Miracle-dz/UniFAR-FTUs huggingface dataset:
The Tumour Suppressor Fhit Protein Activates C-Raf Ubiquitination and Degradation in Human Melanoma Cells by Interacting with Hsp90

Fhit protein expression is reduced in the majority of human tumors; moreover, its restoration both triggers apoptosis of cancer cells and suppresses tumor formation in a large number of preclinical models of cancers. In the following study, we observed that Fhit expression is significantly reduced in human melanoma cells, and their in vivo growth is blocked by a recombinant adenovirus carrying the FHIT gene. Importantly, we found here that Fhit physically interacts with Hsp90. Since Hsp90 is a chaperone with a crucial function in the conformational maturation and stabilization of C-Raf, we also investigated whether Fhit could interfere with the Hsp90/C-Raf protein complex in melanoma. Interestingly, the administration of the Hsp90 inhibitor 17-AAG, in combination with Fhit protein overexpression in melanoma cells, reacts synergistically to increase C-Raf ubiquitination and degradation. These data reveal Hsp90 as a novel interactor of Fhit and suggest that FHIT activity restoration could represent a helpful strategy for suppressing the oncogenic C-Raf pathway in the therapy of human melanoma.
Motivations and Barriers to Participation in a Randomized Trial on Melanoma Genomic Risk: A Mixed-Methods Analysis

The evolution of polygenic scores for use in for disease prevention and control compels the development of guidelines to optimize their effectiveness and promote equitable use. Understanding the motivations and barriers to participation in genomics research can assist in drafting these standards. We investigated these in a community-based randomized controlled trial that examined the health behavioral impact of receiving personalized melanoma genomic risk information. We examined participant responses in a baseline questionnaire and conducted interviews post-trial participation. Motivations differed in two ways: (1) by gender, with those identifying as women placing greater importance on learning about their personal risk or familial risk, and how to reduce risk; and (2) by age in relation to learning about personal risk, and fear of developing melanoma. A barrier to participation was distrust in the handling of genomic data. Our findings provide new insights into the motivations for participating in genomics research and highlight the need to better target population subgroups including younger men, which will aid in tailoring recruitment for future genomic studies.
Force-dependent remodeling of cytoplasmic ZO-1 condensates contributes to robust cell-cell adhesion

Although the physiological importance of biomolecular condensates is widely recognized, how it is controlled in time and space during development is largely unknown. Here we show that a tight junction protein ZO-1 forms cytoplasmic condensates in the trophectoderm (TE) of the mouse embryo before E4.0. These disappear via dissolution, and ZO-1 accumulates at the cell junction as the blastocyst cavity grows and internal pressure on TE cells increases. In contrast, this dissolution was less evident in TE cells attached to the inner cell mass, as they receive weaker tensile forces. Furthermore, analyses using MDCK cells have demonstrated that the ZO-1 condensates are generated and maintained by liquid-liquid phase separation. Our study also highlights that the dynamics of these condensates depends on the physical environment via an interaction between ZO-1 and F-actin. We propose that the force-dependent regulation of ZO-1 condensation contributes to establishing robust cell-cell adhesion during early development.
Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease Inhibitors

We report the results of the COVID Moonshot, a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a non-covalent, non-peptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.
Expectations and Bank Lending

We study the properties and the impact of lenders’ expectations using a new dataset on banks’ economic projections about all MSAs in the US, reported annually for normal and downside scenarios. By combining these projections with comprehensive information on bank lending, we document several ﬁndings. First, banks’ expectations about economic conditions under normal and downside scenarios have different determinants (e.g., opposite loading on MSA outcomes in the Great Reces-sion). Second, expectations at a given point in time display substantial dispersion across banks for the same MSA and across MSAs for the same bank. Third, ﬁrms have lower loan growth when their banks are more pessimistic about the downside scenario. The results hold with ﬁrm-year ﬁxed effects: for the same ﬁrm in a given year, there is less lending from more pessimistic banks. Lenders’ pessimism is also associated with higher interest rates, which further indicate reductions in credit supply. Moreover, there are negative real effects on ﬁrm-level total borrowing and capital expenditures, especially among ﬁrms with limited sources of ﬁnancing, and on MSA-level output growth. Finally, banks that were more pessimistic about the downside pre-COVID have fewer past due loans after the pandemic (stronger balance sheets), but continue to lend less due to persistent pessimism.
Relativistic iron lines in accretion disks: the contribution of higher order images in the strong deflection limit

The shapes of relativistic iron lines observed in spectra of candidate black holes carry the signatures of the strong gravitational fields in which the accretion disks lie. These lines result from the sum of the contributions of all images of the disk created by gravitational lensing, with the direct and first-order images largely dominating the overall shapes. Higher order images created by photons tightly winding around the black holes are often neglected in the modeling of these lines, since they require a substantially higher computational effort. With the help of the strong deflection limit, we present the most accurate semi-analytical calculation of these higher order contributions to the iron lines for Schwarzschild black holes. We show that two regimes exist depending on the inclination of the disk with respect to the line of sight. Many useful analytical formulae can be also derived in this framework.
Automated multimodal fluorescence microscopy for hyperplex spatial-proteomics: Coupling microfluidic-based immunofluorescence to high resolution, high sensitivity, three-dimensional analysis of histological slides

In situ multiplexing analysis and in situ transcriptomics are now providing revolutionary tools to achieve the comprehension of the molecular basis of cancer and to progress towards personalized medicine to fight the disease. The complexity of these tasks requires a continuous interplay among different technologies during all the phases of the experimental procedures. New tools are thus needed and their characterization in terms of performances and limits is mandatory to reach the best resolution and sensitivity. We propose here a new experimental pipeline to obtain an optimized costs-to-benefits ratio thanks to the alternate employment of automated and manual procedures during all the phases of a multiplexing experiment from sample preparation to image collection and analysis. A comparison between ultra-fast and automated immunofluorescence staining and standard staining protocols has been carried out to compare the performances in terms of antigen saturation, background, signal-to-noise ratio and total duration. We then developed specific computational tools to collect data by automated analysis-driven fluorescence microscopy. Computer assisted selection of targeted areas with variable magnification and resolution allows employing confocal microscopy for a 3D high resolution analysis. Spatial resolution and sensitivity were thus maximized in a framework where the amount of stored data and the total requested time for the procedure were optimized and reduced with respect to a standard experimental approach.
Philanthropic sales in live-streaming shopping: The impact of online interaction on consumer impulse buying

As philanthropic sales via live-streaming shopping have played an important role in alleviating the huge backlog of agricultural products during the outbreak of the COVID-19 pandemic, this paper aims to study how online interaction in philanthropic marketing exerts influence on consumer impulse buying behaviors. We empirically explore four major dimensions of online interactions in philanthropic live-streaming sales, i.e., the live streamers’ image, the herd effect of consumers, the responsiveness of sellers, and the mutual trust between consumers. The results reveal that the herd effect of consumers and the responsiveness of sellers could promote consumers’ empathy ability toward the growers of the products sold lively, whereas the live streamers’ image and the mutual trust between consumers have little effect on empathy promotions. Meanwhile, both the consumers’ empathy ability and the live streamers’ image positively affect consumers’ impulse buying behavior, which suggests a partial moderating role of consumers’ empathy ability. Lastly, by taking both social and business perspectives, we provide managerial implications for improving the effectiveness and efficiency of philanthropic live-streaming sales to alleviate social and economic pressure in emergencies.
Grazing preference and isotopic contributions of kelp to Zostera marina mesograzers

In seagrass food webs, small invertebrate mesograzers often exert top-down control on algal epiphytes growing on seagrass blades, which in turn releases the seagrass from competition for light and nutrients. Yet, nearshore habitat boundaries are permeable, and allochthonous subsidies can provide alternative food sources to in-situ production in seagrass meadows, which may in turn alter mesograzer-epiphyte interactions. We examined the contribution of allochthonous kelp (Nereocystis luetkeana), autochthonous epiphytic macroalgal (Smithora naiadum), Ulva lactuca, and seagrass production to mesograzer diets in a subtidal Zostera marina (eelgrass) meadow. In both choice feeding experiments and isotopic analysis, mesograzer diets revealed a preference for allochthonous N. luetkeana over Z. marina, S. naiadum, and U. lactuca. Notably, Idotea resecata showed an ~20x greater consumption rate for N. luetkeana in feeding experiments over other macrophytes. In the meadow, we found a positive relationship between epiphytic S. naiadum and gammarid amphipod biomass suggesting weak top-down control on the S. naiadum biomass. Epiphyte biomass may be driven by bottom-up factors such as environmental conditions, or the availability and preference of allochthonous kelp, though further work is needed to disentangle these interactions. Additionally, we found that gammarid and caprellid amphipod biomass were positively influenced by adjacency to kelp at seagrass meadow edges. Our findings suggest that N. luetkeana kelp subsidies are important to the diets of mesograzers in Z. marina meadows. Spatial planning and management of marine areas should consider trophic linkages between kelp and eelgrass habitats as a critical seascape feature if the goal is to conserve nearshore food web structure and function.
False memory and COVID-19: How people fall for fake news about COVID-19 in digital contexts

People are often exposed to fake news. Such an exposure to misleading information might lead to false memory creation. We examined whether people can form false memories for COVID-19-related fake news. Furthermore, we investigated which individual factors might predict false memory formation for fake news. In two experiments, we provided participants with two pieces of COVID-19-related fake news along with a non-probative photograph. In Experiment 1, 41% (n = 66/161) of our sample reported at least one false memory for COVID-19-related fake news. In Experiment 2, even a higher percentage emerged (54.9%; n = 185/337). Moreover, in Experiment 2, participants with conspiracy beliefs were more likely to report false memories for fake news than those without such beliefs, irrespective of the conspiratorial nature of the materials. Finally, while well-being was found to be positively associated with both true and false memories (Experiment 1), only analytical thinking was negatively linked to the vulnerability to form false memories for COVID-19-related fake news (Experiment 2). Overall, our data demonstrated that false memories can occur following exposure to fake news about COVID-19, and that governmental and social media interventions are needed to increase individuals’ discriminability between true and false COVID-19-related news.
Subjective reward processing and catechol-O- methyltransferase Val158Met polymorphism as potential research domain criteria in addiction: A pilot study

The Research Domain Criteria (RDoC) approach seeks to understand mental functioning in continuous valid dimensions ranging from functional to pathological. Reward processing is a transdiagnostic functioning domain of the RDoC. Due to prototypical abnormalities, addictions are especially applicable for the investigation of reward processing. Subjective reward processing is challenging to determine and differs between genotypes of the catechol-O-methyltransferase gene (COMT) Val158Met polymorphism for incomparable daily life experiences. Thus, we implemented the monetary incentive delay (MID) task with comparable reward cues and visual analog scales (VAS) to assess subjective reward processing in male abstinent cannabis-dependent individuals (N = 13) and a control group of nicotine smokers (N = 13). COMT Val158Met genotypes were nominally associated with differences in cigarettes smoked per day and motivation in the MID Task (p = 0.028; p = 0.017). For feedback gain, activation of the right insula was increased in controls, and activation correlated with gain expectancy and satisfaction about gain. Subjective value is not detached from reward parameters, but is modulated from expectancy and reward by the insula. The underlying neural mechanisms are a fundamental target point for treatments, interventions, and cognitive behavioral therapy.
Learning to play a musical instrument in the middle school is associated with superior audiovisual working memory and fluid intelligence: A cross-sectional behavioral study

Music training, in all its forms, is known to have an impact on behavior both in childhood and even in aging. In the delicate life period of transition from childhood to adulthood, music training might have a special role for behavioral and cognitive maturation. Among the several kinds of music training programs implemented in the educational communities, we focused on instrumental training incorporated in the public middle school curriculum in Italy that includes both individual, group and collective (orchestral) lessons several times a week. At three middle schools, we tested 285 preadolescent children (aged 10–14 years) with a test and questionnaire battery including adaptive tests for visuo-spatial working memory skills (with the Jack and Jill test), fluid intelligence (with a matrix reasoning test) and music-related perceptual and memory abilities (with listening tests). Of these children, 163 belonged to a music curriculum within the school and 122 to a standard curriculum. Significant differences between students of the music and standard curricula were found in both perceptual and cognitive domains, even when controlling for pre-existing individual differences in musical sophistication. The music children attending the third and last grade of middle school had better performance and showed the largest advantage compared to the control group on both audiovisual working memory and fluid intelligence. Furthermore, some gender differences were found for several tests and across groups in favor of females. The present results indicate that learning to play a musical instrument as part of the middle school curriculum represents a resource for preadolescent education. Even though the current evidence is not sufficient to establish the causality of the found effects, it can still guide future research evaluation with longitudinal data.
Short-chain L-3-hydroxyacyl-CoA dehydrogenase: A novel vital oncogene or tumor suppressor gene in cancers

The reprogramming of cellular metabolism is frequently linked to tumorigenesis. Glucose, fatty acids, and amino acids are the specific substrates involved in how an organism maintains metabolic equilibrium. The HADH gene codes for the short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADH), a crucial enzyme in fatty acid oxidation that catalyzes the third phase of fatty acid oxidation in mitochondria. Increasing data suggest that HADH is differentially expressed in various types of malignancies and is linked to cancer development and progression. The significance of HADH expression in tumors and its potential mechanisms of action in the onset and progression of certain cancers are summarized in this article. The possible roles of HADH as a target and/or biomarker for the detection and treatment of various malignancies is also described here.
Study protocol—Evoked craving in high-dose benzodiazepine users

Benzodiazepine (BDZ) abuse, especially concerning high doses of BDZs, is an impairing substance use disorder (SUD) that is often difficult to treat. Craving and cue reactivity (CR) are two important phenomena that have a prominent role in maintaining addiction and triggering relapses in BDZ abuse; nevertheless, they have rarely been addressed in scientific literature. The present study aims to fill these gaps by implementing a highly innovative virtual reality (VR) design to assess the impact of substance-related environmental cues on BDZ craving, as well as their influence on patients’ affective states. Therefore, on one hand, this research will contribute to the assessment of VR feasibility in the study of these phenomena, and, on the other, it will help disentangle the role that CR and craving have on mood and attention, which are equally important factors to consider when treating SUDs. We will recruit a healthy control group and a patient group comprising people seeking treatment for BDZ detoxification. The experimental design will consist of the presentation of three VR scenarios, one neutral, one BDZ-related but without BDZ cues, and another with BDZ cues. The craving will be measured through a virtual analog scale (VAS); the Profile of Mood States (POMS) and Alcohol Attention Scale (AAS) questionnaires in a modified version will also be administered. We will additionally control for VR-induced feelings of sickness by administering the Simulator Sickness Questionnaire (SSQ), and the Presence Questionnaire (PQ) will be used to investigate participants’ sense of presence in virtual environments. We expect patients to exhibit higher levels of craving, and that the craving will be higher after exposure to a cue-related virtual environment as compared to a neutral scenario.
Comprehensive analysis of epigenomics and transcriptome data to identify potential target genes associated with obesity

DNA methylation is closely related to the occurrence and development of many diseases, but its role in obesity is still unclear. This study aimed to find the potential differentially methylated genes associated with obesity occurrence and development. By combining methylation and transcriptome analysis, we identified the key genes in adipose tissue affecting the occurrence and development of obesity and revealed the possible molecular mechanisms involved in obesity pathogenesis. We first screened 14 methylation-related differential genes and verified their expression in adipose tissue by quantitative polymerase chain reaction (qPCR). Seven genes with the same expression pattern were identified as key genes, namely, CCRL2, GPT, LGALS12, PC, SLC27A2, SLC4A4, and TTC36. Then, the immune microenvironment of adipose tissue was quantified by CIBERSORT, and we found that the content of M0 macrophages and T follicular helper cells in adipose tissue was significantly increased and decreased, respectively, in the obese group. Furthermore, the relationship between key genes and the immune microenvironment was analyzed. Additionally, the metabolic pathway activity of each sample was calculated based on the ssGSEA algorithm, and the key gene–metabolic network was constructed. Moreover, we performed a CMAP analysis based on the differential genes in adipose tissue to screen out drugs potentially effective in obesity treatment. In conclusion, we identified seven methylation-related key genes closely related to obesity pathogenesis and explored the potential mechanism of their role in obesity. This study provided novel insights into the molecular mechanisms and management of obesity.
Shaping social behavior in an enriched environment

Access to vital needs shapes social orders. In rats, social systems tend to maintain a certain stability, but alterations in the physical environment can change inter-individual relations, which consequently can alter social orders. Principles governing social systems are, however, difficult to study and most analyses have been restricted to dyads of animals over short periods of time, hardly capturing the complexity and temporal dynamics of social interactions. Herein, we studied social interactions in a colony of six rats living in a customized enriched environment (PhenoWorld, PhW), under variable conditions of access/availability to limited resources. Reductions in food accessibility and availability resulted in a marked heterogeneity in sniffing, chasing and fighting/struggling behaviors, and, in the latter condition, an overall increase of these displays. The introduction of the possibility of interaction with a female rat also increased the amount of sniffing and fighting/struggling in a homogeneous manner. Results also showed that individual food retrieval success had no association with fighting/struggling when food pellets are delivered to the animals. However, there was a statistically significant correlation between fighting/struggling and impulsivity as measured by the amount of premature responses in the Variable-to-Signal-Test outside of the PhW providing external validation to our measures. To sum up, through continuous monitoring of a group of rats in the PhW, we demonstrated how variations in access to reinforcers modulate social behavior.