The Pseudo-Natural Product Rhonin Targets RHOGDI.

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment-based design. We describe the de novo combination of different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented "pseudo-natural products" in an efficient complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP-derived chemotypes, and may have novel biological targets. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases.

Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS trial): Rationale and design for a multi-center randomized controlled trial.

BACKGROUND: The cornerstone of the treatment of vasovagal syncope (VVS) is lifestyle modifications; however, some patients incur life-disturbing attacks despite compliance with these treatments which underscores the importance of pharmacological interventions. METHODS: In this open-label multi-center randomized controlled trial, we are going to randomize 1375 patients with VVS who had ≥2 syncopal episodes in the last year into three parallel arms with a 2:2:1 ratio to receive midodrine, fludrocortisone, or no medication. All patients will be recommended to drink 2 to 3 liters of fluids per day, consume 10 grams of NaCl per day, and practice counter-pressure maneuvers. In medication arms, patients will start on 5 mg of midodrine TDS or 0.05 mg of fludrocortisone BD. After one week the dosage will be up-titrated to midodrine 30 mg/day and fludrocortisone 0.2 mg/day. Patient tolerance will be the principal guide to dosage adjustments. We will follow-up the patients on 3, 6, 9, and 12 months after randomization. The primary outcome is the time to first syncopal episode. Secondary outcomes include the recurrence rate of VVS, time interval between first and second episodes, changes in quality of life (QoL), and major and minor adverse drug reactions. QoL will be examined by the 36-Item Short Form Survey questionnaire at enrollment and 12 months after randomization. CONCLUSION: The COMFORTS trial is the first study that aims to make a head-to-head comparison between midodrine and fludrocortisone, against a background of lifestyle modifications for preventing recurrences of VVS and improving QoL in patients with VVS.

Effect of COVID-19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey.

BACKGROUND: There are some data showing that repurposed drugs used for the Coronavirus disease-19 (COVID-19) have potential to increase the risk of QTc prolongation and torsade de pointes (TdP), and these arrhythmic side effects have not been adequately addressed in COVID-19 patients treated with these repurposed medications. METHODS: This is the prospective study of 2403 patients hospitalised at 13 hospitals within the COVID-19 epicentres of the Iran. These patients were treated with chloroquine, hydroxychloroquine, lopinavir/ritonavir, atazanavir/ritonavir, oseltamivir, favipiravir and remdesivir alone or in combination with azithromycin. The primary outcome of the study was incidence of critical QTc prolongation, and secondary outcomes were incidences of TdP and death. RESULTS: Of the 2403 patients, 2365 met inclusion criteria. The primary outcome of QTc ≥ 500 ms and ∆QTc ≥ 60 ms was observed in 11.2% and 17.6% of the patients, respectively. The secondary outcomes of TdP and death were reported in 0.38% and 9.8% of the patients, respectively. The risk of critical QT prolongation increased in the presence of female gender, history of heart failure, treatment with hydroxychloroquine, azithromycin combination therapy, simultaneous furosemide or beta-blocker therapy and acute renal or hepatic dysfunction. However, the risk of TdP was predicted by treatment with lopinavir-ritonavir, simultaneous amiodarone or furosemide administration and hypokalaemia during treatment. CONCLUSION: This cohort showed significant QTc prolongation with all COVID-19 medications studied, however, life-threatening arrhythmia of TdP occurred rarely. Among the repurposed drugs studied, hydroxychloroquine or lopinavir-ritonavir alone or in combination with azithromycin clearly demonstrated to increase the risk of critical QT prolongation and/or TdP.

Structure Based Design of Bicyclic Peptide Inhibitors of RbAp48.

The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein-protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1-derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar KD value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono- and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure-based design is a suitable strategy for inhibitor development targeting PPIs.

TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics.

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or "hot spot", regions of protein-protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide "hexT", encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.

The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling.

Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram/ml serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram/ml range. Calculations based on intermolecular affinities have suggested that systemic IL-6 is immediately trapped in IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, indicating that sIL-6R and sgp130 constitute a buffer system that increases the serum half-life of IL-6 or restricts systemic IL-6 signaling. However, this scenario has not been experimentally validated. Here, we quantified IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes over a wide concentration range. The amounts of IL-6 used in this study reflect concentrations found during active inflammatory events. Our results indicated that most IL-6 is free and not complexed with sIL-6R or sgp130, indicating that the level of endogenous sgp130 in the bloodstream is not sufficient to block IL-6 trans-signaling via sIL-6R. Importantly, addition of the single-domain antibody VHH6, which specifically stabilizes IL-6·sIL-6R complexes but did not bind to IL-6 or sIL-6R alone, drove free IL-6 into IL-6·sIL-6R complexes and boosted trans-signaling but not classic signaling, demonstrating that endogenous sIL-6R has at least the potential to form complexes with IL-6. Our findings indicate that even though high concentrations of sIL-6R and sgp130 are present in human serum, the relative ratio of free IL-6 to IL-6·sIL-6R allows for simultaneous classic and trans-signaling.

A Scaffold-Diversity Synthesis of Biologically Intriguing Cyclic Sulfonamides.

A "branching-folding" synthetic strategy that affords a range of diverse cyclic benzo-sulfonamide scaffolds is presented. Whereas different annulation reactions on common ketimine substrates build the branching phase of the scaffold synthesis, a common hydrogenative ring-expansion method, facilitated by an increase of the ring-strain during the branching phase, led to sulfonamides bearing medium-sized rings in a folding pathway. Cell painting assay was successfully employed to identify tubulin targeting sulfonamides as novel mitotic inhibitors.

Structural snapshots of RAF kinase interactions.

RAF (rapidly accelerated fibrosarcoma) Ser/Thr kinases (ARAF, BRAF, and CRAF) link the RAS (rat sarcoma) protein family with the MAPK (mitogen-activated protein kinase) pathway and control cell growth, differentiation, development, aging, and tumorigenesis. Their activity is specifically modulated by protein-protein interactions, post-translational modifications, and conformational changes in specific spatiotemporal patterns via various upstream regulators, including the kinases, phosphatase, GTPases, and scaffold and modulator proteins. Dephosphorylation of Ser-259 (CRAF numbering) and dissociation of 14-3-3 release the RAF regulatory domains RAS-binding domain and cysteine-rich domain for interaction with RAS-GTP and membrane lipids. This, in turn, results in RAF phosphorylation at Ser-621 and 14-3-3 reassociation, followed by its dimerization and ultimately substrate binding and phosphorylation. This review focuses on structural understanding of how distinct binding partners trigger a cascade of molecular events that induces RAF kinase activation.

Left ventricular sphericity index analysis for the prediction of appropriate implantable cardioverter-defibrillator therapy.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) is the most effective therapy currently available to prevent sudden cardiac death (SCD) in patients with left ventricular (LV) dysfunction. Although LV ejection fraction (LVEF) is an excellent marker of SCD in these patients, determining other predictors might help to identify patients who will be benefit more from device implantation. The purpose of this study was to determine whether abnormal LV sphericity index (SI) in transthoracic echocardiography is associated with appropriate ICD therapy in these patients. METHODS: A total of 140 patients with primary ICD implantation (mean age 62.59 ± 11.36 years; 98 [70%] male) were included. The patients were classified into "no ICD therapy" or "ICD therapy" group according to the information of their devices for a maximum of 2 previous years. In four-chamber view image of transthoracic echocardiography, SI was calculated by dividing the major-axis dimension to minor-axis dimension of LV in both groups. RESULTS: Compared with patients with no ICD therapy, patients in ICD therapy group had lower LVEF (31.36 ± 9.58 vs 23.24 ± 6.03, P = 0.0001) and lower SI (1.79 ± 0.29 vs 1.57 ± 0.32, P = 0.0001). In multivariant logistic regression analysis, the SI of ≤1.58 was associated with fourfold increase of appropriate ICD therapy, even after adjusting for LVEF (odds ratio, 4.08; 95% confidence interval, 1.71-9.75; P = 0.02). CONCLUSION: Simple echocardiographic sphericity dimension index as a marker of cardiac remodeling may be an important predictor of appropriate ICD therapy in patients with primary prevention ICDs and may provide additive risk stratification in patients with LV systolic dysfunction.

The association between exposure to air pollutants including PM10, PM2.5, ozone, carbon monoxide, sulfur dioxide, and nitrogen dioxide concentration and the relative risk of developing STEMI: A case-crossover design.

BACKGROUND: Unfavorable associations between air pollution and myocardial infarction are broadly investigated in recent studies and some of them revealed considerable associations; however, controversies exists between these investigations with regard to culprit components of air pollution and significance of correlation between myocardial infarction risk and air pollution. METHODS: The association between exposure to PM10, PM2.5, ozone, carbon monoxide, sulfur dioxide, and nitrogen dioxide concentration of background air that residents of Tehran, the capital city of Iran, which is ranked as the most air polluted city of Iran and the relative risk of developing ST-elevation myocardial infarction (STEMI) were investigated by a case-crossover design. Our study included 208 patients admitted with a diagnosis of STEMI and undergone primary percutaneous intervention. Air pollutant concentration was averaged in 24-h windows preceding the time of onset of myocardial infarction for the case period. Besides, the mean level of each element of air pollution of the corresponding time in one week, two weeks and three weeks before onset of myocardial infarction, was averaged separately for each day as one control periods. Thus, 624 control periods were included in our investigation such that. Each patient is matched and compared with him/herself. RESULTS: The mean level of PM10 in case periods (61.47µg/m3) was significantly higher than its level in control periods (57.86µg/m3) (P-value = 0.019, 95% CI: 1.002-1.018, RR = 1.010). Also, the mean level of PM2.5 in case periods (95.40µg/m3) was significantly higher than that in control days (90.88µg/m3) (P-value = 0.044, 95% CI: 1.001-1.011, RR = 1.006). The level of other components including NO2, SO2, CO and O3 showed no significant differences between case and control periods. A 10µg/m3 increase in PM10 and PM2.5 would result in 10.10% and 10.06% increase in STEMI event, respectively. Furthermore, the results of sub-group analysis showed that older patients (equal or more than 60 year-old), diabetic patients, non-hypertensive ones and patients with more than one diseased vessel may be more vulnerable to the harmful effect of particular matters including PM10 and PM2.5 on development of STEMI. CONCLUSION: Air pollution is a worldwide pandemic with great potential to cause terrible events especially cardiovascular ones. PM2.5 and PM10 are amongst ambient air pollutant with a high risk of developing STEMI. Thus, more restrictive legislations should be applied to define a safe level of indoor and outdoor air pollutant production.

Factors affecting ventriculophasic response: An investigation in patients with permanent pacemaker.

BACKGROUND: Ventriculophasic response (VR) refers to the shortening of the atrial cycle length (P-P-interval) that occurs during the heart block when a QRS complex is interposed between two P-waves. The aim of this study was to determine the factors affecting this phenomenon. METHODS: Thirty patients with high grade heart block treated with dual chamber pacemaker were studied. The pacer function of the patients' device was temporarily programmed to the ventricular-inhibited mode at 30 pulses per minute. A total of 330 recordings containing two P-waves with an interposed QRS and its previous P-P interval without any QRS were collected. The VR was defined as being present when the P-P interval with an interposed QRS shortened more than 3% compared to the preceding P-P interval. RESULTS: The VR was present in 45% of the recordings. In the multivariate logistic regression analysis, only a mid position of the interposed QRS was a positive predictor for presence of VR. However, there were no differences between recordings with or without VR groups according to QRS duration, paced or intrinsic interposed QRS. Hypertension and age had a negative correlation with the presence of VR when the QRS was interposed in the mid part. CONCLUSION: We found that the VR was present in approximately half of our cases. This phenomenon was mostly affected by position of the interposed QRS according to the previous P-P interval.

Predictors of pacemaker requirement in patients with implantable loop recorder and unexplained syncope: A systematic review and meta-analysis.

Identifying the underlying cause of unexplained syncope is crucial for appropriate management of recurrent syncopal episodes. Implantable loop recorders (ILRs) have emerged as valuable diagnostic tools for monitoring patients with unexplained syncope. However, the predictors of pacemaker requirement in patients with ILR and unexplained syncope remain unclear. In this study, we shed light on these prognostic factors. PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane CENTRAL were systematically searched until May 04, 2023. Studies that evaluated the predictors of pacemaker requirement in patients with implantable loop recorder and unexplained syncope were included. The "Quality In Prognosis Studies" appraisal tool was used for quality assessment. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was calculated. The publication bias was evaluated using Egger's and Begg's tests. Ten studies (n = 4200) were included. Right bundle branch block (OR: 3.264; 95% CI: 1.907-5.588, p < .0001) and bifascicular block (OR: 2.969; 95% CI: 1.859-4.742, p < .0001) were the strongest predictors for pacemaker implantation. Pacemaker requirement was more than two times in patients with atrial fibrillation, sinus bradycardia and first degree AV block. Valvular heart disease, diabetes mellitus, and hypertension were also significantly more in patients with pacemaker implantation. Age (standardized mean difference [SMD]: 0.560; 95% CI: 0.410/0.710, p < .0001) and PR interval (SMD: 0.351; 95% CI: 0.150/0.553, p = .001) were significantly higher in patients with pacemaker requirement. Heart conduction disorders, atrial arrhythmias and underlying medical conditions are main predictors of pacemaker device implantation following loop recorder installation in unexplained syncopal patients.

Fragmented QRS, a strong predictor of mortality and major arrhythmic events in patients with nonischemic cardiomyopathy: A systematic review and meta-analysis.

Background and Aims: Fragmented QRS (fQRS), which is associated with rhythm disturbances, can predispose the heart to fatal ventricular arrhythmias. Recently, accumulating studies indicates that fQRS is associated with poor prognosis in various types of cardiomyopathies. Therefore, we assessed the association between fQRS with all-cause mortality and major arrhythmic events (MAEs) in patients with nonischemic cardiomyopathy, in this systematic review and meta-analysis study. Methods: We performed a comprehensive search in databases of PubMed/Medline, EMBASE, and Web of Science from the beginning to December 31, 2022. Published observational studies (cohorts, case-control, or analytical cross-sectional studies) were included that report the prognostic value of fQRS in patients with different types of nonischemic cardiomyopathies for MAEs (sudden cardiac death, sudden cardiac arrest, sustained ventricular tachycardia [VT], ventricular fibrillation [VF], and appropriate shock) and all-cause mortality. We pooled risk ratios (RRs) through raw data and adjusted hazard ratios (aHRs) using "Comprehensive Meta-Analysis" software, Version 2.0. Results: Nineteen cohort and three analytical cross-sectional studies were included in this meta-analysis involving a total of 4318 subjects with nonischemic cardiomyopathy (1279 with fQRS and 3039 without fQRS). FQRS was significantly associated with an increased risk of all-cause mortality in patients with nonischemic cardiomyopathy (pooled RR: 1.920; 95% confidence interval [CI]: 1.388-2.656, p < 0.0001/pooled HR: 1.729; 95% CI: 1.327-2.251, p < 0.0001). Also, the risk of developing MAEs in the presence of fQRS was significantly increased (pooled RR: 2.041; 95% CI: 1.644-2.533, p < 0.0001/pooled HR: 3.626; 95% CI: 2.119-6.204, p < 0.0001). In the subgroup analysis, the strongest association between fQRS presence and increased MAEs was observed in patients with hypertrophic cardiomyopathy (HCM) (pooled RR: 3.44; 95% CI: 2.07-5.71, p < 0.0001/pooled HR: 3.21; 95% CI: 2.04-5.06, p < 0.0001). Conclusion: Fragmented QRS could be a prognostic marker for all-cause mortality and MAEs in patients with various types of nonischemic cardiomyopathies, particularly HCM.

Aortic dissection and Covid-19; a comprehensive systematic review.

Coronavirus disease 19 (Covid-19) has been declared as a pandemic disease since March 2020; causing wide array of signs and symptoms, many of which result in increased mortality rates worldwide. Although it was initially known as an acute respiratory disease, Covid-19 is accompanied with several extrapulmonary manifestations, of which the cardiovascular ones are of major importance. Among other cardiovascular complications of Covid-19, aortic dissection has been a significant yet underrated problem. The pathophysiology of aortic dissection consists of various inflammatory pathways, that could be influenced by Covid-19 infection. We herein have reviewed articles inclusive of aortic dissection concurrent with Covid-19 infection in a systematic manner, along with the probable similarities in pathophysiology of aortic dissection with Covid-19 infection.

Estimating Compressive Strength of Concrete Using Neural Electromagnetic Field Optimization.

Concrete compressive strength (CCS) is among the most important mechanical characteristics of this widely used material. This study develops a novel integrative method for efficient prediction of CCS. The suggested method is an artificial neural network (ANN) favorably tuned by electromagnetic field optimization (EFO). The EFO simulates a physics-based strategy, which in this work is employed to find the best contribution of the concrete parameters (i.e., cement (C), blast furnace slag (SBF), fly ash (FA1), water (W), superplasticizer (SP), coarse aggregate (AC), fine aggregate (FA2), and the age of testing (AT)) to the CCS. The same effort is carried out by three benchmark optimizers, namely the water cycle algorithm (WCA), sine cosine algorithm (SCA), and cuttlefish optimization algorithm (CFOA) to be compared with the EFO. The results show that hybridizing the ANN using the mentioned algorithms led to reliable approaches for predicting the CCS. However, comparative analysis indicates that there are appreciable distinctions between the prediction capacity of the ANNs created by the EFO and WCA vs. the SCA and CFOA. For example, the mean absolute error calculated for the testing phase of the ANN-WCA, ANN-SCA, ANN-CFOA, and ANN-EFO was 5.8363, 7.8248, 7.6538, and 5.6236, respectively. Moreover, the EFO was considerably faster than the other strategies. In short, the ANN-EFO is a highly efficient hybrid model, and can be recommended for the early prediction of the CCS. A user-friendly explainable and explicit predictive formula is also derived for the convenient estimation of the CCS.

Associations between short-term exposure to fine particulate matter and acute myocardial infarction: A case-crossover study.

BACKGROUND: Previous studies evaluated the impact of particle matters (PM) on the risk of acute myocardial infarction (AMI) based on local registries. HYPOTHESIS: This study aimed to evaluate possible short term effect of air pollutants on occurrence of AMI based on a specific case report sheet that was designed for this purpose. METHODS: AMI was documented among 982 patients who referred to the emergency departments in Tehran, Iran, between July 2017 to March 2019. For each patient, case period was defined as 24 hour period preceding the time of emergency admission and referent periods were defined as the corresponding time in 1, 2, and 3 weeks before the admission. The associations of particulate matter with an aerodynamic diameter ≤2.5 µm (PM2 .5 ) and particulate matter with an aerodynamic diameter ≤10 µm (PM10 ) with AMI were analyzed using conditional logistic regression in a case-crossover design. RESULT: Increase in PM2.5 and PM10 was significantly associated with the occurrence of AMI with and without adjustment for the temperature and humidity. In the adjusted model each 10 µg/m3 increase of PM10 and PM2.5 in case periods was significantly associated with increase myocardial infarction events (95% CI = 1.041-1.099, OR = 1.069 and 95% CI = 1.073-1.196, and OR = 1.133, respectively). Subgroup analysis showed that increase in PM10 did not increase AMI events in diabetic subgroup, but in all other subgroups PM10 and PM2 .5 concentration showed positive associations with increased AMI events. CONCLUSION: Acute exposure to ambient air pollution was associated with increased risk of AMI irrespective of temperature and humidity.

How to improve information technology strategic planning effectiveness using balanced scorecard, risk and maturity analysis, case study health information technology? A qualitative study.

Background and Aims: Although many health strategic plans have been developed by scholars and organizations, they still suffer from a limited view. Since most health-related strategies in the future will depend on information technology (IT), as the main driver of today's industry, technology, and society, IT merits attention in health strategic plans. While the majority of the health strategic plan developed based on the interviews and questioner and these plans didn't consider the role of IT in their actions, this research will develop a framework to integrate risk and maturity analysis with the strategic planning process in health information technology strategic plan. Methods: The present research introduces an integrated framework based on a balanced scorecard (BSC) and control objectives for information and related technologies (COBIT). Also, The American Productivity & Quality Centre framework and COBIT were employed in this model to define the processes and activities of health IT (HIT) organizations. The organization's maturity and risk are analyzed in terms of information and management criteria using BSC, COBIT, and the analytical hierarchy process. Results: Later this model was implemented in a Remote Health care System to improve the strategic management process for this technology. Using this framework, 17 business goals have been developed and presented for the case. Also, the total related risk was 48% and the maturity level was at 1/18. The results are presented as decision-making parameters and strategies for successful IT implementation. Conclusion: The presented framework provides deeper insight for the decision-maker through integrating risk and maturity analysis in the HIT strategic planning process. The results are presented as decision-making parameters and strategies for successful IT implementation. These strategies help investors decide about resource allocation based on the risk-taking capability, certainty, and uncertainty results of the plan.

Is COVID-19 really a geriatric syndrome?

Geriatric syndromes are a group of medical conditions, such as cognitive impairment, delirium, frailty, dizziness, syncope, and incontinence, associated with age increase. Many studies have reported a higher mortality rate for older COVID-19 patients, which could be explained by the complications of COVID-19, including the components of geriatric syndromes. We read with great interest the paper "Prevalence of unwillingness and uncertainty to vaccinate against COVID-19 in older people: A systematic review and meta-analysis" by Nicola Veronese et al. Their valuable work determines how uncertainty and unwillingness towards receiving the COVID-19 vaccine are more prevalent among older adults and how this hesitancy could affect vaccine uptake, and ultimately, the mortality rate. Regarding this paper, we wish to address some points.

25-Hydroxy Vitamin D Level and Its Correlation with Mean Platelet Volume in Preeclampsia.

Background: Preeclampsia is one of the challenging complications of pregnancy, of which little is known about its etiology and pathogenesis. Many studies have shown higher mean platelet volume (MPV) in preeclamptic patients. Vitamin D deficiency is in association with larger-size platelets. Thus, we aimed to determine the correlation of vitamin D with MPV in preeclamptic patients. Methods: This prospective case-control study was conducted in two tertiary hospitals in Tehran, Iran. Overall, 85 preeclamptic pregnant women and 85 normotensive pregnant women were entered between 2017 and 2018. Serum vitamin D concentration (ng/ml) and MPV (femtoliter) were measured for all patients. Results: MPV was significantly higher in the cases compared to controls (10.59±1.08 vs 8.10±0.95, P=0.0001). In addition, serum vitamin D level in the preeclamptic group was significantly lower in compare to the control group (17.79±11.03 vs 30.24±12.49; P=0.0001). In multivariate logistic regression analysis, high age of mother (OR: 1.13; 95% CI: 1.01-1.27; P=0.03), low level of serum vitamin D (OR: 0.93; 95% CI: 0.87-0.99; P=0.02) and high MPV (OR: 8.83; 95% CI: 4.17-18.67; P=0.0001) were independent predictors of preeclampsia. Moreover, a correlation analysis revealed that vitamin D levels correlated negatively with MPV (r= -0.41, P<0.0001). Conclusion: Low levels of vitamin D in preeclamptic pregnancy are associated with higher platelet activity and thrombosis. In fact, the increment of MPV level might be a potential pathway for adverse outcomes of pregnancy including preeclampsia in the context of vitamin D deficiency.

Morphological profiling by means of the Cell Painting assay enables identification of tubulin-targeting compounds.

In phenotypic compound discovery, conclusive identification of cellular targets and mode of action are often impaired by off-target binding. In particular, microtubules are frequently targeted in cellular assays. However, in vitro tubulin binding assays do not correctly reflect the cellular context, and conclusive high-throughput phenotypic assays monitoring tubulin binding are scarce, such that tubulin binding is rarely identified. We report that morphological profiling using the Cell Painting assay (CPA) can efficiently detect tubulin modulators in compound collections with a high throughput, including annotated reference compounds and unannotated compound classes with unrelated chemotypes and scaffolds. Small-molecule tubulin binders share similar CPA fingerprints, which enables prediction and experimental validation of microtubule-binding activity. Our findings suggest that CPA or a related morphological profiling approach will be an invaluable addition to small-molecule discovery programs in chemical biology and medicinal chemistry, enabling early identification of one of the most frequently observed off-target activities.