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Martin Lund,1 Torben B Pedersen,1 Søren Feddersen,2,3 Louise D Østergaard,1,3 Charlotte A Poulsen,1 Christian Enggaard,2 Mads HA Poulsen,1,3 Lars Lund1,3 1Department of Urology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Lars Lund, Department of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense, 5000, Denmark, Tel +45 5140 8982, Fax +45 6541 1726, Email Lars.Lund@rsyd.dkPurpose: Serum levels of the polypeptide chemokine C-C motif ligand 2 (CCL2) have previously shown potential as a prostate cancer diagnostic and prognostic biomarker. Plasma CCL2 levels may be superior to serum levels as a biomarker because of their potentially lower signal-to-noise ratio.Materials and Methods: Before initiating a large comparative study of plasma and serum CCL2 levels, we performed a prospective, diagnostic pilot study Of 133 individuals from a clinically relevant population. CCL2 plasma levels were measured using a validated assay kit. Plasma was obtained independently of digital rectal examination.Results: In this pilot study, we found no relationship between CCL2 plasma values and risk of proven prostate cancer, whereas previous studies found a strong diagnostic relationship between CCL2 serum values and prostate cancer.Conclusion: Our contribution to the existing literature strengthens the idea that early in the pathological process, CCL2 mainly circulates in large, membrane-enclosed compartments, whereas plasma CCL2 levels increase markedly during disease progression. We conclude that whereas plasma CCL2 levels are not useful as a diagnostic measure, a ratio of CCL2 plasma to serum levels may prove useful as a marker of disease progression, which warrants further study.Keywords: diagnostics, liquid biopsy, CCL2, monocyte chemoattractant protein 1, MCP1

The Fusarium solani species complex (FSSC) is comprised of important pathogens of plants and humans. A distinctive feature of FSSC species is perithecial pigmentation. While the dark perithecial pigments of other Fusarium species are derived from fusarubins synthesized by polyketide synthase 3 (PKS3), the perithecial pigments of FSSC are derived from an unknown metabolite synthesized by PKS35. Here, we confirm in FSSC species Fusarium vanettenii that PKS35 (fsnI) is required for perithecial pigment synthesis by deletion analysis and that fsnI is closely related to phnA from Penicillium herquei, as well as duxI from Talaromyces stipentatus, which produce prephenalenone as an early intermediate in herqueinone and duclauxin synthesis respectively. The production of prephenalenone by expression of fsnI in Saccharomyces cerevisiae indicates that it is also an early intermediate in perithecial pigment synthesis. We next identified a conserved cluster of 10 genes flanking fsnI in F. vanettenii that when expressed in F. graminearum led to the production of a novel corymbiferan lactone F as a likely end product of the phenalenone biosynthetic pathway in FSSC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent advances in attosecond science have made it increasingly important to develop stable, reliable, and accurate algorithms and methods to model the time evolution of atoms and molecules in intense laser fields. A key process in attosecond science is high-harmonic generation, which is challenging to model with fixed Gaussian basis sets, as it produces high-energy electrons, with a resulting rapidly varying and highly oscillatory wave function that extends over dozens of ångström. Recently, Rothe's method, where time evolution is rephrased as an optimization problem, has been applied to the one-dimensional Schrödinger equation. Here, we apply Rothe's method to the hydrogen wave function and demonstrate that thawed, complex-valued Gaussian wave packets with time-dependent width, center, and momentum parameters are able to reproduce spectra obtained from essentially exact grid calculations for high-harmonic generation with only 50-181 Gaussians for field strengths up to 5 × 1014 W/cm2. This paves the way for the inclusion of continuum contributions into real-time, time-dependent electronic-structure theory with Gaussian basis sets for strong fields and eventually accurate simulations of the time evolution of molecules without the Born-Oppenheimer approximation., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The assumptions underpinning the adiabatic Born-Oppenheimer (BO) approximation are broken for molecules interacting with attosecond laser pulses, which generate complicated coupled electronic-nuclear wave packets that generally will have components of electronic and dissociation continua as well as bound-state contributions. The conceptually most straightforward way to overcome this challenge is to treat the electronic and nuclear degrees of freedom on equal quantum-mechanical footing by not invoking the BO approximation at all. Explicitly correlated Gaussian (ECG) basis functions have proved successful for non-BO calculations of stationary molecular states and energies, reproducing rovibrational absorption spectra with very high accuracy. In this Article, we present a proof-of-principle study of the ability of fully flexible ECGs (FFECGs) to capture the intricate electronic and rovibrational dynamics generated by short, high-intensity laser pulses. By fitting linear combinations of FFECGs to accurate wave function histories obtained on a large real-space grid for a regularized 2D model of the hydrogen atom and for the 2D Morse potential, we demonstrate that FFECGs provide a very compact description of laser-driven electronic and rovibrational dynamics.

Fungal polyketides are a large group of secondary metabolites, valuable due to their diverse spectrum of pharmacological activities. Polyketide biosynthesis in filamentous fungi presents some challenges: small yield and low-purity titers. To tackle these issues, we switched to the yeast Yarrowia lipolytica , an easily cultivable heterologous host. As an oleaginous yeast, Y. lipolytica displays a high flux of acetyl- and malonyl-CoA precursors used in lipid synthesis. Likewise, acetyl- and malonyl-CoA are the building blocks of many natural polyketides, and we explored the possibility of redirecting this flux toward polyketide production. Despite its promising prospect, Y. lipolytica has so far only been used for heterologous expression of simple type III polyketide synthases (PKSs) from plants. Therefore, we decided to evaluate the potential of Y. lipolytica by targeting the more complex fungal polyketides synthesized by type I PKSs. We employed a CRISPR-Cas9-mediated genome editing method to achieve markerless gene integration of the genes responsible for bostrycoidin biosynthesis in Fusarium solani ( fsr1 , fsr2 , and fsr3 ) and 6-methylsalicylic acid (6-MSA) biosynthesis in Aspergillus hancockii (6MSAS). Moreover, we attempted titer optimization through metabolic engineering by overexpressing two enzymes, TGL4 and AOX2, involved in lipid β-oxidation, but we did not observe an effect on polyketide production. With maximum titers of 403 mg/L 6-MSA and 35 mg/L bostrycoidin, the latter being substantially higher than our previous results in Saccharomyces cerevisiae (2.2 mg/L), this work demonstrates the potential of Y. lipolytica as a platform for heterologous production of complex fungal polyketides., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bejenari, Spedtsberg, Mathiesen, Jeppesen, Cernat, Toussaint, Apostol, Stoianov, Pedersen, Nielsen and Sørensen.)

Molecular structure, a key concept of chemistry, has remained elusive from the perspective of all-particle quantum mechanics, despite many efforts. Viewing molecular structure as a manifestation of strong statistical correlation between nuclear positions, we propose a practical method based on Markov chain Monte Carlo sampling and unsupervised machine learning. Application to the D 3 + molecule unambiguously shows that it possesses an equilateral triangular structure. These results provide a major step forward in our understanding of the molecular structure from fundamental quantum principles.

We present a numerical approach to magnetic optical rotation based on real-time time-dependent electronic-structure theory. Not relying on perturbation expansions in the magnetic field strength, the formulation allows us to test the range of validity of the linear relation between the rotation angle per unit path length and the magnetic field strength that was established empirically by Verdet 160 years ago. Results obtained from time-dependent coupled-cluster and time-dependent current density-functional theory are presented for the closed-shell molecules H2, HF, and CO in magnetic fields up to 55 kT at standard temperature and pressure conditions. We find that Verdet's linearity remains valid up to roughly 10-20 kT, above which significant deviations from linearity are observed. Among the three current density-functional approximations tested in this work, the current-dependent Tao-Perdew-Staroverov-Scuseria hybrid functional performs the best in comparison with time-dependent coupled-cluster singles and doubles results for the magnetic optical rotation., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Recombinant plasmids are essential tools in molecular biotechnology, and reliable plasmid assembly methods have, therefore, become a prerequisite for the successful cloning and transfer of genes. Among the multitude of available plasmid assembly strategies, in vivo homologous recombinational cloning in yeast has emerged as a cost-effective and relatively simple method. Since we use this method routinely in our group for assembling large plasmids with secondary metabolite gene clusters and for direct heterologous production of polyketides in Saccharomyces cerevisiae , we developed an exercise module for undergraduate students where they would get hands-on experience with these molecular practices. The exercises target several molecular techniques, including PCR, restriction enzyme digestion, and yeast recombinational cloning. The students will learn about plasmid assembly and yeast transformation methods by performing these experiments while inherently acquiring new skills valuable for their subsequent laboratory work or projects., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Bejenari et al.)

We present a novel function fitting method for approximating the propagation of the time-dependent electric dipole moment from real-time electronic structure calculations. Real-time calculations of the electronic absorption spectrum require discrete Fourier transforms of the electric dipole moment. The spectral resolution is determined by the total propagation time, i.e., the trajectory length of the dipole moment, causing a high computational cost. Our developed method uses function fitting on shorter trajectories of the dipole moment, achieving arbitrary spectral resolution through extrapolation. Numerical testing shows that the fitting method can reproduce high-resolution spectra by using short dipole trajectories. The method converges with as little as 100 a.u. dipole trajectories for some systems, though the difficulty converging increases with the spectral density. We also introduce an error estimate of the fit, reliably assessing its convergence and hence the quality of the approximated spectrum.

We propose a novel a posteriori error assessment for the single-reference coupled-cluster (SRCC) method called the S -diagnostic. We provide a derivation of the S -diagnostic that is rooted in the mathematical analysis of different SRCC variants. We numerically scrutinized the S -diagnostic, testing its performance for (1) geometry optimizations, (2) electronic correlation simulations of systems with varying numerical difficulty, and (3) the square-planar copper complexes [CuCl 4 ] 2- , [Cu(NH 3 ) 4 ] 2+ , and [Cu(H 2 O) 4 ] 2+ . Throughout the numerical investigations, the S -diagnostic is compared to other SRCC diagnostic procedures, that is, the T 1 , D 1 , max T 2 , and D 2 diagnostics as well as different indices of multideterminantal and multireference character in coupled-cluster theory. Our numerical investigations show that the S -diagnostic outperforms the T 1 , D 1 , max T 2 and D 2 diagnostics and is comparable to the indices of multideterminantal and multireference character in coupled-cluster theory in their individual fields of applicability. The experiments investigating the performance of the S -diagnostic for geometry optimizations using SRCC reveal that the S -diagnostic correlates well with different error measures at a high level of statistical relevance. The experiments investigating the performance of the S -diagnostic for electronic correlation simulations show that the S -diagnostic correctly predicts strong multireference regimes. The S -diagnostic, moreover, correctly detects the successful SRCC computations for [CuCl 4 ] 2- , [Cu(NH 3 ) 4 ] 2+ , and [Cu(H 2 O) 4 ] 2+ , which have been known to be misdiagnosed by T 1 and D 1 diagnostics in the past. This shows that the S -diagnostic is a promising candidate for an a posteriori diagnostic for SRCC calculations.

Real-time simulations of laser-driven electron dynamics contain information about molecular optical properties through all orders in response theory. These properties can be extracted by assuming convergence of the power series expansion of induced electric and magnetic multipole moments. However, the accuracy relative to analytical results from response theory quickly deteriorates for higher-order responses due to the presence of high-frequency oscillations in the induced multipole moment in the time domain. This problem has been ascribed to missing higher-order corrections. We here demonstrate that the deviations are caused by nonadiabatic effects arising from the finite-time ramping from zero to full strength of the external laser field. Three different approaches, two using a ramped wave and one using a pulsed wave, for extracting electrical properties from real-time time-dependent electronic-structure simulations are investigated. The standard linear ramp is compared to a quadratic ramp, which is found to yield highly accurate results for polarizabilities, and first and second hyperpolarizabilities, at roughly half the computational cost. Results for the third hyperpolarizability are presented along with a simple, computable measure of reliability., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Prostate needle biopsies are an essential step in the diagnostic evaluation of prostate cancer. The conventional ultrasound-guided transrectal needle biopsy entails a significant risk of infection, which with increasing antibiotic resistance is thought to increase in the future. This has sparked a renewed interest in transperineal prostate biopsies, as this approach avoids the multiple passages of the rectal mucosa, thus reducing the risk of infection significantly. This review describes the devolvement, technical aspects, and current recommendations of transperineal biopsies.

Introduction: Direct biopsy of the prostate is used for diagnosing prostate cancer and most prostate biopsies are performed transrectally with ultrasonic guidance (TRUS-BX). The transrectal approach carries a risk of sepsis as bacteria may transfer directly into the prostate from the rectum. Approximately 6% of the patients will be hospitalised within seven days after TRUX-BX. Increasing antibiotic resistance has spurred a renewed interest in the transperineal approach (TP-BX). Aseptic TP-BX may be performed, significantly reducing the risk of infection. We described the first Danish experience with multiparametric MRI-guided freehand TP-BX., Methods: Men scheduled for TP-BX were included. Patient age, prostate-specific antigen level, previous biopsy history, weight and height were recorded. We employed a visual analogue scale (VAS) for the various procedure parts and the patients rated their satisfaction. Complications and International Society of Urological Pathology scores were recorded and cancer detection rates calculated., Results: A total of 143 men had TP-BX performed in a consecutive series. The cancer detection rate was 81.8% (95% confidence interval: 74.5-87.8%). The procedure was well tolerated with a median VAS of 2 (range: 0-7), and patients expressed a high degree of satisfaction with the procedure. One patient was hospitalised due to infection., Conclusion: TP-BX is well tolerated and feasible as an outpatient procedure performed in local anaesthesia. Transperineal biopsies have a low risk of infection., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Laser-induced molecular alignment is well understood within the framework of the Born-Oppenheimer (BO) approximation. Without the BO approximation, however, the concept of molecular structure is lost, making it hard to precisely define alignment. In this work, we demonstrate the emergence of alignment from the first-ever non-BO quantum dynamics simulations, using the HD molecule exposed to ultrashort laser pulses as a few-body test case. We extract the degree of alignment from the non-BO wave function by means of an operator expressed in terms of pseudo-proton coordinates that mimics the BO-based definition of alignment. The only essential approximation, in addition to the semiclassical electric-dipole approximation for the matter-field interaction, is the choice of time-independent explicitly correlated Gaussian basis functions. We use a variational, electric-field-dependent basis-set construction procedure, which allows us to keep the basis-set dimension low while capturing the main effects of electric polarization on the nuclear and electronic degrees of freedom. The basis-set construction procedure is validated by comparing with virtually exact grid-based simulations for two one-dimensional model systems: laser-driven electron dynamics in a soft attractive Coulomb potential and nuclear rovibrational dynamics in a Morse potential.

Objective: Sacral neuromodulation (SNM) is a well-established treatment modality for idiopathic overactive bladder and urgency incontinence, idiopathic fecal incontinence and non-obstructive urinary retention. This study describes the start-up phase of establishing the SNM service. Primary objective: To investigate the patient-reported outcome measures of SNM on lower urinary tract dysfunction symptoms. Secondary objectives : To investigate bowel function, sexual satisfaction and to monitor SNM safety., Materials and Methods: Twenty-two patients with refractory idiopathic and neurogenic lower urinary tract dysfunction were offered a two-stage test-phase procedure and SNM device implantation. On completing the study, the patients rated their satisfaction with the treatment using a five-point Likert scale and a bother score of urinary, bowel and sexual symptoms on a scale of 1-10 (the worst). Their complications were assessed., Results: Nineteen patients (86%) were responders during the test phase and had the pulse generator implanted. Seventeen patients were very satisfied/satisfied. A statistically significant change in urinary symptoms bother score was observed in the idiopathic and neurogenic patients, a reduction from 10 to 4 ( p  = .0057) and 10 to 3 ( p  = .014), respectively. Eleven patients (58%) had symptoms from two or three pelvic compartments. Nine patients (47%) had complications. All but one event was resolved., Conclusions: SNM is safe in this heterogeneous group of patients with refractory lower urinary tract dysfunction of various etiologies. A substantial improvement was observed in the pelvic organ dysfunction, demanding a multidisciplinary approach. More studies are required to standardize the evaluation of the subjective and objective outcomes of SNM.

A quantum key distribution (QKD) system must fulfill the requirement of universal composability to ensure that any cryptographic application (using the QKD system) is also secure. Furthermore, the theoretical proof responsible for security analysis and key generation should cater to the number N of the distributed quantum states being finite in practice. Continuous-variable (CV) QKD based on coherent states, despite being a suitable candidate for integration in the telecom infrastructure, has so far been unable to demonstrate composability as existing proofs require a rather large N for successful key generation. Here we report a Gaussian-modulated coherent state CVQKD system that is able to overcome these challenges and can generate composable keys secure against collective attacks with N ≈ 2 × 10 8 coherent states. With this advance, possible due to improvements to the security proof and a fast, yet low-noise and highly stable system operation, CVQKD implementations take a significant step towards their discrete-variable counterparts in practicality, performance, and security., (© 2022. The Author(s).)

We present a derivation of real-time (RT) time-dependent orbital-optimized Møller-Plesset (TDOMP2) theory and its biorthogonal companion, time-dependent non-orthogonal OMP2 theory, starting from the time-dependent bivariational principle and a parametrization based on the exponential orbital-rotation operator formulation commonly used in the time-independent molecular electronic structure theory. We apply the TDOMP2 method to extract absorption spectra and frequency-dependent polarizabilities and first hyperpolarizabilities from RT simulations, comparing the results with those obtained from conventional time-dependent coupled-cluster singles and doubles (TDCCSD) simulations and from its second-order approximation, TDCC2. We also compare our results with those from CCSD and CC2 linear and quadratic response theories. Our results indicate that while TDOMP2 absorption spectra are of the same quality as TDCC2 spectra, including core excitations where optimized orbitals might be particularly important, frequency-dependent polarizabilities and hyperpolarizabilities from TDOMP2 simulations are significantly closer to TDCCSD results than those from TDCC2 simulations.

The biosynthetic pathways for the fungal polyketides bikaverin and bostrycoidin, from Fusarium verticillioides and Fusarium solani respectively, were reconstructed and heterologously expressed in S. cerevisiae alongside seven different phosphopantetheinyl transferases (PPTases) from a variety of origins spanning bacterial, yeast and fungal origins. In order to gauge the efficiency of the interaction between the ACP-domains of the polyketide synthases (PKS) and PPTases, each were co-expressed individually and the resulting production of target polyketides were determined after 48 h of growth. In co-expression with both biosynthetic pathways, the PPTase from Fusarium verticillioides (FvPPT1) proved most efficient at producing both bikaverin and bostrycoidin, at 1.4 mg/L and 5.9 mg/L respectively. Furthermore, the remaining PPTases showed the ability to interact with both PKS's, except for a single PKS-PPTase combination. The results indicate that it is possible to boost the production of a target polyketide, simply by utilizing a more optimal PPTase partner, instead of the commonly used PPTases; NpgA, Gsp and Sfp, from Aspergillus nidulans, Brevibacillus brevis and Bacillus subtilis respectively., (© 2022. The Author(s).)

Quinones represent an important group of highly structurally diverse, mainly polyketide-derived secondary metabolites widely distributed among filamentous fungi. Many quinones have been reported to have important biological functions such as inhibition of bacteria or repression of the immune response in insects. Other quinones, such as ubiquinones are known to be essential molecules in cellular respiration, and many quinones are known to protect their producing organisms from exposure to sunlight. Most recently, quinones have also attracted a lot of industrial interest since their electron-donating and -accepting properties make them good candidates as electrolytes in redox flow batteries, like their often highly conjugated double bond systems make them attractive as pigments. On an industrial level, quinones are mainly synthesized from raw components in coal tar. However, the possibility of producing quinones by fungal cultivation has great prospects since fungi can often be grown in industrially scaled bioreactors, producing valuable metabolites on cheap substrates. In order to give a better overview of the secondary metabolite quinones produced by and shared between various fungi, mainly belonging to the genera Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium, this review categorizes quinones into families such as emodins, fumigatins, sorbicillinoids, yanuthones, and xanthomegnins, depending on structural similarities and information about the biosynthetic pathway from which they are derived, whenever applicable. The production of these quinone families is compared between the different genera, based on recently revised taxonomy. KEY POINTS: • Quinones represent an important group of secondary metabolites widely distributed in important fungal genera such as Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium. • Quinones are of industrial interest and can be used in pharmacology, as colorants and pigments, and as electrolytes in redox flow batteries. • Quinones are grouped into families and compared between genera according to the revised taxonomy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Natural products display a large structural variation and different uses within a broad spectrum of industries. In this study, we investigate the influence of carbohydrates and nitrogen sources on the production and selectivity of production of four different polyketides produced by Fusarium solani , fusarubin, javanicin, bostrycoidin and anhydrofusarubin. We introduce four different carbohydrates and two types of nitrogen sources. Hereafter, a full factorial design was applied using combinations of three levels of sucrose and three levels of the two types of nitrogen. Each combination displayed different selectivity and production yields for all the compounds of interest. Response surface design was utilized to investigate possible maximum yields for the surrounding combinations of media. It was also shown that the maximum yields were not always the ones illustrating high selectivity, which is an important factor for making purification steps easier. We visualized the production over time for one of the media types, illustrating high yields and selectivity.

Objective: Overactive bladder (OAB) affects hundreds of millions of people worldwide and has significant detrimental effects on quality-of-life. Percutaneous tibial nerve stimulation (PTNS) is endorsed in the European guidelines of Urology as second-line therapy - on par with pharmacological treatment for women with OAB., Methods: This prospective cohort study describes our clinical experience with PTNS in a daily outpatient clinic, on a consecutive cohort. The cohort of 116 patients was mixed; including both men and women with idiopathic (iOAB) and neurogenic (nOAB) overactive bladder. Patients were treated with a 12-week course of PTNS followed by monthly maintenance treatment. Data were collected during 4 years., Results: The most common indication for PTNS was OAB with urge incontinence (53%) followed by OAB-dry and nocturia (both 16%). One hundred and ten (95%) patients completed follow-up and 68 patients (62%) continued to maintenance treatment. A total of 68 patients reported an effect on PROM, BD and ICIQ-OAB, which is the same 62% that continue in maintenance PTNS. A significant decline was seen in overall ICIQ-OAB score, with a median drop from 87 to 54, a significant decline in overall frequency and nocturia on bladder diary and a shift in pad test group in 19% of the incontinence patients., Conclusion: PTNS shows an equally significant effect on men as well as women both in the iOAB and nOAB subgroups in a daily outpatient clinic. In our opinion, PTNS should be a standard treatment option available at urological departments, where both men and women in both sub-groups could benefit from treatment. Further randomized studies focusing on men with iOAB are needed.

Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.

Quantum random number generators promise perfectly unpredictable random numbers. A popular approach to quantum random number generation is homodyne measurements of the vacuum state, the ground state of the electro-magnetic field. Here we experimentally implement such a quantum random number generator, and derive a security proof that considers quantum side-information instead of classical side-information only. Based on the assumptions of Gaussianity and stationarity of noise processes, our security analysis furthermore includes correlations between consecutive measurement outcomes due to finite detection bandwidth, as well as analog-to-digital converter imperfections. We characterize our experimental realization by bounding measured parameters of the stochastic model determining the min-entropy of the system's measurement outcomes, and we demonstrate a real-time generation rate of 2.9 Gbit/s. Our generator follows a trusted, device-dependent, approach. By treating side-information quantum mechanically an important restriction on adversaries is removed, which usually was reserved to semi-device-independent and device-independent schemes.

We demonstrate theoretically and numerically that laser-driven many-electron dynamics, as described by bivariational time-dependent coupled-cluster (CC) theory, may be analyzed in terms of stationary-state populations. Projectors heuristically defined from linear response theory and equation-of-motion CC theory are proposed for the calculation of stationary-state populations during interaction with laser pulses or other external forces, and conservation laws of the populations are discussed. Numerical tests of the proposed projectors, involving both linear and nonlinear optical processes for He and Be atoms and for LiH, CH + , and LiF molecules show that the laser-driven evolution of the stationary-state populations at the coupled-cluster singles-and-doubles (CCSD) level is very close to that obtained by full configuration interaction (FCI) theory, provided that all stationary states actively participating in the dynamics are sufficiently well approximated. When double-excited states are important for the dynamics, the quality of the CCSD results deteriorates. Observing that populations computed from the linear response projector may show spurious small-amplitude, high-frequency oscillations, the equation-of-motion projector emerges as the most promising approach to stationary-state populations.

Through stepwise recreation of the biosynthetic gene cluster containing PKS3 from Fusarium solani , it was possible to produce the core scaffold compound of bostrycoidin, a red aza-anthraquinone pigment in Saccharomyces cerevisiae . This was achieved through sequential transformation associated recombination (TAR) cloning of FvPPT , fsr1 , fsr2 , and fsr3 into the pESC-vector system, utilizing the inducible bidirectional galactose promoter for heterologous expression in S. cerevisiae . The production of the core metabolite bostrycoidin was investigated through triplicate growth cultures for 1-4 days, where the maximum titer of bostrycoidin was achieved after 2 days of induction, yielding 2.2 mg/L.

Purpose: In most cases, squamous cell carcinoma of the anus (SCCA) is treated with chemo-radiotherapy preserving sphincter function and offering good long-term survival and low recurrence rates. However, chemo-radiotherapy has several side effects: dyspareunia, impotence, fecal incontinence, pain, and skin symptoms. Small/T1 tumors, without metastatic disease, can be treated with local excision alone. We aimed to systematically review the literature regarding outcome following local excision of T1 SCCA., Methods: PubMed and Embase databases were searched for studies that investigated outcome following local excision of SCCA., Results: Twenty-three studies were included. Twenty of the studies were retrospective, and three studies included more than 100 patients. Most of the studies were published before the 1980s. Overall there was great heterogeneity and missing data across the included studies when comparing patient demographics, resection margins, definitions on tumor location, and outcome. Overall 5-year survival was 69% (95% CI 66-72) following local excision. Overall 5-year recurrence was 37% (95% CI 30-45) following local excision. No complications were reported following local excision., Conclusion: The current literature on outcome following local excision of T1 anal cancers consists predominantly of smaller, retrospective, and heterogenous studies. Overall 5-year survival is acceptable, but worse than following chemo-radiation therapy. However, local excision seems to have no or only few minor complications. Recurrence rates are high. Therefore, a thorough follow-up program is needed when performing local excision as primary treatment for T1 SCCA. There is an evident need for further studies.

Quinones are produced in organisms and are utilized as electron transfer agents, pigments and in defence mechanisms. Furthermore, naturally occurring quinones can also be cytotoxins with antibacterial properties. These properties can be linked to their redox properties. Recent studies have also shown that quinones can be utilized in flow battery technology, though naturally occurring quinones have not yet been investigated. Here, we have analyzed the properties of 990 different quinones of various biological sources through a computation approach to determine their standard reduction potentials and aqueous solubility. The screening was performed using the PBE functional and the 6-31G** basis set, providing a distribution of reduction potentials of the naturally occurring quinones varying from - 1.4 V to 1.5 V vs. the standard hydrogen electrode. The solvation energy for each quinone, which indicates the solubility in aqueous solution, was calculated at the same level. A large distribution of solubilities was obtained, containing both molecules that show tendencies of good solubilities and molecules that do not. The solubilities are dependent on the nature of the side groups and the size of the molecules. Our study shows that the group containing the quinones of fungal origin, which is also the largest of the groups considered, has the largest antimicrobial and electrochemical potential, when considering the distribution of reduction potentials for the compounds.

Purpose: Definitive diagnosis of prostate cancer is based on biopsies, a procedure associated with side-effects. The use of biomarkers in blood and urine could potentially help clinicians select patients for whom biopsies are needed. The aim of the study was to test a new urine and plasma biomarker test in detecting medium and high grade prostate cancer. Materials and methods: Blood and urine samples were prospectively collected from 41 patients prior to prostate biopsy or TUR-P and again after 3 months. The cohort included patients with suspicion of prostate cancer and patients with prior prostate cancer diagnosis. The mRNA expression of ten selected genes measured by PCR were used together with clinical data in multiple algorithms for prediction of medium-high grade prostate cancer in prostate biopsies. The testing was originally developed and validated in the USA. The method was transferred to a local Danish laboratory. Medium and high grade cancer was defined as Gleason score ≥ 3 + 4. Results: Using the biomarker test, prior to any prostate procedures, the sensitivity for detecting medium-high grade prostate cancer was 100% and the specificity was 56% and 63%, depending on the cut-off point used. When using the biomarker test, following biopsy or TUR-P, the sensitivity and specificity were reduced to 89% and 28-34% respectively. When comparing results, there was a significant difference ( p  < 0.05), favoring the test performed prior to the procedures. Conclusions: We were able to predict the presence of medium-high grade prostate cancer, thereby confirming earlier findings of the biomarker test.

MOLCAS/OpenMolcas is an ab initio electronic structure program providing a large set of computational methods from Hartree-Fock and density functional theory to various implementations of multiconfigurational theory. This article provides a comprehensive overview of the main features of the code, specifically reviewing the use of the code in previously reported chemical applications as well as more recent applications including the calculation of magnetic properties from optimized density matrix renormalization group wave functions.

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.

Objective: Guidelines recommend 4 weeks of thromboembolic prophylaxis in patients who undergo major surgery for solid malignancies. However, there are limited head-to-head comparisons of risk of venous thromboembolic complications in patients with and without cancer undergoing similar surgical procedures. The purpose of this study was to compare risk of venous thromboembolic complications following major renal surgery and cystectomy between patients with and without cancer at the time of surgery., Material and Methods: In the nationwide Danish National Patient Registry, which captures all hospital contacts, including surgical procedures, we identified 8,645 patients who underwent major renal surgery (4,273 without cancer and 4,372 with cancer) and 2,164 patients who underwent cystectomy (359 without cancer and 1,805 with cancer) in 2000-2009. The rate of venous thromboembolic events within 6 months from surgery was compared for patients with and without cancer after stratification on organ using Chi-squared test., Results: There was no difference in the rate of venous thromboembolic complications within the first 6 months after major renal surgery (0.4% and 0.3% [p=0.91]) or cystectomy (1.3% and 0.8% [p=0.44]) for patients with and without cancer. The cost for 28 days of Tinzaparin 4.500 IE administered by the patient was €112, whereas the cost if administered by a community nurse was €1.988., Conclusions: Our study questions the different recommendations in thromboembolic prophylaxis between patients with and without cancer after major renal surgery and cystectomy.

We investigate the numerical stability of time-dependent coupled-cluster theory for many-electron dynamics in intense laser pulses, comparing two coupled-cluster formulations with full configuration interaction theory. Our numerical experiments show that orbital-adaptive time-dependent coupled-cluster doubles (OATDCCD) theory offers significantly improved stability compared with the conventional Hartree-Fock-based time-dependent coupled-cluster singles-and-doubles (TDCCSD) formulation. The improved stability stems from greatly reduced oscillations in the doubles amplitudes, which, in turn, can be traced to the dynamic biorthonormal reference determinants of OATDCCD theory. As long as these are good approximations to the Brueckner determinant, OATDCCD theory is numerically stable. We propose the reference weight as a diagnostic quantity to identify situations where the TDCCSD and OATDCCD theories become unstable.

Introduction: Squamous cell carcinoma of the anus is a rare condition. First line treatment is combined chemo-radio therapy. As many as a third of patients undergoing chemo-radiotherapy will experience recurrence. These patients often undergo salvage surgery with an extended abdominoperineal excision. The aim of this study was to examine the quality of life in disease free survivors following salvage surgery for squamous cell carcinoma of the anus., Material and Methods: Patients undergoing salvage surgery for SCCA at Copenhagen University Hospital Herlev between 1st of January 2011 and 31st December 2016 were identified and quality of life was assessed with EORTC QLQ-C30 and EORTC QLQ-CR29 questionnaires., Results: 47 patients underwent salvage surgery for relapse or residual tumor in the period. From this cohort 25 disease-free survivors were identified. Fourteen (56%) patients returned a completed questionnaire. Overall median global health status was 75(range 20-100). Functional scores were generally high. In General, symptom scores were low, however all men reported impotence with a median symptom score of 100(range 67-100) and half the women reported dyspareunia. Urinary impairment was present in half the patients. Abdominal and buttock pain scores were low., Conclusion: Quality of life following salvage surgery for squamous cell carcinoma of the anus is affected but at an acceptable level. However, there are considerable side-affects in the form of impotence, dyspareunia and urinary impairment., (Copyright © 2019. Published by Elsevier Ltd.)

The formulation of the time-dependent Schrödinger equation in terms of coupled-cluster theory is outlined, with emphasis on the bivariational framework and its classical Hamiltonian structure. An indefinite inner product is introduced, inducing physical interpretation of coupled-cluster states in the form of transition probabilities, autocorrelation functions, and explicitly real values for observables, solving interpretation issues which are present in time-dependent coupled-cluster theory and in ground-state calculations of molecular systems under the influence of external magnetic fields. The problem of the numerical integration of the equations of motion is considered, and a critical evaluation of the standard fourth-order Runge-Kutta scheme and the symplectic Gauss integrator of variable order are given, including several illustrative numerical experiments. While the Gauss integrator is stable even for laser pulses well above the perturbation limit, our experiments indicate that a system-dependent upper limit exists for the external field strengths. Above this limit, time-dependent coupled-cluster calculations become very challenging numerically, even in the full configuration interaction limit. The source of these numerical instabilities is shown to be rapid increases of the amplitudes as ultrashort high-intensity laser pulses pump the system out of the ground state into states that are virtually orthogonal to the static Hartree-Fock reference determinant.

Fusarium pseudograminearum is a significant pathogen of cereals in arid regions worldwide and has the ability to produce numerous bioactive secondary metabolites. The genome sequences of seven F. pseudograminearum strains have been published and in one of these strains, C5834, we identified an intact gene cluster responsible for biosynthesis of the cyclic lipopeptide fusaristatin A. The high level of sequence identity of the fusaristatin cluster remnant in strains that do not produce fusaristatin suggests that the absence of the cluster evolved once, and subsequently the resulting locus with the cluster fragments became widely dispersed among strains of F. pseudograminearum in Australia. We examined a selection of 99 Australian F. pseudograminearum isolates to determine how widespread the ability to produce fusaristatin A is in F. pseudograminearum. We identified 15 fusaristatin producing strains, all originating from Western Australia. Phylogenetic analyses could not support a division of F. pseudograminearum into fusaristatin producing and nonproducing populations, which could indicate the loss has occurred relatively recent., (Copyright © 2018 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

Introduction: Squamous cell carcinoma of the anus (SCCA) is a rare condition. First line treatment is combined chemo-radio therapy. As many as a third of patients undergoing CRT will experience recurrence. These patients often undergo salvage surgery with an extended abdominoperineal excision. The aims of this study were 1) to assess and evaluate 30-day postoperative morbidity and mortality after salvage surgery for recurrent SCCA, and furthermore, 2) to examine secondary recurrence and long-term mortality after salvage surgery for recurrent SCCA., Material and Methods: Retrospective evaluation of all patients undergoing salvage surgery for SCCA at Copenhagen University Hospital Herlev between 1st of January 2011 and 31th December 2016., Results: Forty-seven patients were identified. 30-day postoperative mortality was 4%. The most common postoperative complication was perineal wound defects. Within the follow-up period of median 20 (1-80) months, secondary recurrence occurred in 30% of patients. Median disease free survival was 32 months. Secondary recurrence was significantly more frequent in patients with R1 resection and pN ≥ 1. Within the follow-up period of median 25 (0-80) months, mortality was 40%. Overall median survival was 39 months. Secondary recurrence was associated with a significantly higher risk of death within the follow-up period., Conclusion: Salvage surgery for relapse of squamous cell carcinoma of the anus is a safe procedure with a good short-term outcome. Secondary recurrence was more frequent in patients with R1-resection and pN ≥ 1. More than one third of the patients died within the follow-up period, and mortality was significantly higher in the group of patients with secondary recurrence., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

We present a generalization of the divide-expand-consolidate (DEC) framework for local coupled-cluster calculations to periodic systems and test it at the second-order Møller-Plesset (MP2) level of theory. For simple model systems with periodicity in one, two, and three dimensions, comparisons with extrapolated molecular calculations and the local MP2 implementation in the Cryscor program show that the correlation energy errors of the extended DEC (X-DEC) algorithm can be controlled through a single parameter, the fragment optimization threshold. Two computational bottlenecks are identified: the size of the virtual orbital spaces and the number of pair fragments required to achieve a given accuracy of the correlation energy. For the latter, we propose an affordable algorithm based on cubic splines interpolation of a limited number of pair-fragment interaction energies to determine a pair cutoff distance in accordance with the specified fragment optimization threshold.

The definiteness of the Mulliken and Dirac electron repulsion integral (ERI) matrices is examined for different classes of resolution-of-the-identity (RI) ERI approximations with particular focus on local fitting techniques. For global RI, robust local RI, and nonrobust local RI we discuss the definiteness of the approximated ERI matrices as well as the resulting bounds of Hartree, exchange, and total energies. Lower bounds of Hartree and exchange energy contributions are crucial as their absence may lead to variational instabilities, causing severe convergence problems or even convergence to a spurious state in self-consistent-field optimizations. While the global RI approximation guarantees lower bounds of Hartree and exchange energies, local RI approximations are generally unbounded. The robust local RI approximation guarantees a lower bound of the exchange energy but not of the Hartree energy. The nonrobust local RI approximation guarantees a lower bound of the Hartree energy but not of the exchange energy. These issues are demonstrated by sample calculations on carbon dioxide and benzene using the pair atomic RI approximation.

Objective: This study aimed to evaluate the efficacy of treatment for incontinence due to neurogenic detrusor overactivity (NDO) and idiopathic detrusor overactivity (IDO) with onabotulinumtoxinA (BoNT-A) at Aarhus University Hospital, Skejby, Denmark., Materials and Methods: The data were collected retrospectively by systematic review of the patient records from March 2003 to May 2012. Patients treated with BoNT-A over the age of 18 years were included. Treatment indication, diagnosis, adverse events, treatment interval, duration of effect and effect grade were registered. Follow-up data were collected by a telephone interview 4 weeks after treatment., Results: The study identified 219 patients, who received a total of 657 treatments during the period. Full effect of the treatment was experienced in 71%, intermediate effect was seen in 16% and low effect in 3%. There was no difference in effect duration between the IDO and NDO groups. The most common adverse event was the need to perform clean intermittent self-catheterization; 27% of all patients experienced this. Urinary tract infections were reported in 5% of procedures and significant haematuria in 1%. These findings correspond with the results of other published studies., Conclusion: BoNT-A is a safe and effective treatment for incontinence in IDO and NDO.

Chemical and electrochemical oxidation or reduction of our recently reported Ir(IV,IV) mono-μ-oxo dimers results in the formation of fully characterized Ir(IV,V) and Ir(III,III) complexes. The Ir(IV,V) dimers are unprecedented and exhibit remarkable stability under ambient conditions. This stability and modest reduction potential of 0.99 V vs NHE is in part attributed to complete charge delocalization across both Ir centers. Trends in crystallographic bond lengths and angles shed light on the structural changes accompanying oxidation and reduction. The similarity of these mono-μ-oxo dimers to our Ir "blue solution" water-oxidation catalyst gives insight into potential reactive intermediates of this structurally elusive catalyst. Additionally, a highly reactive material, proposed to be a Ir(V,V) μ-oxo species, is formed on electrochemical oxidation of the Ir(IV,V) complex in organic solvents at 1.9 V vs NHE. Spectroelectrochemistry shows reversible conversion between the Ir(IV,V) and proposed Ir(V,V) species without any degradation, highlighting the exceptional oxidation resistance of the 2-(2-pyridinyl)-2-propanolate (pyalk) ligand and robustness of these dimers. The Ir(III,III), Ir(IV,IV) and Ir(IV,V) redox states have been computationally studied both with DFT and multiconfigurational calculations. The calculations support the stability of these complexes and provide further insight into their electronic structures.

Researchers performing experiments on animals should always strive towards the refinement of experiments, minimization of stress and provision of better animal welfare. An adequate analgesic strategy is important to improve post-operative recovery and welfare in laboratory rats and mice. In addition, it is desirable to provide post-operative analgesia using methods that are minimally invasive and stressful. This study investigated the antinociceptive effects of orally administered buprenorphine ingested in Nutella® in comparison with subcutaneous buprenorphine administration. By exposing the animal to a thermal stimulus using a hot plate, significant antinociceptive effects of voluntarily ingested buprenorphine administered in Nutella® were demonstrated. This was evident at doses of 1.0 mg/kg 60 and 120 min post administration ( P < 0.01), although antinociceptive effects were not as marked as with subcutaneous administration, and had a later onset. It is advised to administer the oral formulation of buprenorphine in Nutella® in a 10-fold higher dose, as well as approximately 60 min earlier, than with the more commonly employed subcutaneous route of administration.

Undefined mesophilic mixed (DL-type) starter cultures are composed of predominantly Lactococcus lactis subspecies and 1-10% Leuconostoc spp. The composition of the Leuconostoc population in the starter culture ultimately affects the characteristics and the quality of the final product. The scientific basis for the taxonomy of dairy relevant leuconostocs can be traced back 50 years, and no documentation on the genomic diversity of leuconostocs in starter cultures exists. We present data on the Leuconostoc population in five DL-type starter cultures commonly used by the dairy industry. The analyses were performed using traditional cultivation methods, and further augmented by next-generation DNA sequencing methods. Bacterial counts for starter cultures cultivated on two different media, MRS and MPCA, revealed large differences in the relative abundance of leuconostocs. Most of the leuconostocs in two of the starter cultures were unable to grow on MRS, emphasizing the limitations of culture-based methods and the importance of careful media selection or use of culture independent methods. Pan-genomic analysis of 59 Leuconostoc genomes enabled differentiation into twelve robust lineages. The genomic analyses show that the dairy-associated leuconostocs are highly adapted to their environment, characterized by the acquisition of genotype traits, such as the ability to metabolize citrate. In particular, Leuconostoc mesenteroides subsp. cremoris display telltale signs of a degenerative evolution, likely resulting from a long period of growth in milk in association with lactococci. Great differences in the metabolic potential between Leuconostoc species and subspecies were revealed. Using targeted amplicon sequencing, the composition of the Leuconostoc population in the five commercial starter cultures was shown to be significantly different. Three of the cultures were dominated by Ln. mesenteroides subspecies cremoris. Leuconostoc pseudomesenteroides dominated in two of the cultures while Leuconostoc lactis , reported to be a major constituent in fermented dairy products, was only present in low amounts in one of the cultures. This is the first in-depth study of Leuconostoc genomics and diversity in dairy starter cultures. The results and the techniques presented may be of great value for the dairy industry.

We compare the performance of three approximate methods for speeding up evaluation of the exchange contribution in Hartree-Fock and hybrid Kohn-Sham calculations: the chain-of-spheres algorithm (COSX; Neese , F. Chem. Phys. 2008 , 356 , 98 - 109 ), the pair-atomic resolution-of-identity method (PARI-K; Merlot , P. J. Comput. Chem. 2013 , 34 , 1486 - 1496 ), and the auxiliary density matrix method (ADMM; Guidon , M. J. Chem. Theory Comput. 2010 , 6 , 2348 - 2364 ). Both the efficiency relative to that of a conventional linear-scaling algorithm and the accuracy of total, atomization, and orbital energies are compared for a subset containing 25 of the 200 molecules in the Rx200 set using double-, triple-, and quadruple-ζ basis sets. The accuracy of relative energies is further compared for small alkane conformers (ACONF test set) and Diels-Alder reactions (DARC test set). Overall, we find that the COSX method provides good accuracy for orbital energies as well as total and relative energies, and the method delivers a satisfactory speedup. The PARI-K and in particular ADMM algorithms require further development and optimization to fully exploit their indisputable potential.

Analytical state-average complete-active-space self-consistent field derivative (nonadiabatic) coupling vectors are implemented. Existing formulations are modified such that the implementation is compatible with Cholesky-based density fitting of two-electron integrals, which results in efficient calculations especially with large basis sets. Using analytical nonadiabatic coupling vectors, the optimization of conical intersections is implemented within the projected constrained optimization method. The standard description and characterization of conical intersections is reviewed and clarified, and a practical and unambiguous system for their classification and interpretation is put forward. These new tools are subsequently tested and benchmarked for 19 different conical intersections. The accuracy of the derivative coupling vectors is validated, and the information that can be drawn from the proposed characterization is discussed, demonstrating its usefulness.

In this report, we summarize and describe the recent unique updates and additions to the Molcas quantum chemistry program suite as contained in release version 8. These updates include natural and spin orbitals for studies of magnetic properties, local and linear scaling methods for the Douglas-Kroll-Hess transformation, the generalized active space concept in MCSCF methods, a combination of multiconfigurational wave functions with density functional theory in the MC-PDFT method, additional methods for computation of magnetic properties, methods for diabatization, analytical gradients of state average complete active space SCF in association with density fitting, methods for constrained fragment optimization, large-scale parallel multireference configuration interaction including analytic gradients via the interface to the Columbus package, and approximations of the CASPT2 method to be used for computations of large systems. In addition, the report includes the description of a computational machinery for nonlinear optical spectroscopy through an interface to the QM/MM package Cobramm. Further, a module to run molecular dynamics simulations is added, two surface hopping algorithms are included to enable nonadiabatic calculations, and the DQ method for diabatization is added. Finally, we report on the subject of improvements with respects to alternative file options and parallelization., (© 2015 Wiley Periodicals, Inc.)