Search

We formulate and implement the Variational Quantum Eigensolver Self Consistent Field (VQE-SCF) algorithm in combination with polarizable embedding (PE), thereby extending PE to the regime of quantum computing. We test the resulting algorithm, PE-VQE-SCF, on quantum simulators and demonstrate that the computational stress on the quantum device is only slightly increased in terms of gate counts compared to regular VQE-SCF. On the other hand, no increase in shot noise was observed. We illustrate how PE-VQE-SCF may lead to the modeling of real chemical systems using a simulation of the reaction barrier of the Diels–Alder reaction between furan and ethene as an example. [ABSTRACT FROM AUTHOR]

The polarizable density embedding (PDE) model is an advanced fragment‐based QM/QM embedding model closely related to the earlier polarizable embedding (PE) model. PDE features an improved description of permanent electrostatics and further includes non‐electrostatic repulsion. We present an implementation of analytic geometric gradients for the PDE model, which allows for partial geometry optimizations of QM regions embedded in large molecular environments. We benchmark the quality of structures from PE‐QM and PDE‐QM geometry optimizations on a diverse set of small organic molecules embedded in four solvents. The PDE model performs well when targeting Hartree–Fock calculations, but density functional theory (DFT) calculations prove more challenging. We suggest a hybrid PDE‐LJ model which produces solute–solvent structures of good quality for DFT. Finally, we apply the developed model to a theoretical estimation of the solvatochromic shift on the fluorescence emission energy of the environment‐sensitive 4‐aminophthalimide probe based on state‐specific multiconfigurational PDE‐QM calculations. [ABSTRACT FROM AUTHOR]

The Dalton Project provides a uniform platform access to the underlying full-fledged quantum chemistry codes Dalton and LSDalton as well as the PyFraME package for automatized fragmentation and parameterization of complex molecular environments. The platform is written in Python and defines a means for library communication and interaction. Intermediate data such as integrals are exposed to the platform and made accessible to the user in the form of NumPy arrays, and the resulting data are extracted, analyzed, and visualized. Complex computational protocols that may, for instance, arise due to a need for environment fragmentation and configuration-space sampling of biochemical systems are readily assisted by the platform. The platform is designed to host additional software libraries and will serve as a hub for future modular software development efforts in the distributed Dalton community. [ABSTRACT FROM AUTHOR]

Chemical fine‐tuning of fluorophores is a pivotal step towards development of next generation fluorescent dyes for microscopy. With the advent of high‐resolution two‐photon excitation fluorescence imaging, there is a growing demand for very sensitive laser dyes that can be efficiently excited using commercial Ti:sapphire laser sources in the first near‐infrared window (NIR‐I, 780–1020 nm). Using the fluorescent dye Nile Red as the lead structure, we report a robust and concise Suzuki coupling approach for the synthesis of 14 new Nile Red analogues that feature extended π ring systems and diverse functionalities. For this set, we gauged their two‐photon excitation efficiency in NIR‐I as well as evaluated their general fluorescent properties (emission wavelength, Stokes shift, quantum yield and solvatochromism). Several of the new fluorophores were found to display very favorable characteristics. In particular, the derivative featuring a 4‐aminophenyl group in the 2‐position of Nile Red exhibited extreme solvent sensitivity, and the thien‐2‐yl substituted Nile Red derivative showed significantly redshifted emission, large Stokes shift and high two‐photon brightness. [ABSTRACT FROM AUTHOR]

In this work, 242 NMR spin–spin coupling constants (SSCC) in 20 molecules are calculated, either with correlated wave function methods, SOPPA and HRPA(D), or with density functional theory based on the B3LYP, BHandH, or PBE0 functionals. The calculations were carried out with and without treatment of solvation via a polarizable continuum model in both the geometry optimization step and/or the SSCC calculation, and thereby, four series of calculations were considered (the full-vacuum calculation, the full-solvent calculation, and the two cross combinations). The results were compared with experimental results measured in a solvent. With the goal of reproducing experimental values, we find that the performance of the PBE0 and BHandH SSCCs improves upon including solvation effects. On the other hand, the quality of the B3LYP SSCCs worsens with the inclusion of solvation. Solvation had almost no effect on the performance of the SOPPA and HRPA(D) calculations. We find that the PBE0-based calculations of the spin–spin coupling constants have the best agreement with the experimental data. [ABSTRACT FROM AUTHOR]

The malononitrile group is considered one of the strongest natural electron-withdrawing groups in a chemist's arsenal. However, surprisingly little is known about how this group functions in push–pull fluorophores. In a recent computational study, we reported that replacing the ketone group of the traditional push–pull dye Laurdan with a malononitrile group significantly improves the optical properties while retaining the membrane behavior of the parent molecule Laurdan. Motivated by these results, we report here the synthesis and photophysical characterization of the said compound, 6-(1-undecyl-2,2-dicyanovinyl)-N,N-dimethyl-2-naphthylamine (CN-Laurdan). To our surprise, this new CN-Laurdan probe is found to be much less bright than the parent Laurdan due to a large drop in the fluorescence quantum yield. Using computational methods, we determine that the origin of this low quantum yield is related to the existence of a non-radiative decay pathway related to a rotation of the malononitrile moiety, suggesting that the molecule could nonetheless function very well as a molecular rotor. We confirm experimentally that CN-Laurdan functions as a molecular rotor by measuring the quantum yield in methanol/glycerol mixtures of increasing viscosity. Specifically, we found a consistent increase in the quantum yield across the entire range of tested viscosities. [ABSTRACT FROM AUTHOR]

The polarizable embedding (PE) method is a fully self‐consistent fragment‐based QM/MM approach that uses advanced polarizable force fields and can be applied for various environments, including solvents and DNA. However, lack of proper electronic description of the MM environment can result in electron density leakage from the QM to the MM region, an effect known as electron spill‐out (ESO). ESO can be avoided by applying effective core potentials (ECPs) on MM atoms in PE (PE‐ECP) or by including repulsion operators to model the orthogonality between the two regions, as in the polarizable density embedding (PDE) approach. In this study, the one‐ and two‐photon absorptions of 4′‐(hydroxymethyl)‐4,5′,8‐trimethylpsoralen in complex with DNA and in aqueous solution are investigated. The effect of the missing non‐electrostatic repulsion of the MM region on result accuracy is showcased. While ESO errors are not readily visible for one‐photon absorption spectra, they become significant when computing two‐photon absorption, as more than one excited state is considered. Including ECPs on environment atoms sufficiently addresses the ESO problem, yielding correct structure for excited states. Comparisons with the more advanced PDE model show that PE‐ECP leads to qualitatively correct one‐ and two‐photon absorption spectra. [ABSTRACT FROM AUTHOR]

The solvatochromic fluorophore Nile Red, 9-diethylamino-5H-benzo[a]phenoxazine-5-one, is one of the most commonly used stains to enhance contrast of lipid-rich areas of microscopic biosamples. Quite surprisingly, relatively little is known about the spectrally-resolved two-photon absorption (2PA) properties of this dye despite its promising features for two-photon microscopy of biological matter. For this reason, the two-photon solvatochromism of Nile Red still remains an uncharted territory as well. Also, no study has yet reported on how electron-withdrawing substituents attached to the Nile Red backbone affect its solvatochromic properties and two-photon brightness. In this paper, we demonstrate how solvent polarity influences the one- and two-photon absorption spectra of Nile Red as well as its fluorescence parameters, and we present new analogues that contain –CF3, –F and –Br substituents on its eastern side. Two-photon excited fluorescence experiments in a broad spectral range (780–1240 nm) and electronic structure calculations show that both the nature and location of the substituent have particular influence on the strength of 2PA, peaking in all cases at approx. 860 and 1050 nm. 2PA cross sections are higher at 1050 nm than at 860 nm, which suggests that Nile Red and its analogues are best suited for two-photon imaging employing excitation in the NIR-II optical transparency window of biological tissues. [ABSTRACT FROM AUTHOR]

In this paper we show a theoretical rational design approach on a series of intrinsically fluorescent analogues of cholesterol (FLACs), called polyene-sterols (P-sterols), followed by a step-by-step selection of potential candidates, employing, sequentially, state-of-the-art quantum mechanical (QM) computations of the optical properties (single- and multiphoton absorption electronic spectroscopies and emission), molecular dynamics (MD) simulations in model membranes, and multiscale approaches (polarizable embedding). This selection converged to a promising candidate that shows simultaneously interesting single- and multiphoton absorption properties as well as emitting properties and good abilities to mimic cholesterol order effects in model membranes. [ABSTRACT FROM AUTHOR]

Nystatin is an antifungal polyene macrolide which is widely applied to treat yeast infections. Nystatin has also been used as a laboratory tool to inhibit endocytic processes in mammalian cells. The interaction of nystatin with model membranes has been studied thoroughly by various spectroscopic methods, making use of its weak fluorescence in the ultraviolet (UV). Studying its interaction with cells would require direct imaging, which, so far, required attachment of a fluorophore to nystatin. Using UV-sensitive microscopy, we show here how to visualize the interaction of nystatin with the plasma membrane (PM) directly. We find that nystatin forms micron-sized aggregates in buffer, and molecular dynamics simulations confirm that nystatin rapidly self-assembles into aggregates in aqueous solution. Using UV-sensitive microscopy, we find that large nystatin aggregates adhere to the surface of Chinese Hamster Ovarian (CHO) cells, causing slow spreading of nystatin fluorescence into the PM. Binding of nystatin to CHO cells does not interfere with cellular uptake or lateral membrane diffusion of the cholesterol analogue TopFluor-cholesterol (TF-Chol). Nystatin binds extensively to the PM of yeast cells as inferred from a strong UV signal in this membrane. Loading a yeast mutant unable to synthesize ergosterol with cholesterol gave much less nystatin membrane staining compared to loading such cells with ergosterol. These results explain the selective fungicidal effect of nystatin by differential interaction of nystatin with yeast membranes containing ergosterol compared to the mammalian cholesterol. Our combined experimental and computational approach provides a toolset for future design of new polyene macrolides. • Label-free imaging of nystatin–membrane interaction is demonstrated. • Nystatin forms aggregates, which can adhere to mammalian cells. • Membrane interaction of nystatin does not change diffusion of TopFluor-cholesterol. • Nystatin binds extensively to yeast cells containing ergosterol but not cholesterol. [ABSTRACT FROM AUTHOR]

Side-chain oxidized cholesterol derivatives, like 25-hydroxycholesterol (25-OH-Chol) are important regulators of cellular cholesterol homeostasis. How transport of oxysterols through the endo -lysosomal pathway contributes to their biological function is not clear. The Niemann-Pick C2 protein (NPC2) is a small lysosomal sterol transfer protein required for export of cholesterol from late endosomes and lysosomes (LE/LYSs). Here, we show that 25-hydroxy-cholestatrienol, (25-OH-CTL), an intrinsically fluorescent analogue of 25-OH-Chol, becomes trapped in LE/LYSs of NPC2-deficient fibroblasts, but can efflux from the cells even in the absence of NPC2 upon removal of the sterol source. Fluorescence recovery after photobleaching (FRAP) of 25-OH-CTL in endo -lysosomes was rapid and extensive and only partially dependent on NPC2 function. Using quenching of NPC2's intrinsic fluorescence, we show that 25-OH-Chol and 25-OH-CTL can bind to NPC2 though with lower affinity compared to cholesterol and its fluorescent analogues, cholestatrienol (CTL) and dehydroergosterol (DHE). This is confirmed by calculations of binding energies which additionally show that 25-OH-CTL can bind in two orientations to NPC2, in stark contrast to cholesterol and its analogues. We conclude that NPC2's affinity for all sterols is energetically favored over their self-aggregation in the lysosomal lumen. Lysosomal export of 25-OH-Chol is not strictly dependent on the NPC2 protein. Unlabelled Image • NPC2 binds the oxysterol 25-hydroxycholesterol in two orientations. • Transport of 25-hydroxycholesterol through lysosomes depends only little on NPC2. • Binding of oxysterols by NPC2 might prevent their aggregation in the lysosome. [ABSTRACT FROM AUTHOR]

The polarizable embedding (PE) model is a fragment‐based quantum‐classical approach aimed at accurate inclusion of environment effects in quantum‐mechanical response property calculations. The aim of this tutorial review is to give insight into the practical use of the PE model. Starting from a set of molecular structures and until you arrive at the final property, there are many crucial details to consider in order to obtain trustworthy results in an efficient manner. To lower the threshold for new users wanting to explore the use of the PE model, we describe and discuss important aspects related to its practical use. This includes directions on how to generate input files and how to run a calculation. This tutorial review is an introduction to the practical use of the quantum‐classical polarizable embedding model for computing response properties of molecules embedded in complex atomistic environments. It includes a getting‐started guide that illustrates how input files are generated and how to run calculations. Aspects that are crucial for efficiently obtaining reliable results are described and discussed. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Surgical treatments for postamputation pain: study protocol for an international, double-blind, randomized controlled trial." The correction addresses two changes that need to be made to the original article. One change is to the exclusion criteria, specifying that prior RPNI or TMR surgery should be included. The other change is to the patient selection process, clarifying that at least one of the listed methods should be used to document the presence of neuroma pain. Additionally, the sponsor of the trial has been changed from Chalmers University of Technology to the Center for Bionics and Pain Research. The correction notice provides the updated information and acknowledges the authors involved in the original article. [Extracted from the article]

Background: Painful conditions such as residual limb pain (RLP) and phantom limb pain (PLP) can manifest after amputation. The mechanisms underlying such postamputation pains are diverse and should be addressed accordingly. Different surgical treatment methods have shown potential for alleviating RLP due to neuroma formation — commonly known as neuroma pain — and to a lesser degree PLP. Two reconstructive surgical interventions, namely targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI), are gaining popularity in postamputation pain treatment with promising results. However, these two methods have not been directly compared in a randomised controlled trial (RCT). Here, we present a study protocol for an international, double-blind, RCT to assess the effectiveness of TMR, RPNI, and a non-reconstructive procedure called neuroma transposition (active control) in alleviating RLP, neuroma pain, and PLP. Methods: One hundred ten upper and lower limb amputees suffering from RLP will be recruited and assigned randomly to one of the surgical interventions (TMR, RPNI, or neuroma transposition) in an equal allocation ratio. Complete evaluations will be performed during a baseline period prior to the surgical intervention, and follow-ups will be conducted in short term (1, 3, 6, and 12 months post-surgery) and in long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participant is unsatisfied with the outcome of the treatment at that time, further treatment including one of the other procedures will be discussed in consultation with the clinical investigator at that site. Discussion: A double-blind RCT is necessary for the establishment of evidence-based procedures, hence the motivation for this work. In addition, studies on pain are challenging due to the subjectivity of the experience and the lack of objective evaluation methods. Here, we mitigate this problem by including different pain evaluation methods known to have clinical relevance. We plan to analyse the primary variable, mean change in NRS (0–10) between baseline and the 12-month follow-up, using the intention-to-treat (ITT) approach to minimise bias and keep the advantage of randomisation. The secondary outcomes will be analysed on both ITT and per-protocol (PP). An adherence protocol (PP population) analysis will be used for estimating a more realistic effect of treatment. Trial registration: ClinicalTrials.gov NCT05009394. [ABSTRACT FROM AUTHOR]

Background: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin's effects on cognitive function have not been widely or systematically studied. Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support – each participant having an assigned, dedicated therapist available throughout the session. Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing. Clinical Trial Registration: EudraCT (https://www.clinicaltrialsregister.eu/) number: 2018-000978-30. [ABSTRACT FROM AUTHOR]

• An intrinsically fluorescent analogue of 27-hydroxycholesterol, 27-hydroxy-cholestatrienol (27-OH-CTL) is presented. • Molecular simulations reveal the close similarity of 27-OH-CTL and 27-hydroxycholesterol but reveal differences to cholesterol. • 27-OH-CTL differs from the cholesterol analogue cholestatrienol (CTL) only in having one additional hydroxyl group. • UV-sensitive microscopy shows different trafficking itineraries of 27-OH-CTL and CTL in living human fibroblasts. • Fibroblasts can efflux 27-OH-CTL more efficiently than CTL, while both sterols move partly by non-vesicular transport in cells. Oxysterols are cholesterol metabolites with multiple functions in controlling cellular homeostasis. In particular, 27-hydroxycholesterol (27-OH-Chol) has been shown to regulate a variety of physiological functions, but little is known about its uptake, intracellular trafficking, and efflux from cells. This is largely due to a lack of suitable analogs of 27-OH-Chol, which mimic this oxysterol closely. Here, we present the intrinsically fluorescent 27-hydroxy-cholestatrienol (27-OH-CTL), which differs from 27-OH-Chol only by having two additional double bonds in the steroid ring system. Based on molecular dynamics (MD) simulations, we show that 27-OH-CTL possesses almost identical membrane properties compared to 27-OH-Chol. By comparative imaging of 27-OH-CTL and of the cholesterol analogue cholestatrienol (CTL) in living cells, we assess the impact of a single hydroxy group on sterol trafficking. We find that human fibroblasts take up more CTL than 27-OH-CTL, but efflux the oxysterol analogue more efficiently. For both sterols, efflux includes shedding of vesicles from the plasma membrane. Intracellular, 27-OH-CTL accumulates primarily in lipid droplets (LDs), while CTL is mostly found in endosomes and lysosomes. Using fluorescence recovery after photobleaching (FRAP), we find for both sterols a rapidly exchanging pool, which moves orders of magnitude faster than sterol containing vesicles and LDs. In summary, by applying a new fluorescent derivative of 27-OH-Chol we demonstrate that human cells can distinguish sterols based on a single hydroxy group in the side chain, resulting in different transport itineraries, dynamics, and efflux kinetics. Both intrinsically fluorescent cholesterol and oxysterol analogues show rapid non-vesicular transport in human fibroblasts. [ABSTRACT FROM AUTHOR]

In Denmark, biennial population screening for colorectal cancer was introduced in 2014 for all aged 50–74 years. Five laboratories representative for the regional division of Denmark perform the immunochemical testing of faecal occult blood in the screening samples (iFOBT, OC-Sensor (Eiken Chemical, cut-off 100 µg/L)). In July 2016, a new agreement on the public post-delivery entailed an increased lag time (five days) from the screening participant drops the screening sample into a mail-box until sample arrival at the laboratories. Previous work had reported that a lag time above five days led to more false negative iFOBT tests. We investigated if this was true also under Danish conditions. We performed two stability tests; one with sample storage at 30 °C for 14 days (N = 60), and another with sample storage at room temperature for 13 days (N = 10). We extracted data from our laboratory information system (LABKA) on all iFOBT tests performed in the entire Central Denmark Region (N = 104,328 patients) during the last six months for each calendar year 2014–16. For each year, we computed the distribution of iFOBT tests below and above cut-off. Our stability tests showed no positive samples switching to false negative after storage; however, some negative samples turned false positive, especially at 30 °C. The data showed no change in the distribution of iFOBT tests below and above cut-off after July 2016. We found no evidence that an enhanced lag time increased the number of false negative iFOBT tests in the Danish screening program for colorectal cancer. [ABSTRACT FROM PUBLISHER]