Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovery of RNA-targeted small molecules through the merging of experimental and computational technologies

ABSTRACT Introduction The field of RNA-targeted small molecules is rapidly evolving, owing to the advances in experimental and computational technologies. With the identification of several bioactive small molecules that target RNA, including the FDA-approved risdiplam, the biopharmaceutical industry is gaining confidence in the field. This review, based on the literature obtained from PubMed, aims to disseminate information about the various technologies developed for targeting RNA with small molecules and propose areas for improvement to develop drugs more efficiently, particularly those linked to diseases with unmet medical needs. Areas covered The technologies for the identification of RNA targets, screening of chemical libraries against RNA, assessing the bioactivity and target engagement of the hit compounds, structure determination, and hit-to-lead optimization are reviewed. Along with the description of the technologies, their strengths, limitations, and examples of how they can impact drug discovery are provided. Expert opinion Many existing technologies employed for protein targets have been repurposed for use in the discovery of RNA-targeted small molecules. In addition, technologies tailored for RNA targets have been developed. Nevertheless, more improvements are necessary, such as artificial intelligence to dissect important RNA structures and RNA–small-molecule interactions and more powerful chemical probing and structure prediction techniques.
LY3041658/ interleukin-8 complex structure as targets for IL-8 small molecule inhibitors discovery using a combination of in silico methods

ABSTRACT Since interleukin-8 (IL-8/CXCL8) and its receptor, CXCR1 and CXCR2, were known in the early 1990s, biological pathways related to these proteins were proven to have high clinical value in cancer and inﬂammatory/autoimmune conditions treatment. Recently, IL-8 has been identified as biomarker for severe COVID-19 patients and COVID-19 prognosis. Boyles et al. (mAbs 12 (2020), pp. 1831880) have published a high-resolution X-ray crystal structure of the LY3041658 Fab in a complex human CXCL8. They described the ability to bind to IL-8 and the blocking of IL-8/its receptors interaction by the LY3041658 monoclonal antibody. Therefore, the study has been designed to identify potential small molecules inhibiting interleukin-8 by targeting LY3041658/IL-8 complex structure using an in silico approach. A structure‑based pharmacophore and molecular docking models of the protein active site cavity were generated to identify possible candidates, followed by virtual screening with the ZINC database. ADME analysis of hit compounds was also conducted. Molecular dynamics simulations were then performed to survey the behaviour and stability of the ligand-protein complexes. Furthermore, the MM/PBSA technique has been utilized to evaluate the free binding energy. The final data confirmed that one newly obtained compound, ZINC21882765, may serve as the best potential inhibitor for IL-8.
Oxidation of Catechols at the Air–Water Interface by Nitrate Radicals

Abundant substituted catechols are emitted to, and created in, the atmosphere during wildfires and anthropogenic combustion and agro-industrial processes. While ozone (O3) and hydroxyl radicals (HO•) efficiently react in a 1 μs contact time with catechols at the air–water interface, the nighttime reactivity dominated by nitrate radicals (NO3) remains unexplored. Herein, online electrospray ionization mass spectrometry (OESI-MS) is used to explore the reaction of NO3(g) with a series of representative catechols (catechol, pyrogallol, 3-methylcatechol, 4-methylcatechol, and 3-methoxycatechol) on the surface of aqueous microdroplets. The work detects the ultrafast generation of nitrocatechol (aromatic) compounds, which are major constituents of atmospheric brown carbon. Two mechanisms are proposed to produce nitrocatechols, one (equivalent to H atom abstraction) following fast electron transfer from the catechols (QH2) to NO3, forming NO3– and QH2•+ that quickly deprotonates into a semiquinone radical (QH•). The second mechanism proceeds via cyclohexadienyl radical intermediates from NO3 attack to the ring. Experiments in the pH range from 4 to 8 showed that the production of nitrocatechols was favored under the most acidic conditions. Mechanistically, the results explain the interfacial production of chromophoric nitrocatechols that modify the absorption properties of tropospheric particles, making them more susceptible to photooxidation, and alter the Earth’s radiative forcing.
Black hole mass estimation for active galactic nuclei from a new angle

The scaling relations between supermassive black holes and their host galaxy properties are of fundamental importance in the context black hole-host galaxy co-evolution throughout cosmic time. In this work, we use a novel algorithm that identifies smooth trends in complex data sets and apply it to a sample of 2000 type 1 active galactic nuclei (AGNs) spectra. We detect a sequence in emission line shapes and strengths which reveals a correlation between the narrow L([O iii])/L(H β) line ratio and the width of the broad H α. This scaling relation ties the kinematics of the gas clouds in the broad line region to the ionization state of the narrow line region, connecting the properties of gas clouds kiloparsecs away from the black hole to material gravitationally bound to it on sub-parsec scales. This relation can be used to estimate black hole masses from narrow emission lines only. It therefore enables black hole mass estimation for obscured type 2 AGNs and allows us to explore the connection between black holes and host galaxy properties for thousands of objects, well beyond the local Universe. Using this technique, we present the MBH–σ and MBH–M* scaling relations for a sample of about 10 000 type 2 AGNs from Sloan Digital Sky Survey. These relations are remarkably consistent with those observed for type 1 AGNs, suggesting that this new method may perform as reliably as the classical estimate used in non-obscured type 1 AGNs. These findings open a new window for studies of black hole-host galaxy co-evolution throughout cosmic time.
A rapid high throughput bioprinted colorectal cancer spheroid platform for in vitro drug- and radiation-response

We describe the development of a high-throughput bioprinted colorectal cancer (CRC) spheroid platform with high levels of automation, information content, and low cell number requirement. This is achieved via the formulation of a hydrogel bioink with a compressive Young’s modulus that is commensurate with that of colonic tissue (1–3 kPa), which supports exponential growth of spheroids from a wide range of CRC cell lines. The resulting spheroids display tight cell–cell junctions, bioink matrix-cell interactions and necrotic hypoxic cores. By combining high content light microscopy imaging and processing with rapid multiwell plate bioprinting, dose-response profiles are generated from CRC spheroids challenged with oxaliplatin (OX) and fluorouracil (5FU), as well as radiotherapy. Bioprinted CRC spheroids are shown to exhibit high levels of chemoresistance relative to cell monolayers, and OX was found to be significantly less effective against tumour spheroids than in monolayer culture, when compared to 5FU.
University students’ experience of the Beirut port explosion: associations with subjective well-being and subjective symptoms of mental strain

Abstract Background On 4 August 2020, an explosion shook Beirut, killing more than 200 people and leaving thousands injured or homeless. Aims This study examined mental health of university students through a cross-sectional online survey between December 2020 and January 2021. Methods The questionnaire consisted of the WHO-5, sense of coherence (SoC), future anxiety, self-developed subjective symptoms of mental strain (SSMS), and items assessing proximity to explosion, extent of injury and house damage. Gender, study level and social status were used as sociodemographic characteristics. Results Of 1042 participants, 30.8% were at 0–7 km from explosion; 38.1% reported physical injuries; and 12.4% saw their home damaged. Two third (60.3%) reported ≥3 SSMS, and 73.4% reported low well-being. Students with low well-being were more often female and master students (p < 0.001). Females were more often affected by ≥3 SSMS (p < 0.001). Regression analysis with low well-being as dependent variable revealed significant associations with study level (OR: 2.30–2.94), future anxiety (OR: 2.72–4.34) and SoC (OR: 1.81–5.61). For ≥3 SSMS, females (OR: 3.09), moderate/very close distance (OR: 2.13–4.98), injury/death of family member or friend (OR: 2.07–2.06), house damage (OR: 1.72) future anxiety (OR: 1.97–3.11) and SoC (1.79–2.88) were significant predictors. Discussion Preventive mental health strategies that strengthen SoC and outlook on future could protect against SSMS and low well-being following major trauma.
Local Ancestry‐Informed Candidate Pathway Analysis of Warfarin Stable Dose in Latino Populations

Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K‐related genetic pathways for association with warfarin dose requirements in two admixed Latino populations in standard‐principal component adjusted and contemporary‐local ancestry adjusted regression models. A total of five variants from vitamin K‐related genes/pathways were associated with warfarin dose in both cohorts (P < 0.0125) in standard models. Local ancestry‐adjusted analysis unveiled 35 associated variants with absolute effects ranging from β = 9.04 ( ±2.23) to 39.18 ( ±10.89) per ancestral allele in the discovery cohort and β = 6.47 (± 2.02) to 17.82 (± 6.83) in the replication cohort. Importantly, we demonstrate the technical validity of the Tractor model in cohorts with admixed ancestry from three founder populations and bring attention to the technical hurdles obstructing the inclusion of diverse, especially admixed, populations in pharmacogenomic research.
Predictive molecular biomarkers for determining neoadjuvant chemosensitivity in muscle invasive bladder cancer

Introduction: Identifying neoadjuvant chemotherapy (NAC) response in patients with muscle invasive bladder cancer (MIBC) has had limited success based on clinicopathological features and molecular subtyping. Identification of chemotherapy responsive cohorts would facilitate delivery to those most likely to benefit. Objective: Develop a molecular signature that can identify MIBC NAC responders (R) and non-responders (NR) using a cohort of known NAC response phenotypes, and better understand differences in molecular pathways and subtype classifications between NAC R and NR. Materials and Methods: Presented are the messenger RNA (mRNA) and microRNA (miRNA) differential expression profiles from initial transurethral resection of bladder tumor (TURBT) specimens of a discovery cohort of MIBC patients consisting of 7 known NAC R and 11 NR, and a validation cohort consisting of 3 R and 5 NR. Pathological response at time of cystectomy after NAC was used to classify initial TURBT specimens as R (pT0) versus NR (≥pT2). RNA and miRNA from FFPE blocks were sequenced using RNAseq and qPCR, respectively. Results: The discovery cohort had 2309 genes, while the validation cohort had 602 genes and 13 miRNA differentially expressed between R and NR. Gene set enrichment analysis identified mitochondrial gene expression, DNA replication initiation, DNA unwinding in the R discovery cohort and positive regulation of vascular associated smooth muscle cell proliferation in the NR discovery cohort. Canonical correlation (CC) analysis was applied to differentiate R versus NR. 3 CCs (CC13, CC16, and CC17) had an AUC >0.65 in the discovery and validation dataset. Gene ontology enrichment showed CC13 as nucleoside triphosphate metabolic process, CC16 as cell cycle and cellular response to DNA damage, CC17 as DNA packaging complex. All patients were classified using established molecular subtypes: Baylor, UNC, CIT, Lund, MD Anderson, TCGA, and Consensus Class. The MD Anderson p53-like subtype, CIT MC4 subtype and Consensus Class stroma rich subtype had the strongest correlation with a NR phenotype, while no subtype had a strong correlation with the R phenotype. Conclusions: Our results identify molecular signatures that can be used to differentiate MIBC NAC R versus NR, salient molecular pathway differences, and highlight the utility of molecular subtyping in relation to NAC response.
Can the CIB constrain the dark energy

Galaxies are often used as tracers of the large scale structure (LSS) to measure the Integrated Sachs-Wolfe effect (ISW) by cross-correlating the galaxy survey maps with the Cosmic Microwave Background (CMB) map. We use the Cosmic Infrared Background (CIB) as a tracer of the LSS to perform a theoretical CIB-CMB cross-correlation to measure the ISW for different Planck HFI frequencies. We discuss the detectability of this ISW signal using a Signal-to-noise ratio analysis and find that the ISW detected this way can provide us with the highest SNR for a single tracer ranging from 5 to 6.7 (maximum being for 857 GHz) with the CIB and CMB maps extracted over the whole sky. A Fisher matrix analysis showed that this measurement of the ISW can improve the constraints on the cosmological parameters; especially the equation of state of the dark energy $w$ by $\sim 47\%$. Performing a more realistic analysis including the galactic dust residuals in the CIB maps over realistic sky fractions shows that the dust power spectra dominate over the CIB power spectra at $\ell < 100$ and ISW can't be detected with high SNR. We perform the cross-correlation on the existing CIB-CMB maps over $\sim 11\%$ of the sky in the southern hemisphere and find that the ISW is not detected with the existing CIB maps over such small sky fractions.
Effect of tranexamic acid on endothelial von Willebrand factor/ADAMTS-13 response to in vitro shock conditions

Salutary effects of TXA on trauma induced coagulopathy have been described and these effects appear apart from antifibrinolytic actions of TXA. We hypothesisized that TXA would mitigate the effects on shock conditions on endothelial vWF/ADAMTS 13 release and activity. BACKGROUND Traumatic/hemorrhagic shock, sepsis and other inflammatory processes lead to endothelial activation and a loss of the endothelial glycocalyx. von Willebrand factor (vWF) is an acute phase reactant that is released from endothelial cells and megakaryocytes. Stimulated but not basal vWF leads to significant formation of ultralarge multimers (ultralarge vWF [ULvWF]) and risk for thrombotic complications. Ultralarge vWF is cleaved by a disintegrin and metalloproteinase with a thrombospondin type motif 13 (ADAMTS 13); alterations in ULvWF/ADAMTS 13 ratio may contribute to trauma-induced coagulopathy. Salutary effects of tranexamic acid (TXA) on trauma-induced coagulopathy have been described. These effects appear apart from antifibrinolytic actions of TXA and include protection of the endothelial glycocalyx. Ultralarge vWF is in part anchored to the glycocalyx layer of the endothelium. Tranexamic acid protected the endothelial glycocalyx layer from degradation using a microfluidic model of the microcirculation subjected to hypoxia-reoxygenation and catecholamine excess. We hypothesized that TXA administration following shock conditions would impact the vWF-ADAMTS-13 axis by protecting the glycocalyx from degradation. This was studied in a endothelial microfluidic flow study. METHODS Human umbilical vein endothelial cells were established under flow conditions and subjected to biomimetic shock. Tranexamic acid was added after 90 minutes of perfusion. von Willebrand factor antigen and ADAMTS-13 activity were measured. Western blot analysis was performed for vWF characterization from perfusion media. RESULTS Shock conditions increased vWF antigen and decreased ADAMTS 13 activity. Tranexamic acid ameliorated shock induced cleavage in the ADAMTS 13-vWF axis with a reduction of the thrombogenic ULvWF. CONCLUSION These results suggest another mechanism whereby administration of TXA early following traumatic/hemorrhagic shock mitigates microvascular perfusion abnormalities and subsequent organ failure. The resultant effects on platelet adhesion and aggregation require further study.
A Monitoring and Early Intervention Program for At-Risk Students on Advanced Pharmacy Practice Experiences

Objective. To describe a monitoring and early intervention process for students at risk of substandard performance on advanced pharmacy practice experiences (APPEs). Methods. Using a dashboard of key indicators, students with potential deficits in knowledge, skills, or noncognitive attributes were identified as at risk of substandard performance on APPEs and placed on a list of students to be monitored during the APPE year. Employing a traffic light–based approach, at-risk students were initially designated with a monitoring status of red. If no issues were identified, students were de-escalated to yellow status and, subsequently, to green status. Monitored students who had issues or received a substandard evaluation on APPEs had a deficit-specific action plan implemented. Results. For the 2018-2019 and 2019-2020 academic years, 87 of 499 students entering APPEs were monitored. Of those 87 students, 77 (88.5%) completed experiences successfully on the first attempt, but 66 (75.9%) did require extended higher-level (red or yellow) monitoring. Over these two years, 54 (62.1%) of the 87 students deemed at risk did not have a substandard performance on APPEs, with 26 in the 2018-2019 year and 28 in the 2019-2020 year. Conclusion. A student monitoring and early intervention process may be beneficial in assisting at-risk students to successfully complete APPEs.
Training diversity promotes absolute-value-guided choice

Many decision-making studies have demonstrated that humans learn either expected values or relative preferences among choice options, yet little is known about what environmental conditions promote one strategy over the other. Here, we test the novel hypothesis that humans adapt the degree to which they form absolute values to the diversity of the learning environment. Since absolute values generalize better to new sets of options, we predicted that the more options a person learns about the more likely they would be to form absolute values. To test this, we designed a multi-day learning experiment comprising twenty learning sessions in which subjects chose among pairs of images each associated with a different probability of reward. We assessed the degree to which subjects formed absolute values and relative preferences by asking them to choose between images they learned about in separate sessions. We found that concurrently learning about more images within a session enhanced absolute-value, and suppressed relative-preference, learning. Conversely, cumulatively pitting each image against a larger number of other images across multiple sessions did not impact the form of learning. These results show that the way humans encode preferences is adapted to the diversity of experiences offered by the immediate learning context.
Extreme Galactic-Winds and Starburst in IR Mergers and IR QSOs

We report -as a part of a long-term study of mergers and IR QSOs- detailed spectroscopic evidences for outflow (OF) and/or Wolf Rayet features in: (i) low velocity OF in the ongoing mergers NGC 4038/39 and IRAS 23128-5919; (ii) extreme velocity OF (EVOF) in the QSOs IRAS 01003-2238 and IRAS 13218+0552; (iii) OF and EVOF in a complete sample of ultra-luminous IR galaxies/QSOs ("The IRAS 1 Jy MKO-KPNO Survey", of 118 objects). We found EVOF in IRAS 11119+3257, 14394+5332, 15130+1958 and 15462-0450. The OF components detected in these objects were mainly associated to starburst processes: i.e., to galactic-winds generated in multiple type II SN explosions and massive stars. The EVOF were detected in objects with strong starburst plus obscured IR QSOs; which suggest that interaction of both processes could generate EVOF. In addition, we analyze the presence of Wolf Rayet features in the large sample of Bright PG-QSOs (Boroson and Green 1992), and nearby mergers and galactic-wind galaxies. We found clear WR features in the Fe II QSOs (type I): PG 1244+026, 1444+407, 1448+273, 1535+547; and in the IR merger Arp 220. HST archive images of IR+BAL QSOs show in practically all of these objects "arc or shell" features probably associated to galactic-winds (i.e., to multiple type II SN explosions) and/or merger processes. Finally, we discuss the presence of extreme starburst and galactic wind as a possible evolutive link between IR merger and IR QSOs; where the relation between mergers and extreme starburst (with powerful galactic-winds) plays in important role, in the evolution of galaxies.
Online Health Information Seeking Among Patients With Chronic Conditions: Integrating the Health Belief Model and Social Support Theory

Background Chronic diseases are the leading causes of death and disability. With the growing patient population and climbing health care expenditures, researchers and policy makers are seeking new approaches to improve the accessibility of health information on chronic diseases while lowering costs. Online health information sources can play a substantial role in effective patient education and health communication. However, some contradictory evidence suggests that patients with chronic conditions may not necessarily seek online health information. Objective This study aims to integrate 2 theories (ie, the health belief model and social support theory) and a critical health literacy perspective to understand online health information seeking (OHIS) among patients with chronic conditions. Methods We used the survey method to collect data from online chronic disease communities and groups on social media platforms. Eligible participants were consumers with at least 1 chronic condition and those who have experience with OHIS. A total of 390 valid questionnaires were collected. The partial least squares approach to structural equation modeling was employed to analyze the data. Results The results suggested that perceived risk (t=3.989, P<.001) and perceived benefits (t=3.632, P<.001) significantly affected patients’ OHIS. Perceived susceptibility (t=7.743, P<.001) and perceived severity (t=8.852, P<.001) were found to influence the perceived risk of chronic diseases significantly. Informational support (t=5.761, P<.001) and emotional support (t=5.748, P<.001) also impacted the perceived benefits of online sources for patients. In addition, moderation analysis showed that critical health literacy significantly moderated the link between perceived risk and OHIS (t=3.097, P=.002) but not the relationship between perceived benefits and OHIS (t=0.288, P=.774). Conclusions This study shows that the health belief model, when combined with social support theory, can predict patients’ OHIS. The perceived susceptibility and severity can effectively explain perceived risk, further predicting patients’ OHIS. Informational support and emotional support can contribute to perceived benefits, thereby positively affecting patients’ OHIS. This study also demonstrated the important negative moderating effects of critical health literacy on the association between perceived risk and OHIS.