Is hope good for motivating collective action in the context of climate change? Differentiating hope's emotion- and problem-focused coping functions

Climate change may be the most fundamental collective action problem of all time. To solve it through collective action, collective motivation is required. Yet, given the complexity and scale of the collective problem, it may be difficult for individuals to experience such motivation. Intriguingly, the experience of hope may increase collective motivation and action. We offer an integrative coping perspective on hope and collective action in the context of climate change. It explains how hope stimulates individuals' collective motivation to act against climate change (serving a problem-focused coping function), or fails to do so (serving an emotion-focused coping function). Testing these competing hypotheses, we conducted three studies that experimentally manipulated a core antecedent of hope (i.e., the perceived possibility of change) among US participants (total N = 1020). Across the board, this manipulation increased individuals' hope but not their collective motivation and action. Furthermore, collective motivation predicted collective action intentions across all three studies. Hoping thus seems to serve an emotion-focused coping function and hence may not increase the collective motivation required for collective action in the context of climate change

1-Chromonyl-5-Imidazolylpentadienone Demonstrates Anti-Cancer Action against TNBC and Exhibits Synergism with Paclitaxel

Curcumin has been well studied for its anti-oxidant, anti-inflammatory, and anti-cancer action. Its potential as a therapy is limited due to its low bioavailability and rapid metabolism. To overcome these challenges, investigators are developing curcumin analogs, nanoparticle formulations, and combining curcumin with other compounds or dietary components. In the present study, we used a 1-chromonyl-5-imidazolylpentadienone named KY-20-22 that contains both the pharmacophore of curcumin and 1,4 benzopyrone (chromone) moiety typical for flavonoids, and also included specific moieties to enhance the bioavailability. When we tested the in vitro effect of KY-20-22 in triple-negative breast cancer (TNBC) cell lines, we found that it decreased the cell survival and colony formation of MDA-MB-231 and MDA-MB-468 cells. An increase in mitochondrial reactive oxygen species was also observed in TNBC cells exposed to KY-20-22. Furthermore, KY-20-22 decreased epithelial-mesenchymal formation (EMT) as evidenced by the modulation of the EMT markers E-cadherin and N-cadherin. Based on the fact that KY-20-22 regulates interleukin-6, a cytokine involved in chemotherapy resistance, we combined it with paclitaxel and found that it synergistically induced anti-proliferative action in TNBC cells. The results from this study suggested that 1-chromonyl-5-imidazolylpentadienone KY-20-22 exhibited anti-cancer action in MDA-MB-231 and MDA-MB-468 cells. Future studies are required to evaluate the anti-cancer ability and bioavailability of KY-20-22 in the TNBC animal model

FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca\u3csup\u3e2+\u3c/sup\u3e], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats

Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca2+ release, reverses aging-induced memory impairment and neuronal Ca2+ dysregulation. Here, we tested the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13 months of age (long-term, LT) or 19 months of age (short-term, ST) and tested memory performance in the Morris water maze at 21 months of age. Aged rats treated ST or LT with FKBP1b substantially outperformed age-matched vector controls and performed similarly to each other and young controls (YCs). Transcriptional profiling in the same animals identified 2342 genes with hippocampal expression that was upregulated/downregulated in aged controls (ACs) compared with YCs (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged FKBP1b-treated rats compared with ACs, with FKBP1b restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in YCs. This inverse relationship between the aging and FKBP1b effects suggests that the aging effects arise from FKBP1b deficiency. Functional category analysis revealed that genes downregulated with aging and restored by FKBP1b were associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by FKBP1b associated primarily with glial–neuroinflammatory, ribosomal, and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction and FKBP1b-mediated restoration of neuronal microtubular structure. Therefore, a previously unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by FKBP1b overexpression

Reversal of Aging-Related Neuronal Ca\u3csup\u3e2+\u3c/sup\u3e Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus

Brain Ca(2+) regulatory processes are altered during aging, disrupting neuronal, and cognitive functions. In hippocampal pyramidal neurons, the Ca(2+)-dependent slow afterhyperpolarization (sAHP) exhibits an increase with aging, which correlates with memory impairment. The increased sAHP results from elevated L-type Ca(2+) channel activity and ryanodine receptor (RyR)-mediated Ca(2+) release, but underlying molecular mechanisms are poorly understood. Previously, we found that expression of the gene encoding FK506-binding protein 12.6/1b (FKBP1b), a small immunophilin that stabilizes RyR-mediated Ca(2+) release in cardiomyocytes, declines in hippocampus of aged rats and Alzheimer\u27s disease subjects. Additionally, knockdown/disruption of hippocampal FKBP1b in young rats augments neuronal Ca(2+) responses. Here, we test the hypothesis that declining FKBP1b underlies aging-related hippocampal Ca(2+) dysregulation. Using microinjection of adeno-associated viral vector bearing a transgene encoding FKBP1b into the hippocampus of aged male rats, we assessed the critical prediction that overexpressing FKBP1b should reverse Ca(2+)-mediated manifestations of brain aging. Immunohistochemistry and qRT-PCR confirmed hippocampal FKBP1b overexpression 4-6 weeks after injection. Compared to aged vector controls, aged rats overexpressing FKBP1b showed dramatic enhancement of spatial memory, which correlated with marked reduction of sAHP magnitude. Furthermore, simultaneous electrophysiological recording and Ca(2+) imaging in hippocampal neurons revealed that the sAHP reduction was associated with a decrease in parallel RyR-mediated Ca(2+) transients. Thus, hippocampal FKBP1b overexpression reversed key aspects of Ca(2+) dysregulation and cognitive impairment in aging rats, supporting the novel hypothesis that declining FKBP1b is a molecular mechanism underlying aging-related Ca(2+) dysregulation and unhealthy brain aging and pointing to FKBP1b as a potential therapeutic target. Significance Statement This paper reports critical tests of a novel hypothesis that proposes a molecular mechanism of unhealthy brain aging and possibly, Alzheimer\u27s disease. For more than 30 years, evidence has been accumulating that brain aging is associated with dysregulation of calcium in neurons. Recently, we found that FK506-binding protein 12.6/1b (FKBP1b), a small protein that regulates calcium, declines with aging in the hippocampus, a brain region important for memory. Here we used gene therapy approaches and found that raising FKBP1b reversed calcium dysregulation and memory impairment in aging rats, allowing them to perform a memory task as well as young rats. These studies identify a potential molecular mechanism of brain aging and may also have implications for treatment of Alzheimer\u27s disease

Arabidopsis BRUTUS-LIKE E3 ligases negatively regulate iron uptake by targeting transcription factor FIT for recycling

Organisms need to balance sufficient uptake of iron (Fe) with possible toxicity. In plant roots, a regulon of uptake genes is transcriptionally activated under Fe deficiency, but it is unknown how this response is inactivated when Fe becomes available. Here we describe the function of 2 partially redundant E3 ubiquitin ligases, BRUTUS-LIKE1 (BTSL1) and BTSL2, in Arabidopsis thaliana and provide evidence that they target the transcription factor FIT, a key regulator of Fe uptake, for degradation. The btsl double mutant failed to effectively down-regulate the transcription of genes controlled by FIT, and accumulated toxic levels of Fe in roots and leaves. The C-terminal domains of BTSL1 and BTSL2 exhibited E3 ligase activity, and interacted with FIT but not its dimeric partner bHLH39. The BTSL proteins were able to poly-ubiquitinate FIT in vitro and promote FIT degradation in vivo. Thus, posttranslational control of FIT is critical to prevent excess Fe uptake

Arabidopsis BRUTUS-LIKE E3 ligases negatively regulate iron uptake by targeting transcription factor FIT for recycling

Organisms need to balance sufficient uptake of iron (Fe) with possible toxicity. In plant roots, a regulon of uptake genes is transcriptionally activated under Fe deficiency, but it is unknown how this response is inactivated when Fe becomes available. Here we describe the function of 2 partially redundant E3 ubiquitin ligases, BRUTUS-LIKE1 (BTSL1) and BTSL2, in Arabidopsis thaliana and provide evidence that they target the transcription factor FIT, a key regulator of Fe uptake, for degradation. The btsl double mutant failed to effectively down-regulate the transcription of genes controlled by FIT, and accumulated toxic levels of Fe in roots and leaves. The C-terminal domains of BTSL1 and BTSL2 exhibited E3 ligase activity, and interacted with FIT but not its dimeric partner bHLH39. The BTSL proteins were able to poly-ubiquitinate FIT in vitro and promote FIT degradation in vivo. Thus, posttranslational control of FIT is critical to prevent excess Fe uptake

ALMA Resolves CI Emission from the beta Pictoris Debris Disk

The debris disk around $\beta$~Pictoris is known to contain gas. Previous ALMA observations revealed a CO belt at $\sim$85 au with a distinct clump, interpreted as a location of enhanced gas production. Photodissociation converts CO into C and O within $\sim$50 years. We resolve CI emission at 492 GHz using ALMA and study its spatial distribution. CI shows the same clump as seen for CO. This is surprising, as C is expected to quickly spread in azimuth. We derive a low C mass (between $5\times10^{-4}$ and $3.1\times10^{-3}$ M$_\oplus$), indicating that gas production started only recently (within $\sim$5000 years). No evidence is seen for an atomic accretion disk inwards of the CO belt, perhaps because the gas did not yet have time to spread radially. The fact that C and CO share the same asymmetry argues against a previously proposed scenario where the clump is due to an outward migrating planet trapping planetesimals in an resonance; nor can the observations be explained by an eccentric planetesimal belt secularly forced by a planet. Instead, we suggest that the dust and gas disks should be eccentric. Such a configuration, we further speculate, might be produced by a recent tidal disruption event. Assuming that the disrupted body has had a CO mass fraction of 10%, its total mass would be $\gtrsim$3 $M_\mathrm{Moon}$.Comment: 30 pages, 15 figures, accepted by Ap

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive VH81X from both pool

Associations between Serial Intravitreal Injections and Dry Eye

Purpose To investigate the effects of serial intravitreal injections (IVIs) on the ocular surface and meibomian glands (MGs) in patients treated with anti-vascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD). Design Retrospective, controlled, observational study. Participants Patients with nAMD receiving unilateral IVIs with anti-VEGF agents. The fellow eye was used as control. Methods Tear film and ocular surface examinations were performed on a single occasion at a minimum of 4 weeks after IVI. A pre-IVI asepsis protocol with povidone-iodine (PVP-I) was applied. Main Outcome Measures Upper and lower MG loss, tear meniscus height (TMH), bulbar redness (BR) score, noninvasive tear break-up time (NIBUT), tear film osmolarity (TOsm), Schirmer test, corneal staining, fluorescein tear film break-up time (TBUT), meibomian gland expressibility (ME), and meibum quality. Results Ninety patients with a mean age of 77.5 years (standard deviation [SD], 8.4; range 54–95) were included. The median number of IVIs in treated eyes was 19.5 (range, 2–132). Mean MG loss in the upper eyelid was 19.1% (SD, 11.3) in treated eyes and 25.5% (SD, 14.6) in untreated fellow eyes (P = 0.001). For the lower eyelid, median MG loss was 17.4% (interquartile range [IQR], 9.4–29.9) in treated eyes and 24.5% (IQR, 14.2–35.2) in fellow eyes (P < 0.001). Mean BR was 1.32 (SD, 0.46) in treated eyes versus 1.44 (SD, 0.45) in fellow eyes (P = 0.017). Median TMH was 0.36 mm (IQR, 0.28–0.52) in treated eyes and 0.32 mm (IQR, 0.24–0.49) in fellow eyes (P = 0.02). There were no differences between treated and fellow eyes regarding NIBUT, TOsm, Schirmer test, corneal staining, fluorescein TBUT, ME, or meibum quality. Conclusions Repeated IVIs with anti-VEGF with preoperative PVP-I application was associated with reduced MG loss, increased tear volume, and reduced signs of inflammation compared with fellow nontreated eyes in patients with nAMD. This regimen may thus have a beneficial effect on the ocular surface.publishedVersio

Relationship between DNA methylation and mutational patterns induced by a sequence selective minor groove methylating agent.

Me-lex, a methyl sulfonate ester appended to a neutral N-methylpyrrolecarboxamide-based dipeptide, was synthesized to preferentially generate N3-methyladenine (3-MeA) adducts which are expected to be cytotoxic rather than mutagenic DNA lesions. In the present study, the sequence specificity for DNA alkylation by Me-lex was determined in the p53 cDNA through the conversion of the adducted sites into single strand breaks and sequencing gel analysis. In order to establish the mutagenic and lethal properties of Me-lex lesions, a yeast expression vector harboring the human wild-type p53 cDNA was treated in vitro with Me-lex, and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. The results showed that: 1) more than 99% of the lesions induced by Me-lex are 3-MeA; 2) the co-addition of distamycin quantitatively inhibited methylation at all minor groove sites; 3) Me-lex selectively methylated A's that are in, or immediately adjacent to, the lex equilibrium binding sites; 4) all but 6 of the 33 independent mutations were base pair substitutions, the majority of which (17/33; 52%) were AT-targeted; 5) AT --TA transversions were the predominant mutations observed (13/33; 39%); 6) 13 out of 33 (39%) independent mutations involved a single lex-binding site encompassing positions A600-602 and 9 occurred at position 602 which is a real Me-lex mutation hotspot (n = 9, p10(-6), Poisson's normal distribution). A hypothetical model for the interpretation of mutational events at this site is proposed. The present work is the first report on mutational properties of Me-lex. Our results suggest that 3-MeA is not only a cytotoxic but also a premutagenic lesion which exerts this unexpected property in a strict sequence-dependent manner