UV-A-Induced Photoisomerization and Photodimerization of Curcumin: An Ion Mobility Mass Spectrometry Study.

Curcumin, the bioactive compound present in spice plant turmeric, has been shown to exhibit selective phototoxic activities toward mammalian cancer cells, and it is being used extensively as a photosensitizer (PS) in photodynamic therapies (PDT). However, so far, the fate of curcumin toward photochemical transformations is not well understood. Here we report our findings of a number of novel photochemical reaction channels of curcumin in water-methanol mixture, like photoisomerization, photodimerization, and photooxidation (H2-loss). The reaction was performed by irradiating the curcumin solution with ultraviolet (UV) light of wavelength 350 nm, which is abundant in the earth's troposphere. Product identification and structure elucidation are done by employing an integrated method of drift tube ion mobility mass spectrometry (DTIMS) in combination with high-performance liquid chromatography (HPLC) and collision-induced dissociation (CID) of the mass-selected molecular ions. Two photoisomers of curcumin produced as a result of trans-cis configurational changes about C═C double bonds in the excited state have been identified, and it has been shown that they could serve as the precursors for formation of isomeric dimers via [2 + 2] cycloaddition and H2-loss products. Comparisons of the experimentally measured collision cross-section (CCS) values of the reactant and product ions obtained by the DTIMS method with those predicted by the electronic structure theory are found to be very effective for the discrimination of the produced photoisomers. The observed photochemical reaction channels are potentially significant toward uses of curcumin as a photosensitizer in photodynamic therapy.

Drug repurposing for COVID-19 using computational screening: Is Fostamatinib/R406 a potential candidate?

With the gradual increase in the COVID-19 mortality rate, there is an urgent need for an effective drug/vaccine. Several drugs like Remdesivir, Azithromycin, Favirapir, Ritonavir, Darunavir, etc., are put under evaluation in more than 300 clinical trials to treat COVID-19. On the other hand, several vaccines like Pfizer-BioNTech, Moderna, Johnson & Johnson's Janssen, Sputnik V, Covishield, Covaxin, etc., also evolved from the research study. While few of them already gets approved, others show encouraging results and are still under assessment. In parallel, there are also significant developments in new drug development. But, since the approval of new molecules takes substantial time, drug repurposing studies have also gained considerable momentum. The primary agent of the disease progression of COVID-19 is SARS-CoV2/nCoV, which is believed to have ~89% genetic resemblance with SARS-CoV, a coronavirus responsible for the massive outbreak in 2003. With this hypothesis, Human-SARS-CoV protein interactions are used to develop an in-silico Human-nCoV network by identifying potential COVID-19 human spreader proteins by applying the SIS model and fuzzy thresholding by a possible COVID-19 FDA drugs target-based validation. At first, the complete list of FDA drugs is identified for the level-1 and level-2 spreader proteins in this network, followed by applying a drug consensus scoring strategy. The same consensus strategy is involved in the second analysis but on a curated overlapping set of key genes/proteins identified from COVID-19 symptoms. Validation using subsequent docking study has also been performed on COVID-19 potential drugs with the available major COVID-19 crystal structures whose PDB IDs are: 6LU7, 6M2Q, 6W9C, 6M0J, 6M71 and 6VXX. Our computational study and docking results suggest that Fostamatinib (R406 as its active promoiety) may also be considered as one of the potential candidates for further clinical trials in pursuit to counter the spread of COVID-19.

Computational modeling of human-nCoV protein-protein interaction network.

Novel coronavirus(SARS-CoV2) replicates the host cell's genome by interacting with the host proteins. Due to this fact, the identification of virus and host protein-protein interactions could be beneficial in understanding the disease transmission behavior of the virus as well as in potential COVID-19 drug identification. International Committee on Taxonomy of Viruses (ICTV) has declared that nCoV is highly genetically similar to the SARS-CoV epidemic in 2003 (∼89% similarity). With this hypothesis, the present work focuses on developing a computational model for the nCoV-Human protein interaction network, using the experimentally validated SARS-CoV-Human protein interactions. Initially, level-1 and level-2 human spreader proteins are identified in the SARS-CoV-Human interaction network, using Susceptible-Infected-Susceptible (SIS) model. These proteins are considered potential human targets for nCoV bait proteins. A gene-ontology-based fuzzy affinity function has been used to construct the nCoV-Human protein interaction network at a ∼99.98% specificity threshold. This also identifies 37 level-1 human spreaders for COVID-19 in the human protein-interaction network. 2474 level-2 human spreaders are subsequently identified using the SIS model. The derived host-pathogen interaction network is finally validated using six potential FDA-listed drugs for COVID-19 with significant overlap between the known drug target proteins and the identified spreader proteins.

Using a handheld UV device for disinfection in the patient care environment: A descriptive qualitative study.

Frontline nurses play a critical role in the prevention of healthcare-acquired infections (HAIs) through daily practices of hand hygiene and decontamination of surfaces. Despite these practices, environmental contamination and HAIs persist. Emerging use of UV light at wavelengths safe for human exposure provides additional strategies for disinfecting the patient care environment. The purpose of this qualitative study is to explore frontline nursing feedback regarding a novel handheld UV device prototype. A convenience sample of nurses were invited to participate in facilitated individual or small group discussions led by one member of the research team. Thematic analysis of discussion transcripts was completed by two members of the research team. Sixteen registered nurses participated. Four themes found in the study were time considerations, complexity, safety (patient and nurse), and characteristics of technology to improve patient care. Findings suggest that while nursing staff are willing to use technology, it must be considered valuable to patient care and should not hinder the provision of care. Inclusion of inputs from nursing staff for development of technology identifies potential barriers to acceptance and use in the practice environment.

Tautomers and Rotamers of Curcumin: A Combined UV Spectroscopy, High-Performance Liquid Chromatography, Ion Mobility Mass Spectrometry, and Electronic Structure Theory Study.

The structures of tautomers and rotameric forms of curcumin, the bioactive compound present in spice plant turmeric, have been investigated using ion mobility mass spectrometry (IMMS) in conjunction with high-performance liquid chromatography (HPLC) and UV-visible spectroscopy. Two tautomeric forms of this ß-diketone compound, keto-enol and diketo, have been chromatographically separated, and the electronic absorption spectra for these two tautomeric forms in methanol solution have been recorded separately for the first time. The molecular identity of the HPLC-separated solution fractions is established unambiguously by recording the mass and fragmentation spectra simultaneously. The ion mobility spectrum for the deprotonated curcumin anion, [Cur-H]-, corresponding to the diketo tautomer, displays only one peak (P), and the collision cross-section (CCS) value is measured to be 185.9 Å2. However, the ion mobility spectrum corresponding to the HPLC-separated keto-enol tautomer shows three distinctly separated peaks, P, Q, and R, with CCS values of 185.9, 194.8, and 203.4 Å2, respectively, whereby peak R appears to be the most intense one, followed by peaks P and Q. The theoretically calculated CCS values of different isomers of [Cur-H]-, optimized by electronic structure theory methods, display satisfactory correlation with the experimentally observed values, corroborating our assignments. The spectral attributes also indicate the occurrence of structural rearrangements in the electrospray ionization process. With the aid of the electronic structure calculation, low-energy pathways for the occurrence of the structural isomerization to surpass the energy barrier are suggested, which are consistent with the assignments of the peaks observed in the IM spectra.

The viral phoenix: enhanced infectivity and immunity evasion of SARS-CoV-2 variants.

SARS-CoV-2 pandemic continues with emergence of new variants of concerns. These variants are fueling the third and fourth waves of pandemic across many nations. Here we describe the new emerging variants of SARS-CoV-2 and why they have enhanced infectivity and possess the ability to evade immunity.

RFCM-PALM: In-Silico Prediction of S-Palmitoylation Sites in the Synaptic Proteins for Male/Female Mouse Data.

S-palmitoylation is a reversible covalent post-translational modification of cysteine thiol side chain by palmitic acid. S-palmitoylation plays a critical role in a variety of biological processes and is engaged in several human diseases. Therefore, identifying specific sites of this modification is crucial for understanding their functional consequences in physiology and pathology. We present a random forest (RF) classifier-based consensus strategy (RFCM-PALM) for predicting the palmitoylated cysteine sites on synaptic proteins from male/female mouse data. To design the prediction model, we have introduced a heuristic strategy for selection of the optimum set of physicochemical features from the AAIndex dataset using (a) K-Best (KB) features, (b) genetic algorithm (GA), and (c) a union (UN) of KB and GA based features. Furthermore, decisions from best-trained models of the KB, GA, and UN-based classifiers are combined by designing a three-star quality consensus strategy to further refine and enhance the scores of the individual models. The experiment is carried out on three categorized synaptic protein datasets of a male mouse, female mouse, and combined (male + female), whereas in each group, weighted data is used as training, and knock-out is used as the hold-out set for performance evaluation and comparison. RFCM-PALM shows ~80% area under curve (AUC) score in all three categories of datasets and achieve 10% average accuracy (male-15%, female-15%, and combined-7%) improvements on the hold-out set compared to the state-of-the-art approaches. To summarize, our method with efficient feature selection and novel consensus strategy shows significant performance gains in the prediction of S-palmitoylation sites in mouse datasets.

Frontline Nurse Feedback During the Development of a System to Track Cleaning of Portable Medical Equipment.

As part of the development and testing of an innovative technology for tracking disinfection of portable medical equipment, end-user feedback was obtained during an initial trial on two acute care hospital units. The disinfection tracking device was installed on the computers-on-wheels and vital signs machines. Each device had the capability of detecting a cleaning event, reporting the event to an online database, and displaying the time since last cleaning event on a visual display. End-user feedback regarding functionality, usefulness of information provided, and impact on workflow was obtained by survey and facilitated group discussions. Seventeen frontline nurses completed the anonymous survey, and 22 participated in the facilitated group discussions. End users found the system functionally easy to use and the information about time since last cleaning useful and reported minimum disruption of workflow. Functionality of the system was confirmed by consistency between recorded and self-reported cleaning patterns. Managers found the data on cleaning of portable medical equipment helpful in validating compliance with hospital equipment cleaning policy. Frontline staff expressed appreciation for technology that helps them and improves outcomes but also discussed concerns about the potential for technology that creates extra work and disruption in the busy frontline nursing care delivery environment. Nurses were appreciative of opportunities to provide feedback and input into efforts to develop and introduce technology. Recorded cleaning events coincided with self-reported equipment cleaning patterns and illustrated that the device efficiently collects information deemed useful by the end user.

Classical and alternative disinfection strategies to control the COVID-19 virus in healthcare facilities: a review.

The coronavirus disease COVID-19 has spread throughout the world and has been declared as a pandemic by the World Health Organization on March 11th, 2020. The COVID-19 is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). One possible mode of virus transmission is through surfaces in the healthcare settings. This paper reviews currently used disinfection strategies to control SARS-CoV-2 at the healthcare facilities. Chemical disinfectants include hypochlorite, peroxymonosulfate, alcohols, quaternary ammonium compounds, and hydrogen peroxide. Advanced strategies include no-touch techniques such as engineered antimicrobial surfaces and automated room disinfection systems using hydrogen peroxide vapor or ultraviolet light.

Current understanding of the surface contamination and contact transmission of SARS-CoV-2 in healthcare settings.

The novel coronavirus disease (COVID-19) has rapidly spread across the world and was subsequently declared as a pandemic in 2020. To overcome this public health challenge, comprehensive understanding of the disease transmission is urgently needed. Recent evidences suggest that the most common route of transmission for SARS-CoV-2 is likely via droplet, aerosol, or direct contact in a person-to-person encounter, although the possibility of transmission via fomites from surfaces cannot be ruled out entirely. Environmental contamination in COVID-19 patient rooms is widely observed due to viral shedding from both asymptomatic and symptomatic patients, and SARS-CoV-2 can survive on hospital surfaces for extended periods. Sequence of contact events can spread the virus from one surface to the other in a hospital setting. Here, we review the studies related to viral shedding by COVID-19 patients that can contaminate surfaces and survival of SARS-CoV-2 on different types of surfaces commonly found in healthcare settings, as well as evaluating the importance of surface to person transmission characteristics. Based on recent evidences from the literature, decontamination of hospital surfaces should constitute an important part of the infection control and prevention of COVID-19.

Barrierless Proton Transfer in the Weak C-H···O Hydrogen Bonded Methacrolein Dimer upon Nonresonant Multiphoton Ionization in the Gas Phase.

Intermolecular proton transfer (IMPT) in a C-H···O hydrogen bonded dimer of an α,ß-unsaturated aldehyde, methacrolein (MC), upon nonresonant multiphoton ionization by 532 nm laser pulses (10 ns), has been investigated using time-of-flight (TOF) mass spectrometry under supersonic cooling condition. The mass peaks corresponding to both the protonated molecular ion [(MC)H+] and intact dimer cation [(MC)2]•+ show up in the mass spectra, and the peak intensity of the former increases proportionately with the latter with betterment of the jet cooling conditions. The observations indicate that [(MC)2]•+ is the likely precursor of (MC)H+ and, on the basis of electronic structure calculations, IMPT in the dimer cation has been shown to be the key reaction for formation of the latter. Laser power dependences of ion yields indicate that at this wavelength the dimer is photoionized by means of 4-photon absorption process, and the total 4-photon energy is nearly the same as the predicted vertical ionization energy of the dimer. Electronic structure calculations reveal that the optimized structures of [(MC)2]•+ correspond to a proton transferred configuration wherein the aldehydic hydrogen is completely shifted to the carbonyl oxygen of the neighboring moiety. Potential energy scans along the C-H···O coordinate also show that the IMPT in [(MC)2]•+ is a barrierless process.

NF-κB mediated miR-130a modulation in lung microvascular cell remodeling: Implication in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease which is associated with pulmonary arterial endothelial cells (PAEC) dysfunction and pulmonary arterial smooth muscle cells proliferation. Moreover, inflammation is contributing a critical role in EC dysfunction and remains elusive. Nuclear factor-kappa B (NF-κB) is a master transcriptional regulator in various cardiovascular pathologies; but, NF-κB's role in EC dysfunction in unknown. Our previous study using cardiac and lung specific IκBα mutant mice (3M and IKBM) showed that PAH induced right ventricular hypertrophy (RVH) was prevented in monocrotaline (MCT) treated 3M and IKBM mice, compared to the wild-type mice. Recently, microRNAs (miRNAs) have emerged as a new class of post-transcriptional regulators in vascular remodeling; but, NF-κB regulated miRNA modulation in EC dysfunction is unknown. Using miRNA array analysis, we identified miR-130a which is upregulated in MCT-induced PAH mouse model, as a possible candidate to study. We showed that overexpressing miR-130a in lung microvascular endothelial cells (MVEC) promoted activation of α-smooth muscle actin, a critical component in endothelial-to-mesenchymal transition in EC remodeling. In this study, we demonstrated that bone morphogenetic protein receptor 2 (BMPR2) was a target for miR-130a and miR-130a was regulated by NF-κB which controlled apoptosis and vascular genes in MVEC. The findings reveal that NF-κB-mediated miR-130a modulation is critical in lung vascular remodeling.

Depletion of MHC class II invariant chain peptide or γ-δ T-cells ameliorates experimental preeclampsia.

Excessive innate immune system activation and inflammation during pregnancy can lead to organ injury and dysfunction and preeclampsia (PE); however, the molecular mechanisms involved are unknown. We tested the hypothesis that Toll-like receptor (TLR) activation induces major histocompatibility complex (MHC) class II invariant chain peptide (CLIP) expression on immune cells, makes them pro-inflammatory, and are necessary to cause PE-like features in mice. Treatment with VG1177, a competitive antagonist peptide for CLIP in the groove of MHC class II, was able to both prevent and treat PE-like features in mice. We then determined that γ-δ T cells are critical for the development of PE-like features in mice since γ-δ T-cell knockout mice, like CLIP deficient mice, are resistant to developing PE-like features. Placentas from women with PE exhibit significantly increased levels of γ-δ T cells. These preclinical data demonstrate that CLIP expression and activated γ-δ T cells are responsible for the development of immunologic PE-like features and that temporarily antagonizing CLIP and/or γ-δ T cells may be a therapeutic strategy for PE.

Toll-like receptor activation, vascular endothelial function, and hypertensive disorders of pregnancy.

Aberrant innate immune system activation in the mother contributes greatly to the development of hypertension during pregnancy. Numerous groups have elicited vascular inflammation, endothelial dysfunction, and hypertension in animals during gestation by directly activating Toll-like receptors. Additionally, several experimental therapies that reduce pro-inflammatory immune cells and cytokines restore vascular endothelial function and normalize blood pressure. This review will summarize the research demonstrating that an excessive maternal innate immune response is sufficient to cause vascular inflammation and endothelial dysfunction, which contributes to the development of hypertension during pregnancy. Dampening the vascular inflammation caused by immune responses may reduce the incidence and severity of hypertensive disorders of pregnancy.

Hydrogen bond induced HF elimination from photoionized fluorophenol dimers in the gas phase.

In this paper, we report finding of a remarkable chemical effect of hydrogen bonding, elimination of hydrogen fluoride (HF) from the hydrogen bonded dimers of 2-fluorophenol (2-FP) and 3-fluorophenol (3-FP), in a supersonic jet expansion upon multi-photon ionization using 4th harmonic wavelength (266 nm) of a Q-switched Nd:YAG laser, and the reaction has been probed by time-of-flight mass spectrometry. No HF elimination is observed to occur by such means from the monomer of 3-FP, but it occurs with a small yield from the monomer of 2-FP. On the other hand, upon dimerization the reaction is triggered on for 3-FP, and for 2-FP it becomes so facile that no intact dimer cation survives and only the HF eliminated product ion appears in the mass spectra. Electronic structure calculation shows that in the cationic ground (D0) state, although the reaction for 2-FP dimer is exothermic, the associated barrier is significantly high (2.75 eV) and for its occurrence, absorption of three photons (2+1 type) is required. However, the reaction is predicted barrierless in the intermediate S1 state of this dimer, and HF loss dimer cation mass peak could appear in the mass spectrum due to an effective two-photon (1+1) ionization process. In the case of 3-FP dimer, the energy barriers both in S1 (neutral) and D0 (ionic) states are high, and it is suggested that for occurrence of HF elimination, dimer cation needs to absorb an additional photon. For facilitation of HF loss from this dimer cation, a rearrangement of the geometry and formation of an intermediate adduct have been suggested, and it is argued that the latter could be produced by nucleophilic attack of the neutral moiety at the ortho site of the cationic counterpart.

Modeling Repeatedly Flaring δ Sunspots.

Active regions (ARs) appearing on the surface of the Sun are classified into α, ß, γ, and δ by the rules of the Mount Wilson Observatory, California on the basis of their topological complexity. Amongst these, the δ sunspots are known to be superactive and produce the most x-ray flares. Here, we present results from a simulation of the Sun by mimicking the upper layers and the corona, but starting at a more primitive stage than any earlier treatment. We find that this initial state consisting of only a thin subphotospheric magnetic sheet breaks into multiple flux tubes which evolve into a colliding-merging system of spots of opposite polarity upon surface emergence, similar to those often seen on the Sun. The simulation goes on to produce many exotic δ sunspot associated phenomena: repeated flaring in the range of typical solar flare energy release and ejective helical flux ropes with embedded cool-dense plasma filaments resembling solar coronal mass ejections.

Human placenta-derived stromal cells decrease inflammation, placental injury and blood pressure in hypertensive pregnant mice.

Pre-eclampsia, the development of hypertension and proteinuria or end-organ damage during pregnancy, is a leading cause of both maternal and fetal morbidity and mortality, and there are no effective clinical treatments for pre-eclampsia aside from delivery. The development of pre-eclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation and endothelial dysfunction. We have reported that detection of extracellular RNA by the Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of pre-eclampsia. PLacental eXpanded (PLX-PAD) cells are human placenta-derived, mesenchymal-like, adherent stromal cells that have anti-inflammatory, proangiogenic, cytoprotective and regenerative properties, secondary to paracrine secretion of various molecules in response to environmental stimulation. We hypothesized that PLX-PAD cells would reduce the associated inflammation and tissue damage and lower blood pressure in mice with pre-eclampsia induced by TLR3 or TLR7 activation. Injection of PLX-PAD cells on gestational day 14 significantly decreased systolic blood pressure by day 17 in TLR3-induced and TLR7-induced hypertensive mice (TLR3 144-111 mmHg; TLR7 145-106 mmHg; both P<0.05), and also normalized their elevated urinary protein:creatinine ratios (TLR3 5.68-3.72; TLR7 5.57-3.84; both P<0.05). On gestational day 17, aortic endothelium-dependent relaxation responses improved significantly in TLR3-induced and TLR7-induced hypertensive mice that received PLX-PAD cells on gestational day 14 (TLR3 35-65%; TLR7 37-63%; both P<0.05). In addition, markers of systemic inflammation and placental injury, increased markedly in both groups of TLR-induced hypertensive mice, were reduced by PLX-PAD cells. Importantly, PLX-PAD cell therapy had no effects on these measures in pregnant control mice or on the fetuses. These data demonstrate that PLX-PAD cell therapy can safely reverse pre-eclampsia-like features during pregnancy and have a potential therapeutic role in pre-eclampsia treatment.

Photo-oxidation of Acetone to Formic Acid in Synthetic Air and Its Atmospheric Implication.

Acetone photo-oxidation in synthetic air under exposure of 311 nm ultraviolet light has been studied, and the photo-oxidation products are identified by means of infrared spectroscopy. Analysis reveals that formic acid is one of the major products, although there have been debates in the past concerning the authenticity of formation of this acid in synthetic air via the photo-oxidation pathway. The quantum yield of formation of this acid is similar to that of other major photoproducts like methanol, formaldehyde, and carbon monoxide. The reaction yield, however, decreases with an increase in total air pressure in the reaction cell, but it is still significant at pressures relevant to tropospheric conditions. A kinetic model has been used to simulate the measured reaction kinetics, and the quantum yields predicted by the model are found to be consistent with the measured yields for different durations of light exposure. The same model has also been used to investigate the effect of atmospheric nitric oxide on the fate of formation of this acid in the troposphere. Although nitric oxide is known to be a quencher of peroxy radicals, the precursors of formaldehyde and formic acid in acetone photo-oxidation, but our model predicts that this oxide plays a positive role in the overall reaction kinetics for production of this acid in the troposphere.

Keto-enol tautomerization and intermolecular proton transfer in photoionized cyclopentanone dimer in the gas phase.

Time-of-flight mass spectra of cyclopentanone and its clusters cooled in a supersonic jet expansion have been measured following 4-, 3-, and 2-photon ionizations by the 2nd, 3rd, and 4th harmonic wavelengths, respectively, of a Q-switched Nd:YAG laser. The mass spectra reveal signatures of energetically favored keto to enol tautomerization of the molecular ion leading to intermolecular proton transfer, and this observation is found sharply dependent on the ionization wavelengths used. Electronic structure calculation predicts that in spite of the energetic preference, keto-enol conversion barrier of isolated molecular ion is high. However, the barrier is significantly reduced in a CH⋯O hydrogen-bonded dimer of the molecule. The transition states associated with tautomeric conversion of both cyclopentanone monomer and dimer cations have been identified by means of intrinsic reaction co-ordinate calculation. In a supersonic jet expansion, although a weakly bound dimer is readily generated, the corresponding cation and also the protonated counterpart are observed only for ionization by 532 nm. For other two ionization wavelengths, these species do not register in the mass spectra, where the competing reaction channels via α-cleavage of the ring become dominant. In contrast to the report of a recent study, we notice that the intact molecular ion largely survives fragmentations when ionized from the 2-photon resonant 3p Rydberg state as intermediate using nanosecond laser pulses, and the corresponding resonant 3-photon ionization spectrum has been recorded probing the intact molecular ion.