to temperature. Water in omphacite of massif eclogites records the temperature of OH equilibrium, allowing reconstruction of the fluid-involved thermal history and tectonics of rock evolution.

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype among breast tumors and remains a challenge even for the most current therapeutic regimes. Here, we demonstrate that oncolytic alphavirus M1 effectively kills both TNBC and non-TNBC. ER-stress and apoptosis pathways are responsible for the cell death in non-TNBC as reported in other cancer types, yet the cell death in TNBC does not depend on these pathways. Transcriptomic analysis reveals that the M1 virus activates necroptosis in TNBC, which can be pharmacologically blocked by necroptosis inhibitors. By screening a library of clinically available compounds commonly used for breast cancer treatment, we find that Doxorubicin enhances the oncolytic effect of the M1 virus by up to 100-fold specifically in TNBC in vitro, and significantly stalls the tumor growth of TNBC in vivo, through promoting intratumoral virus replication and further triggering apoptosis in addition to necroptosis. These findings reveal a novel antitumor mechanism and a new combination regimen of the M1 oncolytic virus in TNBC, and highlight a need to bridge molecular diagnosis with virotherapy.

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor and an oncogene product, which plays a pivotal role in tumor progression. Therefore, targeting persistent STAT3 signaling directly is an attractive anticancer strategy. The aim of this study is to test the efficacy of a novel STAT3 small molecule inhibitor, LLL12B, in suppressing medulloblastoma cells in vitro and tumor growth in vivo. LLL12B selectively inhibited the induction of STAT3 phosphorylation by interleukin-6 but not induction of STAT1 phosphorylation by INF-γ. LLL12B also induced apoptosis in human medulloblastoma cells. In addition, LLL12B exhibited good oral bioavailability in vivo and potent suppressive activity in tumor growth of medulloblastoma cells in vivo. Besides, combining LLL12B with cisplatin showed greater inhibition of cell viability and tumorsphere formation as well as induction of apoptosis comparing to single agent treatment in medulloblastoma cells. Furthermore, LLL12B and cisplatin combination exhibited greater suppression of medulloblastoma tumor growth than monotherapy in vivo. The present study supported that LLL12B is a novel therapeutic agent for medulloblastoma and the combination of LLL12B with a chemotherapeutic agent cisplatin may be an effective approach for medulloblastoma therapy.

Clinopyroxene and orthopyroxene are important constituents of the upper mantle, and determine largely the water budget. Despite considerable efforts on water storage in pyroxenes, however, less attention has been paid to the effect of oxygen fugacity, a key thermodynamic factor in Earth sciences. We have systematically assessed the effect of oxygen fugacity on OH dissolution in pyroxenes, by conducting high-pressure and temperature experiments over a wide range of conditions. The runs were carried out at 0.2–3 GPa, 800–1200 °C and peridotite- and H2O-saturated conditions, with gem-quality natural diopside and enstatite single crystals and a fresh peridotite xenolith as the starting materials. The oxygen fugacities were buffered by Fe-FeO, Ni-NiO, Re-ReO2 and Fe3O4-Fe2O3 pairs, by using a modified double-capsule technique. The water contents of the recovered pyroxenes were determined by polarized analyses with a Fourier-transform infrared spectroscopy. The H-annealed pyroxenes show typical OH-related bands. The samples show no zoned OH distribution at sub-grain scales, and the OH contents are independent of run durations, suggesting the attainments of equilibrium OH incorporation. For each starting mineral, the spectral shapes and OH frequency positions are similar throughout the run conditions. The measured H2O contents are ∼14–394 and 34–227 ppm in the H-annealed clinopyroxene and orthopyroxene, respectively. For each mineral under otherwise identical conditions, the OH content increases with increasing pressure or temperature but decreases with increasing oxygen fugacity. In clinopyroxene, the ratio of either the peak heights or integrated absorbances between the bands at ∼3645 and 3435 cm−1 is less sensitive to a change of pressure, particularly above 1 GPa, but is more sensitive to a change of temperature, if the redox state is maintained as in the upper mantle. The OH groups in the spectra of clinopyroxene can be used to estimate the redox state in the source regions where the sample was finally equilibrated, if the equilibrium temperature is determined by other approach(s). On average, the OH content is enhanced by ∼40% and 60% in Fe-poor clinopyroxene and orthopyroxene, respectively, at Fe-FeO buffered reducing than at Ni-NiO buffered oxidizing conditions. This enhancement appears greater if the pyroxenes are more Fe-enriched, likely due to the enhanced reduction of Fe3+ to Fe2+ and the coupled incorporation of H in the structure toward more reducing conditions. The quantitative dependence of OH solubility on oxygen fugacity differs between pyroxenes and olivine (and other nominally anhydrous minerals), and the partitioning of OH between pyroxenes and coexisting olivine and the inventory of OH in the upper mantle are influenced by oxygen fugacity. The OH storage capacity of the shallow mantle is probably greater in Mars than in the Earth, because of the relatively more reduced state and more Fe-enriched pyroxenes in the former. Finally, the enhanced solubility of OH in pyroxenes under very reducing conditions could be important for insights into the early differentiation of Earth’s shallow mantle, in that hydrous melting may have been induced by redox-involved dehydration of pyroxenes when the shallow mantle evolved into its modern oxidizing state.

Surface-enhanced Raman scattering (SERS) is recognized as one of the most sensitive spectroscopic tools for chemical and biological detections. Hotspots engineering has expedited promotion of SERS performance over the past few decades. Recently, molecular enrichment has proven to be another effective approach to improve the SERS performance. In this work, we propose a concept of "motile hotspots" to realize ultrasensitive SERS sensing by combining hotspots engineering and active molecular enrichment. High-density plasmonic nanostructure-supporting hotspots are assembled on the tubular outer wall of micromotors via nanoimprint and rolling origami techniques. The dense hotspots carried on these hierarchically structured micromotors (HSMs) can be magnet-powered to actively enrich molecules in fluid. The active enrichment manner of HSMs is revealed to be effective in accelerating the process of molecular adsorption. Consequently, SERS intensity increases significantly because of more molecules being adjacent to the hotspots after active molecular enrichment. This "motile hotspots" concept provides a synergistical approach in constructing a SERS platform with high performance. Moreover, the newly developed construction method of HSMs manifests the possibility of tailoring tubular length and diameter as well as surface patterns on the outer wall of HSMs, demonstrating good flexibility in constructing customized micromotors for various applications.

the data for garnet samples in the work

The potential of using cryo-electron microscopic (cryo-EM) structures of 2.5-4.0 Å resolutions for structure-based drug design was proposed recently, but is yet to be materialized. Here we show that a 3.1 Å cryo-EM structure of protein arginine methyltransferase 5 (PRMT5) is sufficient to guide the selection of computed poses of a bound inhibitor and its redesign for much higher potency. PRMT5 is an oncogenic target and its multiple inhibitors are in clinical trials for various cancer types. However, all these PRMT5 inhibitors manifest negative cooperativity with a metabolic co-factor analog --- 2-methylthioadenosine (MTA), which is accumulated substantially in cancer patients carrying defective MTA phosphorylase (MTAP). To achieve MTA-synergetic inhibition, we obtained a pharmacophore from virtual screen and synthesized a specific inhibitor (11-2F). Cryo-EM structures of the 11-2F/MTA-bound human PRMT5: MEP50 complex and its apo form together showed that the inhibitor binding in the catalytic pocket causes a shift of the cofactor-binding site by 1.5 – 2.0 Å, disfavoring cofactor-binding and resulting in positive cooperativity between 11-2F and MTA. Coarse-grained and full-atomistic MD simulations of the ligands in their binding pockets were performed to compare computed poses of 11-2F and its redesigned analogs. Three new analogs were predicted to have much better potency. One of them, after synthesis, was ~4 fold more efficient in PRMT5 inhibition in the presence of MTA than 11-2F itself. Computational analysis also suggests strong subtype specificity of 11-2F among PRMTs. These data demonstrate the feasibility of using cryo-EM structures of near-atomic resolutions and computational analysis of ligand poses for better small molecule therapeutics.

Fourier transform infrared and Raman spectra, electron microprobe data, and resolved band absorbance ratios of samples.

Geophysical, petrological and geochemical studies have shown that the lithospheric mantle is highly heterogeneous in its physical properties and chemical compositions. They provide critical information on the evolution of the lithosphere-asthenosphere boundary (LAB). Considerable efforts by geophysical approaches have demonstrated that LAB is characterized by profound changes in physical properties such as seismic velocities and electrical resistivity at an average depth of ~70 km in the oceanic areas. In the continental regions, however, the variations in the physical properties at LABs are not that significant and their depths vary greatly with tectonic environments (e.g., orogens vs. cratons). Mid-lithospheric discontinuities (MLDs; ~60 to 120 km depths) have been equally well documented by various techniques, including deep seismic reflections and refractions, receiver functions analyses of teleseismic Ps and Sp phases, teleseismic and ambient-noise based surface-waves tomography. Except in some regional cases, MLDs are usually featured by reduced velocities (i.e., negative velocity gradients). It appears that MLDs are statistically correlated with the low-resistivity layers, as imaged for the European continent. Many hypotheses have been proposed to explain the origin of MLDs, including the accumulation of volatile-bearing assemblages due to metasomatism of magmas/fluids and/or metamorphism; the change of deformation patterns of rocks in the lithospheric mantle and finally a “frozen” LAB. Here we review the related advances and try to reconcile available data and models. We first provide a brief introduction about the discovery of MLDs, by summarizing their velocity, radial and azimuthal anisotropies as well as their internal structures across Australian, North American and Euro-Asian continents. Then we discuss the possible origin of MLDs, by considering mantle heterogeneities in mineralogy and petrology and in particular the potential role of volatile-rich minerals such as phlogopite, amphibole and carbonates. Finally, we conclude that MLDs may be frozen LABs. It sheds light on the potential importance of MLDs in Earth’s evolution and especially the global tectonic and the changes over time. We present a working hypothesis using a dynamically-evolved LAB model. MLDs began as oceanic LABs, with their depths increasing gradually from the mid-ocean ridges to subduction zones due to change in temperature and age. During continental accretion, the “inherited” oceanic LAB merged with the continental lithosphere and became deepened along with the cooling of the new continental lithosphere. In brief, the old LAB was “frozen” into the continental lithosphere and produced MLDs. Several possible mechanisms supporting this hypothesis are proposed, and the conditions that are tenable from recent results of geodynamic modeling studies in Africa are presented. The advantages of this hypothesis are highlighted. Its potential in explanation of scientific puzzles of solid earth is evaluated.

Data for High electrical conductivity of olivine at oxidizing conditions of the shallow mantle and geophysical implications

Reestablishing an appropriate balance between T effector cells (Teff) and Tregs is essential for correcting autoimmunity. Multiple sclerosis (MS) is an immune-mediated chronic CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teffs Th1 and Th17 cells. STAT3 is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a potentially novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4+ T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest that selective inhibition of STAT3 by the small molecule LLL12b recalibrates the effector and regulatory arms of CD4+ T responses, representing a potentially clinically translatable therapeutic strategy for MS.

Data for Electrical conductivity of olivine at mantle conditions

Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin- paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cellsand suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.

Activation of the cyclic adenosine monophosphate (cAMP) pathway induces the glial differentiation of glioblastoma (GBM) cells, but the fate of differentiated cells remains poorly understood. Transcriptome analyses have revealed significant changes in the cell cycle- and senescence-related pathways in differentiated GBM cells induced by dibutyryl cAMP (dbcAMP). Further investigations showed that reactive oxygen species (ROS) derived from enhanced mitochondrial function are involved in senescence induction and proliferation inhibition. Moreover, we found that IL-6 from dbcAMP- or temozolomide (TMZ)-induced senescent cells facilitates the glycolytic phenotype of GBM cells and that inhibiting the IL-6-related pathway hinders the proglycolytic effect of either agent. In patient-derived GBM xenograft models, a specific antibody targeting the IL-6 receptor tocilizumab (TCZ) significantly prolongs the survival time of TMZ-treated mice. Taken together, these results suggest that both the differentiation-inducing agent dbcAMP and the chemotherapy drug TMZ are able to drive GBM cells to senescence, and the latter releases IL-6 to potentiate glycolysis, suggesting that IL-6 is a target for adjuvant chemotherapy in GBM treatment.

Electrical conductivity data for Electrical conductivity of olivine at mantle conditions and the origin of the electrical asthenosphere: a new perspective

The effect of water on the kinetics of Fe–Mg interdiffusion in garnet was investigated at 3 GPa and 1373–1673 K using diffusion couples of pyrope and almandine aggregates, over a wide range of water content ( C H 2 O ) from D Fe – Mg ( m 2 / s ) = D 0 C H 2 O r exp ⁡ ( − Δ H / R T ) , where log ⁡ ( D 0 ) = − 1.70 ± 0.50 , r = 1.38 ± 0.06 , and H = 310 ± 33 kJ/mol. The exponent r of 1.38 implies the incorporation mechanism of water is hydrogen associated with metal and partly silicon vacancies to form neutral point defect complexes. While at the same time, it also suggests a profound role of water in enhancing the Fe–Mg interdiffusion in garnet. With increasing water content from 100 to 1260 wt. ppm H2O, the Fe–Mg inter-diffusivity is enhanced by about two orders of magnitude, comparable to the effect of temperature increased by about 300 °C under dry condition. Such large effect of water on the kinetics of garnet is expected to have important implications for evaluating the closure temperature of available geospeedometry and geothermometry.

Background In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM. Methods Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. Results In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state. Conclusion In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.

Fluorine and hydroxyl groups are minor constituents of silicate minerals, and share a lot of similarities concerning their physical and chemical properties. Hydroxyl groups significantly enhance the electrical conductivity of many silicate minerals, and it is expected that fluorine would have a comparable effect. This, however, has never been documented quantitatively. Here we present experimental approaches on this issue, by investigating the electrical conductivity of phlogopite with a wide range of fluorine content (but with broadly similar contents for other major elements). Electrical conductivities of gem-quality single crystal phlogopites, with samples prepared along the same orientation (normal to the (0 0 1) plane), were determined at 1 GPa and 200–650 °C using an end-loaded piston cylinder apparatus and a Solartron-1260 Impedance/Gain Phase Analyzer over the frequency range of 10 6 to 0.1 Hz. The complex spectra usually show an arc in the high frequency range and a short tail in the low frequency range, which are caused by lattice conduction and electrode effects, respectively. The electrical conductivity increases with increasing fluorine content, and the main charge carriers are fluorine. The activation enthalpies are ∼180 to 200 kJ/mol, nearly independent of fluorine content. The conductivity is linearly proportional to the content of fluorine, with an exponent factor of ∼1. The results demonstrate that conduction by fluorine leads to very high electrical conductivity at high temperatures. The influence of fluorine on electrical conductivity may be compared to that of hydrogen in nominally anhydrous minerals. This, along with the close association of fluorine and hydroxyl groups in silicate minerals and their similar crystal-chemical behaviors, suggests a more general role of fluorine in enhancing the electrical conductivity of many silicate minerals. Fluorine-rich assemblages, e.g., phlogopite and amphibole, could be locally enriched in the upper mantle, and if they form connected networks as observed for some natural samples, regionally high electrical conductivities could be produced. It has been recently proposed that the transition zone is probably a major reservoir for fluorine in the mantle, due to the significant dissolution of fluorine in wadsleyite and ringwoodite and the coupled incorporation with hydroxyl groups. As such, geophysically-resolved high electrical conductivities in the transition zone may be accounted for by fluorine in the dominant minerals, rather than by hydroxyl groups. The results of this work would stimulate a wide scope of future studies on the deep fluorine cycle, the deep water cycle and the geodynamical properties of the mantle.

Understanding the concentration and distribution of water in the Earth's mantle plays a substantial role in studying its chemical, physical and dynamic processes. After a decade of research, a comprehensive dataset of water content in upper-mantle samples has been built for eastern China, which is now the only place with water-content data from such diverse types of natural samples, and provides an integrated picture of the water content and its distribution in the upper mantle at a continental scale. The main findings include the following: (i) the temporal heterogeneity of the water content in the lithospheric mantle from early Cretaceous (∼120 Ma) to Cenozoic (

When plotting the representative FTIR spectra of garnet in Fig. 3d and e, an error was made with the thickness normalization, and the spectra were wrongly normalized. We reproduce the correct figure below.

Advances in transcriptome sequencing have revealed that the genome fraction largely encodes for thousands of non‐coding RNAs. Long non‐coding RNAs (lncRNAs), which are a class of non–protein‐coding RNAs longer than approximately 200 nucleotides in length, are emerging as key epigenetic regulators of gene expression recently. Intensive studies have characterized their crucial roles in cutaneous biology and diseases. In this review, we address the promotive or suppressive effects of lncRNAs on cutaneous physiological processes. Then, we focus on the pathogenic role of dysfunctional lncRNAs in a variety of proliferative skin diseases. These evidences suggest that lncRNAs have indispensable roles in the processes of skin biology. Additionally, lncRNAs might be promising biomarkers and therapeutic targets for cutaneous disorders.