Chromatographic and spectroscopic analysis of Dibenzo[b,l]Fluoranthene and its determination in SRM 1597a by laser-excited time-resolved Shpol'skii spectroscopy.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) with molecular mass 302 Da are the most investigated PAHs within the high molecular weight PAHs class. This PAH class contributes to a significant portion of the mutagenic and/or carcinogenic response associated to the PAH fraction present in environmental and combustion-related samples. Several reasons prevent the routine analysis of 302 Da PAHs in environmental samples, including large number of possible isomers, limited number of commercially available reference standards, and low concentration levels. RESULTS: These studies search for a newly synthetized dibenzo-fluoranthene of molecular mass 302 Da, namely dibenzo[b,l]fluoranthene, in a standard reference material (SRM 1597a) from the National Institute of Standards and Technology. The eluting behavior of dibenzo[b,l]fluoranthene is investigated under reversed-phase liquid chromatographic conditions for its determination via absorption and fluorescence detection. Vibrationally resolved spectra and fluorescence lifetimes recorded from octane matrices at 77 K and 4.2 K allow for its qualitative and quantitative analysis at the parts-per-trillion concentration levels. Its unambiguous determination is then reported for the first time in the SRM 1597a. SIGNIFICANCE AND NOVELTY: Of the 89 possible 302 Da PAH isomers, only 23 isomers have been identified in SRMs and/or environmental samples. The determination of dibenzo[b,l]fluoranthene in the SRM 1597a takes a step forward to fulfilling this gap.

Investigation of the Effects of Dioctyl Sulfosuccinate on the Photodegradation of Benzo[a]Pyrene in Aqueous Solutions under Various Wavelength Regimes.

Due to the relatively high concentrations of polycyclic aromatic hydrocarbons (PAHs) in oil samples, oil spills in aquatic ecosystems release significant amounts of PAHs. Although remediation efforts often take place during or immediately after an oil spill incident, a portion of the released PAHs remains in the body of water. A natural phenomenon resulting from the direct exposure of PAHs to sunlight is photodegradation. This article investigates the effect of dioctyl sulfosuccinate (DOSS) on the photodegradation of benzo[a]pyrene (BaP), the most toxic PAH in the priority pollutants list of the US Environmental Protection Agency (EPA). DOSS is a surfactant typically used in the remediation of oil spills. Three lamps with maximum emission wavelengths at 350 nm, 419 nm, and 575 nm were individually and simultaneously used to irradiate aqueous solutions of BaP in the absence and the presence of DOSS. When irradiated with the 419 nm lamp or the 575 lamp, BaP showed no photodegradation. Upon irradiation with the 350 nm lamp and with the simultaneous use of the three lamps, the photodegradation of BaP followed first-order kinetics. Independent of the irradiation wavelength, the presence of DOSS increased the half-life of BaP in the aqueous solution. In the case of the 350 nm lamp, the rate constant of photodegradation in the absence and the presence of DOSS varied from (3.79 ± 0.97) × 10-3 min-1 to (1.10 ± 0.13) × 10-3 min-1, respectively. Under simultaneous irradiation with the lamps, the rate constant of photodegradation varied from (1.12 ± 0.35) × 10-3 min (no DOSS) to (3.30 ± 0.87) × 10-4 (with DOSS). Since the largest rate constants of photodegradation were observed in the absence of DOSS, the longer half-lives of BaP in the presence of surfactant were attributed to the incorporation of PAH molecules into the DOSS micelles.

The influence of the co-exposure to polycyclic aromatic hydrocarbons and toxic metals on DNA damage in brazilian lactating women and their infants: A cross-sectional study using machine learning approaches.

Polycyclic aromatic hydrocarbons (PAHs) and toxic metals are widely spread pollutants of public health concern. The co-contamination of these chemicals in the environment is frequent, but relatively little is known about their combined toxicities. In this context, this study aimed to evaluate the influence of the co-exposure to PAHs and toxic metals on DNA damage in Brazilian lactating women and their infants using machine learning approaches. Data were collected from an observational, cross-sectional study with 96 lactating women and 96 infants living in two cities. The exposure to these pollutants was estimated by determining urinary levels of seven mono-hydroxylated PAH metabolites and the free form of three toxic metals. 8-Hydroxydeoxyguanosine (8-OHdG) levels in the urine were used as the oxidative stress biomarker and set as the outcome. Individual sociodemographic factors were also collected using questionnaires. Sixteen machine learning algorithms were trained using 10-fold cross-validation to investigate the associations of urinary OH-PAHs and metals with 8-OHdG levels. This approach was also compared with models attained by multiple linear regression. The results showed that the urinary concentration of OH-PAHs was highly correlated between the mothers and their infants. Multiple linear regression did not show a statistically significant association between the contaminants and urinary 8OHdG levels. Machine learning models indicated that all investigated variables did not present predictive performance on 8-OHdG concentrations. In conclusion, PAHs and toxic metals were not associated with 8-OHdG levels in Brazilian lactating women and their infants. These novelty and originality results were achieved even after applying sophisticated statistical models to capture non-linear relationships. However, these findings should be interpreted cautiously because the exposure to the studied contaminants was considerably low, which may not reflect other populations at risk.

On the co-elution of benzo[a]pyrene and dibenzo[a,l]pyrene in chromatographic fractions and their unambiguous determination in tobacco extracts via laser-excited time resolved Shpol'skii spectroscopy.

High performance liquid chromatography is widely used for the analysis of polycyclic aromatic hydrocarbons in a wide variety of samples. Of particular concern are benzo[a]pyrene and dibenzo[a,l]pyrene, two of the most toxic polycyclic aromatic hydrocarbons ever tested. Under EPA method 610, these two compounds co-elute with almost identical retention times. Our studies demonstrate the feasibility of directly determining them in a chromatographic fraction without further separation. Their unambiguous determination is based on spectral and lifetime information with a two-step experimental procedure consisting of the evaporation of the chromatographic fraction followed by the dissolution of the residue with microliters of n-octane. With the aid of a 77 K fiber optic probe, limits of detection at the parts-per-billion concentration level (ng mL-1) are obtained from the microliter sample via laser excited time resolved Shpol'skii spectroscopy. This approach is then applied to the analysis of benzo[a]pyrene and dibenzo[a,l]pyrene in tobacco extracts.

Polycyclic aromatic hydrocarbons (PAHs): Updated aspects of their determination, kinetics in the human body, and toxicity.

Polycyclic aromatic hydrocarbons (PAHs) are legacy pollutants of considerable public health concern. Polycyclic aromatic hydrocarbons arise from natural and anthropogenic sources and are ubiquitously present in the environment. Several PAHs are highly toxic to humans with associated carcinogenic and mutagenic properties. Further, more severe harmful effects on human- and environmental health have been attributed to the presence of high molecular weight (HMW) PAHs, that is PAHs with molecular mass greater than 300 Da. However, more research has been conducted using low molecular weight (LMW) PAHs). In addition, no HMW PAHs are on the priority pollutants list of the United States Environmental Protection Agency (US EPA), which is limited to only 16 PAHs. However, limited analytical methodologies for separating and determining HMW PAHs and their potential isomers and lack of readily available commercial standards make research with these compounds challenging. Since most of the PAH kinetic data originate from animal studies, our understanding of the effects of PAHs on humans is still minimal. In addition, current knowledge of toxic effects after exposure to PAHs may be underrepresented since most investigations focused on exposure to a single PAH. Currently, information on PAH mixtures is limited. Thus, this review aims to critically assess the current knowledge of PAH chemical properties, their kinetic disposition, and toxicity to humans. Further, future research needs to improve and provide the missing information and minimize PAH exposure to humans.

Scaling quantum approximate optimization on near-term hardware.

The quantum approximate optimization algorithm (QAOA) is an approach for near-term quantum computers to potentially demonstrate computational advantage in solving combinatorial optimization problems. However, the viability of the QAOA depends on how its performance and resource requirements scale with problem size and complexity for realistic hardware implementations. Here, we quantify scaling of the expected resource requirements by synthesizing optimized circuits for hardware architectures with varying levels of connectivity. Assuming noisy gate operations, we estimate the number of measurements needed to sample the output of the idealized QAOA circuit with high probability. We show the number of measurements, and hence total time to solution, grows exponentially in problem size and problem graph degree as well as depth of the QAOA ansatz, gate infidelities, and inverse hardware graph degree. These problems may be alleviated by increasing hardware connectivity or by recently proposed modifications to the QAOA that achieve higher performance with fewer circuit layers.

Urinary levels of monohydroxylated polycyclic aromatic hydrocarbons in Brazilian children and health risk assessment: a human biomonitoring-based study.

Monitoring human exposure to polycyclic aromatic hydrocarbons (PAHs) is a public health concern. Children are a vulnerable subgroup of the population with limited human biomonitoring data worldwide. Thus, this study aimed to measure the levels of seven PAH metabolites in urine from Brazilian children and provide risk assessment values for this exposure. Our data show naphthalene was the major contributor to children's exposure to PAHs, with a 100% detection rate. Children in urban regions presented higher exposure to PAHs, with higher concentrations of 2-naphthol in the southeast (1.09 ng/mL, p < 0.05). Furthermore, the highest concentration of 2-naphthol was found in older children (p = 0.02), suggesting a possible difference in dietary habits. Exposure to the carbaryl insecticide is suggested based on the high concentrations of 1-naphthol (1.29 ng/mL) and considering the ratio 1-naphthol/2-naphthol (1.78). Moreover, the positive correlation between the metabolites of fluorine and pyrene also suggests exposure to PAHs by petrol combustion. The risk assessment of the PAH exposure was evaluated using the estimated daily intake (EDI) for two naphthalene metabolites in the study with a 100% detection rate. The EDI was 14.47 ng/kg BW/day. The risk assessment to the PAH exposure revealed a non-carcinogenic risk profile, with a hazard quotient of 0.71. To the best of our knowledge, this study is the first to provide levels of PAHs in Brazilian children.

Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19.

Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.

Shpol'skii spectroscopy of metabolites of polycyclic aromatic hydrocarbons in primary alcohols at 77 K and 4.2 K.

We present for the first time experimental evidence on the line-narrowing effect caused by primary alcohols on the spectral features of metabolites of polycyclic aromatic hydrocarbons at 77 K and 4.2 K. The investigated metabolites include 1-hydroxypyrene, 2-hydroxyfluorene, 9-hydroxyphenanthrene, 3-hydroxybenzo[a]pyrene, 4-hydroxybenzo[a]pyrene, 5-hydroxybenzo[a]pyrene, B[a]P-trans-7,8-dihydrodiol (±), B[a]P-trans-9,10-dihydrodiol (±), B[a]P-r-7,t-8-dihydrodiol-c-9,10-epoxide (±) and B[a]P-r-7,t-8-dihydrodiol-t-9,10-epoxide(±). The narrowest spectra and highest fluorescence enhancements were observed by matching the length of the alcohol to the length of the n-alkane that best fits the molecular dimensions of the parent polycyclic aromatic hydrocarbons. The analytical figures of merit show potential for the qualitative and quantitative analysis of PAH metabolites via Shpol'skii Spectroscopy.

Chemotherapy-Induced Peripheral Neuropathy: Causative Agents, Preventative Strategies, and Treatment Approaches.

Chemotherapy-induced peripheral neuropathy (CIPN) is a chronic symptom associated with chemotherapy treatment. Symptoms and severity vary based on chemotherapeutic agent used and dose. At present, effective options for the prevention and treatment of CIPN are inadequate and clinical guidance is limited. Unknown mechanism of action, lack of efficacy in many traditional neuropathic pain medications, and inconsistent evidence in regard to drug therapy have further complicated evaluation of therapeutic options. Twenty-five studies were identified and evaluated for CIPN prevention and treatment potential. Findings for CIPN pharmacological prevention were inconclusive as literature was largely conflicting. Exercise may be an effective non-pharmacological CIPN prevention method with limited adverse effects, however additional supporting data is still required. For treatment of CIPN, pharmacological agents duloxetine and topical combination product containing baclofen, amitriptyline, and ketamine have data supporting use. Early stage trials have shown initial promise for non-pharmacological therapies Scrambler Therapy and Photobiomodulation. Significant research is required as CIPN symptoms can lead to decreased quality of life, chemotherapy dose reduction, and discontinuation of drug therapy.

Instrumental improvements for the trace analysis of structural isomers of polycyclic aromatic hydrocarbons with molecular mass 302 Da.

Polycyclic aromatic hydrocarbons (PAHs) are some of the most common environmental pollutants encountered worldwide. Eco-toxicological studies attribute a significant portion of the biological activity of PAH contaminated samples to the presence of high molecular weight PAHs (HMW-PAHs), i.e. PAHs with molecular mass (MM) greater than 300 Da. The research presented here focuses on the analysis of PAH isomers of MM 302 Da. This is not a trivial task. There are 23 isomers with MM 302 Da available to commercial and academic researchers. Many of them are difficult to separate in the chromatographic column and have virtually identical fragmentation patterns. The selectivity of HPLC absorption and fluorescence detectors is modest for resolving co-eluting isomers. Previous work in our lab demonstrated the potential of laser excited time-resolved Shpol'skii spectroscopy (LETRSS) for the analysis of 302 Da isomers in HPLC fractions. The main limitation of the technique was instrumental and due to the narrow range of excitation wavelengths of the tunable dye laser used for sample excitation. Herein, we remove this limitation with an optical parametric oscillator (OPO)-based wavelength tuning laser that covers the whole excitation range of 302 Da isomers. It is possible now to excite each isomer at its excitation wavelength for maximum fluorescence emission and reach limits of detection at the parts-per-trillion level (pg.mL-1). The excitation bandwidth of the OPO laser (0.2 nm) is a good match for the narrow excitation spectra of 302 Da isomers in n-octane. This feature, associated to unique vibrational fluorescence profiles and lifetime decays, allows for the unambiguous identification of co-eluting isomers in RPLC fractions. The same is true for their quantitative analysis in coal tar samples.

Endothelial cell dynamics during anastomosis in vitro.

Vascular anastomosis - the fusion of vessels from two distinct branches of the vascular system - represents a critical step in vascular growth under both healthy and pathological conditions, in vivo, and presents an important target for engineering of vascularized tissues, in vitro. Recent works in animal models have advanced our understanding of the molecular and cellular players in vascular anastomosis, but questions remain related to cellular dynamics and control of this process, in vitro. In this study, we exploited a three-dimensional (3-D) culture platform to examine the dynamics of endothelial cell (EC) during and after vascular anastomosis by allowing angiogenesis and vasculogenesis to proceed in parallel. We show that anastomosis occurs between sprouts formed by angiogenesis from an endothelium and tubes formed by vasculogenesis in the bulk of a 3-D matrix. This fusion leads to highly connected vessels that span from the surface of the matrix into the bulk in a manner that depends on cell density and identity. Further, we observe and analyze intermixing of endothelial cells of distinct origin (surface versus bulk) within the vessels structures that are formed; we provide evidence that the cells migrate along pre-existing vessels segments as part of this intermixing process. We conclude that anastomosis can occur between vessels emerging by angiogenesis and vasculogenesis and that this process may play an important role in contexts such as wound healing.

A contact line pinning based microfluidic platform for modelling physiological flows.

This work introduces a contact line pinning based microfluidic platform for the generation of interstitial and intramural flows within a three dimensional (3D) microenvironment for cellular behaviour studies. A contact line pinning method was used to confine a natively derived biomatrix, collagen, in microfluidic channels without walls. By patterning collagen in designated wall-less channels, we demonstrated and validated the intramural flows through a microfluidic channel bounded by a monolayer of endothelial cells (mimic of a vascular vessel), as well as slow interstitial flows within a cell laden collagen matrix using the same microfluidic platform. The contact line pinning method ensured the generation of an engineered endothelial tube with straight walls, and spatially uniform interstitial fluid flows through the cell embedded 3D collagen matrix. Using this device, we demonstrated that the breast tumour cells' (MDA-MB-231 cell line) morphology and motility were modulated by the interstitial flows, and the motility of a sub-population of the cells was enhanced by the presence of the flow. The presented microfluidic platform provides a basic framework for studies of cellular behaviour including cell transmigration, growth, and adhesion under well controlled interstitial and intramural flows, and within a physiologically realistic 3D co-culture setting.

Formation of microvascular networks in vitro.

This protocol describes how to form a 3D cell culture with explicit, endothelialized microvessels. The approach leads to fully enclosed, perfusable vessels in a bioremodelable hydrogel (type I collagen). The protocol uses microfabrication to enable user-defined geometries of the vascular network and microfluidic perfusion to control mass transfer and hemodynamic forces. These microvascular networks (µVNs) allow for multiweek cultures of endothelial cells or cocultures with parenchymal or tissue cells in the extra-lumen space. The platform enables real-time fluorescence imaging of living engineered tissues, in situ confocal fluorescence of fixed cultures and transmission electron microscopy (TEM) imaging of histological sections. This protocol enables studies of basic vascular and blood biology, provides a model for diseases such as tumor angiogenesis or thrombosis and serves as a starting point for constructing prevascularized tissues for regenerative medicine. After one-time microfabrication steps, the system can be assembled in less than 1 d and experiments can run for weeks.

In vitro microvessels for the study of angiogenesis and thrombosis.

Microvascular networks support metabolic activity and define microenvironmental conditions within tissues in health and pathology. Recapitulation of functional microvascular structures in vitro could provide a platform for the study of complex vascular phenomena, including angiogenesis and thrombosis. We have engineered living microvascular networks in three-dimensional tissue scaffolds and demonstrated their biofunctionality in vitro. We describe the lithographic technique used to form endothelialized microfluidic vessels within a native collagen matrix; we characterize the morphology, mass transfer processes, and long-term stability of the endothelium; we elucidate the angiogenic activities of the endothelia and differential interactions with perivascular cells seeded in the collagen bulk; and we demonstrate the nonthrombotic nature of the vascular endothelium and its transition to a prothrombotic state during an inflammatory response. The success of these microvascular networks in recapitulating these phenomena points to the broad potential of this platform for the study of cardiovascular biology and pathophysiology.