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We present a lattice determination of the inclusive decay rate of the process τ↦X_{us}ν_{τ} in which the τ lepton decays into a generic hadronic state X_{us} with u[over ¯]s flavor quantum numbers. Our results have been obtained in n_{f}=2+1+1 isosymmetric QCD with full nonperturbative accuracy, without any operator product expansion approximation and, except for the presently missing long-distance isospin-breaking corrections, include a solid estimate of all sources of theoretical uncertainties. This has been possible by using the Hansen-Lupo-Tantalo method [M. Hansen et al., Phys. Rev. D 99, 094508 (2019)PRVDAQ2470-001010.1103/PhysRevD.99.094508] that we have already successfully applied [A. Evangelista et al., Phys. Rev. D 108, 074513 (2023)PRVDAQ2470-001010.1103/PhysRevD.108.074513] to compute the inclusive decay rate of the process τ↦X_{ud}ν_{τ} in the u[over ¯]d flavor channel. By combining our first-principles theoretical results with the presently available experimental data, we extract the Cabibbo-Kobayashi-Maskawa matrix element |V_{us}|, the Cabibbo angle, with a 0.9% accuracy, dominated by the experimental error.

We present a first-principles lattice QCD investigation of the R ratio between the e^{+}e^{-} cross section into hadrons and into muons. By using the method of Ref. [1], that allows one to extract smeared spectral densities from Euclidean correlators, we compute the R ratio convoluted with Gaussian smearing kernels of widths of about 600 MeV and central energies from 220 MeV up to 2.5 GeV. Our theoretical results are compared with the corresponding quantities obtained by smearing the KNT19 compilation [2] of R-ratio experimental measurements with the same kernels and, by centering the Gaussians in the region around the ρ-resonance peak, a tension of about 3 standard deviations is observed. From the phenomenological perspective, we have not included yet in our calculation QED and strong isospin-breaking corrections, and this might affect the observed tension. From the methodological perspective, our calculation demonstrates that it is possible to study the R ratio in Gaussian energy bins on the lattice at the level of accuracy required in order to perform precision tests of the standard model.

Proteases have crucial roles in homeostasis and disease; and protease inhibitors and recombinant proteases in enzyme replacement therapy have become key therapeutic applications of protease biology across several indications. This review briefly summarises therapeutic approaches based on protease activation and focuses on how recent insights into the spatial and temporal control of the proteolytic activation of growth factors and interleukins are leading to unique strategies for the discovery of new medicines. In particular, two emerging areas are covered: the first is based on antibody therapies that target the process of proteolytic activation of the pro-form of proteins rather than their mature form; the second covers a potentially new class of biopharmaceuticals using engineered, proteolytically activable and initially inactive pro-forms of antibodies or effector proteins to increase specificity and improve the therapeutic window., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We perform the first full decomposition of the pion momentum into its gluon and quark contributions. We employ an ensemble generated by the Extended Twisted Mass Collaboration with N_{f}=2+1+1 Wilson twisted mass clover fermions at maximal twist tuned to reproduce the physical pion mass. We present our results in the MS[over ¯] scheme at 2 GeV. We find ⟨x⟩_{u+d}=0.601(28), ⟨x⟩_{s}=0.059(13), ⟨x⟩_{c}=0.019(05), and ⟨x⟩_{g}=0.52(11) for the separate contributions, respectively, whose sum saturates the momentum sum rule.

The infamous strong CP problem in particle physics can in principle be solved by a massless up quark. In particular, it was hypothesized that topological effects could substantially contribute to the observed nonzero up-quark mass without reintroducing CP violation. Alternatively to previous work using fits to chiral perturbation theory, in this Letter, we bound the strength of the topological mass contribution with direct lattice QCD simulations, by computing the dependence of the pion mass on the dynamical strange-quark mass. We find that the size of the topological mass contribution is inconsistent with the massless up-quark solution to the strong CP problem.

Using lattice simulations we demonstrate from first principles the existence of a nonperturbative mechanism for elementary particle mass generation in models with gauge fields, fermions, and scalars, if an exact invariance forbids power divergent fermion masses and fermionic chiral symmetries broken at UV scale are maximally restored. We show that in the Nambu-Goldstone phase a fermion mass term, unrelated to the Yukawa operator, is dynamically generated. In models with electroweak interactions weak boson masses are also generated, opening new scenarios for beyond the standard model physics.

Purpose: It is well known that pathological changes in tissue alter its mechanical properties. This holds also true for brain tissue. In case of the brain, however, obtaining information about these properties is hard due to the surrounding cranial bone. In this paper a novel technique to create an imaging contrast based on the aforementioned properties is presented., Methods: The method is based on an excitation of the brain induced by a short fall. The response of the brain tissue is measured using a motion sensitive MRI sequence., Results: The new method is tested by measurements on phantom material as well as on healthy volunteers. In a proof of principle experiment the capability of the approach to identify local alterations in the mechanical properties is shown by means of measurements on meningioma patients., Conclusion: The presented results show the feasibility of the novel method. Even in this early state of the proposed method, comparisons of measurements on meningioma patients with intraoperative palpation suggest that meningioma tissue responds differently to the excitation depending on their mechanical properties. Magn Reson Med 78:930-940, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

The practical realization of disease modulation by catalytic degradation of a therapeutic target protein suffers from the difficulty to identify candidate proteases, or to engineer their specificity. We identified 23 measurable, specific, and new protease activities using combinatorial screening of 27 human proteases against 24 therapeutic protein targets. We investigate the cleavage of monocyte chemoattractant protein 1, interleukin-6 (IL-6), and IL-13 by matrix metalloproteinases (MMPs) and serine proteases, and demonstrate that cleavage of IL-13 leads to potent inhibition of its biological activity in vitro. MMP-8 degraded human IL-13 most efficiently in vitro and ex vivo in human IL-13 transgenic mouse bronchoalveolar lavage. Hence, MMP-8 is a therapeutic protease lead against IL-13 for inflammatory conditions whereby reported genetic and genomics data suggest an involvement of MMP-8. This work describes the first exploitation of human enzyme promiscuity for therapeutic applications, and reveals both starting points for protease-based therapies and potential new regulatory networks in inflammatory disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Painful pseudarthrosis is one of the most important indications for (revision) surgery after spinal fusion procedures. If pseudarthrosis is the source of recurrent pain it may require revision surgery. It is therefore of great clinical importance to ascertain if it is the source of such pain. The correlation between findings on conventional imaging (plain radiography and CT) and clinical well-being has been shown to be moderate. The goal of this study was to determine the possible role of (18)F-fluoride PET in patients after lumbar spinal interbody fusion by investigating the relationship between PET/CT findings and clinical function and pain., Methods: A cohort of 36 patients was retrospectively included in the study after (18)F-fluoride PET/CT for either persistent or recurrent low back pain (18 patients) or during routine postoperative investigation (18 patients) between 9 and 76 months and 11 and 14 months after posterior lumbar interbody fusion, respectively. Sixty minutes after intravenous injection of 156 - 263 MBq (mean 199 MBq, median 196 MBq) (18)F-fluoride, PET and CT images were acquired using an integrated PET/CT scanner, followed by a diagnostic CT scan. Two observers independently scored the images. The number of bony bridges between vertebrae was scored on the CT images to quantify interbody fusion (0, 1 or 2). Vertebral endplate and intervertebral disc space uptake were evaluated visually as well as semiquantitatively following (18)F-fluoride PET. Findings on PET and CT were correlated with clinical wellbeing as measured by validated questionnaires concerning general daily functioning (Oswestry Disability Index), pain (visual analogue scale) and general health status (EuroQol). Patients were divided into three categories based on these questionnaire scores., Results: No correlation was found between symptom severity and fusion status. However, (18)F-fluoride activity in the vertebral endplates was significantly higher in patients in the lowest Oswestry Disability Index category (i.e. with the worst clinical performance) than in patients in higher categories (p = 0.01 between categories 1 and 2 and 1 and 3). The visual analogue scale and EuroQol results were similar although less pronounced, with only SUVmax between category 1 and 2 being significantly different (p = 0.04)., Conclusion: We hypothesize that (18)F-fluoride PET/CT may be able to provide support for the diagnosis of painful pseudarthrosis and could serve as a tool to discriminate between symptomatic and asymptomatic pseudarthrosis for revision surgery, as CT defines the consolidation status and PET pinpoints the 'stress reaction' at the vertebral endplates which significantly correlates with Oswestry Disability Index score.

We report the enzymatic synthesis of α-D-glucopyranosyl-(1→4)-α-L-rhamnopyranoside and α-D-glucopyranosyl-(1→3)-α-L-rhamnopyranoside by using a wild-type transglucosidase in combination with glucoamylase and glucose oxidase. It was shown that Bacillus circulans 251 cyclodextrin glucanotransferase (CGTase, EC 2.1.4.19) can efficiently couple an α-L-rhamnosyl acceptor to a maltodextrin molecule with an α-(1→4) linkage, albeit in mixture with the α-(1→3) regioisomer, thus giving two glucosylated acceptors in a single reaction. Optimisation of the CGTase coupling reaction with β-cyclodextrin as the donor substrate and methyl or allyl α-L-rhamnopyranoside as acceptors resulted in good conversion yields (42-70%) with adjustable glycosylation regioselectivity. Moreover, the efficient chemical conversion of the products of CGTase-mediated cis-glucosylation into protected building blocks (previously used in the synthesis of O-antigen fragments of several Shigella flexneri serotypes) was substantiated. These novel chemoenzymatic strategies towards useful, convenient intermediates in the synthesis of S. flexneri serotypes 2a and 3a oligosaccharides might find applications in developments towards synthetic carbohydrate-based vaccine candidates against bacillary dysentery., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We present a lattice QCD computation of η and η' masses and mixing angles, for the first time controlling continuum and quark mass extrapolations. The results for M(η) = 551(8)(stat) (6)(yst) MeV and M(η') = 1006(54)(stat)(38)(syst)(+61)(ex) MeV are in excellent agreement with experiment. Our data show that the mixing in the quark flavor basis can be described by a single mixing angle of Ø = 46(1)(stat)(3)(syst)° indicating that the η' is mainly a flavor singlet state.

Aim: The hard beta and gamma radiation of 124I can cause high doses to PET/CT workers. In this study we tried to quantify this occupational exposure and to optimize radioprotection., Methods: Thin MCP-Ns thermoluminescent dosimeters suitable for measuring beta and gamma radiation were used for extremity dosimetry, active personal dosimeters for whole-body dosimetry. Extremity doses were determined during dispensing of 124I and oral administration of the activity to the patient, the body dose during all phases of the PET/CT procedure. In addition, dose rates of vials and syringes as used in clinical practice were measured. The procedure for dispensing 124I was optimized using newly developed shielding., Results: Skin dose rates up to 100 mSv/min were measured when in contact with the manufacturer's vial containing 370 MBq of 124I. For an unshielded 5 ml syringe the positron skin dose was about seven times the gamma dose. Before optimization of the preparation of 124I, using an already reasonably safe technique, the highest mean skin dose caused by handling 370 MBq was 1.9 mSv (max. 4.4 mSv). After optimization the skin dose was below 0.2 mSv., Conclusion: The highly energetic positrons emitted by 124I can cause high skin doses if radioprotection is poor. Under optimized conditions occupational doses are acceptable. Education of workers is of paramount importance.

Molecular evolution has always been a subject of discussions, and researchers are interested in understanding how proteins with similar scaffolds can catalyze different reactions. In the superfamily of serine penicillin-recognizing enzymes, D-alanyl-D-alanine peptidases and beta-lactamases are phylogenetically linked but feature large differences of reactivity towards their respective substrates. In particular, while beta-lactamases hydrolyze penicillins very fast, leading to their inactivation, these molecules inhibit d-alanyl-d-alanine peptidases by forming stable covalent penicilloyl enzymes. In cyanobacteria, we have discovered a new family of penicillin-binding proteins (PBPs) presenting all the sequence features of class A beta-lactamases but having a six-amino-acid deletion in the conserved Omega-loop and lacking the essential Glu166 known to be involved in the penicillin hydrolysis mechanism. With the aim of evolving a member of this family into a beta-lactamase, PBP-A from Thermosynechococcus elongatus has been chosen because of its thermostability. Based on sequence alignments, introduction of a glutamate in position 158 of the shorter Omega-loop afforded an enzyme with a 50-fold increase in the rate of penicillin hydrolysis. The crystal structures of PBP-A in the free and penicilloylated forms at 1.9 A resolution and of L158E mutant at 1.5 A resolution were also solved, giving insights in the catalytic mechanism of the proteins. Since all the active-site elements of PBP-A-L158E, including an essential water molecule, are almost perfectly superimposed with those of a class A beta-lactamase such as TEM-1, the question why our mutant is still 5 orders of magnitude less active as a penicillinase remains and our results emphasize how far we are from understanding the secrets of enzymes. Based on the few minor differences between the active sites of PBP-A and TEM-1, mutations were introduced in the L158E enzyme, but while activities on D-Ala-D-Ala mimicking substrates were severely impaired, further improvement in penicillinase activity was unsuccessful.

It is largely accepted that serine beta-lactamases evolved from some ancestral DD-peptidases involved in the biosynthesis and maintenance of the bacterial peptidoglycan. DD-peptidases are also called penicillin-binding proteins (PBPs), since they form stable acyl-enzymes with beta-lactam antibiotics, such as penicillins. On the other hand, beta-lactamases react similarly with these antibiotics, but the acyl-enzymes are unstable and rapidly hydrolyzed. Besides, all known PBPs and beta-lactamases share very low sequence similarities, thus rendering it difficult to understand how a PBP could evolve into a beta-lactamase. In this study, we identified a new family of cyanobacterial PBPs featuring the highest sequence similarity with the most widespread class A beta-lactamases. Interestingly, the Omega-loop, which, in the beta-lactamases, carries an essential glutamate involved in the deacylation process, is six amino acids shorter and does not contain any glutamate residue. From this new family of proteins, we characterized PBP-A from Thermosynechococcus elongatus and discovered hydrolytic activity with synthetic thiolesters that are usually good substrates of DD-peptidases. Penicillin degradation pathways as well as acylation and deacylation rates are characteristic of PBPs. In a first attempt to generate beta-lactamase activity, a 90-fold increase in deacylation rate was obtained by introducing a glutamate in the shorter Omega-loop.