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Well-informed individual and collective decision-making is aided by access to high-quality, factual information. What motivates people to share high-quality news, and how can these motives be leveraged to promote news sharing? Based on the theory that self-related and social motives encourage sharing behavior, we designed and tested interventions to increase news sharing. In the interventions, individuals were exposed to actual news stories and were prompted to identify why the content was relevant to themselves (self-relevance) or people they know (social relevance). Across four studies (Nparticipants = 2,559, Nobservations = 18,780), we systematically examined the effectiveness of these interventions, their generalizability across news topics (climate change and health) and cultures (the United States of America and the Netherlands), their translation to more naturalistic contexts, and their underlying neuropsychological mechanisms. In all studies, we observed expected positive correlations among perceived self and social relevance and sharing intentions. In a neuroimaging study, we also observed corresponding increases in activity in self-referential and social cognitive brain regions. Using the content-framing interventions to test causal relationships, we found that the interventions increased sharing intentions and behavior. Furthermore, we observed generalizability across news topics and cultural contexts and translation to an ecologically valid news exposure context. These findings advance theory by adding neural and behavioral evidence that self-related and social motives prompt people to share information, and demonstrate the ability of content-framing interventions to harness these motives to encourage high-quality news sharing.

Persuasive communication in marketing, political, and health domains influences sales, elections, and public health. We present a mega-analysis (a pooled analysis of raw data) of 16 functional MRI datasets (572 participants, 739 messages, and 21,688 experimental trials) assessing the neural correlates of the effectiveness of messages in individual message receivers and at scale (in large groups of message receivers who did not undergo neuroimaging). Existing theories suggest that decision-making is driven by expected rewards and perceived social relevance associated with the expected outcomes of a given choice. Consistent with these theories, we find that (i) brain activity implicated in reward and social processing is associated with message effectiveness in individuals and at scale across diverse domains (e.g. marketing and health campaigns); (ii) exploratory analysis further suggests language, emotion, and sensorimotor processes as pertinent to message effectiveness; and (iii) brain activity provides complementary information on message effectiveness at scale beyond self-reports provided by the same neuroimaging participants. This study offers novel insights into the neurocognitive mechanisms underlying effective messaging, highlights a path toward greater unity and efficiency in persuasion research, and suggests practical intervention targets for message design.

This study provides a comprehensive overview of past and recent developments in the field of Bioremediation. The study also describes the discovery of a new and economical method of making bioremediation products utilizing non-pathogenic organisms that degrade hydrocarbon-based substances. Organisms are encapsulated in wax to form organism-containing microshells that are used for removing oil-based substances such as crude oil whether on land in water. The organism is preferably of the genus Candida that produce lipase. The microshells may contain nutrients that sustain the organisms. The wax is paraffin or beeswax and the microshells may be coated with talc or carbon powder to provide insulation and to prevent one microshell from sticking to another. When used for remediating an oil spill on water the microshells are preferably contained in a buoyant container that acts as a floatation device. The flotation device may contain floatation means such as gas-filled microballoons that facilitate floatation. A Mesocosm study is included in the Project Demonstrating Excellence Appendix which demonstrates operability of the method via a Tier IV Mesocosm Study scenario. Detailed tables are presented in the Appendix in the Project Demonstrating Excellence containing the Tier IV Study as undertaken by the National Technology Applications Corporation (“NETAC”) at the University of Pittsburgh. Three-dimensional color charts comparing relative bioactivity data are included in the Appendix. Copies of four documents are included in the Appendix which demonstrate commercial viability of the invention and associated products.

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease. The SARS-CoV-2 main protease is an important target for the development of COVID-19 therapeutics. Here, the authors combine X-ray crystallography and mass spectrometry and performed a large scale fragment screening campaign, which yielded 96 liganded structures of this essential viral protein that are of interest for further drug development efforts.

Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas ( n =105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFN γ including IDO-1 , WARS (tRNA(trp)), GBP1 , GBP4 , GBP5 , PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas ( P <0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas ( P <0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups ( P <0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

Multiple human diseases ensue from a hereditary or acquired deficiency of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Here we report that a small-molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule–mediated site- and direction-selective restoration of iron transport. They also suggest that small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.

Fatty acid-binding protein 1 (FABP1) is an intracellular protein responsible for the transportation of long chain fatty acids. Aside from its functions in lipid metabolism and cellular differentiation, FABP1 also plays a role in inflammation through its interaction with peroxisome proliferator-activated receptors (PPARs). Previously, we compared expression of colonic epithelium genes in a subset of microsatellite instable (MSI) colorectal carcinomas (medullary carcinomas) to normal colonic mucosa and found that FABP1 expression was markedly decreased in the tumors. Further analysis of RNA expression in the colorectal subtypes and The Cancer Genome Atlas data set found that FABP1 expression is decreased in the CMS1 subset of colorectal carcinomas, which is characterized by microsatellite instability. As MSI colorectal carcinomas are known for their robust immune response, we then aimed to link FABP1 to the immune microenvironment of MSI carcinomas. To confirm the gene expression results, we performed immunohistochemical analysis of a cohort of colorectal carcinomas. FABP1 was preferentially lost in MSI carcinomas (123/133, 93%) compared with microsatellite stable carcinomas (240/562, 43%, P<0.0001). In addition, higher numbers of tumor-infiltrating lymphocytes were present in tumors with loss of FABP1 (P<0.0001). Decreased expression of the fatty acid storage and glucose regulator, PPARγ, was associated with the loss of FABP1 (P<0.0001). Colorectal cancer cell lines treated with interferon γ exhibited decreased expression of FABP1. FABP1 expression was partially recovered with the treatment of the cell lines with rosiglitazone, a PPARγ agonist. This study demonstrated that the loss of FABP1 expression is associated with MSI carcinomas and that interferon γ stimulation plays a role in this process via its interaction with PPARγ.

Background Biofluid proteomics can enhance our understanding of the neurodegenerative mechanisms underlying Alzheimer’s disease and related dementias (ADRDs). Oligodendrocyte myelin glycoprotein (OMG) is a brain-specific protein implicated in myelination, but its potential mechanistic, biomarker, and therapeutic roles in ADRDs requires further elucidation. Methods After detecting an inverse association between its abundance in peripheral circulation and cortical amyloid deposition in two community-based cohorts, the current study characterized OMG’s role in ADRDs with high-throughput proteomics from sixteen independent cohorts. Data included a variety of cross-sectional and longitudinal community-based and clinical cohorts from North America, Europe, and Asia, and incorporated complementary biofluids, biospecimens, and proteomic platforms. Statistical analyses were conducted separately in each cohort. Results We detected lower plasma OMG in individuals with cortical amyloid deposition, compromised brain structure, dementia, and multiple sclerosis, as well as in individuals who developed dementia over 7- to 20-year follow-up periods. OMG’s CSF and brain proteomic signatures reflected broader neuroprotective mechanisms, especially axonal structural integrity, and two-sample Mendelian randomization causally implicated OMG as protective against multiple neurodegenerative diseases. Conclusions Our findings implicate OMG as a mechanistic determinant of neurodegenerative resiliency among older adults, which is reliably captured by its abundance in peripheral circulation

A common challenge in drug design pertains to finding chemical modifications to a ligand that increases its affinity to the target protein. An underutilized advance is the increase in structural biology throughput, which has progressed from an artisanal endeavor to a monthly throughput of hundreds of different ligands against a protein in modern synchrotrons. However, the missing piece is a framework that turns high-throughput crystallography data into predictive models for ligand design. Here, we designed a simple machine learning approach that predicts protein–ligand affinity from experimental structures of diverse ligands against a single protein paired with biochemical measurements. Our key insight is using physics-based energy descriptors to represent protein–ligand complexes and a learning-to-rank approach that infers the relevant differences between binding modes. We ran a high-throughput crystallography campaign against the SARS-CoV-2 main protease (MPro), obtaining parallel measurements of over 200 protein–ligand complexes and their binding activities. This allows us to design one-step library syntheses which improved the potency of two distinct micromolar hits by over 10-fold, arriving at a noncovalent and nonpeptidomimetic inhibitor with 120 nM antiviral efficacy. Crucially, our approach successfully extends ligands to unexplored regions of the binding pocket, executing large and fruitful moves in chemical space with simple chemistry.