Discovery of potent small-molecule inhibitors of lipoprotein(a) formation.

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3-7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7-8. We identify compounds that bind to apo(a) KIV7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).

Measuring and understanding information storage and transfer in a simulated human gut microbiome.

Considering biological systems as information processing entities and analyzing their organizational structure via information-theoretic measures has become an established approach in life sciences. We transfer this framework to a field of broad general interest, the human gut microbiome. We use BacArena, a software combining agent-based modelling and flux-balance analysis, to simulate a simplified human intestinal microbiome (SIHUMI). In a first step, we derive information theoretic measures from the simulated abundance data, and, in a second step, relate them to the metabolic processes underlying the abundance data. Our study provides further evidence on the role of active information storage as an indicator of unexpected structural change in the observed system. Besides, we show that information transfer reflects coherent behavior in the microbial community, both as a reaction to environmental changes and as a result of direct effective interaction. In this sense, purely abundance-based information theoretic measures can provide meaningful insight on metabolic interactions within bacterial communities. Furthermore, we shed light on the important however little noticed technical aspect of distinguishing immediate and delayed effects in the interpretation of local information theoretical measures.

Excitonic Quantum Coherence in Light Emission from CsPbBr3 Metal-Halide Perovskite Nanocrystals.

The decay of excited states via radiative and nonradiative paths is well understood in molecules and bulk semiconductors but less so in nanocrystals. Here, we perform time-resolved photoluminescence (t-PL) experiments on CsPbBr3 metal-halide perovskite nanocrystals, with a time resolution of 3 ps, sufficient to observe the decay of both excitons and biexcitons as a function of temperature. The striking result is that the radiative rate constant of the single exciton increases at low temperatures with an exponential functional form, suggesting quantum coherent effects with dephasing at high temperatures. The opposing directions of the radiative and nonradiative decay rate constants enable enhanced brightening of PL from excitons to biexcitons due to quantum effects, promoting a faster approach to the quantum theoretical limits of light emission. Ab initio quantum dynamics simulations reproduce the experimental observations of radiation controlled by quantum spatial coherence enhanced at low temperatures.

Superior Phonon-Limited Exciton Mobility in Lead-Free Two-Dimensional Perovskites.

Tin-based two-dimensional (2D) perovskites are emerging as lead-free alternatives in halide perovskite materials, yet their exciton dynamics and transport remain less understood due to defect scattering. Addressing this, we employed temperature-dependent transient photoluminescence (PL) microscopy to investigate intrinsic exciton transport in three structurally analogous Sn- and Pb-based 2D perovskites. Employing conjugated ligands, we synthesized high-quality crystals with enhanced phase stability at various temperatures. Our results revealed phonon-limited exciton transport in Sn perovskites, with diffusion constants increasing from 0.2 cm2 s-1 at room temperature to 0.6 cm2 s-1 at 40 K, and a narrowing PL line width. Notably, Sn-based perovskites exhibited greater exciton mobility than their Pb-based equivalents, which is attributed to lighter effective masses. Thermally activated optical phonon scattering was observed in Sn-based compounds but was absent in Pb-based materials. These findings, supported by molecular dynamics simulations, demonstrate that the phonon scattering mechanism in Sn-based halide perovskites can be distinct from their Pb counterparts.

Tunneling-Driven Marcus-Inverted Triplet Energy Transfer in a Two-Dimensional Perovskite.

Quantum tunneling, a phenomenon that allows particles to pass through potential barriers, can play a critical role in energy transfer processes. Here, we demonstrate that the proper design of organic-inorganic interfaces in two-dimensional (2D) hybrid perovskites allows for efficient triplet energy transfer (TET), where quantum tunneling of the excitons is the key driving force. By employing temperature-dependent and time-resolved photoluminescence and pump-probe spectroscopy techniques, we establish that triplet excitons can transfer from the inorganic lead-iodide sublattices to the pyrene ligands with rapid and weakly temperature-dependent characteristic times of approximately 50 ps. The energy transfer rates obtained based on the Marcus theory and first-principles calculations show good agreement with the experiments, indicating that the efficient tunneling of triplet excitons within the Marcus-inverted regime is facilitated by high-frequency molecular vibrations. These findings offer valuable insights into how one can effectively manipulate the energy landscape in 2D hybrid perovskites for energy transfer and the creation of diverse excitonic states.

Counterion Loss from Charged Surface-Bound Complexes Drives the Formation of Loosely Packed Monolayers.

The functionality of multicomponent self-assembled monolayers (SAMs) can be severely diminished by the segregation of like components into nanoscale domains, a process that maximizes favorable short-range intermolecular interactions. Here, we explore the use of a modular family of sulfur-functionalized metal bis(terpyridine) complexes ([M(tpy-R)2]2+(PF6-)2) to prepare mixed SAMs, considering that the comparable structure, dimensions, and ionic composition of these species should render them interchangeable within the adsorbed surface layer. While surface voltammetry experiments show that these SAMs do exhibit compositions representative of their assembly solutions, they also suggest, in line with previous reports, that adjacent complexes in the monolayer are separated by a gap of ∼ 1 nm. Remarkably, X-ray photoelectron spectroscopy studies reveal no F 1s peak features that would confirm the proliferation of PF6- counterions on the surface. We propose that the loosely packed structure of these SAMs results from the loss or exchange of PF6- counterions, which introduces significant repulsive Coulomb interactions between the adsorbed 2+ charged complexes. The hypothesis is supported by an electrostatic model which indicates that these complexes should form close-packed SAMs if mobile counterions are present. First-principles calculations demonstrate that complex-counterion binding interactions are weakened by charge transfer to the gold substrate, suggesting that this may play an important role in the formation of such low-coverage SAMs. Together, this study raises important questions regarding the assembly, organization, and composition of charged SAMs and highlights new opportunities in the design of multicomponent monolayer assemblies with free volume, for example, to facilitate surface-based reactions or support molecular switches.

Revisiting Sub-Band Gap Emission Mechanism in 2D Halide Perovskites: The Role of Defect States.

Understanding the sub-band gap luminescence in Ruddlesden-Popper 2D metal halide hybrid perovskites (2D HaPs) is essential for efficient charge injection and collection in optoelectronic devices. Still, its origins are still under debate with respect to the role of self-trapped excitons or radiative recombination via defect states. In this study, we characterized charge separation, recombination, and transport in single crystals, exfoliated layers, and polycrystalline thin films of butylammonium lead iodide (BA2PbI4), one of the most prominent 2D HaPs. We combined complementary defect- and exciton-sensitive methods such as photoluminescence (PL) spectroscopy, modulated and time-resolved surface photovoltage (SPV) spectroscopy, constant final state photoelectron yield spectroscopy (CFSYS), and constant light-induced magneto transport (CLIMAT), to demonstrate striking differences between charge separation induced by dissociation of excitons and by excitation of mobile charge carriers from defect states. Our results suggest that the broad sub-band gap emission in BA2PbI4 and other 2D HaPs is caused by radiative recombination via defect states (shallow as well as midgap states) rather than self-trapped excitons. Density functional theory (DFT) results show that common defects can readily occur and produce an energetic profile that agrees well with the experimental results. The DFT results suggest that the formation of iodine interstitials is the initial process leading to degradation, responsible for the emergence of midgap states, and that defect engineering will play a key role in enhancing the optoelectronic properties of 2D HaPs in the future.

Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays.

Antithrombin deficiency, the most severe congenital thrombophilia, might be underestimated, as some pathogenic variants are not detected by routine functional methods. We have identified 2 new SERPINC1 variants, p.Glu227Lys and p.Asn224His, in 4 unrelated thrombophilic patients with early and recurrent thrombosis that had normal antithrombin activity. In one case, the mutation was identified by whole genome sequencing, while in the 3 remaining cases, the mutation was identified by sequencing SERPINC1 based on a single functional positive finding supporting deficiency. The 2 variants shared a common functional defect, an impaired or null N-glycosylation of Asn224 according to a eukaryotic expression model. Carriers had normal anti-FXa or anti-FIIa activities but impaired anti-FVIIa activity and a detectable loss of inhibitory function when incubating the plasma for 1 hour at 41°C. Moreover, the ß glycoform of the variants, lacking 2 N-glycans, had reduced secretion, increased heparin affinity, no inhibitory activity, and a potential dominant-negative effect. These results explain the increased thrombin generation observed in carriers. Mutation experiments reflected the role that Lysine residues close to the N-glycosylation sequon have in impairing the efficacy of N-glycosylation. Our study shows new elements involved in the regulation of N-glycosylation, a key posttranslational modification that, according to our results, affects folding, secretion, and function, providing new evidence of the pathogenic consequence of an incorrect N-glycosylation of antithrombin. This study supports that antithrombin deficiency is underestimated and encourages the development of new functional and genetic tests to diagnose this severe thrombophilia.

Combining phylogeny and coevolution improves the inference of interaction partners among paralogous proteins.

Predicting protein-protein interactions from sequences is an important goal of computational biology. Various sources of information can be used to this end. Starting from the sequences of two interacting protein families, one can use phylogeny or residue coevolution to infer which paralogs are specific interaction partners within each species. We show that these two signals can be combined to improve the performance of the inference of interaction partners among paralogs. For this, we first align the sequence-similarity graphs of the two families through simulated annealing, yielding a robust partial pairing. We next use this partial pairing to seed a coevolution-based iterative pairing algorithm. This combined method improves performance over either separate method. The improvement obtained is striking in the difficult cases where the average number of paralogs per species is large or where the total number of sequences is modest.

Profiles of muscle-specific oxygenation responses and thresholds during graded cycling incremental test.

Compared to the determination of exercise thresholds based on systemic changes in blood lactate concentrations or gas exchange data, the determination of breakpoints based on muscle oxygen saturation offers a valid alternative to provide specific information on muscle-derived thresholds. Our study explored the profiles and timing of the second muscle oxygenation threshold (MOT2) in different muscles. Twenty-six cyclists and triathletes (15 male: age = 23 ± 7 years, height = 178 ± 5 cm, body mass = 70.2 ± 5.3 kg; 11 female: age = 22 ± 4 years, height = 164 ± 4 cm, body mass = 58.3 ± 8.1 kg) performed a graded exercise test (GXT), on a cycle ergometer. Power output, blood lactate concentration, heart rate, rating of perceived exertion, skinfolds and muscle oxygen saturation were registered in five muscles (vastus lateralis, biceps femoris, gastrocnemius medialis, tibialis anterior and triceps brachii) and percentage at which MOT2 occurred for each muscle was determinated using the Exponential Dmax. The results of Statistical Parametric Mapping and ANOVA showed that, although muscle oxygenation displayed different profiles in each muscle during a GXT, MOT2 occurred at a similar percentage of the GXT in each muscle (77% biceps femoris, 75% tibalis anterior, 76% gastrocnemius medialis and 72% vastus lateralis) and it was similar that systemic threshold (73% of the GXT). In conclusion, this study showed different profiles of muscle oxygen saturation in different muscles, but without notable differences in the timing for MOT2 and concordance with systemic threshold. Finally, we suggest the analysis of the whole signal and not to simplify it to a breakpoint.