The symmetric quasi-classical model using on-the-fly time-dependent density functional theory within the Tamm-Dancoff approximation

The primary computational challenge when simulating nonadiabatic ab initio molecular dynamics is the unfavorable compute costs of electronic structure calculations with molecular size. Simple electronic structure theories, like time-dependent density functional theory within the Tamm-Dancoff approximation (TDDFT/TDA), alleviate this cost for moderately sized molecular systems simulated on realistic time scales. Although TDDFT/TDA does have some limitations in accuracy, an appealing feature is that, in addition to including electron correlation through the use of a density functional, the cost of calculating analytic nuclear gradients and nonadiabatic coupling vectors is often computationally feasible even for moderately-sized basis sets. In this work, some of the benefits and limitations of TDDFT/TDA are discussed and analyzed with regard to its applicability as a "back-end" electronic structure method for the symmetric quasi-classical Meyer-Miller model (SQC/MM). In order to investigate the benefits and limitations of TDDFT/TDA, SQC/MM is employed to predict and analyze a prototypical example of excited-state hydrogen transfer in gas-phase malonaldehyde. Then, the ring-opening dynamics of selenophene are simulated which highlight some of the deficiencies of TDDFT/TDA. Additionally, some new algorithms are proposed that speed up the calculation of analytic nuclear gradients and nonadiabatic coupling vectors for a set of excited electronic states.Comment: 35 pages, 8 figures, 2 table

DECIPHERING THE EXCITED-STATE VIBRATIONAL SIGNATURES OF THE WATER-IODIDE BINARY COMPLEX THROUGH QUANTUM SIMULATIONS.

The water-iodide monomer (I$^{-}$H$_{2}$O), nominally the simplest of the halide-water complexes, challenges our current understanding of ion hydration. Most notably, this seemingly simple complex displays multiple resonant vibrational transitions, a low tunneling barrier, and a strong transition dipole moment along the bound OH-I coordinate. These effects combine to yield spectroscopic signatures that deviate strongly from traditional harmonic analyses and are even difficult to qualitatively reproduce with anharmonic methodologies. Among these signatures is a quartet of peaks in the 3300 – 3500 cm-1 range that is unexplained using traditional single-photon spectroscopy. Challenging both experiment and theory alike, this situation required the interpretation of newly developed IR-IR 2-color photodissociation spectroscopy that probes well below the dissociation threshold. In this work, we use both exact eigensolver techniques and a newly developed vibrationally adiabatic model, along with a new potential energy surface$^a$ to computationally explore the excited-state spectra. The resulting analyses identify the source of the strength of the resonant transitions, directly assign the vibrational and rotational spectroscopic signatures, and discern the electronic origin of these surprising effects in this fundamental model of ion hydration. $^a$Bajaj, P. Gotz, A.W., Paesani, F. Journal of Chemical Theory and Computation, 2016, 12 (6), 2698-2705

Fantastical Excited State Optimized Structures and Where to Find Them

The quantum chemistry community has developed analytic forces for approximate electronic excited states to enable walking on excited state potential energy surfaces (PES). One can thereby computationally characterize excited state minima and saddle points. Always implicit in using this machinery is the fact that an excited state PES only exists within the realm of the Born-Oppenheimer approximation, where the nuclear and electronic degrees of freedom separate. This work demonstrates through ab initio calculations and simple nonadiabatic dynamics that some excited state minimum structures are fantastical: they appear to exist as stable configurations only as a consequence of the PES construct, rather than being physically observable. One such case is the S2 excited state of phosphine and a second case are local minima of a number of states of tris(bipyridine)ruthenium(II). Each fantastical structure exhibits an unphysically high predicted harmonic frequency and associated force constant. This fact can serve as a valuable diagnostic of when an optimized excited state structure is non-observable. Their origin lies in the coupling between different electronic states, and the resulting avoided crossings. The upper state may exhibit a minimum very close to the crossing, where the force constant relates to the strength of the electronic coupling rather than to any characteristic excited state vibration. Nonadiabatic dynamics results using a Landau-Zener model illustrate that fantastical excited state structures have extremely short lifetimes on the order of a few femtoseconds. Their appearance in a calculation signals the presence of a nearby avoided crossing or conical intersection through which the system will rapidly cross to a lower surface.Comment: 7 pages, 4 figure

Quantum and classical criticality in a dimerized quantum antiferromagnet

A quantum critical point (QCP) is a singularity in the phase diagram arising due to quantum mechanical fluctuations. The exotic properties of some of the most enigmatic physical systems, including unconventional metals and superconductors, quantum magnets, and ultracold atomic condensates, have been related to the importance of the critical quantum and thermal fluctuations near such a point. However, direct and continuous control of these fluctuations has been difficult to realize, and complete thermodynamic and spectroscopic information is required to disentangle the effects of quantum and classical physics around a QCP. Here we achieve this control in a high-pressure, high-resolution neutron scattering experiment on the quantum dimer material TlCuCl3. By measuring the magnetic excitation spectrum across the entire quantum critical phase diagram, we illustrate the similarities between quantum and thermal melting of magnetic order. We prove the critical nature of the unconventional longitudinal ("Higgs") mode of the ordered phase by damping it thermally. We demonstrate the development of two types of criticality, quantum and classical, and use their static and dynamic scaling properties to conclude that quantum and thermal fluctuations can behave largely independently near a QCP.Comment: 6 pages, 4 figures. Original version, published version available from Nature Physics websit

The Seventeenth Data Release of the Sloan Digital Sky Surveys: Complete Release of MaNGA, MaStar and APOGEE-2 Data

This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library (MaStar) accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) survey which publicly releases infra-red spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the sub-survey Time Domain Spectroscopic Survey (TDSS) data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey (SPIDERS) sub-survey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated Value Added Catalogs (VACs). This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper (MWM), Local Volume Mapper (LVM) and Black Hole Mapper (BHM) surveys

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

Moderators of the effect of therapeutic exercise for knee and hip osteoarthritis: a systematic review and individual participant data meta-analysis

Background Many international clinical guidelines recommend therapeutic exercise as a core treatment for knee and hip osteoarthritis. We aimed to identify individual patient-level moderators of the effect of therapeutic exercise for reducing pain and improving physical function in people with knee osteoarthritis, hip osteoarthritis, or both. Methods We did a systematic review and individual participant data (IPD) meta-analysis of randomised controlled trials comparing therapeutic exercise with non-exercise controls in people with knee osteoathritis, hip osteoarthritis, or both. We searched ten databases from March 1, 2012, to Feb 25, 2019, for randomised controlled trials comparing the effects of exercise with non-exercise or other exercise controls on pain and physical function outcomes among people with knee osteoarthritis, hip osteoarthritis, or both. IPD were requested from leads of all eligible randomised controlled trials. 12 potential moderators of interest were explored to ascertain whether they were associated with short-term (12 weeks), medium-term (6 months), and long-term (12 months) effects of exercise on self-reported pain and physical function, in comparison with non-exercise controls. Overall intervention effects were also summarised. This study is prospectively registered on PROSPERO (CRD42017054049). Findings Of 91 eligible randomised controlled trials that compared exercise with non-exercise controls, IPD from 31 randomised controlled trials (n=4241 participants) were included in the meta-analysis. Randomised controlled trials included participants with knee osteoarthritis (18 [58%] of 31 trials), hip osteoarthritis (six [19%]), or both (seven [23%]) and tested heterogeneous exercise interventions versus heterogeneous non-exercise controls, with variable risk of bias. Summary meta-analysis results showed that, on average, compared with non-exercise controls, therapeutic exercise reduced pain on a standardised 0–100 scale (with 100 corresponding to worst pain), with a difference of –6·36 points (95% CI –8·45 to –4·27, borrowing of strength [BoS] 10·3%, between-study variance [τ2] 21·6) in the short term, –3·77 points (–5·97 to –1·57, BoS 30·0%, τ2 14·4) in the medium term, and –3·43 points (–5·18 to –1·69, BoS 31·7%, τ2 4·5) in the long term. Therapeutic exercise also improved physical function on a standardised 0–100 scale (with 100 corresponding to worst physical function), with a difference of –4·46 points in the short term (95% CI –5·95 to –2·98, BoS 10·5%, τ2 10·1), –2·71 points in the medium term (–4·63 to –0·78, BoS 33·6%, τ2 11·9), and –3·39 points in the long term (–4·97 to –1·81, BoS 34·1%, τ2 6·4). Baseline pain and physical function moderated the effect of exercise on pain and physical function outcomes. Those with higher self-reported pain and physical function scores at baseline (ie, poorer physical function) generally benefited more than those with lower self-reported pain and physical function scores at baseline, with the evidence most certain in the short term (12 weeks). Interpretation There was evidence of a small, positive overall effect of therapeutic exercise on pain and physical function compared with non-exercise controls. However, this effect is of questionable clinical importance, particularly in the medium and long term. As individuals with higher pain severity and poorer physical function at baseline benefited more than those with lower pain severity and better physical function at baseline, targeting individuals with higher levels of osteoarthritis-related pain and disability for therapeutic exercise might be of merit

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies