Functional central limit theorems for rough volatility

We extend Donsker's approximation of Brownian motion to fractional Brownian motion with Hurst exponent $H \in (0,1)$ and to Volterra-like processes. Some of the most relevant consequences of our `rough Donsker (rDonsker) Theorem' are convergence results for discrete approximations of a large class of rough models. This justifies the validity of simple and easy-to-implement Monte-Carlo methods, for which we provide detailed numerical recipes. We test these against the current benchmark Hybrid scheme \cite{BLP15} and find remarkable agreement (for a large range of values of~$H$). This rDonsker Theorem further provides a weak convergence proof for the Hybrid scheme itself, and allows to construct binomial trees for rough volatility models, the first available scheme (in the rough volatility context) for early exercise options such as American or Bermudan.Comment: 30 pages, 11 figure

Bird's-eye view on Noise-Based Logic

Noise-based logic is a practically deterministic logic scheme inspired by the randomness of neural spikes and uses a system of uncorrelated stochastic processes and their superposition to represent the logic state. We briefly discuss various questions such as (i) What does practical determinism mean? (ii) Is noise-based logic a Turing machine? (iii) Is there hope to beat (the dreams of) quantum computation by a classical physical noise-based processor, and what are the minimum hardware requirements for that? Finally, (iv) we address the problem of random number generators and show that the common belief that quantum number generators are superior to classical (thermal) noise-based generators is nothing but a myth.Comment: paper in pres

Filtered topological structure of the QCD vacuum: Effects of dynamical quarks

We systematically compare filtering methods used to extract topological structures on SU(3) lattice configurations. We show that there is a strong correlation of the topological charge densities obtained by APE and Stout smearing. To get rid of artifacts of these methods, we analyse structures that are also seen by Laplace filtering and indeed identify artifacts for strong smearing. The topological charge density in this combined analysis is more fragmented in the presence of dynamical quarks. A power law exponent that characterises the distribution of filtered topological clusters turns out to be not far off the values of an instanton gas model.Comment: 7 pages, 6 figures, final version to appear in PL

T cells can mediate viral clearance from ependyma but not from brain parenchyma in a major histocompatibility class I- and perforin-independent manner

Viral infection of the central nervous system can lead to disability and death. Yet the majority of viral infections with central nervous system involvement resolve with only mild clinical manifestations, if any. This is generally attributed to efficient elimination of the infection from the brain coverings, i.e. the meninges, ependyma and chorioplexus, which are the primary targets of haematogeneous viral spread. How the immune system is able to purge these structures from viral infection with only minimal detrimental effects is still poorly understood. In the present work we studied how an attenuated lymphocytic choriomeningitis virus can be cleared from the central nervous system in the absence of overt disease. We show that elimination of the virus from brain ependyma, but not from brain parenchyma, could be achieved by a T cell-dependent mechanism operating independently of major histocompatibility class I antigens and perforin. Considering that cytotoxic T lymphocyte-mediated cytotoxicity is a leading cause of viral immunopathology and tissue damage, our findings may explain why the most common viral intruders of the central nervous system rarely represent a serious threat to our healt

Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes

Arenaviruses such as Lassa virus (LASV) cause significant morbidity and mortality in endemic areas. Using a glycoprotein (GP) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rLCMV/VSVG) based on lymphocytic choriomeningitis virus (LCMV), a close relative of LASV. rLCMV/VSVG induced long-term CD8+ T cell immunity against wild-type virus challenge and exhibited a stably attenuated phenotype in vivo. Here we elucidated the innate and adaptive immune requirements for the control of rLCMV/VSVG. Infection of RAG−/− mice resulted in persisting viral RNA in blood but not in overt viremia. The latter was only found in mice lacking both RAG and IFN type I receptor. Conversely, absence of IFN type II signaling or NK cells on an RAG-deficient background had only minor effects on vaccine virus load or none at all. rLCMV/VSVG infection of wild-type mice induced less type I IFN than did wild-type LCMV, and type I as well as type II IFNs were dispensable for the induction of virus-specific memory CD8 T cells and virus-neutralizing antibodies by rLCMV/VSVG. In conclusion, the adaptive immune systems are essential for elimination of rLCMV/VSVG, and type I but not type II IFN plays a major contributive role in lowering rLCMV/VSVG loads in vivo, attesting to the attenuation profile of the vaccine. Nevertheless, IFNs are not required for the induction of potent vaccine responses. These results provide a better understanding of the immunobiology of rLCMV/VSVG and will contribute to the further development of GP exchange vaccines for combating arenaviral hemorrhagic fever

Rosacea and perioral dermatitis: a single‐center retrospective analysis of the clinical presentation of 1032 patients

Background Rosacea is a common chronic inflammatory cutaneous disorder affecting nearly 5.5 % of the adult population. Our aim was to evaluate the prevalence and epidemiology of rosacea and perioral dermatitis (POD) in an ambulatory care setting. Methods We retrospectively analyzed medical data of patients with a confirmed diagnosis of rosacea or perioral dermatitis (POD) presenting at our university hospital outpatient clinic during a 3‐year period. Results Out of 1032 patients, 81.5 % were diagnosed with rosacea and 18.5 % with POD. Overall prevalence was 1.4 % for rosacea and 0.3 % for POD. 69.3 % of the analyzed patients were female. Overall mean age was 49.3 ± 7.7 (1–92) years; the women’s average age was less than the men’s. Patients with POD were younger and predominantly female, whereas patients with phymatous rosacea were older and predominantly male. The most common phenotypes were papulopustular rosacea (68.4 %), erythematotelangiectatic rosacea (22.5 %), and phymatous rosacea (8.0 %). Special forms of rosacea were diagnosed in 15.8 % of the patients; the most frequent were ocular rosacea (6.9 %) and steroid‐induced rosacea (5.4 %). Conclusions The large patient cohort analyzed in our study provides a good estimate of the frequency of the rosacea subtypes, special forms and of perioral dermatitis in a hospital‐based outpatient care setting

Envelope Exchange for the Generation of Live-Attenuated Arenavirus Vaccines

Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell–mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates

Experimental implementation of precisely tailored light-matter interaction via inverse engineering

Accurate and efficient quantum control in the presence of constraints and decoherence is a requirement and a challenge in quantum information processing. Shortcuts to adiabaticity, originally proposed to speed up the slow adiabatic process, have nowadays become versatile toolboxes for preparing states or controlling the quantum dynamics. Unique shortcut designs are required for each quantum system with intrinsic physical constraints, imperfections, and noise. Here, we implement fast and robust control for the state preparation and state engineering in a rare-earth ions system. Specifically, the interacting pulses are inversely engineered and further optimized with respect to inhomogeneities of the ensemble and the unwanted interaction with other qubits. We demonstrate that our protocols surpass the conventional adiabatic schemes, by reducing the decoherence from the excited-state decay and inhomogeneous broadening. The results presented here are applicable to other noisy intermediate-scale quantum systems.We acknowledge the support from National Natural Science Foundation of China (NSFC) (61505133, 61674112, 62074107); Natural Science Foundation of Jiang Su Province (BK20150308); The International Cooperation and Exchange of the National Natural Science Foundation of China NSFC-STINT (61811530020); S.K. acknowledges the support from the Swedish Research Council (no. 2016-04375, no. 2019-04949), the Knut and Alice Wallenberg Foundation (KAW2016.0081) and Wallenberg Center for Quantum Technology (WACQT) (KAW2017.0449); European Union's Horizon 2020 research and innovation program (712721); NanOQ Tech and the Lund Laser Centre (LLC) through a project grant under the Lund Linneaus environment. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 820391 (SQUARE) and no. 654148 Laserlab-Europe. A.W. acknowledges the support from the Swedish Research Counc[.R. acknowledges the support from the Swedish Research Council (no. 2016-05121). X.C. acknowledges the support by the Spanish Ministry of Science and the European Regional Development Fund through PGC2018-101355-B-I00 (MCIU/AEI/FEDER, UE) and the Basque Government through Grant No. IT986-16, the EU FET Open Grant Quromorphic (Grant No. 828826), and EPIQUS (Grant No. 899368) and the Ramon y Cajal program (Grant No. RYC-2017-22482)

Identification of Cellular Pathogenicity Markers for SIL1 Mutations Linked to Marinesco-Sjögren Syndrome.

Background and objective: Recessive mutations in the SIL1 gene cause Marinesco-Sjögren syndrome (MSS), a rare neuropediatric disorder. MSS-patients typically present with congenital cataracts, intellectual disability, cerebellar ataxia and progressive vacuolar myopathy. However, atypical clinical presentations associated with SIL1 mutations have been described over the last years; compound heterozygosity of SIL1 missense mutations even resulted in a phenotype not fulfilling the clinical diagnostic criteria of MSS. Thus, a read-out system to evaluate reliably the pathogenicity of amino acid changes in SIL1 is needed. Here, we aim to provide suitable cellular biomarkers enabling the robust evaluation of pathogenicity of SIL1 mutations. Methods: Five SIL1 variants including one polymorphism (p.K132Q), three known pathogenic mutations (p.V231_I232del, p.G312R, and p.L457P) and one ambiguous missense variant (p.R92W) were studied along with the wild-type proteins in Hek293 in vitro models by cell biological assays, immunoprecipitation, immunoblotting, and immunofluorescence as well as electron microscopy. Moreover, the SIL1-interactomes were interrogated by tandem-affinity-purification and subsequent mass spectrometry. Results: Our combined studies confirmed the pathogenicity of p.V231_I232del, p.G312R, and p.L457P by showing instability of the proteins as well as tendency to form aggregates. This observation is in line with altered structure of the ER-Golgi system and vacuole formation upon expression of these pathogenic SIL1-mutants as well as the presence of oxidative or ER-stress. Reduced cellular fitness along with abnormal mitochondrial architecture could also be observed. Notably, both the polymorphic p.K132Q and the ambiguous p.R92W variants did not elicit such alterations. Study of the SIL1-interactome identified POC1A as a novel binding partner of wild-type SIL1; the interaction is disrupted upon the presence of pathogenic mutants but not influenced by the presence of benign variants. Disrupted SIL1-POC1A interaction is associated with centrosome disintegration. Conclusions: We developed a combination of cellular outcome measures to evaluate the pathogenicity of SIL1 variants in suitable in vitro models and demonstrated that the p. R92W missense variant is a polymorphism rather than a pathogenic mutation leading to MSS

Identification of Candidate Protein Markers in Skeletal Muscle of Laminin-211-Deficient CMD Type 1A-Patients

Laminin-211 deficiency leads to the most common form of congenital muscular dystrophy in childhood, MDC1A. The clinical picture is characterized by severe muscle weakness, brain abnormalities and delayed motor milestones defining MDC1A as one of the most severe forms of congenital muscular diseases. Although the molecular genetic basis of this neurological disease is well-known and molecular studies of mouse muscle and human cultured muscle cells allowed first insights into the underlying pathophysiology, the definition of marker proteins in human vulnerable tissue such as skeletal muscle is still lacking. To systematically address this need, we analyzed the proteomic signature of laminin-211-deficient vastus muscle derived from four patients and identified 86 proteins (35 were increased and 51 decreased) as skeletal muscle markers and verified paradigmatic findings in a total of two further MDC1A muscle biopsies. Functions of proteins suggests fibrosis but also hints at altered synaptic transmission and accords with central nervous system alterations as part of the clinical spectrum of MDC1A. In addition, a profound mitochondrial vulnerability of the laminin-211-deficient muscle is indicated and also altered abundances of other proteins support the concept that metabolic alterations could be novel mechanisms that underline MDC1A and might constitute therapeutic targets. Intersection of our data with the proteomic signature of murine laminin-211-deficient gastrocnemius and diaphragm allowed the definition of nine common vulnerable proteins representing potential tissue markers