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Abstract The strongest genetic risk factor for Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (ApoE ε4). A high fat diet also adds to the risk of dementia and AD. In addition, there are sex differences as women carriers have a higher risk of an earlier onset and rapid decline in memory than men. The present study looked at the effect of the genetic risk of ApoE ε4 together with a high fat/high sucrose diet (HFD/HSD) on brain function in male and female rats using magnetic resonance imaging. We hypothesized female carriers would present with deficits in cognitive behavior together with changes in functional connectivity as compared to male carriers. Four-month-old wildtype and human ApoE ε4 knock-in (TGRA8960), male and female Sprague Dawley rats were put on a HFD/HSD for four months. Afterwards they were imaged for changes in function using resting state BOLD functional connectivity. Images were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on 173 different brain areas. Resting state functional connectivity showed male wildtype had greater connectivity between areas involved in feeding and metabolism while there were no differences between female and male carriers and wildtype females. The data were unexpected. The genetic risk was overshadowed by the diet. Male wildtype rats were most sensitive to the HFD/HSD presenting with a deficit in cognitive performance with enhanced functional connectivity in neural circuitry associated with food consumption and metabolism.

Abstract Background Cardiogenic shock (CS) is associated with high in‐hospital mortality. Objective assessment of its severity and prognosis is paramount for timely therapeutic interventions. This study aimed to evaluate the efficacy of the shock index (SI) and its variants as prognostic indicators for in‐hospital mortality. Methods A retrospective study involving 1282 CS patients were evaluated. Baseline patient characteristics, clinical trajectory, hospital outcomes, and shock indices were collected and analysed. Receiver operating characteristic (ROC) curves were employed to determine the predictive accuracy of shock indices in predicting in‐hospital mortality. Results Of those evaluated, 866 (67.6%) survived until discharge. Non‐survivors were older (66.0 ± 13.7 vs. 57.4 ± 16.2, P

Background Neoantigens are promising immunogens for cancer vaccines and are often delivered as adjuvanted peptide vaccines. Adenoviral (Ad) vectors have been shown to induce strong CD8+ T cell responses as vaccines against SARS-CoV-2, Ebola, and Zika, but their utility as neoantigen delivery vectors remains largely unexplored. In this study, we examine how an Ad-vectored neoantigen vaccine would impact tumor immunity compared with a peptide neoantigen vaccine.Methods We generated Ad serotype 26 (Ad26) vaccine candidates encoding B16-F10-ovalbumin (OVA) and MC38-specific neoantigens. Ad26 vaccines were compared with adjuvanted peptide delivery as prophylactic vaccines in B16-F10-OVA and MC38 challenge models. Immune responses induced by the best Ad26 vaccine (Ad26.VP22.7Epi) were compared with peptide vaccination systemically and within the tumor. Following vaccination with Ad26.VP22.7Epi, peptide, or sham, tumor-infiltrating CD45+ cells were analyzed using single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) to identify vaccine-induced differences in the tumor microenvironment.Results Single-shot Ad26 vaccines induced greater neoantigen-specific interferon-γ CD8+ T cell immune responses than two-shot adjuvanted peptide vaccines in mice, and Ad26.VP22.7Epi also provided superior protective efficacy compared with the peptide vaccine following tumor challenge. Ad26.VP22.7Epi induced a robust immunodominant CD8+ T cell response against the Adpgk neoantigen, while the peptide vaccine-induced lower responses against both Adpgk and Reps1 neoantigens. scRNA-seq analysis of CD45+ tumor-infiltrating cells demonstrated that both Ad26.VP22.7Epi and peptide vaccine-induced similar numbers of infiltrating CD8+ T cells. However, Ad26.VP22.7Epi induced CD8+ T cells showed more upregulation of T cell maturation, activation, and Th1 pathways compared with peptide vaccine induced CD8+ T cells, suggesting improved functional T cell quality. TCR-seq of these tumor-infiltrating lymphocytes also demonstrated that Ad26.VP22.7Epi generated larger T cell hyperexpanded clones compared with the peptide vaccine.Conclusions These results suggest that the Ad26.VP22.7Epi vaccine led to improved tumor control compared with the peptide vaccine due to increased T cell hyperexpansion and functional activation. Our data suggest that future cancer vaccine development strategies should focus on inducing functional hyperexpanded CD8+ T cell responses and not only maximizing tumor infiltrating CD8+ T cell numbers.

Abstract Dengue is the most prevalent mosquito-borne viral disease in humans, and cases are continuing to rise globally. In particular, islands in the Caribbean have experienced more frequent outbreaks, and all four dengue virus (DENV) serotypes have been reported in the region, leading to hyperendemicity and increased rates of severe disease. However, there is significant variability regarding virus surveillance and reporting between islands, making it difficult to obtain an accurate understanding of the epidemiological patterns in the Caribbean. To investigate this, we used travel surveillance and genomic epidemiology to reconstruct outbreak dynamics, DENV serotype turnover, and patterns of spread within the region from 2009-2022. We uncovered two recent DENV-3 introductions from Asia, one of which resulted in a large outbreak in Cuba, which was previously under-reported. We also show that while outbreaks can be synchronized between islands, they are often caused by different serotypes. Our study highlights the importance of surveillance of infected travelers to provide a snapshot of local introductions and transmission in areas with limited local surveillance and suggests that the recent DENV-3 introductions may pose a major public health threat in the region.

The common bean (Phaseolus vulgaris L.) is one of the oldest food crops in the world. In this study, the ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-MS/MS) technique was used to characterize the polar lipid composition and polyphenolic fraction of five bean varieties commonly consumed in Italy: Cannellino (PVCA), Controne (PVCO), Borlotti (PVBO), Stregoni (PVST), and Vellutina (PVVE). Lipid content represents a minor fraction of the whole metabolome in dry beans, and little is known about their polar lipids, which could be potentially bioactive components. Thirty-three compounds were detected through UHPLC-MS/MS, including oxylipins, phospholipids, N-acyl glycerolipids, and several fatty acids. The dichloromethane extracts were subjected to principal component analysis (PCA), with the results showing greater differentiation for the Borlotti variety. Moreover, 27 components belonging to different polyphenol classes, such as phenolic acids, flavonoids, catechins, anthocyanins and their glycosides, and some saponins, were identified in the hydroalcoholic seed extracts. In addition, the mineral content of the beans was determined. Considering the high number of compounds in the five apolar seed extracts, all samples were examined to determine their in vitro inhibitory activity against the enzyme cyclooxygenase-2 (COX-2), which is inducible in inflammatory cells and mediates inflammatory responses. Only PVCO showed the best inhibition of the COX-2 enzyme with an IC50 = 31.15 ± 2.16 µg/mL. In light of these results, the potential anti-inflammatory properties of PVCO were evaluated in the LPS-stimulated murine macrophage cell line J774A.1. Herein, we demonstrate, for the first time, that PVCO at 30 µg/mL can significantly reduce the release of TNF-α, with a less significant anti-inflammatory effect being observed in terms of IL-6 release.

A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays. Compounds 2, 5, and 6 showed high affinity for BRD4, with IC50 values of 0.60 ± 0.25 µM, 3.46 ± 1.22 µM, and 4.66 ± 0.52 µM, respectively. Additionally, these compounds were tested against two other bromodomains, BRD3 and BRD9, and two of them showed high selectivity for BRD4. The reported 3D structure-based pharmacophore model proves to be a straightforward and useful tool for selecting novel BRD4 ligands.

Laurus nobilis L. is commonly used in folk medicine in the form of infusion or decoction to treat gastrointestinal diseases and flatulence as a carminative, antiseptic, and anti-inflammatory agent. In this study, the essential oil (EO) composition of wild-grown L. nobilis L. leaves collected from seven different altitudinal locations in the Molise region and adjacent regions (Abruzzo and Campania) was investigated. EOs from the leaves were obtained by hydrodistillation and analyzed by GC-FID and GC/MS, and 78 compounds were identified. The major oil components were 1,8-cineol (43.52–31.31%), methyl-eugenol (14.96–4.07%), α-terpinyl acetate (13.00–8.51%), linalool (11.72–1.08%), sabinene (10.57–4.85%), α-pinene (7.41–3.61%), eugenol (4.12–1.97%), and terpinen-4-ol (2.33–1.25%). Chemometric techniques have been applied to compare the chemical composition. To shed light on the nutraceutical properties of the main hydrophobic secondary metabolites (≥1.0%) of laurel EOs, we assessed the in vitro antioxidant activities based on 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging activity and the reducing antioxidant power by using a ferric reducing power (FRAP) assay. Furthermore, we highlighted the anti-inflammatory effects of seven EOs able to interfere with the enzyme soluble epoxide hydrolase (sEH), a key enzyme in the arachidonic acid cascade, in concentrations ranging from 16.5 ± 4.3 to 8062.3 ± 580.9 mg/mL. Thanks to in silico studies, we investigated and rationalized the observed anti-inflammatory properties, ascribing the inhibitory activity toward the disclosed target to the most abundant volatile phytochemicals (≥1.0%) of seven EOs.

This study set out to assess the microbiological quality of shellfish collected over a six-year period of time in the Campania Region Sea. A total of 1459 samples were examined in order to determine whether Escherichia coli was present. To investigate potential correlations between the E. coli counts and environmental parameters (salinity, pH, dissolved oxygen, seawater temperature, turbidity, rainfall) and pollution variables (density and distance of heavy and light discharges), data were gathered. With only roughly 19% of the samples not meeting European and Italian criteria (E. coli counts more than 230 most likely number MPN per 100 g of pulp and intravalvar liquid), the results showed that the microbiological quality of the shellfish was good.A correlation between microbial contamination, season, rainfall, and dissolved oxygen was found using statistical analysis. However, the discharge density along the coast per spatial unit (a 200 × 200 MT cell), which was determined using the ''quartic'' Kernel function, showed found to be the primary factor determining the E. coli concentration in the shellfish.An increase in rain millimeters was found to be associated with a higher risk of heightened E. coli contamination, according to a model that was fitted to assess the probability of detecting a higher E. coli count in connection to environmental parameters. This outcome could be explained by the discharge density near the coast as well as the increased availability of coliforms, particularly E. coli, and nutrients during periods of heavier rainfall.

The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure–activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials.

Abstract Background A significant fraction of the human proteome is still inaccessible to in vitro studies since the recombinant production of several proteins failed in conventional cell factories. Eukaryotic protein kinases are difficult-to-express in heterologous hosts due to folding issues both related to their catalytic and regulatory domains. Human CDKL5 belongs to this category. It is a serine/threonine protein kinase whose mutations are involved in CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental pathology still lacking a therapeutic intervention. The lack of successful CDKL5 manufacture hampered the exploitation of the otherwise highly promising enzyme replacement therapy. As almost two-thirds of the enzyme sequence is predicted to be intrinsically disordered, the recombinant product is either subjected to a massive proteolytic attack by host-encoded proteases or tends to form aggregates. Therefore, the use of an unconventional expression system can constitute a valid alternative to solve these issues. Results Using a multiparametric approach we managed to optimize the transcription of the CDKL5 gene and the synthesis of the recombinant protein in the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125 applying a bicistronic expression strategy, whose generalization for recombinant expression in the cold has been here confirmed with the use of a fluorescent reporter. The recombinant protein largely accumulated as a full-length product in the soluble cell lysate. We also demonstrated for the first time that full-length CDKL5 produced in Antarctic bacteria is catalytically active by using two independent assays, making feasible its recovery in native conditions from bacterial lysates as an active product, a result unmet in other bacteria so far. Finally, the setup of an in cellulo kinase assay allowed us to measure the impact of several CDD missense mutations on the kinase activity, providing new information towards a better understanding of CDD pathophysiology. Conclusions Collectively, our data indicate that P. haloplanktis TAC125 can be a valuable platform for both the preparation of soluble active human CDKL5 and the study of structural–functional relationships in wild type and mutant CDKL5 forms. Furthermore, this paper further confirms the more general potentialities of exploitation of Antarctic bacteria to produce “intractable” proteins, especially those containing large intrinsically disordered regions.

Technological advancements in biology and microscopy have empowered a transition from bioimaging as an observational method to a quantitative one. However, as biologists are adopting quantitative bioimaging and these experiments become more complex, researchers need additional expertise to carry out this work in a rigorous and reproducible manner. This Essay provides a navigational guide for experimental biologists to aid understanding of quantitative bioimaging from sample preparation through to image acquisition, image analysis, and data interpretation. We discuss the interconnectedness of these steps, and for each, we provide general recommendations, key questions to consider, and links to high-quality open-access resources for further learning. This synthesis of information will empower biologists to plan and execute rigorous quantitative bioimaging experiments efficiently.

Bradley A Colarusso,1 Shannon M Bligdon,2 Allen Y Ganjei,3 Alan Kwok,4 Daniel Brocks,4 Zhonghui K Luo1 1Massachusetts Eye and Ear, Boston, MA, USA; 2Ajax Eye Care, Ajax, ON, Canada; 3Drexel University College of Medicine, Philadelphia, PA, USA; 4BostonSight, Needham, MA, USACorrespondence: Zhonghui K Luo, Massachusetts Eye and Ear, 800 Huntington Avenue, Boston, MA, 02115, USA, Tel +1-617-936-6092, Fax +1-617-936-6186, Email Zhonghui_luo@meei.harvard.eduPurpose: To understand the degree and explore the possible causes of ocular graft-versus-host disease (oGVHD) underdiagnosis in patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).Patients and Methods: A 15-question survey was emailed to 6032 subscribers to the Blood and Marrow Transplant Information Network. A total of 371 respondents confirmed the history of allo-HSCT, of which 335 were symptomatic. Their self-reported symptoms, onset, treatments tried, degree of symptom control and established diagnoses of systemic chronic graft-versus-host disease (cGVHD) and oGVHD were analyzed.Results: Among the 335 symptomatic survey respondents, 306 reported their ocular symptom onset was after allo-HSCT, with only 170 [55.6% (170/306)] ever receiving a diagnosis of oGVHD; 23 reported worsening pre-existing ocular symptoms after allo-HSCT, with only 5 [21.7% (5/23)] ever receiving a diagnosis of oGVHD; 6 reported stable symptoms before and after allo-HSCT, with 1 ever receiving a diagnosis of oGVHD. Of the 176 respondents carrying the diagnosis of oGVHD, 167 [94.9% (167/176)] also had the diagnosis of cGVHD. Logistic regression analysis showed that the diagnosis of oGVHD was highly correlated with the number of symptoms and treatments one reported. Furthermore, 35% of the respondents with new onset ocular symptoms reported onset within the first 6 months after allo-HSCT (previously reported), as well as 39% of the respondents with worsened existing symptoms.Conclusion: oGVHD underdiagnosis is likely associated with the previous diagnostic criteria, in which cGVHD of another organ system was required. The correct notion that oGVHD commonly causes severe dry eye disease has likely led to its underdiagnosis in patients with fewer number of symptoms and/or who tried fewer treatments.Keywords: oGVHD, cGVHD, dry eye, keratoconjunctivitis sicca, hematopoietic stem cell transplantation

In this work, we report the identification of novel bromodomain‐containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure‐based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit (1) featuring the 1‐ethyl‐1H‐pyrazolo[3,4‐b]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C‐4 and C‐6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives (2–20) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds (5, 11, 12, and 19) stood out in biophysical assays as new valuable BRD9 ligands featuring IC50 values in the low‐micromolar range. Noteworthy, a promising antiproliferative activity was detected in vitro for compound 5 on HeLa and A375 cancer cell line. The successful combination and application of in silico tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target. [ABSTRACT FROM AUTHOR]

Shannon M Bligdon,1 Bradley A Colarusso,2 Allen Y Ganjei,3 Alan Kwok,4 Zhonghui Katie Luo,2 Daniel Brocks4 1Ajax Eye Care, Ajax, ON, Canada; 2Massachusetts Eye and Ear, Boston, MA, USA; 3Drexel University College of Medicine, Philadelphia, PA, USA; 4BostonSight, Needham, MA, USACorrespondence: Alan KwokBostonSight, 464 Hillside Ave, Unit 205, Needham, MA, 02494, USATel +1 781 726 7337Fax +1 781 726 7310Email akwok@bostonsight.orgPurpose: To evaluate the utilization of scleral lenses and prosthetic replacement of the ocular surface ecosystem devices (SL/PDs) in the management of ocular graft-versus-host disease (oGVHD).Patients and Methods: A survey of 15 questions was sent via email to 6032 subjects registered with the Blood and Marrow Transplant Information Network. The survey reviewed transplant history, graft-versus-host disease history, as well as oGVHD symptoms and onset. Additional questions surveyed treatments used for oGVHD, as well as the degree of ocular symptom control and experience with SL/PDs. A total of 306 respondents met the eligibility requirements to be part of the analyzed cohort.Results: The mean number of symptoms reported from the analyzed cohort was 4.79 ± 2.44, median (IQR) of 5.0 (3.0 to 7.0), with the most common symptom being gritty, dry eyes (87%). The mean number of treatments utilized across the analyzed cohort was 3.21 ± 2.55, median (IQR) of 2.5 (1.0 to 5.0), with the most common treatment being artificial tears (86%). Wearing scleral lenses resulted in a mean of 5.42 ± 1.86, median (IQR) of 6.0 (4.0 to 7.0) symptoms improving, with improved dryness/grittiness of the eyes (94%), improved eye pain (92%) and improved quality of life (89%) being the most commonly improved symptoms. Fifty-six percent of those wearing scleral lenses wished the lenses had been recommended sooner. The most common reason patients cited for not wearing scleral lenses was that they had never heard of them (63%).Conclusion: SL/PDs help to control the symptoms of oGVHD. With their use, clinicians are able to improve the quality of life of this patient population. Despite the known benefits, SL/PDs still remain underutilized in oGVHD care. A majority of current SL/PD wearers wish that they had been recommended sooner as a treatment option. SL/PDs should be considered a component of comprehensive oGVHD management.Keywords: GVHD, oGVHD, dry eye, keratoconjunctivitis sicca, QOL, HSCT, allo-HSCT

Here we report the application of a multi-disciplinary protocol for investigating thiazolidin-4-one-based compounds as new promising anti-inflammatory agents interfering with the eicosanoid biosynthesis pathways. The workflow foresaw the generation of a focused virtual library of ∼4.2 ​× ​104 molecules featuring the thiazolidin-4-one core based on the related one-pot synthetical combinatorial route. The built library was initially screened in silico against the microsomal prostaglandin E2 synthase-1 (mPGES-1) enzyme and, afterwards, 23 selected chemical items were synthesized for the subsequent biological screening, applying the one-pot multicomponent synthetic strategy. Preliminary results highlighted the moderate ability of several tested thiazolidin-4-one-based compounds in inhibiting mPGES-1. On the other hand, further computational repurposing investigations were performed on a set of synthesized compounds, highlighting the promising binding of a several items against the soluble epoxide hydrolase (sEH) enzyme, whose inhibition leads to an increase of epoxyeicosatrienoic acids (EETs) that are anti-inflammatory mediators. Three molecules (3, 9 and 21) were able to inhibit sEH featuring IC50 values in the low micromolar range. In order to further profile their anti-inflammatory properties, additional investigations of the three identified hits highlighted their ability to inhibit 5-lipoxygenase (5-LO) and thus to interfere with leukotriene biosynthesis in neutrophils, devoid of activity against cyclooxygenases (COXs) and cytotoxic effects on human monocytes. Our results, obtained by applying a multidisciplinary approach, highlight the thiazolidin-4-one-core as a valuable template for developing novel anti-inflammatory compounds able to synergistically inhibit different targets involved in the arachidonic acid cascade.

The smart city framework, while initially received with enthusiasm, has been critiqued for reproducing urban inequalities rather than reducing marginalisation. This paper demonstrates how application of an equity lens within a smart city framework can advance justice by addressing air quality inequities in a diverse coastal city. We conducted a pilot study in which integrated air quality sensors are deployed for criteria pollutants in two contrasting neighbourhoods, to demonstrate that the smart city framework can be used with an equity lens for baseline data collection and analysis to support communities of colour in advocating on their own behalf. Communities of colour are disproportionately impacted by poor air quality, pollution exposure, and health burdens. Research shows that marginalised communities often lack air quality sensors installed by traditional regulatory measures. Thus, smart city technology using targeted deployment of air quality sensors can aid neighbourhood-level sampling, and data can be leveraged by marginalised communities for policy development to address inequities in pollution exposure and health impacts. In this study, air quality sensors were deployed and integrated with a web-based interactive platform called Community Resiliency Information Systems (CRIS) to compare a white, affluent neighbourhood with a marginalised, predominantly Black neighbourhood in Saint Petersburg, Florida. Data collected indicates significant differences in concentrations of air pollutants in the study neighbourhoods; exposure levels are higher in the poor, minority-dominated neighbourhood. CRIS facilitates two-way communication between residents and policy makers, demonstrating that careful application of technology can produce data to support community advocacy and address environmental inequalities. Key policy highlights: The smart city framework integrated with air quality sensors has the potential to advance justice when applied through an equity lens. This pilot project demonstrates air quality inequities at neighbourhood level comparisons (affluent vs marginalised) in a coastal city – exposure levels are higher in the poor, minority-dominated neighbourhood. The CRIS platform facilitates two-way communication between residents and policy makers, demonstrating that careful application of technology can produce data to support community advocacy and address environmental inequalities. [ABSTRACT FROM AUTHOR]

Background: Cardiogenic shock (CS) is associated with high in‐hospital mortality. Objective assessment of its severity and prognosis is paramount for timely therapeutic interventions. This study aimed to evaluate the efficacy of the shock index (SI) and its variants as prognostic indicators for in‐hospital mortality. Methods: A retrospective study involving 1282 CS patients were evaluated. Baseline patient characteristics, clinical trajectory, hospital outcomes, and shock indices were collected and analysed. Receiver operating characteristic (ROC) curves were employed to determine the predictive accuracy of shock indices in predicting in‐hospital mortality. Results: Of those evaluated, 866 (67.6%) survived until discharge. Non‐survivors were older (66.0 ± 13.7 vs. 57.4 ± 16.2, P < 0.001), had a higher incidence of cardiac risk factors, and were more likely to present with acute coronary syndrome (33.4% vs. 16.1%, P < 0.001) and out‐of‐hospital cardiac arrest (11.3% vs. 5.3%, P < 0.001). All mean shock indices were significantly higher in non‐survivors compared with survivors. ROC curves demonstrated that adjusted shock index (ASI), age‐modified shock index (AMSI), and shock index‐C (SIC) had the highest predictive accuracy for in‐hospital mortality, with AUC values of 0.654, 0.667, and 0.659, respectively. Subgroup analysis revealed that SIC had good predictive ability in patients with STEMI (AUC: 0.714) and ACS (AUC: 0.696) while AMSI and ASI were notably predictive in the OHCA group (AUC: 0.707 and 0.701, respectively). Conclusions: Shock index and its variants, especially ASI, AMSI, and SIC, may be helpful in predicting in‐hospital mortality in CS patients. Their application could guide clinicians in upfront risk stratification. SIC, ASI, and AMSI show potential in predicting in‐hospital mortality in specific CS subsets (STEMI and OHCA). This is the first study to evaluate SI and its variants in CS patients. [ABSTRACT FROM AUTHOR]

Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual Screening (IVS) approach is aimed at the evaluation of one or a small set of molecules against a panel of targets for addressing target identification. In this work, a focused library of benzothiazole‐based compounds was re‐investigated by IVS. Four items, originally synthesized and tested on bromodomain‐containing protein 9 (BRD9) but yielding poor binding, were critically re‐analyzed, disclosing only a partial fit with 3D structure‐based pharmacophore models, which, in the meanwhile, were developed for this target. Afterwards, these compounds were re‐evaluated through IVS on a panel of proteins involved in inflammation and cancer, identifying soluble epoxide hydrolase (sEH) as a putative interacting target. Three items were subsequently confirmed as able to interfere with sEH activity, leading to inhibition percentages spanning from 70 % up to 30 % when tested at 10 μM. Finally, one benzothiazole‐based compound emerged as the most promising inhibitor featuring an IC50 in the low micromolar range (IC50=6.62±0.13 μM). Our data confirm IVS as a predictive tool for accelerating the target identification and repositioning processes. [ABSTRACT FROM AUTHOR]