Cyanotoxin accumulation and growth patterns of biocrust communities under variable environmental conditions.

Biocrusts dominate the soil surface in deserts and are composed of diverse microbial communities that provide important ecosystem services. Cyanobacteria in biocrusts produce many secondary metabolites, including the neurotoxins BMAA, AEG, DAB, anatoxin-a(S) (guanitoxin), and the microcystin hepatotoxins, all known or suspected to cause disease or illness in humans and other animals. We examined cyanobacterial growth and prevalence of these toxins in biocrusts at millimeter-scales, under a desert-relevant illumination gradient. In contrast to previous work, we showed that hydration had an overall positive effect on growth and toxin accumulation, that nitrogen was not correlated with growth or toxin production, and that phosphorus enrichment negatively affected AEG and BMAA concentrations. Excess illumination positively correlated with AEG, and negatively correlated with all other toxins and growth. Basic pH negatively affected only the accumulation of BMAA. Anatoxin-a(S) (guanitoxin) was not correlated with any tested variables, while microcystins were not detected in any of the samples. Concerning toxin pools, AEG and BMAA were good predictors of the presence of one another. In a newly conceptualized scheme, we integrate aspects of biocrust growth and toxin pool accumulations with arid-relevant desertification drivers.

Psychoanalysis-More Than a Profession: Presidential Address, American Psychoanalytic Association, New York, February 3, 2023.

This plenary address was delivered just before learning the successful outcome of a bylaw amendment extending full American Psychoanalytic Association (APsA) membership to psychoanalytic psychotherapists, researchers, scholars, and all who share a commitment to psychoanalysis. This historic change culminated efforts over the previous four decades to rectify exclusionary harms and revitalize psychoanalysis in the United States as a clinical practice and a cultural force. Membership expansion is discussed in the historical and sociological context of psychoanalysis as a profession with a focus on organizational resistance to change. Professionalization established and legitimized psychoanalysis but also contained the seeds of gradual decline as monopoly over training and practice distanced APsA from the wider psychoanalytic community. Expanding membership beyond the profession is a step toward uniting the community and strengthening all applications of psychoanalysis, including the traditional form. These developments at APsA reflect changes in other disciplines that feature inclusion, generosity, situated learning, and distributed subjectivity in epistemic communities of practice.

Multistate, Polarizable QM/MM Embedding Scheme Based on the Direct Reaction Field Method: Solvatochromic Shifts, Analytical Gradients and Optimizations of Conical Intersections in Solution.

We recently introduced a polarizable embedding scheme based on an integral-exact reformulation of the direct reaction field method (IEDRF) that accounts for the differential solvation of ground and excited states in QM/MM simulations. The polarization and dispersion interactions between the quantum-mechanical (QM) and molecular-mechanical (MM) regions are described by the DRF Hamiltonian, while the Pauli repulsion between explicitly treated QM electrons and the implicit electron density around MM atoms is modeled with effective core potentials. A single Hamiltonian is used for all electronic states so that Born-Oppenheimer states belonging to the same geometry are orthogonal and state crossings are well-defined. In this work, we describe the implementation of the method using graphical processing unit acceleration in TeraChem, where it is combined with multiple electronic structure methods, including Hartree-Fock, time-dependent density functional theory, and complete active space self-consistent field. In contrast with older implementations of the DRF method, integrals of the polarization operators are evaluated exactly. Expressions for ingredients needed to construct analytical gradients and nonadiabatic coupling vectors are derived and tested by optimizing a conical intersection between two excited states in the presence of a polarizable solvent shell. The method is applied to estimate the solvent shifts of absorption energies of a series of donor-acceptor dyes having low-lying charge-transfer states. Even for a nonpolar solvent such as n-hexane, the inclusion of its static polarizability leads to non-negligible shifts that improve the agreement to essentially quantitative levels (0.03 eV) with full-system calculations. Good agreement with the positions of the experimental absorption maxima measured in solution is also observed.

Access to COVID-19 testing by individuals with housing insecurity during the early days of the COVID-19 pandemic in the United States: a scoping review.

Introduction: The COVID-19 pandemic focused attention on healthcare disparities and inequities faced by individuals within marginalized and structurally disadvantaged groups in the United States. These individuals bore the heaviest burden across this pandemic as they faced increased risk of infection and difficulty in accessing testing and medical care. Individuals experiencing housing insecurity are a particularly vulnerable population given the additional barriers they face. In this scoping review, we identify some of the barriers this high-risk group experienced during the early days of the pandemic and assess novel solutions to overcome these barriers. Methods: A scoping review was performed following PRISMA-Sc guidelines looking for studies focusing on COVID-19 testing among individuals experiencing housing insecurity. Barriers as well as solutions to barriers were identified as applicable and summarized using qualitative methods, highlighting particular ways that proved effective in facilitating access to testing access and delivery. Results: Ultimately, 42 studies were included in the scoping review, with 143 barriers grouped into four categories: lack of cultural understanding, systemic racism, and stigma; medical care cost, insurance, and logistics; immigration policies, language, and fear of deportation; and other. Out of these 42 studies, 30 of these studies also suggested solutions to address them. Conclusion: A paucity of studies have analyzed COVID-19 testing barriers among those experiencing housing insecurity, and this is even more pronounced in terms of solutions to address those barriers. Expanding resources and supporting investigators within this space is necessary to ensure equitable healthcare delivery.

RADx-UP Testing Core: Access to COVID-19 Diagnostics in Community-Engaged Research with Underserved Populations.

Research on the COVID-19 pandemic revealed a disproportionate burden of COVID-19 infection and death among underserved populations and exposed low rates of SARS-CoV-2 testing in these communities. A landmark National Institutes of Health (NIH) funding initiative, the Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) program, was developed to address the research gap in understanding the adoption of COVID-19 testing in underserved populations. This program is the single largest investment in health disparities and community-engaged research in the history of the NIH. The RADx-UP Testing Core (TC) provides community-based investigators with essential scientific expertise and guidance on COVID-19 diagnostics. This commentary describes the first 2 years of the TC's experience, highlighting the challenges faced and insights gained to safely and effectively deploy large-scale diagnostics for community-initiated research in underserved populations during a pandemic. The success of RADx-UP shows that community-based research to increase access and uptake of testing among underserved populations can be accomplished during a pandemic with tools, resources, and multidisciplinary expertise provided by a centralized testing-specific coordinating center. We developed adaptive tools to support individual testing strategies and frameworks for these diverse studies and ensured continuous monitoring of testing strategies and use of study data. In a rapidly evolving setting of tremendous uncertainty, the TC provided essential and real-time technical expertise to support safe, effective, and adaptive testing. The lessons learned go beyond this pandemic and can serve as a framework for rapid deployment of testing in response to future crises, especially when populations are affected inequitably.

Use of Next-Generation Sequencing in a State-Wide Strategy of HIV-1 Surveillance: Impact of the SARS-COV-2 Pandemic on HIV-1 Diagnosis and Transmission.

BACKGROUND: The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic posed an unpreceded threat to the management of other pandemics such as human immunodeficiency virus-1 (HIV-1) in the United States. The full impact of the SARS-CoV-2 pandemic on the HIV-1 pandemic needs to be evaluated. METHODS: All individuals with newly reported HIV-1 diagnoses from NC State Laboratory of Public Health were enrolled in this prospective observational study, 2018-2021. We used a sequencing-based recency assay to identify recent HIV-1 infections and to determine the days postinfection (DPI) for each person at the time of diagnosis. RESULTS: Sequencing used diagnostic serum samples from 814 individuals with new HIV-1 diagnoses spanning this 4-year period. Characteristics of individuals diagnosed in 2020 differed from those in other years. People of color diagnosed in 2021 were on average 6 months delayed in their diagnosis compared to those diagnosed in 2020. There was a trend that genetic networks were more known for individuals diagnosed in 2021. We observed no major integrase resistance mutations over the course of the study. CONCLUSIONS: SARS-CoV-2 pandemic may contribute to the spread of HIV-1. Public health resources need to focus on restoring HIV-1 testing and interrupting active, ongoing, transmission.

Efficient analytical gradients of property-based diabatic states: Geometry optimizations for localized holes.

We present efficient analytical gradients of property-based diabatic states and couplings using a Lagrangian formalism. Unlike previous formulations, the method achieves a computational scaling that is independent of the number of adiabatic states used to construct the diabats. The approach is generalizable to other property-based diabatization schemes and electronic structure methods as long as analytical energy gradients are available and integral derivatives with the property operator can be formed. We also introduce a scheme to phase and reorder diabats to ensure their continuity between molecular configurations. We demonstrate this for the specific case of Boys diabatic states obtained from state-averaged complete active space self-consistent field electronic structure calculations with GPU acceleration in the TeraChem package. The method is used to test the Condon approximation for the hole transfer in an explicitly solvated model DNA oligomer.

Machine learning the Hohenberg-Kohn map for molecular excited states.

The Hohenberg-Kohn theorem of density-functional theory establishes the existence of a bijection between the ground-state electron density and the external potential of a many-body system. This guarantees a one-to-one map from the electron density to all observables of interest including electronic excited-state energies. Time-Dependent Density-Functional Theory (TDDFT) provides one framework to resolve this map; however, the approximations inherent in practical TDDFT calculations, together with their computational expense, motivate finding a cheaper, more direct map for electronic excitations. Here, we show that determining density and energy functionals via machine learning allows the equations of TDDFT to be bypassed. The framework we introduce is used to perform the first excited-state molecular dynamics simulations with a machine-learned functional on malonaldehyde and correctly capture the kinetics of its excited-state intramolecular proton transfer, allowing insight into how mechanical constraints can be used to control the proton transfer reaction in this molecule. This development opens the door to using machine-learned functionals for highly efficient excited-state dynamics simulations.

Conical Intersections in Solution with Polarizable Embedding: Integral-Exact Direct Reaction Field.

A common strategy to exploring the properties and reactivity of complex systems is to use quantum mechanics/molecular mechanics (QM/MM) embedding, wherein a QM region is defined and treated with electronic structure theory, and the remainder of the system is treated with a force field. Important to the description of electronic excited states, especially those of charge-transfer character, is the treatment of the coupling between the QM and MM subsystems. The state of the art is to use a polarizable force field for the MM region and mutually couple the QM wavefunction and MM induced dipoles, in addition to the usual electrostatic embedding, yielding a polarizable embedding (QM/MM-Pol) approach. However, we showed previously that current popular QM/MM-Pol approaches exhibit issues of root flipping and/or incorrect descriptions of electronic crossings in multistate calculations [J. Chem. Theory Comput. 14, 2137 (2018)]. Here, we demonstrate a solution to these problems with an integral-exact reformulation of the direct reaction field approach of Thole and Van Duijnen (QM/MM-IEDRF). The resulting embedding potential includes one- and two-electron operators and many-body dipole-induced dipole interactions and thus includes a natural description of the screening of electron-electron interactions by the MM induced dipoles. Pauli repulsion from the environment is mimicked by effective core potentials on the MM atoms. Inherent to the DRF approach is the assumption that MM dipoles respond instantaneously to the positions of the QM electrons; therefore, dispersion interactions are captured approximately. All electronic states are eigenfunctions of the same Hamiltonian, while the polarization induced in the environment and the associated energetic stabilization are unique to each state. This allows for a consistent definition of transition properties and state crossings. We demonstrate QM/MM-IEDRF by exploring the influence of a (polarizable) inert xenon matrix environment on the conical intersection underlying the photoisomerization of ethylene.

Evidence for Water Antibonding Orbital Mixing in the Hydrated Electron from Its Oxygen 1s X-ray Absorption Spectrum.

The X-ray absorption spectrum (XAS) of the hydrated electron (e(aq)-) has been simulated using time-dependent density functional theory with a quantum mechanics/molecular mechanics description. A unique XAS peak at 533 eV is observed with an energy and intensity in quantitative agreement with recent time-resolved experiments, allowing its assignment as arising from water O1s transitions to the singly occupied molecular orbital (SOMO) in which the excess electron resides. The transitions acquire oscillator strength due to the SOMO comprising an admixture of a cavity-localized orbital and water 4a1 and 2b2 antibonding orbitals. The mixing of antibonding orbitals has implications for the strength of couplings between e(aq)- and intramolecular modes of water.

Ultrafast Photoisomerization of Ethylene Studied Using Time-Resolved Extreme Ultraviolet Photoelectron Spectroscopy.

The photoisomerization of isolated ethylene (ethene) was observed in real time from the Franck-Condon region in the 1ππ* state to ground-state products using time-resolved photoelectron spectroscopy with extreme ultraviolet (EUV, 21.7 eV) probe pulses. A combination of filamentation four-wave mixing and high-order harmonic generation was employed to obtain a temporal resolution of 31 ± 2 fs. The nuclear wave packet created by a 160 nm pump pulse accesses C═C twisted geometries within 10 fs, and the population transfer from the excited to the ground state occurs within the next 20-30 fs. Formation of vibrationally highly excited ground-state molecules was observed in less than 45 fs, and they decayed with two time constants of 0.87 and >5 ps. The interpretation of the photoelectron spectra is supported by vertical ionization energies calculated using XMS-CASPT2 along geodesically interpolated reaction paths from the Franck-Condon region to the products.

Flexible boundary layer using exchange for embedding theories. II. QM/MM dynamics of the hydrated electron.

The FlexiBLE embedding method introduced in Paper I [Z. Shen and W. J. Glover, J. Chem. Phys. 155, 224112 (2021)] is applied to explore the structure and dynamics of the aqueous solvated electron at an all-electron density functional theory Quantum Mechanics/Molecular Mechanics level. Compared to a one-electron mixed quantum/classical description, we find the dynamics of the many-electron model of the hydrated electron exhibits enhanced coupling to water OH stretch modes. Natural bond orbital analysis reveals this coupling is due to significant population of water OH σ* orbitals, reaching 20%. Based on this, we develop a minimal frontier orbital picture of the hydrated electron involving a cavity orbital and important coupling to 4-5 coordinating OH σ* orbitals. Implications for the interpretation of the spectroscopy of this interesting species are discussed.

Flexible boundary layer using exchange for embedding theories. I. Theory and implementation.

Embedding theory is a powerful computational chemistry approach to exploring the electronic structure and dynamics of complex systems, with Quantum Mechanical/Molecular Mechanics (QM/MM) being the prime example. A challenge arises when trying to apply embedding methodology to systems with diffusible particles, e.g., solvents, if some of them must be included in the QM region, for example, in the description of solvent-supported electronic states or reactions involving proton transfer or charge-transfer-to-solvent: without a special treatment, inter-diffusion of QM and MM particles will eventually lead to a loss of QM/MM separation. We have developed a new method called Flexible Boundary Layer using Exchange (FlexiBLE) that solves the problem by adding a biasing potential to the system that closely maintains QM/MM separation. The method rigorously preserves ensemble averages by leveraging their invariance to an exchange of identical particles. With a careful choice of the biasing potential and the use of a tree algorithm to include only important QM and MM exchanges, we find that the method has an MM-forcefield-like computational cost and thus adds negligible overhead to a QM/MM simulation. Furthermore, we show that molecular dynamics with the FlexiBLE bias conserves total energy, and remarkably, sub-diffusional dynamical quantities in the inner QM region are unaffected by the applied bias. FlexiBLE thus widens the range of chemistry that can be studied with embedding theory.

Active orbital preservation for multiconfigurational self-consistent field.

We introduce Active Orbital Preservation for Multiconfigurational Self-Consistent Field (AOP-MCSCF), an automated approach to improving the consistency of active space orbitals over multiple molecular configurations. Our approach is based on maximum overlap with a reference set of active space orbitals taken from a single geometry of a chromophore in the gas phase and can be used to automatically preserve the appropriate orbitals of the chromophore across multiple thermally sampled configurations, even when the chromophore is solvated by quantum-mechanically treated water molecules. In particular, using the singular value decomposition of a Molecular Orbital (MO) overlap matrix between the system and reference, we rotate the MOs of the system to align with the reference active space orbitals and use the resulting rotated orbitals as an initial guess to a MCSCF calculation. We demonstrate the approach on aqueous p-hydroxybenzylidene-imidazolinone (HBI) and find that AOP-MCSCF converges to the "correct" orbitals for over 90% of 3000 thermally sampled configurations. In addition, we compute the linear absorption spectrum and find excellent agreement with new experimental measurements up to 5.4 eV (230 nm). We show that electrostatic contributions to the solvation energy of HBI largely explain the observed state-dependent solvatochromism.

Accurate Prediction of Absorption Spectral Shifts of Proteorhodopsin Using a Fragment-Based Quantum Mechanical Method.

Many experiments have been carried out to display different colors of Proteorhodopsin (PR) and its mutants, but the mechanism of color tuning of PR was not fully elucidated. In this study, we applied the Electrostatically Embedded Generalized Molecular Fractionation with Conjugate Caps (EE-GMFCC) method to the prediction of excitation energies of PRs. Excitation energies of 10 variants of Blue Proteorhodopsin (BPR-PR105Q) in residue 105GLN were calculated with the EE-GMFCC method at the TD-B3LYP/6-31G* level. The calculated results show good correlation with the experimental values of absorption wavelengths, although the experimental wavelength range among these systems is less than 50 nm. The ensemble-averaged electric fields along the polyene chain of retinal correlated well with EE-GMFCC calculated excitation energies for these 10 PRs, suggesting that electrostatic interactions from nearby residues are responsible for the color tuning. We also utilized the GMFCC method to decompose the excitation energy contribution per residue surrounding the chromophore. Our results show that residues ASP97 and ASP227 have the largest contribution to the absorption spectral shift of PR among the nearby residues of retinal. This work demonstrates that the EE-GMFCC method can be applied to accurately predict the absorption spectral shifts for biomacromolecules.

Diabatic Many-Body Expansion: Development and Application to Charge-Transfer Reactions.

We explore the convergence of the many-body expansion for a prototypical hole-transfer reaction between Zn(0) and Zn(I) in a condensed-phase environment. Poor convergence of state energies is seen when the adiabatic representation is used, which can be understood from the fragment single-point calculations at low orders of the many-body expansion incorrectly localizing charges compared to the full system, thus leading to qualitative errors in the electronic structure of the adiabatic states between fragments. Using a charge-localized representation of the electronic Hamiltonian, we introduce a diabatic many-body expansion method with quantitative accuracy for ground- and excited-state potential energy surfaces of a charge-transfer reaction. Combining with a multiconfigurational self-consistent field affords a fragmentation approach that scales quadratically with system size while retaining chemical accuracy (<1 kcal/mol) in total energies compared to full system calculations.

Fragment Quantum Mechanical Method for Excited States of Proteins: Development and Application to the Green Fluorescent Protein.

Understanding the excited-state properties of luminescent biomolecules is of central importance to their biophysical applications. In this study, we develop the Electrostatically Embedded Generalized Molecular Fractionation with Conjugate Caps (EE-GMFCC) method for quantitatively characterizing properties of covalently bonded systems with localized excitations (i.e., involving a single chromophore), such as fluorescent proteins. The excitation energy, transition dipole moment, and oscillator strength of wild-type Green Fluorescent Protein (wt-GFP) calculated by EE-GMFCC are found to be in excellent agreement with full system time-dependent density functional theory results. We also applied the Polarized Protein-Specific Charge model to wt-GFP, and found that electronic polarization of the protein is critical in stabilizing hydrogen bonding interactions in wt-GFP, which influences its absorption spectrum. The predicted absorption spectra of wt-GFP in the A and B states qualitatively agree with experiment. The fragmentation approach further allows a straightforward per residue decomposition of the excitation which reveals the influence of the protein environment on the absorption spectra of wt-GFP A and B states. Our results demonstrate that the EE-GMFCC method is both accurate and efficient for excited-state property calculations on proteins.

SSAIMS-Stochastic-Selection Ab Initio Multiple Spawning for Efficient Nonadiabatic Molecular Dynamics.

Ab initio multiple spawning provides a powerful and accurate way of describing the excited-state dynamics of molecular systems, whose strength resides in the proper description of coherence effects during nonadiabatic processes thanks to the coupling of trajectory basis functions. However, the simultaneous propagation of a large number of trajectory basis functions can be numerically inconvenient. We propose here an elegant and simple solution to this issue, which consists of (i) detecting uncoupled groups of coupled trajectory basis functions and (ii) selecting stochastically one of these groups to continue the ab initio multiple spawning dynamics. We show that this procedure can reproduce the results of full ab initio multiple spawning dynamics in cases where the uncoupled groups of trajectory basis functions stay uncoupled throughout the dynamics (which is often the case in high-dimensional problems). We present and discuss the aforementioned idea in detail and provide simple numerical applications on indole, ethylene, and protonated formaldimine, highlighting the potential of stochastic-selection ab initio multiple spawning.

Statewide surveillance of carbapenemase-producing carbapenem-resistant Escherichia coli and Klebsiella species in Washington state, October 2012-December 2017.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) are common causes of healthcare-associated infections and are often multidrug resistant with limited therapeutic options. Additionally, CRE can spread within and between healthcare facilities, amplifying potential harms. OBJECTIVE: To better understand the burden, risk factors, and source of acquisition of carbapenemase genes in clinical Escherichia coli and Klebsiella spp isolates from patients in Washington to guide prevention efforts. DESIGN: Multicenter prospective surveillance study. METHODS: Escherichia coli and Klebsiella spp isolates meeting the Washington state CRE surveillance case definition were solicited from clinical laboratories and tested at Washington Public Health Laboratories using polymerase chain reaction (PCR) for the 5 most common carbapenemase genes: blaKPC, blaNDM, blaIMP, blaVIM, and blaOXA-48. Case patients positive by PCR were investigated by the public health department. RESULTS: From October 2012 through December 2017, 363 carbapenem-resistant E. coli and Klebsiella spp isolates were tested. Overall, 45 of 115 carbapenem-resistant K. pneumoniae (39%), 1 of 8 K. oxytoca (12.5%), and 28 of 239 carbapenem-resistant E. coli (11.7%) were carbapenemase positive. Of 74 carbapenemase-positive isolates, blaKPC was most common (47%), followed by blaNDM (30%), blaOXA-48 (22%), and blaIMP (1%). Although all cases had healthcare exposure, blaKPC acquisition was associated with US health care, whereas non-blaKPC acquisition was associated with international health care or travel. CONCLUSIONS: We report that blaKPC, the most prevalent carbapenemase in the United States, accounts for nearly half of carbapenemase cases in Washington state and that most KPC-cases are likely acquired through in-state health care.

The Fluxional Nature of the Hydrated Electron: Energy and Entropy Contributions to Aqueous Electron Free Energies.

There has been a great deal of recent controversy over the structure of the hydrated electron and whether it occupies a cavity or contains a significant number of interior waters (noncavity). The questions we address in this work are, from a free energy perspective, how different are these proposed structures? Do the different structures all lie along a single continuum, or are there significant differences (i.e., free energy barriers) between them? To address these questions, we have performed a series of one-electron calculations using umbrella sampling with quantum biased molecular dynamics along a coordinate that directly reflects the number of water molecules in the hydrated electron's interior. We verify that a standard cavity model of the hydrated electron behaves essentially as a hard sphere: the model is dominated by repulsion at short range such that water is expelled from a local volume around the electron, leading to a water solvation shell like that of a pseudohalide ion. The repulsion is much larger than thermal energies near room temperature, explaining why such models exhibit properties with little temperature dependence. On the other hand, our calculations reveal that a noncavity model is highly fluxional, meaning that thermal motions cause the number of interior waters to fluctuate from effectively zero (i.e., a cavity-type electron) to potentially above the bulk water density. The energetic contributions in the noncavity model are still repulsive in the sense that they favor cavity formation, so the fluctuations in structure are driven largely by entropy: the entropic cost for expelling water from a region of space is large enough that some water is still driven into the electron's interior. As the temperature is lowered and entropy becomes less important, the noncavity electron's structure is predicted to become more cavity-like, consistent with the observed temperature dependence of the hydrated electron's properties. Thus, we argue that although the specific noncavity model we study overestimates the preponderance of fluctuations involving interior water molecules, with appropriate refinements to correctly capture the true average number of interior waters and molar solvation volume, a fluxional model likely makes the most sense for understanding the various experimental properties of the hydrated electron.