Mapping the Fine-Scale Organization and Plasticity of the Brain Vasculature.

The cerebral vasculature is a dense network of arteries, capillaries, and veins. Quantifying variations of the vascular organization across individuals, brain regions, or disease models is challenging. We used immunolabeling and tissue clearing to image the vascular network of adult mouse brains and developed a pipeline to segment terabyte-sized multichannel images from light sheet microscopy, enabling the construction, analysis, and visualization of vascular graphs composed of over 100 million vessel segments. We generated datasets from over 20 mouse brains, with labeled arteries, veins, and capillaries according to their anatomical regions. We characterized the organization of the vascular network across brain regions, highlighting local adaptations and functional correlates. We propose a classification of cortical regions based on the vascular topology. Finally, we analysed brain-wide rearrangements of the vasculature in animal models of congenital deafness and ischemic stroke, revealing that vascular plasticity and remodeling adopt diverging rules in different models.

The resentful undergrowth of nostalgia: Ontological insecurity, relative deprivation and powerlessness.

This article untangles competing conceptualisations of nostalgia and identifies a specific form of collective-restorative nostalgia as politically significant. We argue that the link between resentment and this type of nostalgia emerges from their joint critique of the socio-political realities of the present. Nostalgia provides spatial and temporal orientations for a group's experiences of resentment through highly selective recollections of the heartland and an idealised golden age. We hypothesize that nostalgia leverages the heartland and the golden age to formulate claims for recognition and restored status on behalf of those who feel left behind by late modernity. Next, the article uses structural equation modelling and the 2019 Belgian National Election Study to reveal how resentment (consisting of ontological insecurity, group relative deprivation, and powerlessness) mediates between structural characteristics and nostalgia. Our findings suggest that each component of resentment individually contributes to explaining the nostalgia of less educated and economically deprived individuals.

Identification with all humanity-A test of the factorial structure and measurement invariance of the scale in five countries.

Identification with all humanity measured as an individual characteristic is an important factor related to social and international relations, such as concern for global issues and human rights, prosocial attitudes, intergroup forgiveness, attitudes toward immigrants, solving global problems, reactions to hate crimes and dehumanisation. We examine the factorial structure, psychometric properties and measurement invariance of the Identification with All Humanity (IWAH) scale in student samples from five countries (the United States, Poland, France, Mexico and Chile; N = 1930). Separate confirmatory factor analyses (CFAs) for each country showed a second-order model of one superordinate factor with two subfactors. The cross-country validation of the scale, based on multigroup CFA, confirmed configural and metric invariance between countries for raw scores, and full metric invariance for "pure" scores. This study showed that the IWAH scale can be successfully used for cross-country research and the results from different countries can be compared and integrated.

Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin.

We describe the design, synthesis, and antitumor activity of an 18 carbon α,ω-dicarboxylic acid monoconjugated via an ester linkage to paclitaxel (PTX). This 1,18-octadecanedioic acid-PTX (ODDA-PTX) prodrug readily forms a noncovalent complex with human serum albumin (HSA). Preservation of the terminal carboxylic acid moiety on ODDA-PTX enables binding to HSA in the same manner as native long-chain fatty acids (LCFAs), within hydrophobic pockets, maintaining favorable electrostatic contacts between the ω-carboxylate of ODDA-PTX and positively charged amino acid residues of the protein. This carrier strategy for small molecule drugs is based on naturally evolved interactions between LCFAs and HSA, demonstrated here for PTX. ODDA-PTX shows differentiated pharmacokinetics, higher maximum tolerated doses and increased efficacy in vivo in multiple subcutaneous murine xenograft models of human cancer, as compared to two FDA-approved clinical formulations, Cremophor EL-formulated paclitaxel (crPTX) and Abraxane (nanoparticle albumin-bound (nab)-paclitaxel).

Populism, Economic Distress, Cultural Backlash, and Identity Threat: Integrating Patterns and Testing Cross-National Validity.

Populism is on the rise across liberal democracies. The sociopsychological underpinnings of this increasing endorsement of populist ideology should be uncovered. In an online cross-sectional survey study among adult samples from five countries (Chile, France, Italy, Romania, and the United Kingdom; N = 9,105), we aimed to replicate an economic distress pattern in which relative deprivation and identity threat are associated with populism. We further tested a cultural backlash pattern-including perceived anomie, collective narcissism, and identity threat as predictors of populism. Multigroup structural equation models supported both economic distress and cultural backlash paths as predictors of populist thin ideology endorsement. In both paths, identity threat to belonging played a significant role as partial mediator. Furthermore, an integrative model showed that the two patterns were not mutually exclusive. These findings emphasize the implication of identity threat to belonging as an explanatory mediator and demonstrate the cross-national generalizability of these patterns.

Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers.

Successful and selective inhibition of the cytosolic protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off-target effects, or are otherwise limited by poor cellular permeability. Peptide-based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer-based proteomimetics. The protein-like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1-binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell-penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2-inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.

Addressing climate change with behavioral science: A global intervention tournament in 63 countries.

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions' effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior-several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people's initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors.

PSA enzymatic activity: a new biomarker for assessing prostate cancer aggressiveness.

BACKGROUND: With the advent of widespread prostate-specific antigen (PSA) testing in recent decades, prostate cancer (PCa) has emerged as the most frequently diagnosed non-skin cancer among men in the U.S. and Europe. Greater screening rates coupled with improved detection methods have caused a controversial upsurge in the number of men undergoing prostate biopsy and subsequent treatment. However, current diagnostic techniques generally suffer from limited ability to identify which seemingly indolent cancers are biologically aggressive. METHODS: We collected prostatic fluid from 778 post-radical prostatectomy specimens and randomly selected samples from both the clinically confirmed aggressive (n = 50) and non-aggressive (n = 50) prostate cancer populations. We measured the level of proteolytic enzyme activity of PSA (aPSA) in each sample and used receiver operating characteristic (ROC) analysis to correlate aPSA levels with prostate cancer aggressiveness. RESULTS: We found aPSA in prostatic fluid to be inversely proportional to disease stage, such that patients with the most aggressive PCa have on average significantly reduced aPSA compared to those with less aggressive disease. Significantly, our results suggest that many (22% in our study population) of the diagnosed patients with non-aggressive PCa could have averted or delayed radical prostatectomy. CONCLUSIONS: Given the high level of debate surrounding PSA screening effectiveness [3-5] and the recent U.S. Preventative Services Task Force recommendation to discontinue PSA screening [6], our results provide renewed hope that a clinical monitoring tool may emerge that truly refines PCa treatment decision-making.

RECOVER identifies synergistic drug combinations in vitro through sequential model optimization.

For large libraries of small molecules, exhaustive combinatorial chemical screens become infeasible to perform when considering a range of disease models, assay conditions, and dose ranges. Deep learning models have achieved state-of-the-art results in silico for the prediction of synergy scores. However, databases of drug combinations are biased toward synergistic agents and results do not generalize out of distribution. During 5 rounds of experimentation, we employ sequential model optimization with a deep learning model to select drug combinations increasingly enriched for synergism and active against a cancer cell line-evaluating only ∼5% of the total search space. Moreover, we find that learned drug embeddings (using structural information) begin to reflect biological mechanisms. In silico benchmarking suggests search queries are ∼5-10× enriched for highly synergistic drug combinations by using sequential rounds of evaluation when compared with random selection or ∼3× when using a pretrained model.

Conspiracy theories as opportunistic attributions of power.

A significant trend of research construes conspiracy theories as a power challenging phenomenon. Yet, there is evidence that conspiracy theories are sometimes promoted by members of relatively powerful groups (e.g., a national majority) in order to target relatively powerless groups (e.g., immigrants). Thus, conspiracy theories are not necessarily beliefs held by the relatively powerless. However, they always attribute power to the allegedly conspiring parties. As a matter of fact, without such power, the groups accused of conspiring would be unable to carry out their plans. In contrast to assuming conspiracy theories reflect objective power imbalances, we propose that they may be construed as opportunistic attributions of power that allow individuals to advance their interests (e.g., validate their worldview, strengthen or challenge social hierarchies).

Conspiracy Beliefs, Rejection of Vaccination, and Support for hydroxychloroquine: A Conceptual Replication-Extension in the COVID-19 Pandemic Context.

Many conspiracy theories appeared along with the COVID-19 pandemic. Since it is documented that conspiracy theories negatively affect vaccination intentions, these beliefs might become a crucial matter in the near future. We conducted two cross-sectional studies examining the relationship between COVID-19 conspiracy beliefs, vaccine attitudes, and the intention to be vaccinated against COVID-19 when a vaccine becomes available. We also examined how these beliefs predicted support for a controversial medical treatment, namely, chloroquine. In an exploratory study 1 (N = 409), two subdimensions of COVID-19 conspiracy beliefs were associated with negative attitudes toward vaccine science. These results were partly replicated and extended in a pre-registered study 2 (N = 396). Moreover, we found that COVID-19 conspiracy beliefs (among which, conspiracy beliefs about chloroquine), as well as a conspiracy mentality (i.e., predisposition to believe in conspiracy theories) negatively predicted participants' intentions to be vaccinated against COVID-19 in the future. Lastly, conspiracy beliefs predicted support for chloroquine as a treatment for COVID-19. Interestingly, none of the conspiracy beliefs referred to the dangers of the vaccines. Implications for the pandemic and potential responses are discussed.

Control of carboxylic acid and ester groups on chromium (VI) binding to functionalized silica/water interfaces studied by second harmonic generation.

Resonantly enhanced surface second harmonic generation (SHG) measurements carried out at pH 7 and room temperature were performed to study how surface-bound carboxylic acid and methyl ester functional groups control the interaction of chromate ions with fused silica/water interfaces. These functional groups were chosen because of their high abundance in humic and fulvic acids and related biopolymers commonly found in soils. They were anchored to the silica surface using organosilane chemistry to avoid competing complexation processes in the aqueous solution as well as competitive adsorption of the organic compounds and chromate. The SHG experiments were carried out at room temperature and pH 7 while using environmentally representative chromate concentrations ranging from 1 x10(-6) to 2 x 10(-4) M. Chromate is found to bind to the acid- and ester-functionalized silica/water interfaces in a reversible fashion. In contrast to the plain silica/water interface, chromate binding studies performed on the functionalized silica/water interfaces show S-shaped adsorption isotherms that can be modeled using the Frumkin-Fowler-Guggenheim (FFG) model. This model predicts a coverage-dependent binding constant of K(ads) x exp(gtheta). Values for g are found to be 3.2(2), 2.1(2), and 1.3(2) for the carboxylic acid-, the ester-, and the nonfunctionalized silica/water interfaces, respectively, and are consistent with stabilizing lateral adsorbate-adsorbate interactions among the Cr(VI) species adsorbed to the functionalized surfaces. The FFG model allows for the parametrization of the solid-liquid partition coefficient and chromate retardation factors in silica-rich soil particles whose surfaces contain organic adlayers rich in carboxylic acid and methyl ester groups. The straightforward model presented here predicts that chromate retardation increases by up to 200% when carboxylic acid functional groups are present at the silica/water interface. Increases up to 50% are predicted for methyl ester-containing organic adlayers, and the retardation factor remains effectively near unity for the plain silica/water interface (no siloxanes present).

High-density doxorubicin-conjugated polymeric nanoparticles via ring-opening metathesis polymerization.

High-density doxorubicin-conjugated polymeric nanoparticles are prepared via ring-opening metathesis polymerization and sustained release of nearly 50% of the anticancer agent is observed after 24 h in mildly acidic aqueous solution.

Spectroscopic and redox properties of amine-functionalized K2[OsII(bpy)(CN)4] complexes.

We report the first examples of amine-functionalized K(2)[Os(II)(bpy)(CN)(4)] (bpy = 2,2'-bipyridine) complexes. The tetracyanoosmate complexes were prepared by UV irradiation (λ = 254 nm) of K(4)[Os(II)(CN)(6)] and primary amine-functionalized bpy ligands in acidic aqueous media. The aqueous solution pH dependences of the spectroscopic and redox properties of 4,4'- and 5,5'-substituted complexes have been investigated. The pendant amine functional groups and coordinated cyanide ligands are basic sites that can be sequentially protonated, thereby allowing systematic tuning of electrochemical and optical spectroscopic properties.

Ferrocene and maleimide-functionalized disulfide scaffolds for self-assembled monolayers on gold.

A series of ferrocene-based electroactive molecules (EAMs) containing maleimide and disulfide groups in different asymmetric and branched architectures were designed and synthesized. Stable monolayers of each EAM on gold electrodes were confirmed by cyclic voltammetry. Importantly, these EAMs expand the repertoire of monolayer building blocks amenable to modular biofunctionalization for applications in electrochemical biosensor fabrication.

Synthesis and In vitro activity of ROMP-based polymer nanoparticles.

A new type of polymer nanoparticle (PNP) containing a high density of covalently linked doxorubicin, attached via a non-cleavable amine linkage (amine-linked Dox-PNP) was prepared. Together with a previously reported cleavable carbamate-linked Dox-PNP, this new amine-linked Dox-PNP was subsequently evaluated against free doxorubicin for its cytotoxicity and inhibitory effects on SKNSH wild-type and SKrDOX6 doxorubicin-resistant human neuroblastoma cell lines. Analogous cholesterol-containing PNPs (Chol-PNPs) and indomethacin-containing PNPs (IND-PNPs) were also synthesized and used as the non-cytotoxic controls. While neither cell line was affected by Chol-PNPs or IND-PNPs, SKrDOX6 doxorubicin-resistant cells exhibited similar cytotoxic responses to free doxorubicin and both amine- and carbamate-linked Dox-PNPs, suggesting that doxorubicin or the doxorubicin-containing polymer must be the active agent in the latter case. SKNSH wild-type cells also responded to both Dox-PNPs, albeit at a higher apparent concentration than free doxorubicin alone. The growth of SKNSH wild-type cells was significantly inhibited upon incubation with carbamate-linked Dox-PNPs, as with free doxorubicin, over a 7-day period. In comparison to free doxorubicin, carbamate-linked Dox-PNPs produced a longer (72-h) period of initial inhibition in SKrDOX6 doxorubicin-resistant cells.

Electroactive self-assembled monolayers on gold via bipodal dithiazepane anchoring groups.

Novel dithiazepane-functionalized ferrocenyl-phenylethynyl oligomers 1 and 2 have been synthesized. Self-assembled monolayers (SAMs) of these ferrocene derivatives have been studied by X-ray photoelectron spectroscopy, ellipsometry, and cyclic voltammetry. It has been shown by XPS that monolayers of the dithiazepane-anchored molecules on gold electrodes contain gold-thiolate species. Cyclic voltammetry of the SAMs were characteristic of stable electroactive monolayers even for single-component SAMs of 1 and 2, with the more ideal responses recorded for the two-component SAMs diluted with undecanethiol. The small variation in peak splittings at progressively higher scan rates in these SAMs makes dithiazepane-bridged redox species promising candidates for further studies on molecular wires with bipodal anchoring.

Multifunctional polymeric nanoparticles from diverse bioactive agents.

We present a rational approach for assembling diverse bioactive agents, such as DNA, proteins, and drug molecules, into core-shell multifunctional polymeric nanoparticles (PNPs) that can be internalized in human breast cancer cells. Using ring-opening metathesis polymerization (ROMP), block copolymers containing small-molecule drug segments (>50% w/w) and tosylated hexaethylene glycol segments were prepared and assembled into PNPs that allowed for the surface conjugation of single-stranded DNA sequences and/or tumor-targeting antibodies. The resulting antibody-functionalized particles were readily uptaken by breast cancer cells that overexpressed the corresponding antigens.

Chromium(VI) binding to functionalized silica/water interfaces studied by nonlinear optical spectroscopy.

Organic adlayers can significantly alter the interactions of environmentally relevant surfaces with their surroundings. We present the first second harmonic and broadband sum frequency generation (SHG and BBSFG) study that illustrates how organic surface functional groups can control the mobility of the priority pollutant chromium(VI) in soil: Cr(VI) binds to ester- and acid-functionalized surfaces but not to alkane-functionalized surfaces. The implications with respect to toxic metal transport across organic adlayers at liquid-solid interfaces are that aqueous Cr(VI) can be retained by polar groups common in biopolymers but not by hydrophobic groups common in surfactants.

A supramolecular approach to an allosteric catalyst.

The design and synthesis of a novel, supramolecular allosteric catalyst system, assembled via the weak-link approach, is presented. The catalyst contains two structural Rh(I) centers in thioether- and phosphine-rich hemilabile pockets, and two functional Cr(III) centers bound within salen-based moieties. The catalytic properties of the supramolecular catalyst are compared to those of a Cr(III)-salen monomeric analogue in the context of the asymmetric ring opening of cyclohexene oxide by TMSN3. Allosteric control is afforded via reactions that occur at distal sites which open the macrocyclic cavity and facilitate the catalytic reaction. Kinetic data show a significant rate increase upon opening of the catalyst's flexible macrocyclic cavity and enhanced selectivity and reactivity with respect to the monomeric Cr(III)-salen analogue. The work presented represents a new approach to the construction of abiotic allosteric catalysts.