Direct reprogramming (DR) involves inducing cell differentiation by converting somatic cells directly into target cells without bypassing induced pluripotent stem cells. Small molecule-induced DR reduces tumorigenic risk relative to transcription factor-triggered DR. However, identifying small molecules for DR through experimental exploration alone remains challenging. This study presents a computational method, SuperDIRECTEUR, to predict small molecules for DR using single-cell temporal transcriptome data. The cellular conversion processes in DR were simulated by calculating the RNA velocity in each cell. These processes were then classified into multiple stages (i.e., primal, immature, and mature stages), and a variant of simulated annealing was employed to search for the combination of small molecules that mimic stage-specific gene expression patterns during DR. We applied SuperDIRECTEUR to identifying candidate small molecules for DR converting mouse embryonic fibroblasts to induced neurons, and were able to reproduce experimentally verified and functionally related molecules inducing the corresponding conversions in a temporal stage-specific manner. The target proteins of the predicted small molecules in the early and later stages were distinctively involved in biologically relevant pathways toward neuronal differentiation and maturation. The proposed method has potential for practical applications in regenerative medicine.

At high concentrations, therapeutic monoclonal antibodies (mAbs) often display increased self-association, which may result in liquid-liquid phase separation (LLPS) or high opalescence alone. Due to a suspected link with aggregation, formulation strategies aim at preventing their occurrence. However, the molecular underpinnings of LLPS and opalescence remain unclear, complicating their forecasting at early stages. By combining light and X-ray scattering with microscopy and microfluidics, we report the phase behavior of a model mAb(mAb1). This is characterized by clustering and LLPS in a narrow NaCl range, above which it transitions into an opalescent state devoid of micron-sized assemblies, yet retaining similar self-interaction fingerprints. Using Monte Carlo simulations, we show that the behavior of mAb1 is controlled by a positive patch in its Fab domain, whose degree of charge screening determines solution fate. Finally, we show that LLPS and opalescence are decoupled from stirring-induced aggregation.

Quantum-mechanical simulations provide the most fundamental description of matter, yet their computational cost commonly limits applications to systems containing at most thousands of atoms. Here, we present an all-electron quantum-mechanical framework focused on very fast calculations up to the multimillion-atom regime which is achieved by scaling down the accuracy of the framework while still maintaining agreement with experimental results. By combining algorithmically optimised Hartree-Fock with divide-and-conquer, using a minimal basis set and truncating long-range interactions, our approach efficiently handles million-atom structures while remaining accessible for smaller computation clusters and saving energy due to fast run times. We demonstrate this approach on very large biological systems, including a bacteriophage in water, totalling over 150 million electrons, representing, to our knowledge, the largest Hartree-Fock calculation performed to date. Our framework allows computing spectral data for DNA and drugs and enables protein structure assessments in strong agreement with structure evaluations by AlphaFold.

Studying the rovibrational spectra of hydrogen cyanide (HCN) has become increasingly relevant due to growing concerns about the molecule's environmental and health risks and its special role in astronomy. Empirical rovibrational energy levels are determined based on the MARVEL (Measured Active Rotational-Vibrational Energy Levels) protocol for H12C14N, the most abundant HCNisotopologue. The spectroscopic analysis is based on 23 225 measured transitions, of which 14 728 are unique, collected from 39 literature sources. In contrast to most previous MARVEL studies, which utilized a very large number of experimental sources, for H12C14N 70 % of the measured transitions are contained in two literature sources. The experimental transitions used in the final MARVEL analysis form a spectroscopic network with a single principal and just a few floating components, but a large number of orphans. To ensure the reliability of the final empirical rovibrational energy level set, the final MARVEL analysis involved artificial transitions determined from accurately fitted effective Hamiltonian models. The transitions collected and validated span the spectral range of 0-13 018 cm-1. Altogether 5564 empirical rovibrational energies, which make ca. 30% of states determined through effective Hamiltonian fits for the [H,C,N] system, with an average expanded uncertainty of 0.006 cm-1, are obtained for H12C14N; they are associated with 174 vibrational bands. A comparison of the empirical rovibrational energy levels obtained in this study, and the transitions that can be generated from them, with those in the composite experimental/empirical/first-principles-computed HITRAN2020, ExoMol, and MOMeNT-90 datasets reveals excellent overall agreement. Nevertheless, there are particularly notable exceptions in the case of HITRAN2020, for which there appear to be problems with the published labels of many lines.

Efficient and sustainable catalysts for oxygen evolution and antimicrobial applications are important for energy conversion and biomedical technologies. Here we show that interface-engineered Fe2O3-ZnO nanocomposites with ZnFe2O4 bridges are explored as multifunctional applications. Fe2O3 nanoparticles were synthesized via a Bos taurus indicus urine assisted-route and Fe2O3-ZnO (10-20 wt%Fe) composites by solvent-free solid-state reaction. XRD/Rietveld, FTIR/Raman, BET, SEM-EDS and XPS confirmed rhombohedral Fe2O3, wurtzite ZnO and interfacial ZnFe2O4 with modified cation distribution. Fe2O3 showed the best oxygen evolution performance, requiring 142 mV to reach 10 mA/cm2 with a Tafel slope of 85 mV/dec, high electrochemically active surface area and low charge-transfer resistance. Density functional theory on α-Fe2O3 (110) indicated balanced adsorption of *OH, *O and *OOH with *OH → *O as the potential-determining step. Antibacterial assays and anti-inflammatory tests revealed enhanced responses for the composites. This solvent-free strategy yields Fe2O3-ZnO-ZnFe2O4 architectures that couple efficient alkaline OER with antimicrobial and anti-inflammatory activity.

A uniform, dense suspension of silica particles forms a colloidal crystal, which undergoes shear-induced melting upon the application of flow. Shear melting induced by impact-shear typically initiates within milliseconds and completes within a few seconds, making the transition difficult to observe. Here, we developed a rheometric technique integrating fast time-resolved small-angle X-ray scattering (SAXS) with millisecond time resolution, which revealed the evolution of Bragg peaks characteristic of crystalline order, allowing direct observation of the melting transition. We report thatanisotropic disordering induced by the impact shear indicates momentary particle clustering and is attributed to rapid interlayer sliding within the close-packed colloidal structure. These findings uncover a fast shear melting mechanism inaccessible to conventional rheological techniques and highlight the utility of the high-speed structural characterization. The developed rheometric technique, integrating fast time-resolved SAXS, brings valuable insights into shear-responsive colloidal systems and holds potential for applications in colloid-based technologies.

9-Cyanopyronin derivatives have been used as resonance Raman probes for highly sensitive and multiplexed vibrational biological imaging. Here, we synthesized a series of fourteen 9-cyanopyronin derivatives in which the 10th core atom is substituted with various group 13, 14, 15 or 16 elements, and systematically evaluated their properties using electronic pre-resonance stimulated Raman scattering (EPR-SRS) microscopy. Substitution at the 10th position modulates not only the vibrational frequency of the nitrile (C ≡ N) group in the silent region, but also the conjugated double-bond stretching frequency (C = C) in the fingerprint region, and additionally alters the subcellular localization of the probes. By employing different combinations of probes, we were able to utilize the distinct patterns of C ≡ N or C = C bond vibrations together with the different subcellular localizations of the probes to achieve live-cell three-color imaging. These 9-cyanopyronin derivatives greatly expand the vibrational palette available for multiplexed SRS imaging.

Metal-ligand covalency is not fully understood for the actinides and studies comparing group IV transition metals with isostructural Th and U complexes are limited. Herein, we report the synthesis and characterization of [(C5Me5)2(2,6-iPr2C6H3O)M(H)], M = Hf, Th, and U, which can be compared to the previously reported Zr analog, to explore the differences between transition metal and actinide bonding situations. The 1H NMR chemical shifts of each complex, including the paramagnetic U(IV) compound, showed reasonable agreement with the computed shifts and benchmark the covalency of the metal-hydride bonds.

TraH, a fungal decarboxylase from Penicillium crustosum, belongs to the isopenicillin N synthase (IPNS) subfamily of non-heme iron/α-ketoglutarate (αKG)-dependent enzymes. IPNS enzymes are characterized by N- and C-terminal insertions that can reshape the active site. However, the functional and mechanistic roles of these elements, particularly in fungal decarboxylases, remain largely unexplored. Here, we report crystal structures of TraH in complex with various substrates, revealing a N-terminal loop, serving as lid and undergoes substrate-dependent dynamic conformational rearrangements. Upon binding of crustosic acid, this lid loop forms a hydrogen-bonding network to stabilize a water molecule, which mediates interaction between the conserved K191 residue in the DSBH (double-stranded β-helix) core and the substrate. Mutagenesis and QM/MM metadynamics simulations suggest that proton transfer from K191 is mediated by water molecules stabilized by the lid loop, supporting a decarboxylation mechanism distinct from the canonical strategy of direct carboxylate stabilization by DBSH core-located basic residues in other αKG-dependent decarboxylases. Interestingly, this loop is dispensable for the desaturation of crustosic acid methyl ester, thereby pinpointing its essential role to the precise positioning of the carboxylate substrate for proton transfer during decarboxylation. Evolutionary and structural analyses reveal significant variation in lid loop composition across IPNS enzymes, indicating its contribution to substrate recognition and functional diversification. Overall, our findings uncover a regulatory element in iron/αKG-dependent enzymes and offer insights into how non-core structural elements contribute to catalytic mechanism and evolution.