Search

We study the change of the Laughlin states under large deformations of the geometry of the sphere and the plane, associated with Mabuchi geodesics on the space of metrics with Hamiltonian $S^1$-symmetry. For geodesics associated with the square of the symmetry generator, as the geodesic time goes to infinity, the geometry of the sphere becomes that of a thin cigar collapsing to a line and the Laughlin states become concentrated on a discrete set of $S^1$--orbits, corresponding to Bohr-Sommerfeld orbits of geometric quantization. The lifting of the Mabuchi geodesics to the bundle of quantum states, to which the Laughlin states belong, is achieved via generalized coherent state transforms, which correspond to the KZ parallel transport of Chern-Simons theory.

The purpose of this study was to investigate the effects of supplementation of whey protein (WP) versus leucine-matched collagen peptides (CP) on muscle thickness MT and performance after a resistance training (RT) program in young adults. Twenty-two healthy untrained participants were randomly assigned to either a WP (n = 11) or leucine-matched CP (n = 11) group and then submitted to a supervised 10-week RT program (3 days/week). The groups were supplemented with an equivalent amount of WP (35 g, containing 3.0 g of leucine) and CP (35 g, containing 1.0 g of leucine and 2.0 g of free leucine) during the intervention period (after each workout and in the evening on nontraining days). MT of the vastus lateralis and biceps brachii, isokinetic peak torque and mean power output of the elbow flexors, and peak power output of the lower body were assessed before and after the RT program. The WP group experienced a greater (interaction,p p

Elevated levels of the estrone metabolite, 16α-hydroxyestrone (16αOHE1), have been linked with multiple diseases. As an electrophilic reactive metabolite, covalent binding to proteins is thought to constitute one of the possible mechanisms in the onset of deleterious health outcomes associated with 16αOHE1. Whereas mass spectrometry (MS)-based methodologies are currently considered the best suited to monitor the formation of protein covalent adducts, the application of these approaches for the identification of covalent adducts of 16αOHE1 is yet to be provided. In the present study, with the ultimate goal of determining the most adequate methodology for searching for 16αOHE1-derived covalent adducts, we explored multiple liquid chromatography-electrospray ionization tandem high-resolution mass spectrometry (LC-ESI-HRMS/MS)-based approaches to investigate the nature and specific locations of the covalent adducts produced in human hemoglobin (Hb) and human serum albumin (HSA) modified

The ‘gasotransmitters’ hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO) act as second messengers in human physiology, mediating signal transduction via interaction with or chemical modification of protein targets, thereby regulating processes such as neurotransmission, blood flow, immunomodulation, or energy metabolism. Due to their broad reactivity and potential toxicity, the biosynthesis and breakdown of H2S, NO, and CO are tightly regulated. Growing evidence highlights the active role of gasotransmitters in their mutual cross-regulation. In human physiology, the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are prominent H2S enzymatic sources. While CBS is known to be inhibited by NO and CO, little is known about CSE regulation by gasotransmitters. Herein, we investigated the effect of s-nitrosation on CSE catalytic activity. H2S production by recombinant human CSE was found to be inhibited by the physiological nitrosating agent s-nitrosoglutathione (GSNO), while reduced glutathione had no effect. GSNO-induced inhibition was partially reverted by ascorbate and accompanied by the disappearance of one solvent accessible protein thiol. By combining differential derivatization procedures and mass spectrometry-based analysis with functional assays, seven out of the ten protein cysteine residues, namely Cys84, Cys109, Cys137, Cys172, Cys229, Cys307, and Cys310, were identified as targets of s-nitrosation. By generating conservative Cys-to-Ser variants of the identified s-nitrosated cysteines, Cys137 was identified as most significantly contributing to the GSNO-mediated CSE inhibition. These results highlight a new mechanism of crosstalk between gasotransmitters.

The Cauchy problem for (real analytic) geodesics in the space of Kahler metrics with a fixed cohomology class on a compact complex manifold M can be effectively reduced to the problem of finding the flow of a related Hamiltonian vector field $$X_H$$, followed by analytic continuation of the time to complex time. This opens the possibility of expressing the geodesic $$\omega _t$$ in terms of Grobner Lie series of the form $$\exp (\sqrt{-1} \, tX_H)(f)$$, for local holomorphic functions f. The main goal of this paper is to use truncated Lie series as a new way of constructing approximate solutions to the geodesic equation. For the case of an elliptic curve and H a certain Morse function squared, we approximate the relevant Lie series by the first twelve terms, calculated with the help of Mathematica. This leads to approximate geodesics which hit the boundary of the space of Kahler metrics in finite geodesic time. For quantum mechanical applications, one is interested also on the non-Kahler polarizations that one obtains by crossing the boundary of the space of Kahler structures.

This paper summarizes the work of CAMEPP, the IST Commission that was charged in 2018 with the analysis of pedagogical practice at IST, as well as of the curricula of its first and second cycle degrees. As a consequence of this work, IST changed significantly the curricular structure of its degrees and pedagogical methods, with a new design that will begin its implementation in 2021/22.

In this paper, we study the analytic continuation to complex time of the Hamiltonian flow of certain G × T -invariant functions on the cotangent bundle of a compact connected Lie group G with maximal torus T. Namely, we will take the Hamiltonian flows of one G × G -invariant function, h, and one G × T -invariant function, f. Acting with these complex time Hamiltonian flows on G × G -invariant Kahler structures gives new G × T -invariant, but not G × G -invariant, Kahler structures on T ⁎ G . We study the Hilbert spaces H τ , σ corresponding to the quantization of T ⁎ G with respect to these non-invariant Kahler structures. On the other hand, by taking the vertical Schrodinger polarization as a starting point, the above G × T -invariant Hamiltonian flows also generate families of mixed polarizations P 0 , σ , σ ∈ C , Im σ > 0 . Each of these mixed polarizations is globally given by a direct sum of an integrable real distribution and of a complex distribution that defines a Kahler structure on the leaves of a foliation of T ⁎ G . The geometric quantization of T ⁎ G with respect to these mixed polarizations gives rise to unitary partial coherent state transforms, corresponding to KSH maps as defined in [11] , [12] .

This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal, through projects UID/QUI/00100/2019, IF/01091/2013/CP1163/CT0001 and PTDC/QUIQAN/32242/2017 as well as doctoral fellowships SFRH/BD/102846/2014 (to CC) and SFRH/BD/140157/2018 (to JN);joint funding from FCT and the COMPETE Program is also acknowledge through RNEM-LISBOA-01-0145-FEDER-022125-funded postdoctoral fellowship (to JM). Identification of protein covalent modifications (adducts) is a challenging task mainly due to the lack of data processing approaches for adductomics studies. Despite the huge technological advances in mass spectrometry (MS) instrumentation and bioinformatics tools for proteomics studies, these methodologies have very limited success on the identification of low abundant protein adducts. Herein we report a novel strategy inspired on the metabolomics workflows for the identification of covalently-modified peptides that consists on LC-MS data preprocessing followed by statistical analysis. The usefulness of this strategy was evaluated using experimental LC-MS data of histones isolated from HepG2 and THLE2 cells exposed to the chemical carcinogen glycidamide. LC-MS data was preprocessed using the open-source software MZmine and potential adducts were selected based on the m/z increments corresponding to glycidamide incorporation. Then, statistical analysis was applied to reveal the potential adducts as those ions are differently present in cells exposed and not exposed to glycidamide. The results were compared with the ones obtained upon the standard proteomics methodology, which relies on producing comprehensive MS/MS data by data dependent acquisition and analysis with proteomics data search engines. Our novel strategy was able to differentiate HepG2 and THLE2 and to identify adducts that were not detected by the standard methodology of adductomics. Thus, this metabolomics driven approach in adductomics will not only open new opportunities for the identification of protein epigenetic modifications, but also adducts formed by endogenous and exogenous exposure to chemical agents. publishersversion published

Protein covalent adducts formed upon exposure to reactive (mainly electrophilic) chemicals may lead to the development of a wide range of deleterious health outcomes. Therefore, the identification of protein covalent adducts constitutes a huge opportunity for a better understanding of events underlying diseases and for the development of biomarkers which may constitute effective tools for disease diagnosis/prognosis, for the application of personalized medicine approaches and for accurately assessing human exposure to chemical toxicants. The currently available mass spectrometry (MS)-based methodologies, are clearly the most suitable for the analysis of protein covalent modifications, providing accuracy, sensitivity, unbiased identification of the modified residue and conjugates along with quantitative information. However, despite the huge technological advances in MS instrumentation and bioinformatics tools, the identification of low abundant protein covalent adducts is still challenging. This review is aimed at summarizing the MS-based methodologies currently used for the identification of protein covalent adducts and the strategies developed to overcome the analytical challenges, involving not only sample pre-treatment procedures but also distinct MS and data analysis approaches.

We consider the imaginary time flow of a quadratic hyperbolic Hamiltonian on the symplectic plane, apply it to the Schrodinger polarization and study the corresponding evolution of polarized sections. The flow is periodic in imaginary time and the evolution of polarized sections has interesting features. On the time intervals for which the polarization is real or Kahler, the half–form corrected time evolution of polarized sections is given by unitary operators which turn out to be equivalent to the classical Segal-Bargmann transforms (which are usually associated to the quadratic elliptic Hamiltonian H = 1 2 p 2 and to the heat operator). At the right endpoint of these intervals, the evolution of polarized sections is given by the Fourier transform from the Schrodinger to the momentum representation. In the complementary intervals of imaginary time, the polarizations are anti–Kahler and the Hilbert space of polarized sections collapses to H = { 0 } . Hyperbolic quadratic Hamiltonians thus give rise to a new factorization of the Segal-Bargmann transform, which is very different from the usual one, where one first applies a bounded contraction operator (the heat kernel operator), mapping L 2 –states to real analytic functions with unique analytic continuation, and then one applies analytic continuation. In the factorization induced by an hyperbolic complexifier, both factors are unbounded operators but their composition is, in the Kahler or real sectors, unitary. In another paper [24] , we explore the application of the above family of unitary transforms to the definition of new holomorphic fractional Fourier transforms.

Herein we report the use of pyridazinediones to functionalise the native solvent accessible interstrand disulfide bonds in trastuzumab with monomethyl auristatin E (MMAE). This method of conjugation delivers serum stable antibody–drug conjugates (ADCs) with a controlled drug loading of 4. Moreover, we demonstrate that the MMAE-bearing ADCs are potent, selective and efficacious against cancer cell lines in both in vitro and in vivo models.

The cyclopentenone unit is a very powerful synthon for the synthesis of a variety of bioactive target molecules. This is due to the broad diversity of chemical modifications available for the enone structural motif. In particular, chiral cyclopentenones are important precursors in the asymmetric synthesis of target chiral molecules. This Review provides an overview of reported methods for enantioselective and asymmetric syntheses of cyclopentenones, including chemical and enzymatic resolution, asymmetric synthesis via Pauson-Khand reaction, Nazarov cyclization and organocatalyzed reactions, asymmetric functionalization of the existing cyclopentenone unit, and functionalization of chiral building blocks.

Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs by both adults and children. Despite its widespread use, CBZ is associated with central nervous system toxicity and severe hypersensitivity reactions, which raise concerns about its chronic use. While the precise mechanisms of CBZ-induced adverse events are still unclear, metabolic activation to the epoxide (CBZ-EP) has been thought to play a significant role. This work reports first-hand evidence that CBZ reacts readily with biologically relevant thiyl radicals with no need for bioactivation. Using liquid chromatography coupled with high resolution mass spectrometry, multiple products from direct reaction of CBZ with glutathione (GSH) and N-acetyl-L-cysteine (NAC) were unequivocally identified, including the same product obtained upon ring-opening of CBZ-EP. The product profile is complex and consistent with radical-mediated mechanisms. Importantly, side products and adducts compatible with this non-enzymatic pathway were identified in liver extracts from CBZ-treated Wistar rats. The reaction of CBZ with GSH and NAC is more extensive in the presence of oxygen. Taking into consideration that GSH conjugation is, in general, a detoxification pathway, these results suggest that under hyperoxia/oxidative stress conditions the bioavailability of the parent drug may be compromised. Additionally, this non-enzymatic process can be anticipated to play, at least in part, a role in the onset of CBZ-induced adverse reactions due to the concomitant generation of reactive oxygen species. Therefore, the search for causal relationships between the formation of non-enzymatically-driven CBZ products and the occurrence of CBZ-induced adverse events in human patients merits further research, aiming the translation of basic mechanistic findings into a clinical context that may ultimately lead to a safer CBZ prescription.

Let $$P$$ be a Delzant polytope. We show that the quantization of the corresponding toric manifold $$X_{P}$$ in toric Kahler polarizations and in the toric real polarization are related by analytic continuation of Hamiltonian flows evaluated at time $$t = {\sqrt{-1}}s$$ . We relate the quantization of $$X_{P}$$ in two different toric Kahler polarizations by taking the time- $${\sqrt{-1}}s$$ Hamiltonian “flow” of strongly convex functions on the moment polytope $$P$$ . By taking $$s$$ to infinity, we obtain the quantization of $$X_{P}$$ in the (singular) real toric polarization. Recall that $$X_{P}$$ has an open dense subset which is biholomorphic to $$({\mathbb {C}}^{*})^{n}$$ . The quantization of $$X_{P}$$ in a toric Kahler polarization can also be described by applying the complexified Hamiltonian flow of the Abreu–Guillemin symplectic potential $$g$$ , at time $$t={\sqrt{-1}}$$ , to an appropriate finite-dimensional subspace of quantum states in the quantization of $$T^{*}{\mathbb {T}}^{n}$$ in the vertical polarization. By taking other imaginary times, $$t= k {\sqrt{-1}}, k\in {\mathbb {R}}$$ , we describe toric Kahler metrics with cone singularities along the toric divisors in $$X_{P}$$ . For convex Hamiltonian functions and sufficiently negative imaginary part of the complex time, we obtain degenerate Kahler structures which are negative definite in some regions of $$X_{P}$$ . We show that the pointwise and $$L^2$$ -norms of quantum states are asymptotically vanishing on negative-definite regions.

Herein we report the use of next generation maleimides (NGMs) for the construction of a potent antibody-drug conjugate (ADC) via functional disulfide bridging. The linker has excellent stability in blood serum and the ADC, armed with monomethyl auristatin E (MMAE), shows excellent potency and cancer cell selectivity in vitro.

Drug bioactivation to reactive metabolites capable of covalent adduct formation with bionucleophiles is a major cause of drug-induced adverse reactions. Therefore, elucidation of reactive metabolites is essential to unravel the toxicity mechanisms induced by drugs and thereby identify patient subgroups at higher risk. Etravirine (ETR) was the first second-generation Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) to be approved, as a therapeutic option for HIV-infected patients who developed resistance to the first-generation NNRTIs. Additionally, ETR came into market aiming to overcome some adverse effects associated with the previously used efavirenz (neurotoxicity) and nevirapine (hepatotoxicity) therapies. Nonetheless, post-marketing reports of severe ETR-induced skin rash and hypersensitivity reactions have prompted the U.S. FDA to issue a safety alert on ETR. Taking into consideration that ETR usage may increase in the near future, due to the possible use of the drug for coinfection with malaria and HIV, the development of reliable prognostic tools for early risk/benefit estimations is urgent. In the current study, high resolution mass spectrometry-based methodologies were integrated with MS3 experiments for the identification of reactive ETR metabolites/adducts: 1) in vitro incubation of the drug with human and rat liver S9 fractions in the presence of Phase I and II co-factors, including glutathione, as a trapping bionucleophile; and 2) in vivo, using urine samples from HIV-infected patients on ETR therapy. We obtained evidence for multiple bioactivation pathways leading to the formation of covalent adducts with glutathione and N-acetyl-L-cysteine. These results suggest that similar reactions may occur with cysteine residues of proteins, supporting a role for ETR bioactivation in the onset of the toxic effects elicited by the drug. Additionally, ETR metabolites stemming from amine oxidation, with potential toxicological significance, were identified in vitro and in vivo. Also noteworthy is the fact that new metabolic conjugation pathways of glucuronide metabolites were demonstrated for the first time, raising questions about their potential toxicological implications. In conclusion, these results represent not only a contribution towards the elucidation of new metabolic pathways of drugs in general but also an important step towards the elucidation of potentially toxic ETR pathways, whose understanding may be crucial for reliable risk/benefit estimations of ETR-based regimens.

This study analyzed the effects of a 12-week resistance training (RT) program without dietary interventions on metabolic syndrome (MetS) components and inflammatory biomarkers in older women.Fifty-three older women (mean [±SD] age 70.4 ± 5.7 years; mean body mass index 26.7 ± 4.0 kg/mAfter the 12-week period, there were significantly reductions (P 0.05) in glucose levels (-20.4% vs -0.3%), waist circumference (-1.5% vs +2.0%), and systolic BP (-6.2% vs +0.9%), and complete normalization of MetS prevalence (18% at baseline vs. 0% after 12-weeks RT) in the TG. Moreover, C-reactive protein and tumor necrosis factor-α concentrations decreased in the TG (-28.6% and -21.6%, respectively), but increased in the CG (+34.5% and +13.3%, respectively). In addition there were positive improvements in the MetS Z-score in the TG but not CG (-21.6% vs +13.3%, respectively).The results suggest that a 12-week RT program seems to effectively reduce MetS components and inflammatory biomarkers in older women, regardless of dietary intervention. The RT-induced adaptations in body composition and inflammatory biomarkers appear to be related to healthy adaptations in risk factors for MetS.

Highly homogeneous ADCs are generated by the efficient bridging of interchain disulfide bonds in trastuzumab, using next generation maleimides., The advent of Adcetris™ and Kadcyla™, two recently FDA-approved antibody–drug conjugates (ADCs), in the clinic has had a major impact on the treatment of lymphoma and breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages of development, often due to shortcomings in the methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds and allow the efficient conjugation of small molecules to antibodies, without the need for engineering of the target antibody. The method is site-specific and generates near homogeneous products in good yields. Moreover, adjustment of the reaction conditions allows control of the conjugation in terms of stoichiometry (drug-loading) and site selectivity. Using this method we prepared a series of ADCs from trastuzumab and doxorubicin (DOX) with a controlled drug-to-antibody ratio (DAR) of 1, 2, 3 and 4. All of these constructs were fully active by ELISA and had more than 90% of re-bridged disulfide bonds by CE-SDS when compared to clinical grade antibody. Furthermore, digest experiments of the DAR 2 material revealed that almost all of the drug had been targeted to the Fab arms of the antibody. Thus, NGMs offer a flexible and simple platform for the controlled assembly of ADCs from an antibody.

Soil Compaction results from compressive forces applied to compressible soil by machinery wheels, combined with tillage operations. Draft animal‐pulled equipment may also cause soil compaction, but a huge gap exists on experimental data to adequately assess their impacts and, actually, animal traction is an option seen with increasing potential to contribute to sustainable agriculture, especially in mountain areas. This study was conducted to assess the impacts on soil compaction of tillage operations with motor tractor and draft animals. In a farm plot (Vale de Frades, NE Portugal) treatments were applied in sub‐plots (30 m x 3 m), consisting in a two way tillage with tractor (T), a pair of cows (C) and a pair of donkeys (D). Undisturbed soil samples (120) were taken before and after operations for bulk density (BD) and saturated hydraulic conductivity (Ks). The relative changes in BD observed after tillage in the 0-0.05 m soil depth increased after operations in all treatments. The increase was higher in the tractor sub-plot (15%) than in those where animal traction was used (8%). Before operation Ks class was rapid and fast in all samples, and after operation this value was reduced to 33% in T, whereas it reached 83% in C. Electrical Resistivity Tomography (ERT) was useful as a tool to identify the alterations caused by tillage operations on soil physical status. These preliminary results confirm the potential of animal traction as an option for mountain agri‐environments, yet it requires much wider research to soundly ground its assets. Authors wish to acknowledge the most relevant contribution of the farmers of Vale de Frades involved in the experiment, for their enthusiasm and refined performance in the field, accepting to freely provide their time, their work and their draft animals to carry out the required operations. info:eu-repo/semantics/publishedVersion