The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair.

P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.

Recent developments in the PySCF program package.

PySCF is a Python-based general-purpose electronic structure platform that supports first-principles simulations of molecules and solids as well as accelerates the development of new methodology and complex computational workflows. This paper explains the design and philosophy behind PySCF that enables it to meet these twin objectives. With several case studies, we show how users can easily implement their own methods using PySCF as a development environment. We then summarize the capabilities of PySCF for molecular and solid-state simulations. Finally, we describe the growing ecosystem of projects that use PySCF across the domains of quantum chemistry, materials science, machine learning, and quantum information science.

Towards a Single Chemical Model for Understanding Lanthanide Hexaborides.

Lanthanide hexaborides (LnB6 ) have disparate and often anomalous properties, from structurally homogeneous mixed valency, to superconductivity, spectral anomalies, and unexplained phase transitions. It is unclear how such a diversity of properties may arise in the solids of identical crystal structures and seemingly very similar electronic structures. Building on our previous model for SmB6 (mixed valent, with a peak in specific heat, and pressure induced magnetic phase transitions), we present a unifying dynamic bonding model for LnB6 that explains simultaneously EuB6 (possessing an anomalous peak in specific heat at low T, magnetic phase transitions, and no mixed valency), YbB6 (mixed valent topological insulator), and rather ordinary LaB6 . We show that Ln can engage in covalent bonding with boron, and, in some members of the LnB6 family, also easily access alternative bonding states through the electron-phonon coupling. The accessibility, relative energetics, and bonding nature of the states involved dictate the properties.

Dynamical Bonding Driving Mixed Valency in a Metal Boride.

Samarium hexaboride is an anomaly, having many exotic and seemingly mutually incompatible properties. It was proposed to be a mixed-valent semiconductor, and later a topological Kondo insulator, and yet has a Fermi surface despite being an insulator. We propose a new and unified understanding of SmB6 centered on the hitherto unrecognized dynamical bonding effect: the coexistence of two Sm-B bonding modes within SmB6 , corresponding to different oxidation states of the Sm. The mixed valency arises in SmB6 from thermal population of these distinct minima enabled by motion of B. Our model simultaneously explains the thermal valence fluctuations, appearance of magnetic Fermi surface, excess entropy at low temperatures, pressure-induced phase transitions, and related features in Raman spectra and their unexpected dependence on temperature and boron isotope.

SmB6- Cluster Anion: Covalency Involving f Orbitals.

While boride clusters of alkali and transition metals have been observed and extensively characterized, so far little is known about lanthanide-boron clusters. Lanthanide-boride solids are intriguing, however, and therefore it is of interest to understand the fundamental electronic properties of such systems, also on the subnano scale. We report a joint experimental photoelectron spectroscopic and theoretical study of the SmB6- anion, iso-stoichiometric to the SmB6 solid-a topological Kondo insulator. The cluster is found to feature strong static and dynamic electron correlations and relativistic components, calling for treatment with CASPT2 and up sixth-order Douglass-Kroll-Hess (DKH) relativistic correction. The cluster has a C2v structure and covalent Sm-B bonds facilitated by f atomic orbitals on Sm, which are typically thought to be contracted and inert. Additionally, the cluster retains the double antiaromaticity of the B62- cluster.

Excitation variance matching with limited configuration interaction expansions in variational Monte Carlo.

In the regime where traditional approaches to electronic structure cannot afford to achieve accurate energy differences via exhaustive wave function flexibility, rigorous approaches to balancing different states' accuracies become desirable. As a direct measure of a wave function's accuracy, the energy variance offers one route to achieving such a balance. Here, we develop and test a variance matching approach for predicting excitation energies within the context of variational Monte Carlo and selective configuration interaction. In a series of tests on small but difficult molecules, we demonstrate that the approach is effective at delivering accurate excitation energies when the wave function is far from the exhaustive flexibility limit. Results in C3, where we combine this approach with variational Monte Carlo orbital optimization, are especially encouraging.

Assessing the Bonding Properties of Individual Molecular Orbitals.

Molecular orbitals (MOs), while one of the most widely used representations of the electronic structure of a system, are often too complex to intuit properties. Aside from the simplest of cases, it is not necessarily possible to visually tell which orbitals are bonding or antibonding along particular directions, especially in cases of highly delocalized and nontrivial bonding like metal clusters or solids. We propose a method for easily assessing and comparing the relative bonding contributions of MOs, by calculating their response to stress (e.g., compression). We find that this approach accurately describes relative bonding or antibonding character in both the simplest cases and provides new insight in more complex cases. We test the approach on four systems: H2, Am2, benzene, and the Pt4 cluster. In exploring this methodology, a scheme became elucidated, for predicting changes in the ground electronic configuration upon compression, including changes in bonding order, angular momenta of occupied MOs, and trends in MO ordering. We note that the applications of this work go beyond simple molecules and could be straightforwardly extended to, for example, solids and their response to stress along the specific crystallographic plane. Additionally, predictions of structures and properties of chemical systems under stress could result from the emerging intuition about changes in the electronic structure.

Photoelectron spectroscopic and theoretical study of the [HPd(η(2)-H2)](-) cluster anion.

Anion photoelectron spectroscopic and theoretical studies were conducted for the PdH(-) and PdH3 (-) cluster anions. Experimentally observed electron affinities and vertical detachment energies agree well with theoretical predictions. The PdH3 (-) anionic complex is made up of a PdH(-) sub-anion ligated by a H2 molecule, in which the H-H bond is lengthened compared to free H2. Detailed molecular orbital analysis of PdH(-), H2, and PdH3 (-) reveals that back donation from a d-type orbital of PdH(-) to the σ* orbital of H2 causes the H-H elongation, and hence, its activation. The H2 binding energy to PdH(-) is calculated to be 89.2 kJ/mol, which is even higher than that between CO and Pd. The unusually high binding energy as well as the H-H bond activation may have practical applications, e.g., hydrogen storage and catalysis.

Pilot study of losartan for pulmonary hypertension in chronic obstructive pulmonary disease.

BACKGROUND: Morbidity in COPD results from a combination of factors including hypoxia-induced pulmonary hypertension, in part due to pulmonary vascular remodelling. Animal studies suggest a role of angiotensin II and acute studies in man concur. Whether chronic angiotensin-II blockade is beneficial is unknown. We studied the effects of an angiotensin-II antagonist losartan, on haemodynamic variables, exercise capacity and symptoms. METHODS: This was a double-blind, randomized, parallel group, placebo- controlled study of 48 weeks duration. Forty patients with COPD and pulmonary hypertension (Tran tricuspid pressure gradient (TTPG) = 30 mmHg) were randomised to losartan 50 mg or placebo. Changes in TTPG were assessed at 3, 6 and 12 months. RESULTS: There was a trend for TTPG to increase in the placebo group (baseline 43.4 versus 48.4 mmHg at endpoint) and stay constant in the losartan group (baseline 42.8 versus 43.6 mmHg). More patients in the losartan group (50%) than in the placebo group (22%) showed a clinically meaningful reduction in TTPG at any timepoint; these effects seemed more marked in patients with higher baseline TTPG. There were no clear improvements in exercise capacity or symptoms. CONCLUSION: In this 12-month pilot study, losartan 50 mg had no statistically significant beneficial effect on TTPG, exercise capacity or symptoms in pulmonary hypertension secondary to obstructive disease. A sub-group of patients with higher TTPG may benefit.