Contributions to a Yb+ single-ion optical frequency standard

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Substratspezifität und Funktionalität von Epimerisierungsdomänen in der nichtribosomalen Peptidsynthese

Naturstoffe mit einem außerordentlich breiten Spektrum an Strukturen und pharmakologischen Bedeutungen werden fließbandartig an multimodular aufgebauten nichtribosomalen Peptidsynthetasen (NRPS) assembliert. Jedes Modul dieser Megaenzyme umfasst dabei eine Anzahl von katalytisch eigenständigen Domänen, deren spezifische Interaktion den Einbau und die Modifikation eines Bausteins sichert. Sehr häufig enthalten die Produkte D-Aminosäuren, die zum Großteil durch modulintegrierte Epimerisierungs- (E-) Domänen aus den entsprechenden über einen Thioester peptidyl carrier protein (PCP) gebundenen L-Intermediaten in einer Gleichgewichtsreaktion erzeugt werden. Im Rahmen dieser Arbeit wurde ein chemoenzymatischer Ansatz zur quantitativen Untersuchung der nativen Substratspezifität von vier unterschiedlichen Synthetasen entstam-menden E-Domänen entwickelt. Dazu wurden entsprechende PCP-E-Didomänen auf geneti-scher Ebene isoliert. Zwei dieser Konstrukte (TycB3- und FenD2-PCP-E) enstammten Elongationsmodulen und enthielten sogenannte Peptidyl-E-Domänen, während die beiden anderen (TycA- und GrsA-PCP-E) Initiationsmodulen entnommen wurden und entsprechend Aminoacyl-E-Domänen trugen. Die Apo-Proteine wurden überproduziert und unter Verwen-dung der promiskuitiven 4´-Phophopantethein- (Ppant-) Transferase Sfp mit einer Auswahl synthetisierter Peptidyl-CoAs fehlmodifiziert. Enzymgebundene Peptidyl-S-Ppant Reaktions-produkte der darauffolgenden, durch die E-Domänen katalysierten Stereoinversion wurden chemisch abgespalten und auf ihr L zu D-Verhältnis untersucht. Wie anhand von jeweils berechneten kobs-Werten und vorgefundenen L/D-Endgleichgewichten evaluiert wurde, tolerieren alle vier getesteten E-Domänen eine Vielfalt von Peptidyl-S-Ppant-Substraten. Es zeigte sich, dass kein Zusammenhang zwischen der Spezifität (aktivierter Aminosäure) eines Moduls und der Toleranz der ihm entstammenden E-Domäne existiert. Veränderungen am N-terminalen Ende des Substrats können dabei gleiche Auswirkungen auf die Epimerisierungs-aktivität haben wie Variationen des C-Terminus (der Thioester gebundenen Aminosäure). Die E-Domänen invertierten N-methylierte Substrate besonders effizient. Hervorzuheben ist die entdeckte Fähigkeit von Aminoacyl-E-Domänen zur Epimerisierung von Peptidyl-Substraten. Außerdem konnte deutlich gemacht werden, dass die Kondensations (C-) Domäne von TycB1 ebenso in der Lage ist, Peptidyl-Substrate von TycA zu empfangen und zu prozessieren. Da E-Domänen in vielen Systemen am C-Terminus einer Synthetase stehen, wurde angenommen, dass sie in dieser Position an der gezielten Interaktion mit dem nachfolgenden Enzym und dem geregelten Transfer von Intermediaten beteiligt sind. Deshalb setzte sich der zweite Teil der vorliegenden Arbeit mit der Beleuchtung dieser funktionellen Rolle auseinander. Es wurden dimodulare Derivate aus der Tyrocidin-Synthetase B auf genetischer Ebene konstruiert und die überproduzierten rekombinanten Proteine charakterisiert. Zunächst wurde eine optimierte Abfolge aus tryptischer Proteolyse und hochauflösender Massenspek-trometrie eingesetzt, um die Bildung von Intermediaten am TycB3-PCP des TycB2-3-Wildtyps und des E-Domänen-Austauschproteins TycB2-3-AT.CAT/EtycA direkt zu verfolgen. Der E-Domänen-Austausch beeinträchtigte die Dipeptid- (Phe-Phe-) Bildung signifikant. Ferner wurden die beiden genannten Enzyme und ein weiteres, bei dem die Kommunikation vermittelnde (COM-) Domäne gegen die entsprechende von TycA ausgetauscht worden war, mit dem Akzeptor TycB1 getestet. Funktionelle Unterschiede zwischen Peptidyl- und Aminoacyl-E-Domänen im Kontext der in trans Interaktion wurden hierbei deutlich. Peptidyl-E-Domänen scheinen für die Regulation von Kondensation, Epimerisierung und Transfer von Zwischenstufen zum downstream Modul optimiert zu sein, während Aminoacyl-E-Domänen die upstream Kondensation beeinträchtigen und Misinitiation hervorrufen. Diese Erkenntnisse werden für die erfolgreiche Gestaltung neuer Wirkstoffe per Biokombinatorik mit NRPS unter Einbeziehung von E-Domänen von Bedeutung sein

Versatile ytterbium ion trap experiment for operation of scalable ion-trap chips with motional heating and transition-frequency measurements

We present the design and operation of an ytterbium ion trap experiment with a setup offering versatile optical access and 90 electrical interconnects that can host advanced surface and multilayer ion trap chips mounted on chip carriers. We operate a macroscopic ion trap compatible with this chip carrier design and characterize its performance, demonstrating secular frequencies >1 MHz, and trap and cool nearly all of the stable isotopes, including 171Yb+ ions, as well as ion crystals. For this particular trap we measure the motional heating rate 〈ṅ〉 and observe an 〈ṅ〉∝1/ω2 behavior for different secular frequencies ω. We also determine a spectral noise density SE(1 MHz)=3.6(9)×10-11 V2 m-2 Hz-1 at an ion electrode spacing of 310(10) μm. We describe the experimental setup for trapping and cooling Yb+ ions and provide frequency measurements of the 2S1/2↔2P1/2 and 2D3/2↔3D[3/2]1/2 transitions for the stable 170Yb+, 171Yb+, 172Yb+, 174Yb+, and 176Yb+ isotopes which are more precise than previously published work

Cavity Enhanced Optical Vernier Spectroscopy, Broad Band, High Resolution, High Sensitivity

A femtosecond frequency comb provides a vast number of equidistantly spaced narrow band laser modes that can be simultaneously tuned and frequency calibrated with 15 digits accuracy. Our Vernier spectrometer utilizes all of theses modes in a massively parallel manner to rapidly record both absorption and dispersion spectra with a sensitivity that is provided by a high finesse broad band optical resonator and a resolution that is only limited by the frequency comb line width while keeping the required setup simple.Comment: 11 pages, 3 figures, submitted to PR

Quantum Denoising Diffusion Models

In recent years, machine learning models like DALL-E, Craiyon, and Stable Diffusion have gained significant attention for their ability to generate high-resolution images from concise descriptions. Concurrently, quantum computing is showing promising advances, especially with quantum machine learning which capitalizes on quantum mechanics to meet the increasing computational requirements of traditional machine learning algorithms. This paper explores the integration of quantum machine learning and variational quantum circuits to augment the efficacy of diffusion-based image generation models. Specifically, we address two challenges of classical diffusion models: their low sampling speed and the extensive parameter requirements. We introduce two quantum diffusion models and benchmark their capabilities against their classical counterparts using MNIST digits, Fashion MNIST, and CIFAR-10. Our models surpass the classical models with similar parameter counts in terms of performance metrics FID, SSIM, and PSNR. Moreover, we introduce a consistency model unitary single sampling architecture that combines the diffusion procedure into a single step, enabling a fast one-step image generation

Computing on Authenticated Data for Adjustable Predicates

The notion of P-homomorphic signatures, introduced by Ahn et al. (TCC 2012), generalizes various approaches for public computations on authenticated data. For a given predicate P anyone can derive a signature for a message m\u27 from the signatures of a set of messages M, as long as P(M,m\u27)=1. This definition hence comprises notions and constructions for concrete predicates P such as homomorphic signatures and redactable signatures. In our work we address the question of how to combine Pi-homomorphic schemes for different predicates P1,P2,... to create a richer and more flexible class of supported predicates. One approach is to statically combine schemes for predicates into new schemes for logical formulas over the predicates, such as a scheme for AND (P1 AND P2). The other approach for more flexibility is to derive schemes which allow the signer to dynamically decide which predicate to use when signing a message, instead of supporting only a single, fixed predicate. We present two main results. One is to show that one can indeed devise solutions for the static combination for AND, and for dynamically adjustable solutions for choosing the predicate on the fly. Moreover, our constructions are practical and add only a negligible overhead. The other main result is an impossibility result for static combinations. Namely, we prove that, in contrast to the case of AND, many other formulas like the logical OR (P1 OR P2) and the NOT (NOT P) do not admit generic combinations through so-called canonical constructions. This implies that one cannot rely on general constructions in these cases, but must use other methods instead, like finding new predicate-specific solutions from scratch

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)

SIMPLE SUMMARY: Anaplastic large cell lymphoma (ALCL) is a lymphoid malignancy considered to be derived from T cells. Currently, two types of systemic ALCL are distinguished: anaplastic lymphoma kinase (ALK)-positive and ALK-negative ALCL. Although ALK(+) and ALK(−) ALCL differ at the genomic and molecular levels, various key biological and molecular features are highly similar between both entities. We have developed the concept that both ALCL entities share a common principle of pathogenesis. In support of this concept, we here describe a common deregulation of CD74, which is usually not expressed in T cells, in ALCL. Ligation of CD74 induces cell death of ALCL cells in various conditions, and an anti-CD74-directed antibody-drug conjugate efficiently kills ALCL cell lines. Furthermore, we reveal expression of the proto-oncogene and known CD74 interaction partner MET in a fraction of ALCL cases. These data give insights into ALCL pathogenesis and might help to develop new treatment strategies for ALCL. ABSTRACT: In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK(+)) ALCL. Key pathogenic events in ALK-negative (ALK(−)) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK(+) and ALK(−) ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK(+) ALCL or of CD95 death-receptor signaling in ALK(−) ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity

Insomnia is a frequent finding in adults with Asperger syndrome

BACKGROUND: Asperger syndrome (AS) is a neurodevelopmental disorder belonging to autism spectrum disorders with prevalence rate of 0,35% in school-age children. It has been most extensively studied in childhood while there is scarcity of reports concerning adulthood of AS subjects despite the lifelong nature of this syndrome. In children with Asperger syndrome the initiation and continuity of sleep is disturbed because of the neuropsychiatric deficits inherent of AS. It is probable that sleep difficulties are present in adulthood as well. Our hypothesis was that adults with AS suffer from difficulty in initiating and maintaining sleep and nonrestorative sleep (insomnia). METHODS: 20 AS without medication were compared with 10 healthy controls devoid of neuropsychiatric anamnesis. Clinical examination, blood test battery and head MRI excluded confounding somatic illnesses. Structured psychiatric interview for axis-I and axis-II disorders were given to both groups as well as Beck Depression Inventory and Wechsler adult intelligence scale, revised version. Sleep quality was assessed with sleep questionnaire, sleep diary during 6 consecutive days and description of possible sleep problems by the participants own words was requested. RESULTS: compared with controls and with normative values of good sleep, AS adults had frequent insomnia. In sleep questionnaire 90% (18/20), in sleep diary 75% (15/20) and in free description 85% (17/20) displayed insomnia. There was a substantial psychiatric comorbidity with only 4 AS subject devoid of other axis-I or axis-II disorders besides AS. Also these persons displayed insomnia. It can be noted that the distribution of psychiatric diagnoses in AS subjects was virtually similar to that found among patient with chronic insomnia. CONCLUSIONS: the neuropsychiatric deficits inherent of AS predispose both to insomnia and to anxiety and mood disorders. Therefore a careful assessment of sleep quality should be an integral part of the treatment plan in these individuals. Conversely, when assessing adults with chronic insomnia the possibility of autism spectrum disorders as one of the potential causes of this condition should be kept in mind