The carbonyl nucleobase adduct MAde is a potent antigen for adaptive polyclonal MR1-restricted T cells.

The major histocompatibility complex (MHC) class I-related molecule MHC-class-I-related protein 1 (MR1) presents metabolites to distinct MR1-restricted T cell subsets, including mucosal-associated invariant T (MAIT) and MR1T cells. However, self-reactive MR1T cells and the nature of recognized antigens remain underexplored. Here, we report a cell endogenous carbonyl adduct of adenine (8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.

Combining real-space and local range separation-The MH24 locally range-separated local hybrid functional.

In this work, the development of a new general-purpose exchange-correlation hybrid functional based on the recent locally range-separated local hybrid approach is presented. In particular, the new functional, denoted as MH24, combines a non-empirical treatment of the admixture of locally range-separated long-range exact exchange with a new real-space separation approach for the real-space exact-exchange admixture governed by the local mixing function (LMF) and a new empirical LYP-based approach for the correlation functional to enable a flexible description of same- and opposite-spin correlation effects. The nine empirical parameters of the MH24 model have been optimized using a state-of-the-art super-self-consistent-field approach, which exploits the sensitivity of specific properties, such as core ionization potentials, electron affinities, and atomization energies, to the exact-exchange admixture in specific regions in real space and the separation of the LMF into a core, valence, and asymptotic part.

Recombinase polymerase amplification in combination with electrochemical readout for sensitive and specific detection of PIK3CA point mutations.

As part of the ongoing evolution towards personalized anticancer therapy, mutation screening is becoming increasingly important and, therefore, also alternative detection strategies that allow for fast genetic diagnostics at the point of care. In the case of breast cancer, detecting cancer-associated point mutations in the PIK3CA gene is of particular importance for treatment decisions. We developed a recombinase polymerase amplification assay combined with an enzyme-linked electrochemical assay on multi-channel screen-printed gold sensors for specific and highly sensitive detection of three PIK3CA point mutations (H1047R, E545K, and E542K).

Nitro-fatty acids: promising agents for the development of new cancer therapeutics.

Nitro-fatty acids (NO-FAs) are endogenous pleiotropic lipid mediators regarded as promising drug candidates for treating inflammatory and fibrotic diseases. Over the past two decades, the anti-inflammatory and cytoprotective actions of NO-FAs and several molecular targets have been identified. More recently, preclinical studies have demonstrated their potential as prospective cancer therapeutics with favorable safety and tumor-selective profiles.

Best supportive care for patients with primary progressive multiple sclerosis (PPMS) in Germany prior to ocrelizumab treatment: Final results from the RETRO PPMS study.

Background: Best supportive care (BSC) measures are an essential component for the management of primary progressive multiple sclerosis (PPMS).

Objectives: RETRO PPMS (ML39631) is the first study to systematically analyze the therapeutic journey and standard of BSC of patients with PPMS in Germany.

Design: This multicenter, non-interventional study retrospectively analyzed patient charts.

Prediction of s^{±}-Wave Superconductivity Enhanced by Electronic Doping in Trilayer Nickelates La_{4}Ni_{3}O_{10} under Pressure.

Motivated by the recently reported signatures of superconductivity in trilayer La_{4}Ni_{3}O_{10} under pressure, we comprehensively study this system using ab initio and random-phase approximation techniques. Without electronic interactions, the Ni d_{3z^{2}-r^{2}} orbitals show a bonding-antibonding and nonbonding splitting behavior via the O p_{z} orbitals inducing a "trimer" lattice in La_{4}Ni_{3}O_{10}, analogous to the dimers of La_{3}Ni_{2}O_{7}. The Fermi surface consists of three electron sheets with mixed e_{g} orbitals, and a hole and an electron pocket made up of the d_{3z^{2}-r^{2}} orbital, suggesting a Ni two-orbital minimum model.

The Soybean Cyst Nematode Effector Cysteine Protease 1 (CPR1) Targets a Mitochondrial Soybean Branched-Chain Amino Acid Aminotransferase (GmBCAT1).

The soybean cyst nematode (SCN; ) facilitates infection by secreting a repertoire of effector proteins into host cells to establish a permanent feeding site composed of a syncytium of root cells. Among the diverse proteins secreted by the nematode, we were specifically interested in identifying proteases to pursue our goal of engineering decoy substrates that elicit an immune response when cleaved by an SCN protease. We identified a cysteine protease that we named Cysteine Protease 1 (CPR1), which was predicted to be a secreted effector based on transcriptomic data obtained from SCN esophageal gland cells, the presence of a signal peptide, and the lack of transmembrane domains.

Strengthening an Intramolecular Non-Classical Hydrogen Bond to Get in Shape for Binding.

In this research article, we report on the strengthening of a non-classical hydrogen bond (C-H⋅⋅⋅O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E-selectin ligand sialyl Lewis (1, sLe). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre-organization of sLe in its binding conformation.

Parylene C Coating Efficacy Studies: Enhancing Biocompatibility of 3D Printed Polyurethane Parts for Biopharmaceutical and CGT Applications.

Additive manufacturing, particularly Vat photopolymerization, presents a promising technique for producing complex, tailor-made structures, making it an attractive option for generating single-use components used in biopharmaceutical manufacturing equipment or cell culture devices. However, the potential leaching of cytotoxic compounds from Vat photopolymer resins poses a significant concern, especially regarding cell growth and viability in cell culture applications. This study explores the potential of parylene C coating to enhance the inertness of a polyurethane-based photopolymer resin, aiming to prevent cytotoxicity and improve biocompatibility.

An evolved artificial radical cyclase enables the construction of bicyclic terpenoid scaffolds via an H-atom transfer pathway.

While natural terpenoid cyclases generate complex terpenoid structures via cationic mechanisms, alternative radical cyclization pathways are underexplored. The metal-catalysed H-atom transfer reaction (M-HAT) offers an attractive means for hydrofunctionalizing olefins, providing access to terpenoid-like structures. Artificial metalloenzymes offer a promising strategy for introducing M-HAT reactivity into a protein scaffold.

Comparative Transcriptomic Analysis of Soybean Cyst Nematode Inbred Populations Non-adapted or Adapted on Soybean /-Mediated Resistance.

Soybean cyst nematode (SCN, ) is most effectively managed through planting resistant soybean cultivars, but the repeated use of the same resistance sources has led to a widespread emergence of virulent SCN populations that can overcome soybean resistance. Resistance to SCN HG type 0 (Race 3) in soybean cultivar Forrest is mediated by an epistatic interaction between the soybean resistance genes and . We previously developed two SCN inbred populations by mass-selecting SCN HG type 0 (Race 3) on susceptible and resistant recombinant inbred lines, derived from a cross between Forrest and the SCN-susceptible cultivar Essex, which differ for .

Correction: Iannuzzi et al. Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer's Disease Patients. 2020, , 1807.

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Biosynthesis of the bacterial antibiotic 3,7-dihydroxytropolone through enzymatic salvaging of catabolic shunt products.

The non-benzenoid aromatic tropone ring is a structural motif of numerous microbial and plant natural products with potent bioactivities. In bacteria, tropone biosynthesis involves early steps of the widespread CoA-dependent phenylacetic acid (paa) catabolon, from which a shunt product is sequestered and surprisingly further utilized as a universal precursor for structurally and functionally diverse tropone derivatives such as tropodithietic acid or (hydroxy)tropolones. Here, we elucidate the biosynthesis of the antibiotic 3,7-dihydroxytropolone in Actinobacteria by pathway reconstitution using paa catabolic enzymes as well as dedicated downstream tailoring enzymes, including a thioesterase (TrlF) and two flavoprotein monooxygenases (TrlCD and TrlE).

Thermodynamics-Guided Design Reveals a Cooperative Hydrogen Bond in DC-SIGN-targeted Glycomimetics.

Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections.

Analogues of the pan-selectin antagonist rivipansel (GMI-1070).

The selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewis (sLe, 1) binds to all selectins, albeit with very different affinities.

A genetically encoded biosensor to monitor dynamic changes of c-di-GMP with high temporal resolution.

Monitoring changes of signaling molecules and metabolites with high temporal resolution is key to understanding dynamic biological systems. Here, we use directed evolution to develop a genetically encoded ratiometric biosensor for c-di-GMP, a ubiquitous bacterial second messenger regulating important biological processes like motility, surface attachment, virulence and persistence. The resulting biosensor, cdGreen2, faithfully tracks c-di-GMP in single cells and with high temporal resolution over extended imaging times, making it possible to resolve regulatory networks driving bimodal developmental programs in different bacterial model organisms.

Three-year follow-up analysis of the short-stitch versus long-stitch technique for elective midline abdominal closure randomized-controlled (ESTOIH) trial.

Background: Clinical trials have shown reduced incisional hernia rates 1 year after elective median laparotomy closure using a short-stitch technique. With hernia development continuing beyond the first postoperative year, we aimed to compare incisional hernias 3 years after midline closure using short or long stitches in patients from the ESTOIH trial.

Methods: The ESTOIH trial was a prospective, multicenter, parallel-group, double-blind, randomized-controlled study of primary elective midline closure.

Structural phase transition, s-wave pairing, and magnetic stripe order in bilayered superconductor LaNiO under pressure.

Motivated by the recently discovered high-T superconductor LaNiO, we comprehensively study this system using density functional theory and random phase approximation calculations. At low pressures, the Amam phase is stable, containing the Y mode distortion from the Fmmm phase, while the Fmmm phase is unstable. Because of small differences in enthalpy and a considerable Y mode amplitude, the two phases may coexist in the range between 10.

An artificial nickel chlorinase based on the biotin-streptavidin technology.

Herein, we report on an artificial nickel chlorinase (ANCase) resulting from anchoring a biotinylated nickel-based cofactor within streptavidin (Sav). The resulting ANCase was efficient for the chlorination of diverse C(sp)-H bonds. Guided by the X-ray analysis of the ANCase, the activity of the artificial chlorinase could be significantly improved.

Magnetism and metallicity in moiré transition metal dichalcogenides.

The ability to control the properties of twisted bilayer transition metal dichalcogenides in situ makes them an ideal platform for investigating the interplay of strong correlations and geometric frustration. Of particular interest are the low energy scales, which make it possible to experimentally access both temperature and magnetic fields that are of the order of the bandwidth or the correlation scale. In this manuscript, we analyze the moiré Hubbard model, believed to describe the low energy physics of an important subclass of the twisted bilayer compounds.