The persistence of memory in ionic conduction probed by nonlinear optics.

Predicting practical rates of transport in condensed phases enables the rational design of materials, devices and processes. This is especially critical to developing low-carbon energy technologies such as rechargeable batteries1-3. For ionic conduction, the collective mechanisms4,5, variation of conductivity with timescales6-8 and confinement9,10, and ambiguity in the phononic origin of translation11,12, call for a direct probe of the fundamental steps of ionic diffusion: ion hops. However, such hops are rare-event large-amplitude translations, and are challenging to excite and detect. Here we use single-cycle terahertz pumps to impulsively trigger ionic hopping in battery solid electrolytes. This is visualized by an induced transient birefringence, enabling direct probing of anisotropy in ionic hopping on the picosecond timescale. The relaxation of the transient signal measures the decay of orientational memory, and the production of entropy in diffusion. We extend experimental results using in silico transient birefringence to identify vibrational attempt frequencies for ion hopping. Using nonlinear optical methods, we probe ion transport at its fastest limit, distinguish correlated conduction mechanisms from a true random walk at the atomic scale, and demonstrate the connection between activated transport and the thermodynamics of information.

Subterahertz collective dynamics of polar vortices.

The collective dynamics of topological structures1-6 are of interest from both fundamental and applied perspectives. For example, studies of dynamical properties of magnetic vortices and skyrmions3,4 have not only deepened our understanding of many-body physics but also offered potential applications in data processing and storage7. Topological structures constructed from electrical polarization, rather than electron spin, have recently been realized in ferroelectric superlattices5,6, and these are promising for ultrafast electric-field control of topological orders. However, little is known about the dynamics underlying the functionality of such complex extended nanostructures. Here, using terahertz-field excitation and femtosecond X-ray diffraction measurements, we observe ultrafast collective polarization dynamics that are unique to polar vortices, with orders-of-magnitude higher frequencies and smaller lateral size than those of experimentally realized magnetic vortices3. A previously unseen tunable mode, hereafter referred to as a vortexon, emerges in the form of transient arrays of nanoscale circular patterns of atomic displacements, which reverse their vorticity on picosecond timescales. Its frequency is considerably reduced (softened) at a critical strain, indicating a condensation (freezing) of structural dynamics. We use first-principles-based atomistic calculations and phase-field modelling to reveal the microscopic atomic arrangements and corroborate the frequencies of the vortex modes. The discovery of subterahertz collective dynamics in polar vortices opens opportunities for electric-field-driven data processing in topological structures with ultrahigh speed and density.

Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen.

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.

Non-equilibrium pathways to emergent polar supertextures.

Ultrafast stimuli can stabilize metastable states of matter inaccessible by equilibrium means. Establishing the spatiotemporal link between ultrafast excitation and metastability is crucial to understand these phenomena. Here we utilize single-shot optical pump-X-ray probe measurements to capture snapshots of the emergence of a persistent polar vortex supercrystal in a heterostructure that hosts a fine balance between built-in electrostatic and elastic frustrations by design. By perturbing this balance with photoinduced charges, an initially heterogeneous mixture of polar phase disorders within a few picoseconds, leading to a state composed of disordered ferroelectric and suppressed vortex orders. On the picosecond-nanosecond timescales, transient labyrinthine fluctuations develop, accompanied by the recovery of the vortex order. On longer timescales, these fluctuations are progressively quenched by dynamical strain modulations, which drive the collective emergence of a single vortex supercrystal phase. Our results, corroborated by dynamical phase-field modelling, reveal non-equilibrium pathways following the ultrafast excitation of designer systems to persistent metastability.

An ultrafast symmetry switch in a Weyl semimetal.

Topological quantum materials exhibit fascinating properties1-3, with important applications for dissipationless electronics and fault-tolerant quantum computers4,5. Manipulating the topological invariants in these materials would allow the development of topological switching applications analogous to switching of transistors6. Lattice strain provides the most natural means of tuning these topological invariants because it directly modifies the electron-ion interactions and potentially alters the underlying crystalline symmetry on which the topological properties depend7-9. However, conventional means of applying strain through heteroepitaxial lattice mismatch10 and dislocations11 are not extendable to controllable time-varying protocols, which are required in transistors. Integration into a functional device requires the ability to go beyond the robust, topologically protected properties of materials and to manipulate the topology at high speeds. Here we use crystallographic measurements by relativistic electron diffraction to demonstrate that terahertz light pulses can be used to induce terahertz-frequency interlayer shear strain with large strain amplitude in the Weyl semimetal WTe2, leading to a topologically distinct metastable phase. Separate nonlinear optical measurements indicate that this transition is associated with a symmetry change to a centrosymmetric, topologically trivial phase. We further show that such shear strain provides an ultrafast, energy-efficient way of inducing robust, well separated Weyl points or of annihilating all Weyl points of opposite chirality. This work demonstrates possibilities for ultrafast manipulation of the topological properties of solids and for the development of a topological switch operating at terahertz frequencies.

Giant Terahertz Birefringence in an Ultrathin Anisotropic Semimetal.

Manipulating the polarization of light at the nanoscale is key to the development of next-generation optoelectronic devices. This is typically done via waveplates using optically anisotropic crystals, with thicknesses on the order of the wavelength. Here, using a novel ultrafast electron-beam-based technique sensitive to transient near fields at THz frequencies, we observe a giant anisotropy in the linear optical response in the semimetal WTe2 and demonstrate that one can tune the THz polarization using a 50 nm thick film, acting as a broadband wave plate with thickness 3 orders of magnitude smaller than the wavelength. The observed circular deflections of the electron beam are consistent with simulations tracking the trajectory of the electron beam in the near field of the THz pulse. This finding offers a promising approach to enable atomically thin THz polarization control using anisotropic semimetals and defines new approaches for characterizing THz near-field optical response at far-subwavelength length scales.

Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial.

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. METHODS: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection. CLINICAL TRIALS REGISTRATION: NCT02538172.

Monitoring the Evolution of Relative Product Populations at Early Times during a Photochemical Reaction.

Identifying multiple rival reaction products and transient species formed during ultrafast photochemical reactions and determining their time-evolving relative populations are key steps toward understanding and predicting photochemical outcomes. Yet, most contemporary ultrafast studies struggle with clearly identifying and quantifying competing molecular structures/species among the emerging reaction products. Here, we show that mega-electronvolt ultrafast electron diffraction in combination with ab initio molecular dynamics calculations offer a powerful route to determining time-resolved populations of the various isomeric products formed after UV (266 nm) excitation of the five-membered heterocyclic molecule 2(5H)-thiophenone. This strategy provides experimental validation of the predicted high (∼50%) yield of an episulfide isomer containing a strained three-membered ring within ∼1 ps of photoexcitation and highlights the rapidity of interconversion between the rival highly vibrationally excited photoproducts in their ground electronic state.

Tracing HIV-1 strains that imprint broadly neutralizing antibody responses.

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.

Ultrafast Optomechanical Strain in Layered GeS.

Strong coupling between light and mechanical strain forms the foundation for next-generation optical micro- and nano-electromechanical systems. Such optomechanical responses in two-dimensional materials present novel types of functionalities arising from the weak van der Waals bond between atomic layers. Here, by using structure-sensitive megaelectronvolt ultrafast electron diffraction, we report the experimental observation of optically driven ultrafast in-plane strain in the layered group IV monochalcogenide germanium sulfide (GeS). Surprisingly, the photoinduced structural deformation exhibits strain amplitudes of order 0.1% with a 10 ps fast response time and a significant in-plane anisotropy between zigzag and armchair crystallographic directions. Rather than arising due to heating, experimental and theoretical investigations suggest deformation potentials caused by electronic density redistribution and converse piezoelectric effects generated by photoinduced electric fields are the dominant contributors to the observed dynamic anisotropic strains. Our observations define new avenues for ultrafast optomechanical control and strain engineering within functional devices.

Understanding the Decline of Incident, Active Tuberculosis in People With Human Immunodeficiency Virus in Switzerland.

BACKGROUND: People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear. METHODS: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures. RESULTS: In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio [HR] 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease. CONCLUSIONS: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need.

Genome-scale, single-cell-type resolution of microRNA activities within a whole plant organ.

Loaded into ARGONAUTE(AGO) proteins, eukaryotic micro(mi)RNAs regulate gene expression via cleavage, translational repression, and/or accelerated decay of sequence-complementary target transcripts. Despite their importance in development, cell identity maintenance and stress responses, how individual miRNAs contribute to spatial gene regulation within the complex cell mosaics formed in tissues/organs has remained inaccessible in any organism to date. We have developed a non-invasive methodology to examine, at single-cell-type resolution, the AGO-loading and activity patterns of entire miRNA cohorts in intact organs, applied here to the Arabidopsis root tip. A dual miRNAome-targetome analytical interface allowing intuitive data integration/visualization was developed as the basis for in-depth investigations via single-cell-type experimentation. These uncovered an array of so far speculative or hitherto unknown types of spatial miRNA-mediated gene regulation schemes, including via widespread cell-to-cell movement between contiguous layers of distinct identities. This study provides the proof of principle that minimally invasive, genome-scale analysis of miRNA activities within and between single-cell types of whole organs is achievable.

Terahertz-Driven Local Dipolar Correlation in a Quantum Paraelectric.

Light-induced ferroelectricity in quantum paraelectrics is a new avenue of achieving dynamic stabilization of hidden orders in quantum materials. In this Letter, we explore the possibility of driving a transient ferroelectric phase in the quantum paraelectric KTaO_{3} via intense terahertz excitation of the soft mode. We observe a long-lived relaxation in the terahertz-driven second harmonic generation (SHG) signal that lasts up to 20 ps at 10 K, which may be attributed to light-induced ferroelectricity. Through analyzing the terahertz-induced coherent soft-mode oscillation and finding its hardening with fluence well described by a single-well potential, we demonstrate that intense terahertz pulses up to 500 kV/cm cannot drive a global ferroelectric phase in KTaO_{3}. Instead, we find the unusual long-lived relaxation of the SHG signal comes from a terahertz-driven moderate dipolar correlation between the defect-induced local polar structures. We discuss the impact of our findings on current investigations of the terahertz-induced ferroelectric phase in quantum paraelectrics.

Femtosecond Electronic and Hydrogen Structural Dynamics in Ammonia Imaged with Ultrafast Electron Diffraction.

Directly imaging structural dynamics involving hydrogen atoms by ultrafast diffraction methods is complicated by their low scattering cross sections. Here we demonstrate that megaelectronvolt ultrafast electron diffraction is sufficiently sensitive to follow hydrogen dynamics in isolated molecules. In a study of the photodissociation of gas phase ammonia, we simultaneously observe signatures of the nuclear and corresponding electronic structure changes resulting from the dissociation dynamics in the time-dependent diffraction. Both assignments are confirmed by ab initio simulations of the photochemical dynamics and the resulting diffraction observable. While the temporal resolution of the experiment is insufficient to resolve the dissociation in time, our results represent an important step towards the observation of proton dynamics in real space and time.

Ultrafast X-Ray Scattering Reveals Composite Amplitude Collective Mode in the Weyl Charge Density Wave Material (TaSe_{4})_{2}I.

We report ultrafast x-ray scattering experiments of the quasi-1D charge density wave (CDW) material (TaSe_{4})_{2}I following ultrafast infrared photoexcitation. From the time-dependent diffraction signal at the CDW sidebands we identify a 0.11 THz amplitude mode derived primarily from a transverse acoustic mode of the high-symmetry structure. From our measurements we determine that this mode interacts with the valence charge indirectly through another collective mode, and that the CDW system in (TaSe_{4})_{2}I has a composite nature supporting multiple dynamically active structural degrees of freedom.

Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV.

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed.

Successful use of extracorporeal life support and hemadsorption in the context of venlafaxine intoxication requiring cardiopulmonary resuscitation: a case report.

Venlafaxine is a serotonin and noradrenalin reuptake inhibitor prescribed as an antidepressant. Overdose clinically manifests with neurological, cardiovascular and gastrointestinal abnormalities based on, amongst others, serotonin syndrome and can be life-threatening due to cardiovascular collapse. Besides immediate decontamination via gastric lavage and inhibition of enteral absorption through active charcoal, successful hemadsorption with CytoSorb® has been reported. We present the case of a 17-year-old female who required extracorporeal life support (ECLS) for cardiovascular collapse as a result of life-threatening venlafaxine intoxication. Serial serum blood concentrations of venlafaxine/desmethylvenlafaxine on admission at a tertiary hospital (approx. 24 h after ingestion) and subsequently 6 h and 18 h thereafter, as well as on days 2 and 4, were measured. CytoSorb® was initiated 6 h after admission and changed three times over 72 h. The initial blood concentration of venlafaxine/desmethylvenlafaxine was 53.52 µmol/l. After 6 h, it declined to 30.7 µmol/l and CytoSorb® was initiated at this point. After 12 h of hemadsorption, the blood level decreased to 9.6 µmol/l. On day 2, it was down to 7.17 µmol/l and decreased further to 3.74 µmol/l. Additional continuous renal replacement therapy using CVVHD was implemented on day 5. The combination of hemadsorption, besides traditional decontamination strategies along maximal organ supportive therapy with ECLS, resulted in the intact neurological survival of the highest venlafaxine intoxication reported in the literature to date. Hemadsorption with CytoSorb® might help to reduce blood serum levels of venlafaxine. Swift clearance of toxic blood levels may support cardiovascular recovery after life-threatening intoxications.

Complete Metabolic Response to Combined Immune Checkpoint Inhibition after Progression of Metastatic Colorectal Cancer on Pembrolizumab: A Case Report.

DNA mismatch repair deficient (dMMR) and microsatellite instable (MSI) metastatic colorectal cancer (mCRC) can be successfully treated with FDA- and EMA-approved immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab (as single agents targeting the anti-programmed cell death protein-1 (PD-1)) or combinations of a PD-1 inhibitor with ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-targeting antibody. The best treatment strategy beyond progression on single-agent ICI therapy remains unclear. Here, we present the case of a 63-year-old male with Lynch-syndrome-associated, microsatellite instability-high (MSI-H) mCRC who achieved a rapid normalization of his tumor markers and a complete metabolic remission (CMR), currently lasting for ten months, on sequential ICI treatment with the combination of nivolumab and ipilimumab followed by nivolumab maintenance therapy after progression on single-agent anti-PD-1 ICI therapy. The therapy was well-tolerated, and no immune-related adverse events occurred. To the best of our knowledge, this is the first case of a sustained metabolic complete remission in an MSI-H mCRC patient initially progressing on single-agent anti-PD-1 therapy. Thus, dMMR mCRC patients might benefit from sequential immune checkpoint regimens even with long-term responses. However, further sophistication of clinical algorithms for treatment beyond progression on single-agent ICI therapy in MSI-mCRC is urgently needed.

Photoswitchable Pseudoirreversible Butyrylcholinesterase Inhibitors Allow Optical Control of Inhibition in Vitro and Enable Restoration of Cognition in an Alzheimer's Disease Mouse Model upon Irradiation.

To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and the mechanisms by which BChE affects Alzheimer's disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable BChE inhibitors. The compounds were able to specifically influence different kinetic parameters of the inhibition process by light. For one compound, a 10-fold difference in the IC50-values (44.6 nM cis, 424 nM trans) in vitro was translated to an "all or nothing" response with complete recovery in a murine cognition-deficit AD model at dosages as low as 0.3 mg/kg.