A dynamical measure of the black hole mass in a quasar 11 billion years ago.

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH)1-3. These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase4-6. A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8-12 billion years ago (redshifts 1-3)7. Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-µas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 108 solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 1011 solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems.

Large granulation cells on the surface of the giant star π1 Gruis.

Convection plays a major part in many astrophysical processes, including energy transport, pulsation, dynamos and winds on evolved stars, in dust clouds and on brown dwarfs. Most of our knowledge about stellar convection has come from studying the Sun: about two million convective cells with typical sizes of around 2,000 kilometres across are present on the surface of the Sun-a phenomenon known as granulation. But on the surfaces of giant and supergiant stars there should be only a few large (several tens of thousands of times larger than those on the Sun) convective cells, owing to low surface gravity. Deriving the characteristic properties of convection (such as granule size and contrast) for the most evolved giant and supergiant stars is challenging because their photospheres are obscured by dust, which partially masks the convective patterns. These properties can be inferred from geometric model fitting, but this indirect method does not provide information about the physical origin of the convective cells. Here we report interferometric images of the surface of the evolved giant star π1 Gruis, of spectral type S5,7. Our images show a nearly circular, dust-free atmosphere, which is very compact and only weakly affected by molecular opacity. We find that the stellar surface has a complex convective pattern with an average intensity contrast of 12 per cent, which increases towards shorter wavelengths. We derive a characteristic horizontal granule size of about 1.2 × 1011 metres, which corresponds to 27 per cent of the diameter of the star. Our measurements fall along the scaling relations between granule size, effective temperature and surface gravity that are predicted by simulations of stellar surface convection.

Multichannel Dyson Equation: Coupling Many-Body Green's Functions.

We present the multichannel Dyson equation that combines two or more many-body Green's functions to describe the electronic structure of materials. In this work we use it to model photoemission spectra by coupling the one-body Green's function with the three-body Green's function. We demonstrate that, unlike methods using only the one-body Green's function, our approach puts the description of quasiparticles and satellites on an equal footing. We propose a multichannel self-energy that is static and only contains the bare Coulomb interaction, making frequency convolutions and self-consistency unnecessary. Despite its simplicity, we demonstrate with a diagrammatic analysis that the physics it describes is extremely rich. Finally, we present a framework based on an effective Hamiltonian that can be solved for any many-body system using standard numerical tools. We illustrate our approach by applying it to the Hubbard dimer and show that it is exact both at 1/4 and 1/2 filling.

The role of adjuvant treatment for early-stage uterine clear cell carcinomas.

BACKGROUND: Uterine clear cell carcinoma is a rare and aggressive subtype of endometrial carcinoma. Prospective clinical trials have not been feasible for this rare tumor, and data regarding the optimal adjuvant treatment regimen for early-stage uterine clear cell carcinomas is limited. Our study's objective was to determine if adjuvant chemotherapy or radiation therapy improves patients' outcomes in stage I and II uterine clear cell carcinoma. METHODS: Patients with stage I and II uterine clear cell carcinoma were identified at a single institution. All cases were reviewed by a gynecologic pathologist. Both pure and mixed non-serous uterine clear cell carcinomas were included. Primary outcomes were recurrence free survival and overall survival. RESULTS: A total of 71 patients were identified including 39 (55%) pure and 32 (45%) mixed clear cell carcinoma. Most patients were FIGO stage IA (77.5%). Most patients (n = 58, 82%) received adjuvant therapy, including 43 (61%) receiving chemotherapy, 50 (70%) receiving radiation therapy, and 35 (49%) receiving both. Recurrence free survival was not significantly different among patients receiving no or <6 cycles of chemotherapy versus patients receiving 6 cycles of chemotherapy (p = 0.39). However, median OS was significantly different among patients receiving no or <6 cycles of chemotherapy versus 6 cycles of chemotherapy (p = 0.004). On univariable analysis, 6 cycles of chemotherapy was significantly associated with improved OS (HR 0.1, 95% CI 0.01-0.07). Presence of LVSI, mutated p53, number of pelvic and para-aortic lymph nodes assessed, adjuvant chemotherapy (any number of cycles), and >2 medical co-morbidities were not significant predictors of OS on univariable analysis. On multivariable analysis, 6 cycles of adjuvant chemotherapy remained a significant predictor of improved OS (HR 0.1, 95% CI 0.01-0.8). CONCLUSIONS: In this study, administration of 6 cycles of chemotherapy appears to significantly improve OS. This finding suggests consideration of 6 cycles of adjuvant chemotherapy in patients with early-stage uterine clear cell carcinoma, however clinical trials are needed to confirm these findings.

Mechanical metamaterials at the theoretical limit of isotropic elastic stiffness.

A wide variety of high-performance applications require materials for which shape control is maintained under substantial stress, and that have minimal density. Bio-inspired hexagonal and square honeycomb structures and lattice materials based on repeating unit cells composed of webs or trusses, when made from materials of high elastic stiffness and low density, represent some of the lightest, stiffest and strongest materials available today. Recent advances in 3D printing and automated assembly have enabled such complicated material geometries to be fabricated at low (and declining) cost. These mechanical metamaterials have properties that are a function of their mesoscale geometry as well as their constituents, leading to combinations of properties that are unobtainable in solid materials; however, a material geometry that achieves the theoretical upper bounds for isotropic elasticity and strain energy storage (the Hashin-Shtrikman upper bounds) has yet to be identified. Here we evaluate the manner in which strain energy distributes under load in a representative selection of material geometries, to identify the morphological features associated with high elastic performance. Using finite-element models, supported by analytical methods, and a heuristic optimization scheme, we identify a material geometry that achieves the Hashin-Shtrikman upper bounds on isotropic elastic stiffness. Previous work has focused on truss networks and anisotropic honeycombs, neither of which can achieve this theoretical limit. We find that stiff but well distributed networks of plates are required to transfer loads efficiently between neighbouring members. The resulting low-density mechanical metamaterials have many advantageous properties: their mesoscale geometry can facilitate large crushing strains with high energy absorption, optical bandgaps and mechanically tunable acoustic bandgaps, high thermal insulation, buoyancy, and fluid storage and transport. Our relatively simple design can be manufactured using origami-like sheet folding and bonding methods.

Mapping of Hückel zigzag carbon nanotubes onto independent polyene chains: Application to periodic nanotubes.

The electric polarizability and the spread of the total position tensors are used to characterize the metallic vs insulator nature of large (finite) systems. Finite clusters are usually treated within the open boundary condition formalism. This introduces border effects, which prevent a fast convergence to the thermodynamic limit and can be eliminated within the formalism of periodic boundary conditions. Recently, we introduced an original approach to periodic boundary conditions, named Clifford boundary conditions. It considers a finite fragment extracted from a periodic system and the modification of its topology into that of a Clifford torus. The quantity representing the position is modified in order to fulfill the system periodicity. In this work, we apply the formalism of Clifford boundary conditions to the case of carbon nanotubes, whose treatment results in a particularly simple zigzag geometry. Indeed, we demonstrate that at the Hückel level, these nanotubes, either finite or periodic, are formally equivalent to a collection of non-interacting dimerized linear chains, thus simplifying their treatment. This equivalence is used to describe some nanotube properties as the sum of the contributions of the independent chains and to identify the origin of peculiar behaviors (such as conductivity). Indeed, if the number of hexagons along the circumference is a multiple of three, a metallic behavior is found, namely a divergence of both the (per electron) polarizability and total position spread of at least one linear chain. These results are in agreement with those in the literature from tight-binding calculations.

Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).

BACKGROUND: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. PATIENTS AND METHODS: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). RESULTS: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. CONCLUSIONS: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

Cost-effectiveness analysis of tumor molecular classification in high-risk early-stage endometrial cancer.

PURPOSE: Tumor molecular analyses in endometrial cancer (EC) includes 4 distinct subtypes: (1) POLE-mutated, (2) mismatch repair protein (MMR) deficient, (3) p53 mutant, and (4) no specific molecular profile. Recently, a sub-analysis of PORTEC-3 demonstrated notable differences in treatment response between molecular classification (MC) groups. Cost of testing is one barrier to widespread adoption of MC. Therefore, we sought to determine the cost-effectiveness of MC in patients with stage I and II high-risk EC. METHODS: A Markov decision model was developed to compare tumor molecular classification (TMC) vs. no testing (NT). A healthcare payor's perspective and 5-year time horizon were used. Base case data were abstracted from PORTEC-3 and the molecular sub-analysis. Cost and utility data were derived from public databases, peer-reviewed literature, and expert input. Strategies were compared using the incremental cost-effectiveness ratio (ICER) with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness-to-pay threshold of $100,000 per QALY gained. Sensitivity analyses were performed to test model robustness. RESULTS: When compared to NT, TMC was cost effective with an ICER of $25,578 per QALY gained; incremental cost was $1780 and incremental effectiveness was 0.070 QALYs. In one-way sensitivity analyses, results were most sensitive to the cost of POLE testing, but TMC remained cost-effective over all parameter ranges. CONCLUSIONS: TMC in early-stage high-risk EC is cost-effective, and the model results were robust over a range of parameters. Given that MC can be used to guide adjuvant treatment decisions, these findings support adoption of TMC into routine practice.

Progressive multifocal leukoencephalopathy or immune reconstitution inflammatory syndrome after fingolimod cessation? A case report.

BACKGROUND: Fingolimod is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML); however, its discontinuation may cause severe immune reconstitution inflammatory syndrome (IRIS). As both of these conditions (especially fingolimod induced PML) are rarely described in medical case reports distinguishing between PML-IRIS and MS-IRIS may be diagnostically challenging. CASE PRESENTATION: We report a patient with severe clinical decline (Expanded Disability Status Scale (EDSS) increasing from 3.5 to 7.5) and multiple, large, contrast-enhancing lesions on brain magnetic resonance imaging (MRI) a few months after fingolimod withdrawal. The diagnostic possibilities included IRIS due to fingolimod withdrawal versus PML-IRIS. The JC virus (JCV) antibody index was positive (2.56); however, cerebrospinal fluid (CSF) JCV real-time polymerase chain reaction (JCV-PCR) was negative and brain biopsy was not performed. After a long course of aggressive treatment (several pulsed methylprednisolone infusions, plasmapheresis, intravenous dexamethasone, oral mirtazapine) the patient gradually recovered (EDSS 2.5) and MRI lesions decreased. CONCLUSIONS: This case report demonstrates the importance of monitoring patients carefully after the discontinuation of fingolimod for PML-IRIS and rebound MS with IRIS as these conditions may manifest similarly.

The Wigner localization of interacting electrons in a one-dimensional harmonic potential.

In this work, we study the Wigner localization of interacting electrons that are confined to a quasi-one-dimensional harmonic potential using accurate quantum chemistry approaches. We demonstrate that the Wigner regime can be reached using small values of the confinement parameter. To obtain physical insight in our results, we analyze them with a semi-analytical model for two electrons. Thanks to electronic-structure properties such as the one-body density and the particle-hole entropy, we are able to define a path that connects the Wigner regime to the Fermi-gas regime by varying the confinement parameter. In particular, we show that the particle-hole entropy, as a function of the confinement parameter, smoothly connects the two regimes. Moreover, it exhibits a maximum that could be interpreted as the transition point between the localized and delocalized regimes.

Paneth cell α-defensins HD-5 and HD-6 display differential degradation into active antimicrobial fragments.

Antimicrobial peptides, in particular α-defensins expressed by Paneth cells, control microbiota composition and play a key role in intestinal barrier function and homeostasis. Dynamic conditions in the local microenvironment, such as pH and redox potential, significantly affect the antimicrobial spectrum. In contrast to oxidized peptides, some reduced defensins exhibit increased vulnerability to proteolytic degradation. In this report, we investigated the susceptibility of Paneth-cell-specific human α-defensin 5 (HD-5) and -6 (HD-6) to intestinal proteases using natural human duodenal fluid. We systematically assessed proteolytic degradation using liquid chromatography-mass spectrometry and identified several active defensin fragments capable of impacting bacterial growth of both commensal and pathogenic origins. Of note, incubation of mucus with HD-5 resulted in 255-8,000 new antimicrobial combinations. In contrast, HD-6 remained stable with consistent preserved nanonet formation. In vivo studies demonstrated proof of concept that a HD-5 fragment shifted microbiota composition (e.g., increases of Akkermansia sp.) without decreasing diversity. Our data support the concept that secretion of host peptides results in an environmentally dependent increase of antimicrobial defense by clustering in active peptide fragments. This complex clustering mechanism dramatically increases the host's ability to control pathogens and commensals. These findings broaden our understanding of host modulation of the microbiome as well as the complexity of human mucosal defense mechanisms, thus providing promising avenues to explore for drug development.

A diagonalization-free optimization algorithm for solving Kohn-Sham equations of closed-shell molecules.

A local optimization algorithm for solving the Kohn-Sham equations is presented. It is based on a direct minimization of the energy functional under the equality constraints representing the Grassmann Manifold. The algorithm does not require an eigendecomposition, which may be advantageous in large-scale computations. It is optimized to reduce the number of Kohn-Sham matrix evaluations to one per iteration to be competitive with standard self-consistent field (SCF) approach accelerated by direct inversion of the iterative subspace (DIIS). Numerical experiments include a comparison of the algorithm with DIIS. A high reliability of the algorithm is observed in configurations where SCF iterations fail to converge or find a wrong solution corresponding to a stationary point different from the global minimum. The local optimization algorithm itself does not guarantee that the found minimum is global. However, a randomization of the initial approximation shows a convergence to the right minimum in the vast majority of cases.

Erratum: Azimuthal Anisotropy at the Relativistic Heavy Ion Collider: The First and Fourth Harmonics [Phys. Rev. Lett. 92, 062301 (2004)].

This corrects the article DOI: 10.1103/PhysRevLett.92.062301.

Erratum: Azimuthal Anisotropy of K_{S}

This corrects the article DOI: 10.1103/PhysRevLett.89.132301.

Wigner localization in two and three dimensions: An ab initio approach.

In this work, we investigate the Wigner localization of two interacting electrons at very low density in two and three dimensions using the exact diagonalization of the many-body Hamiltonian. We use our recently developed method based on Clifford periodic boundary conditions with a renormalized distance in the Coulomb potential. To accurately represent the electronic wave function, we use a regular distribution in space of Gaussian-type orbitals and we take advantage of the translational symmetry of the system to efficiently calculate the electronic wave function. We are thus able to accurately describe the wave function up to very low density. We validate our approach by comparing our results to a semi-classical model that becomes exact in the low-density limit. With our approach, we are able to observe the Wigner localization without ambiguity.

The localization spread and polarizability of rings and periodic chains.

The localization spread gives a criterion to decide between metallic and insulating behavior of a material. It is defined as the second moment cumulant of the many-body position operator, divided by the number of electrons. Different operators are used for systems treated with open or periodic boundary conditions. In particular, in the case of periodic systems, we use the complex position definition, which was already used in similar contexts for the treatment of both classical and quantum situations. In this study, we show that the localization spread evaluated on a finite ring system of radius R with open boundary conditions leads, in the large R limit, to the same formula derived by Resta and co-workers [C. Sgiarovello, M. Peressi, and R. Resta, Phys. Rev. B 64, 115202 (2001)] for 1D systems with periodic Born-von Kármán boundary conditions. A second formula, alternative to Resta's, is also given based on the sum-over-state formalism, allowing for an interesting generalization to polarizability and other similar quantities.

[The complete dislocation of the talus or «missing talus¼.] / L'image du mois. Dislocation complète du talus ou «missing talus¼.

The complete dislocation of the talus or «missing talus¼ corresponds to a simultaneous dislocation of the tibiotalar, talocalcaneal and talonavicular joints, without associated talar fracture. This lesion occurs as part of high energy trauma and accounts for 3 to 5 % of talus injuries. It is most frequently anterolateral and in more than 75 % of cases, this dislocation is open. Among the soft tissue lesions that are often associated with the dislocation, vascular lesions leading to avascular necrosis of the talus are found in almost 100 % of cases. This necrosis is generally well tolerated by the patient. A conservative treatment by reimplantation of the talus after debridement of the site should be performed as a first-line treatment as fast as possible. When the avascular necrosis of the talus is not well tolerated by the patient, a talectomy associated with tibiocalcaneal arthrodesis can be performed as a secondary procedure. Talectomy alone should not be done.

La dislocation complète du talus ou «missing talus¼ correspond à une dislocation simultanée des articulations tibiotalienne, talocalcanéenne et talonaviculaire, sans fracture talienne associée. Cette lésion survient dans le cadre d'un traumatisme à haute énergie et représente 3 à 5 % des lésions du talus. Elle est le plus fréquemment antéro-latérale et, dans plus de 75 % des cas, cette dislocation est ouverte. Parmi les lésions des tissus mous qui y sont souvent associées, les lésions vasculaires conduisant à une nécrose avasculaire du talus sont retrouvées dans presque 100 % des cas. Cette nécrose est généralement bien tolérée par le patient. Un traitement conservateur par réimplantation du talus après débridement du site doit être réalisé en première intention et ce, de manière urgente. Lorsque la nécrose avasculaire du talus n'est pas bien tolérée par le patient sur le long terme, une talectomie associée à une arthrodèse tibio-calcannénne peut être réalisée dans un second temps. La talectomie seule doit, quant à elle, être proscrite.

New opportunities at the next-generation neutrino experiments I: BSM neutrino physics and dark matter.

The combination of the high intensity proton beam facilities and massive detectors for precision measurements of neutrino oscillation parameters including the charge-parity violating (CPV) phase will open the door to help make beyond the standard model (BSM) physics reachable even in low energy regimes in the accelerator-based experiments. Large-mass detectors with highly precise tracking and energy measurements, excellent timing resolution, and low energy thresholds will enable the searches for BSM phenomena from cosmogenic origin, as well. Therefore, it is also conceivable that BSM topics in the next-generation neutrino experiments could be the dominant physics topics in the foreseeable future, as the precision of the neutrino oscillation parameter and CPV measurements continue to improve.This paper provides a review of the current landscape of BSM theory in neutrino experiments in two selected areas of the BSM topics-dark matter and neutrino related BSM-and summarizes the current results from existing neutrino experiments to set benchmarks for both theory and experiment. This paper then provides a review of upcoming neutrino experiments throughout the next 10 to 15 year time scale and their capabilities to set the foundation for potential reach in BSM physics in the two aforementioned themes. An important outcome of this paper is to ensure theoretical and simulation tools exist to carry out studies of these new areas of physics, from the first day of the experiments, such as Deep Underground Neutrino Experiment in the U.S. and Hyper-Kamiokande Experiment in Japan.

Is the risk of substantial LVSI in stage I endometrial cancer similar to PORTEC in the North American population? - A single-institution study.

OBJECTIVES: A pooled analysis of PORTEC-1 & 2 identified substantial lymphovascular space invasion (LVSI) in 4.8% of patients, which predicted for pelvic recurrence, distant metastasis, and overall survival. Our institution implemented the PORTEC three-tier system of LVSI reporting (absent, focal, or substantial). We aimed to quantify the incidence of substantial LVSI in a North American population and to correlate extent of LVSI with lymph node (LN) involvement. METHODS: A retrospective review was conducted on patients with clinically uterine-confined, endometrioid type endometrial cancer who underwent surgical staging and were found to have pT1a-b disease. Binary logistic regression was used to assess predictors of LN involvement (defined as ITC, micrometastases, or macrometastases). RESULTS: In total, 438 patients with pT1a-b disease were identified. In the overall cohort and in the subset meeting PORTEC-1 inclusion criteria (n = 195), no LVSI was present in 67.4% and 50.8%; focal LVSI was present in 16.7% and 24.1%; and substantial LVSI was present in 16.0% and 25.1%, respectively. Among patients who underwent surgical LN assessment (79.2%, n = 347), LNs were involved in 3.3% without LVSI, 7.5% with focal LVSI (OR 2.4), and 15.2% with substantial LVSI (OR 5.3) (p = .005), with a similar trend in the PORTEC-1 cohort. Extent of LVSI correlated with disease burden in LN metastases. CONCLUSION: Our incidence of substantial LVSI was three to five times higher than reported by PORTEC and correlated with LN involvement. This questions the reproducibility of the three-tier LVSI reporting system and emphasizes the need for multi-institutional data outside PORTEC for confirmation of our findings.

Optical spectra of 2D monolayers from time-dependent density functional theory.

The optical spectra of two-dimensional (2D) periodic systems provide a challenge for time-dependent density-functional theory (TDDFT) because of the large excitonic effects in these materials. In this work we explore how accurately these spectra can be described within a pure Kohn-Sham time-dependent density-functional framework, i.e., a framework in which no theory beyond Kohn-Sham density-functional theory, such as GW, is required to correct the Kohn-Sham gap. To achieve this goal we adapted a recent approach we developed for the optical spectra of 3D systems [S. Cavo, J. A. Berger and P. Romaniello, Phys. Rev. B, 2020, 101, 115109] to those of 2D systems. Our approach relies on the link between the exchange-correlation kernel of TDDFT and the derivative discontinuity of ground-state density-functional theory, which guarantees a correct quasi-particle gap, and on a generalization of the polarization functional [J. A. Berger, Phys. Rev. Lett., 2015, 115, 137402], which describes the excitonic effects. We applied our approach to two prototypical 2D monolayers, h-BN and MoS2. We find that our protocol gives a qualitatively good description of the optical spectrum of h-BN, whereas improvements are needed for MoS2 to describe the intensity of the excitonic peaks.