Hierarchical bubble size distributions in coarsening wet liquid foams.

Coarsening of two-phase systems is crucial for the stability of dense particle packings such as alloys, foams, emulsions, or supersaturated solutions. Mean field theories predict an asymptotic scaling state with a broad particle size distribution. Aqueous foams are good model systems for investigations of coarsening-induced structures, because the continuous liquid as well as the dispersed gas phases are uniform and isotropic. We present coarsening experiments on wet foams, with liquid fractions up to their unjamming point and beyond, that are performed under microgravity to avoid gravitational drainage. As time elapses, a self-similar regime is reached where the normalized bubble size distribution is invariant. Unexpectedly, the distribution features an excess of small roaming bubbles, mobile within the network of jammed larger bubbles. These roaming bubbles are reminiscent of rattlers in granular materials (grains not subjected to contact forces). We identify a critical liquid fraction [Formula: see text], above which the bubble assembly unjams and the two bubble populations merge into a single narrow distribution of bubbly liquids. Unexpectedly, [Formula: see text] is larger than the random close packing fraction of the foam [Formula: see text]. This is because, between [Formula: see text] and [Formula: see text], the large bubbles remain connected due to a weak adhesion between bubbles. We present models that identify the physical mechanisms explaining our observations. We propose a new comprehensive view of the coarsening phenomenon in wet foams. Our results should be applicable to other phase-separating systems and they may also help to control the elaboration of solid foams with hierarchical structures.

A Dual-Gene Reporter-Amplifier Architecture for Enhancing the Sensitivity of Molecular MRI by Water Exchange.

The development of genetic reporters for magnetic resonance imaging (MRI) is essential for investigating biological functions in vivo. However, current MRI reporters have low sensitivity, making it challenging to create significant contrast against the tissue background, especially when only a small fraction of cells express the reporter. To overcome this limitation, we developed an approach for amplifying the sensitivity of molecular MRI by combining a chemogenetic contrast mechanism with a biophysical approach to increase water diffusion through the co-expression of a dual-gene construct comprising an organic anion transporting polypeptide, Oatp1b3, and a water channel, Aqp1. We first show that the expression of Aqp1 amplifies MRI contrast in cultured cells engineered to express Oatp1b3. We demonstrate that the contrast amplification is caused by Aqp1-driven increase in water exchange, which provides the gadolinium ions internalized by Oatp1b3-expressing cells with access to a larger water pool compared with exchange-limited conditions. We further show that our methodology allows cells to be detected using approximately 10-fold lower concentrations of gadolinium than that in the Aqp1-free scenario. Finally, we show that our approach enables the imaging of mixed-cell cultures containing a low fraction of Oatp1b3-labeled cells that are undetectable on the basis of Oatp1b3 expression alone.

Rational Design of a Circularly Permuted Flavin-Based Fluorescent Protein.

Flavin-based fluorescent proteins are oxygen-independent reporters that hold great promise for imaging anaerobic and hypoxic biological systems. In this study, we explored the feasibility of applying circular permutation, a valuable method for the creation of fluorescent sensors, to flavin-based fluorescent proteins. We used rational design and structural data to identify a suitable location for circular permutation in iLOV, a flavin-based reporter derived from A. thaliana. However, relocating the N- and C-termini to this position resulted in a significant reduction in fluorescence. This loss of fluorescence was reversible, however, by fusing dimerizing coiled coils at the new N- and C-termini to compensate for the increase in local chain entropy. Additionally, by inserting protease cleavage sites in circularly permuted iLOV, we developed two protease sensors and demonstrated their application in mammalian cells. In summary, our work establishes the first approach to engineer circularly permuted FbFPs optimized for high fluorescence and further showcases the utility of circularly permuted FbFPs to serve as a scaffold for sensor engineering.

Similar enzymatic functions in distinct bioluminescence systems: evolutionary recruitment of sulfotransferases in ostracod light organs.

Genes from ancient families are sometimes involved in the convergent evolutionary origins of similar traits, even across vast phylogenetic distances. Sulfotransferases are an ancient family of enzymes that transfer sulfate from a donor to a wide variety of substrates, including probable roles in some bioluminescence systems. Here, we demonstrate multiple sulfotransferases, highly expressed in light organs of the bioluminescent ostracod Vargula tsujii, transfer sulfate in vitro to the luciferin substrate, vargulin. We find luciferin sulfotransferases (LSTs) of ostracods are not orthologous to known LSTs of fireflies or sea pansies; animals with distinct and convergently evolved bioluminescence systems compared to ostracods. Therefore, distantly related sulfotransferases were independently recruited at least three times, leading to parallel evolution of luciferin metabolism in three highly diverged organisms. Reuse of homologous genes is surprising in these bioluminescence systems because the other components, including luciferins and luciferases, are completely distinct. Whether convergently evolved traits incorporate ancient genes with similar functions or instead use distinct, often newer, genes may be constrained by how many genetic solutions exist for a particular function. When fewer solutions exist, as in genetic sulfation of small molecules, evolution may be more constrained to use the same genes time and again.

Unraveling the folding-assisted unbinding mechanism of TCF with its binding partner ß-catenin.

This study utilizes molecular dynamics simulations aided with multiple walker parallel bias metadynamics to investigate the TCF unbinding mechanism from the ß-catenin interface. The results, consistent with experimental binding affinity calculations, unveil a folding-assisted unbinding mechanism.

Structural basis for non-radical catalysis by TsrM, a radical SAM methylase.

Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of L-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase; however, TsrM does not reductively cleave SAM to the universal 5'-deoxyadenosyl 5'-radical intermediate, a hallmark of radical SAM (RS) enzymes. Herein, we report structures of TsrM from Kitasatospora setae, which are the first structures of a cobalamin-dependent radical SAM methylase. Unexpectedly, the structures show an essential arginine residue that resides in the proximal coordination sphere of the cobalamin cofactor, and a [4Fe-4S] cluster that is ligated by a glutamyl residue and three cysteines in a canonical CXXXCXXC RS motif. Structures in the presence of substrates suggest a substrate-assisted mechanism of catalysis, wherein the carboxylate group of SAM serves as a general base to deprotonate N1 of the tryptophan substrate, facilitating the formation of a C2 carbanion.

Charge-transfer-driven enhanced room-temperature ferromagnetism in BiFeO3/Ag nanocomposite.

We report observation of more than an order of magnitude jump in saturation magnetization in BiFeO3/Ag nanocomposite at room temperature compared to what is observed in bare BiFeO3nanoparticles. Using transmission electron microscopy together with energy dispersive x-ray spectra (which maps the element concentration across the BiFeO3/Ag interface) and x-ray photoelectron spectroscopy, we show that both the observed specific self-assembly pattern of BiFeO3and Ag nanoparticles and the charge transfer between Ag and O are responsible for such an enormous rise in room-temperature magnetization. The BiFeO3/Ag nanocomposites, therefore, could prove to be extremely useful for a variety of applications including biomedical.

Designed and synthesizedde novoANTPABA-PDI nanomaterial as an acceptor in inverted solar cell at ambient atmosphere.

In this work, a novel soluble and air-stable electron acceptor containing perylenediimide moiety named ANTPABA-PDI was designed and synthesized with band gap 1.78eV and that was used as non-fullerene acceptor material. ANTPABA-PDI possess not only good solubility but also much lower LUMO (lowest unoccupied molecular orbital) energy level. Furthermore, its excellent electron acceptor capability also supported by density functional theory calculation which validates the experimental observations. Inverted organic solar cell has been fabricated using ANTPABA-PDI along with P3HT as standard donor material in ambient atmosphere. The device, after characterization in open air, exhibited a power conversion efficiency of 1.70%. This is the first ever PDI based organic solar cell that has been fabricated completely in ambient atmosphere. The characterizations of the device have also been performed in ambient atmosphere. This kind of stable organic material can easily be used in fabricating organic solar cell and therefore it can be used as the best alternative as non-fullerene acceptor materials.

Molecular insights into the stereospecificity of arginine in RNA tetraloop folding.

One of the hypotheses for the homochirality of amino acids in the context of the origin of life is that only a particular stereoisomer provides preferential stability to RNA folding by acting as a chemical chaperon. However, the effect at the molecular level is not well understood. This study provides a molecular understanding of such preferential stability for a small GAAA RNA tetraloop in the presence of chiral arginine through a multidimensional free energy landscape constructed using a combination of umbrella sampling and parallel bias metadynamics (PBMetaD) simulations. We show that the origin of the chirality difference in RNA folding-unfolding dynamics is due to differences in the configurational diversity of RNA in adopting various non-natural conformations that accompany the diverse binding modes of D-arginine and L-arginine. We show that while D-arginine stabilizes the native folded state of RNA, L-arginine destabilizes it. Furthermore, free energy calculations on the binding of D- and L-arginine reveal a specific geometric constraint that helps D-arginine to stack with the terminal base pairs of RNA and pushes L-arginine for groove binding.

Synthesis of mesoporous Fe/Al/La trimetallic oxide for photodegradation of various water-soluble dyes: Kinetic, mechanistic, and pH studies.

Phase pure, trigonal, mesoporous Fe/Al/La trimetallic nano-oxide (abbreviated as FAL) was synthesized using energy efficient chemical route with bandgap 1.97 eV and SBET = 50.02 m2/g and an average pore size of 8.95 nm for photodegradation of azo (di and tri) and thiazine class of dyes successfully. The valence band and conduction band potentials were calculated using the Mott-Schottky plot. The highest photodegradation efficiency was 93.85 ± 2% for reactive black 5 (RB5) at pH 7 under solar irradiation. The phase formation of FAL was confirmed by PXRD, TEM, and HRTEM analyses. The other characterizations include FESEM, Raman, EPR, UV, HPLC, LC-MS, etc. The presence of the metal centers and their corresponding oxidation states were confirmed by the SAEDS, elemental mapping, and XPS analyses respectively. FAL was also able to photodegrade direct blue 71 (DB71) and methylene blue (MB) under the same condition at different pH efficiently (pH 2-11). The photodegradation obeyed the pseudo-1st-order kinetics and was reusable up to 5 successive cycles. This study may be an efficient tool to meet UNs' SDG:6.

Marker assisted stacking of Ty3, Mi1.2 and Ph3 resistance alleles for leaf curl, root knot and late blight diseases in tomato.

Developing multiple disease resistance through naturally available host resistance alleles is a challenging as well as rewarding area of research. Availability of host resistance alleles and the reliability of their identification through diagnostic molecular markers have paved the way for stacking of these resistance alleles for developing important genetic resources in tomato. Here we report the marker assisted stacking of Ty3, Mi1.2 and Ph3 alleles, governing leaf curl, root knot and late blight disease resistance, respectively, in superior F4 segregants of tomato derived from two diverse parents (i.e., BRDT-1 and H-88-78-1). Marker assisted selection was applied only on morphologically superior segregants at F2 and F3 generations, which helped us in identifying suitable lines even from a relatively small population. The diagnostic values of the employed molecular markers advocate that the identified superior segregants, carrying all the three aforementioned resistance alleles in homozygous condition, are suitable to be explored as valuable genetic resources for developing multiple disease resistance through rapid introgression of these genes in different genetic background of tomato. Identification of suitable segregants derived from these lines should be promising for obtaining improved cultivars in near future. Nevertheless, these lines might be further explored to decipher the intrinsic details of host's resistance mechanism involving genetic interactions between different resistance factors. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01277-2.

Triggered Functional Dynamics of AsLOV2 by Time-Resolved Electron Paramagnetic Resonance at High Magnetic Fields.

We present time-resolved Gd-Gd electron paramagnetic resonance (TiGGER) at 240 GHz for tracking inter-residue distances during a protein's mechanical cycle in the solution state. TiGGER makes use of Gd-sTPATCN spin labels, whose favorable qualities include a spin-7/2 EPR-active center, short linker, narrow intrinsic linewidth, and virtually no anisotropy at high fields (8.6 T) when compared to nitroxide spin labels. Using TiGGER, we determined that upon light activation, the C-terminus and N-terminus of AsLOV2 separate in less than 1 s and relax back to equilibrium with a time constant of approximately 60 s. TiGGER revealed that the light-activated long-range mechanical motion is slowed in the Q513A variant of AsLOV2 and is correlated to the similarly slowed relaxation of the optically excited chromophore as described in recent literature. TiGGER has the potential to valuably complement existing methods for the study of triggered functional dynamics in proteins.

Capturing surface complementarity in proteins using unsupervised learning and robust curvature measure.

The structure of a protein plays a pivotal role in determining its function. Often, the protein surface's shape and curvature dictate its nature of interaction with other proteins and biomolecules. However, marked by corrugations and roughness, a protein's surface representation poses significant challenges for its curvature-based characterization. In the present study, we employ unsupervised machine learning to segment the protein surface into patches. To measure the surface curvature of a patch, we present an algebraic sphere fitting method that is fast, accurate, and robust. Moreover, we use local curvatures to show the existence of "shape complementarity" in protein-protein, antigen-antibody, and protein-ligand interfaces. We believe that the current approach could help understand the relationship between protein structure and its biological function and can be used to find binding partners of a given protein.

Efficacy and Safety of Extended Induction With Tofacitinib for the Treatment of Ulcerative Colitis.

BACKGROUND & AIMS: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in a dose-ranging phase 2 induction trial, 3 phase 3 randomized, placebo-controlled trials (OCTAVE Induction 1 and 2; and OCTAVE Sustain), and an ongoing, open-label, long-term extension trial (OCTAVE Open) in patients with moderately to severely active UC. Here, we assessed short- and long-term efficacy and safety of extended induction (16 weeks) with tofacitinib 10 mg twice daily (BID) in patients who failed to respond to initial induction (8 weeks) treatment. METHODS: In patients who achieved a clinical response following extended induction (delayed responders), the efficacy and safety of tofacitinib were evaluated up to Month 36 of OCTAVE Open. RESULTS: 52.2% of patients who did not achieve clinical response to 8 weeks' treatment with tofacitinib 10 mg BID in the induction studies achieved a clinical response following extended induction (delayed responders). At Month 12 of OCTAVE Open, 70.3%, 56.8%, and 44.6% of delayed responders maintained clinical response and achieved endoscopic improvement and remission, respectively. Corresponding values at Month 36 were 56.1%, 52.0%, and 44.6%. The safety profile of the subsequent 8 weeks was similar to the initial 8 weeks. CONCLUSIONS: Overall, the majority of patients achieved a clinical response after 8 or 16 weeks' induction therapy with tofacitinib 10 mg BID. Tofacitinib 10 mg BID, administered as induction therapy for up to 16 weeks, had a comparable safety profile to 8 weeks' induction therapy. Most delayed responders at Month 36 were in remission. CLINICALTRIALS: gov: NCT00787202; NCT01465763; NCT01458951; and NCT01470612.

Bis(cholyl)-based chloride channels with oxalamide and hydrazide selectivity filters.

We report the development of supramolecular bis(cholyl) ion channels using oxalamide and hydrazide as selectivity filters. The hydrazide system showed superior chloride transport activity to oxalamide via the formation of a barrel stave channel. The better chloride recognition within the hydrazide channel over the oxalalmide channel was confirmed from the theoretical calculations.

Electrostatically Directed Long-Range Self-Assembly of Nucleotides with Cationic Nanoparticles To Form Multifunctional Bioplasmonic Networks.

Precise control over interparticle interactions is essential to retain the functions of individual components in a self-assembled superstructure. Here, we report the design of a multifunctional bioplasmonic network via an electrostatically directed self-assembly process involving adenosine 5'-triphosphate (ATP). The present study unveils the ability of ATP to undergo a long-range self-assembly in the presence of cations and gold nanoparticles (AuNP). Modelling and NMR studies gave a qualitative insight into the major interactions driving the bioplasmonic network formation. ATP-Ca2+ coordination helps in regulating the electrostatic interaction, which is crucial in transforming an uncontrolled precipitation into a kinetically controlled aggregation process. Remarkably, ATP and AuNP retained their inherent properties in the multifunctional bioplasmonic network. The generality of electrostatically directed self-assembly process was extended to different nucleotide-nanoparticle systems.

Therapeutic Drug Monitoring for Current and Investigational Inflammatory Bowel Disease Treatments.

This article reviews therapeutic drug monitoring (TDM) use for current inflammatory bowel disease (IBD) treatments. IBD comprises Crohn's disease and ulcerative colitis-chronic gastrointestinal inflammatory disorders. Treatment options for moderate to severe IBD include thiopurines; methotrexate; biologic agents targeting tumor necrosis factor, α4ß7 integrin or interleukins 12 and 23; and Janus kinase inhibitors. TDM is recommended to guide treatment decisions for some of these agents. Published literature concerning TDM for IBD treatments was reviewed. S.D.L., R.S., and E.V.L. drew on their clinical experiences. Polymorphisms resulting in altered enzymatic activity inactivating thiopurine metabolites can lead to myelotoxicity and hepatotoxicity. Increased elimination of biologic agents can result from immunogenicity or higher disease activity, leading to low drug concentration and consequent nonresponse or loss of response. TDM may aid treatment and dose decisions for individual patients, based on monitoring metabolite levels for thiopurines, or serum drug trough concentration and antidrug antibody levels for biologic agents. Challenges remain around TDM implementation in IBD, including the lack of uniform assay methods and guidance for interpreting results. The Janus kinase inhibitor tofacitinib is not impacted by enzyme polymorphisms or disease activity, and is not expected to stimulate the formation of neutralizing antidrug antibodies. TDM is associated with implementation challenges, despite the recommendation of its use for guiding many IBD treatments. Newer small molecules with less susceptibility to patient variability factors may fulfill the unmet need of treatment options that do not require TDM, although further study is required to confirm this.

Skin colour, carotenogenesis and chlorophyll degradation mutant alleles: genetic orchestration behind the fruit colour variation in tomato.

The genetics underlying the fruit colour variation in tomato is an interesting area of both basic and applied research in plant biology. There are several factors, like phytohormones, environmental signals and epistatic interactions between genes, which modulate the ripe fruit colour in tomato. However, three aspects: genetic regulation of skin pigmentation, carotenoid biosynthesis and ripening-associated chlorophyll degradation in tomato fruits are of pivotal importance. Different genes along with their mutant alleles governing the aforementioned characters have been characterized in detail. Moreover, the interaction of these mutant alleles has been explored, which has paved the way for developing novel tomato genotypes with unique fruit colour and beneficial phytonutrient composition. In this article, we review the genes and the corresponding mutant alleles underlying the variation in tomato skin pigmentation, carotenoid biosynthesis and ripening-associated chlorophyll degradation. The possibility of generating novel fruit colour-variants using different combinations of these mutant alleles is documented. Furthermore, the involvement of some other mutant alleles (like those governing purple fruit colour and high fruit pigmentation), not belonging to the aforementioned three categories, are discussed in brief. The simplified representation of the assembled information in this article should not only help a broad range of readers in their basic understanding of this complex phenomenon but also trigger them for further exploration of the same. The article would be useful for genetic characterization of fruit colour-variants and molecular breeding for fruit colour improvement in tomato using the well-characterized mutant alleles.

RM12 similar to substance P from tachykinin of freshwater murrel Channa striatus influence intracellular ROS in vitro fish erythrocytes and developmental toxicity and antioxidant enzymes in vivo zebrafish embryo.

In this study, substance P, an antioxidant peptide of tachykinin, was identified using bioinformatics tools from the earlier established muscle transcriptome of a freshwater murrel Channa striatus and the peptide was named RM12. The antioxidant properties of RM12 were screened using various colorimetric assays. The toxicity of RM12 was experimented using fish erythrocytes, and it is observed that the maximum concentration (320 µM) of RM12 was found to have 15 or 20% of hemolytic activity; however, it was not significant with other tested concentrations (10, 20, 40, 80, and 160 µM). Further, the in vivo antioxidant properties of RM12 were experimented on zebrafish embryo, the intracellular ROS level was estimated by 5 mM H2O2 stress in the zebrafish embryo, and inhibition of apoptosis was evaluated. The antioxidant enzymes were extracted from the H2O2-stressed zebrafish embryo, and the intracellular ROS was eliminated due to RM12. Collectively, the experiment showed that the substance P from the freshwater murrel C. striatus possessed potent antioxidant properties; thus, it can further be focused to develop it as antioxidant molecule in aquaculture organisms.

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS: We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS: In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).