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Ultrashort near-infrared femtosecond laser pulses have become the tool of choice for high-precision processing of transparent ultrawide bandgap materials, ranging from material ablation, amorphization, waveguide writing to optical data storage. The processing precision with ultrashort laser pulses is fundamentally limited in the lateral direction by diffraction, while self-absorption and self-reflection are limiting the achievable depth. In this chapter, we present one of the possible pathways to overcome these limits by utilizing temporal pulse-shaping technology. In the following, we review and discuss the main light-matter interaction mechanisms, multiphoton and avalanche excitation, and how ultrashort and temporally shaped femtosecond laser pulses address them differently, allowing the control over the spatial carrier distribution and the subsequent material processing. We demonstrate the potential of temporal pulse shaping as a tool for controlled nanostructuring below the typical limits by discussing our in situ and postmortem experimental and numerical studies on the spatial distribution of laser excitation in water, high-aspect-ratio structuring of fused silica, and the optoporation of cells.

We report chirality detection of structural isomers in a gas phase mixtureusing nanosecond photoelectron circular dichroism (PECD). Combiningpulsed molecular beams with high-resolution resonance enhancedmulti-photon ionization (REMPI) allows specific isolated transitionsbelonging to distinct components in the mixture to be targeted

BACKGROUND AND AIMS: Hepatitis C is poorly documented in migrants. The published studies mainly concern the screening in this population and are limited to some countries in Europe and North America. This study aimed to evaluate the characteristics and care of chronic hepatitis C in this population compared to the nonmigrant population, in the era of direct-acting antivirals (DAAs). METHOD: We performed a retrospective analysis based on data presented at the multidisciplinary team meetings of our tertiary care center between 2015 and 2019. RESULTS: We included 277 migrant- and 1390 nonmigrant patients mono-infected with hepatitis C virus (HCV) and treated with DAAs. The majority of the migrants were from Eastern European countries. In multivariable analysis, BMI classes associated with more obesity (OR = 1.84; 95% CI, 1.37-2.49; P < 0.001) and therapeutic patient education (OR = 3.91; 95% CI, 2.38-6.49; P < 0.001) were positively associated with migrant status, whereas age (OR = 0.92; 95% CI, 0.90-0.94; P < 0.001), female gender (OR = 0.46; 95% CI, 0.28-0.74; P = 0.002), modes of contamination with less drug use, transfusion history or nosocomial risk, as well more unknown mode (OR = 0.70; 95% CI, 0.50-0.96; P = 0.031), alcohol consumption (OR = 0.48; 95% CI, 0.29-0.73; P = 0.001), types of structures with less care in a general hospital or health network of general practitioners and more care in a university hospital or primary addictology center (OR = 0.78; 95% CI, 0.60-0.99; P = 0.046) and opioid substitution therapy (OR = 0.25; 95% CI, 0.08-0.68; P = 0.008) were negatively associated with migrant status. The substained virologic response 12 was close to 97% in both groups. CONCLUSION: Despite multiple differences in characteristics and therapeutic care between the two populations, the chances of healing hepatitis C were the same among migrant- compared with nonmigrant patients.

People who use drugs (PWUDs) are the main group at risk for hepatitis C virus (HCV) transmission and a key population for hepatitis C elimination. Multidisciplinary team (MDT) meetings were set up in France in December 2014 within regional reference centers to supervise the prescriptions and delivery of direct-acting antivirals (DAAs) to optimize the management of HCV infection. The aim of this retrospective study was to analyze the changes in the profile and therapeutic care of PWUDs with HCV mono-infection according to the evolution of MDT meetings in a regional tertiary reference center.Between 2015 and 2019, overall 1912 HCV-infected patients presented at the MDT meetings, 547 were PWUDs with HCV mono-infection treated with DAAs. Five periods were defined according to the evolution of MDT meetings. The profile and management of PWUDs were compared among these five periods.Over time, the frequency of advanced stage of fibrosis decreased from 90.8 to 36.3% (P 0.001), whereas the therapeutic care of the patients in primary addictology centers and networks of general practitioners increased from 17.4 to 55% (P 0.001). The frequency of excessive alcohol consumption varied between 9.1 and 30% (P = 0.003) and that of opioid substitution therapy between 42.5 and 70% (P 0.001). The Sustained virologic response assessed 12 weeks after the end of treatment rate was above 95% for the five periods.Between 2015 and 2019, the changes in the profile and management of PWUDs have followed the evolution of MDT meetings concerning patients with less advanced fibrosis and more therapeutic hepatitis C care made by the primary care centers.

Viral hepatitis is a leading cause of liver morbidity and mortality globally. The mechanisms underlying acute infection and clearance, versus the development of chronic infection, are poorly understood. In vitro models of viral hepatitis circumvent the high costs and ethical considerations of animal models, which also translate poorly to studying the human-specific hepatitis viruses. However, significant challenges are associated with modeling long-term infection in vitro. Differentiated hepatocytes are best able to sustain chronic viral hepatitis infection, but standard two-dimensional models are limited because they fail to mimic the architecture and cellular microenvironment of the liver, and cannot maintain a differentiated hepatocyte phenotype over extended periods. Alternatively, physiomimetic models facilitate important interactions between hepatocytes and their microenvironment by incorporating liver-specific environmental factors such as three-dimensional ECM interactions and co-culture with non-parenchymal cells. These physiologically relevant interactions help maintain a functional hepatocyte phenotype that is critical for sustaining viral hepatitis infection. In this review, we provide an overview of distinct, novel, and innovative in vitro liver models and discuss their functionality and relevance in modeling viral hepatitis. These platforms may provide novel insight into mechanisms that regulate viral clearance versus progression to chronic infections that can drive subsequent liver disease. review journal article 2023 Feb 2022 11 19 imported

We investigate photoelectron circular dichroism (PECD) with coherent light sources whose pulse durations range from femtoseconds to nanoseconds. To that end, we employed an optical parametric amplifier, an ultraviolet optical pulse shaper, and a nanosecond dye laser, all centered around a wavelength of 380 nm. A multiphoton ionization experiment on the gas-phase chiral prototype fenchone found that PECD measured via the 3s intermediate resonance is about 15% and robust over five orders of magnitude of the pulse duration. PECD remains robust despite ongoing molecular dynamics such as rotation, vibration, and internal conversion. We used the Lindblad equation to model the molecular dynamics. Under the assumption of a cascading internal conversion, from the 3p to the 3s and further to the ground state, we estimated the lifetimes of the internal conversion processes in the 100 fs regime.

Single-photon ionisation of enantiopure methyl p-tolyl sulfoxide by circularly polarised light at 133 nm shows remarkably strong photoelectron circular dichroism (PECD), which has been measured in a velocity-map-imaging spectrometer. Both enantiomers were measured, each showing a PECD of a similar magnitude (ca. 25 %). These experiments were carried out with a tabletop high-harmonic source with a photon energy of 9.3 eV, capable of ionising the electronic ground state of most organic and inorganic molecules. Ab-initio scattering calculations provide a theoretical value of the expected chiral asymmetry parameter, and agree very well with the measured values once orbital mixing via configuration interaction in the cation is taken into account. This study demonstrates a simple photoionisation scheme that can be readily applied to study the time-resolved PECD of photochemical reactions and suggests a pronounced sensitivity of PECD to electronic configuration interaction in the cation.

espanolEl presente articulo analiza la relacion del economista Heinrich von Stackelberg (que desempeno un papel fundamental en el desarrollo de la ciencia economica en Espana) con el nacionalsocialismo, partido en el que milito desde 1931. La documentacion consultada —en su gran mayoria inedita hasta la fecha, incluyendo el acta de desnazificacion de von Stackelberg— demuestra que a partir de 1936 se distancio progresiva y rotundamente del regimen hitleriano y del partido nacionalsocialista. A su llegada a Espana en 1943 von Stackelberg habia pasado a colaborar activamente en la resistencia contra Hitler, estando estrechamente vinculado a quienes planificaron y ejecutaron el atentado contra el Fuhrer del 20 de julio de 1944 en la llamada «Operacion Valquiria». EnglishThe present paper studies the relation of the economist Heinrich von Stackelberg (who played a crucial part in the development of economic science in Spain) with national socialism, whose party he had joined in 1931. The original sources employed —most of which, including his denazificaction file, have remained unpublished to this day— show that from 1936 onwards von Stackelberg progressively and outrightly distanced imself from the Hitler regime and the National Socialist Party. At the time of his arrival in Spain, von Stackelberg was actively collaborated in the resistance against Hitler, being also closely involved with those who planed and executed the attack against the Fuhrer on the 20th of July of 1944 in the plot known as “Operation Valkyrie”.

Claudin 1 (CLDN1) is a protein confined within the normal epithelial tight junctions of different tissues. Upon malignant transformation, CLDN1 is overxpressed and epitopes become exposed outside the tight junctions (non-Junctional CLDN1). ALE.C04 is a highly specific humanized monoclonal antibody that recognizes a unique CLDN1 exposed epitope in different solid tumors. Herein we show that non-Junctional CLDN1 (NJ-CLDN1) is frequently overexpressed in solid tumors. Pre-clinically, ALE.C04 drives tumor growth inhibition in different CDXs and PDX in vivo tumor models. Notably, CLDN1 expression on tumor cells positively correlates with T cell exclusion, a mechanism described to hinder the efficacy of Checkpoint inhibitors (CPIs). On this line, the overexpression of Cldn1 in mouse tumor cells promoted T-cell exclusion and resistance to anti-PD1 treatment. Importantly, ALE.C04 restored both T-cell infiltration and anti-PD1 efficacy in tumors. Mechanistically, NJ-CLDN1 interacts with different components involved in extracellular matrix remodeling, thus establishing a physical barrier that exclude immune cells from the tumor nest. ALE.C04 perturbs the interface between CLDN1+ tumor cells and the stroma, thus restoring immune cell infiltration. Our pre-clinical data showed that: i) NJ-CLDN1 is a novel and druggable target in solid tumors ii) ALE.C04 is a selective anti-CLDN1 antibody capable of driving anti-tumor activity as both single agent and in combination with anti-PD1. Citation Format: Alberto Toso, Geoffrey Teixeira, Tina Zimmermann, Stefanie Gill Gill, Daniela Schmitter, Markus Meyer, Marion Muller, Laurent Mailly, Thomas Baumert, Luigi Manenti, Roberto Iacone. CLAUDIN-1 targeting antibody ALE.C04 drives single activity and restores anti-PD1 efficacy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB284.

Consumers’ choices and price-finding decisions are complex processes determined by a series of factors, most of which have been exhaustively studied in the academic and professional literature. However, one factor seems to have passed basically unnoticed until now, namely the brand’s antiquity explicitly announced in the companies’ logos (“Since…”, “Established in…” etc.). The present study is, to the best of our knowledge, the first to analyse how brand antiquity may be perceived by consumers as an indicator of quality —as only brands that sell quality products are supposed to survive in a competitive market in the long run— and to have modelled an experiment to empirically test whether this perception results in a willingness to pay higher prices for products whose brands advertise the company’s antiquity than those which do not. Our results reveal that brand antiquity, indeed, has a statistically significant effect on consumers’ price setting.

Although the number of terrorist casualties has recently decreased, terrorism still presents a threat to society. Within the last 20 years there has been a significant increase in the number of monographic studies about terrorist incidents’ impact on consumer behaviour. However, the present study is the first to analyse whether a terrorist threat specifically alters the consumer behaviour of direct victims. According to the literature, the impact of terrorism on many sectors is lower than originally expected and, if significant, only short term. We hypothesize that this influence is more significant and lasts longer with direct victims, who have undergone traumatic experience. For this purpose, we explore how victims of terrorism in Spain respond to hypothetical scenarios describing a terrorist plot against airplanes at an international airport. In addition, we check if there are significant differences between participants when confronted with situations in which they have to opt between taking or cancelling a planned trip by plane under the menace of a (hypothetical) terrorist attack.

We demonstrate dynamics in the electronic ground state of a chiral molecule via VUV-ionisation in a velocity-map-imaging spectrometer. The dynamics are simplified by measuring time-resolved PECD, which is sensitive to a subset of nuclear motions.

HCV can cause psychiatric disorders. It is crucial to re-evaluate them with direct-acting antiviral treatment (DDAs), since the interferon-based treatments of the past were capable of causing identical psychiatric adverse effects. A system of multidisciplinary team (MDT) meetings was implemented in France in December 2014 in regional reference centers with the aim of controlling the prescription and administration of these new treatments, along with optimizing how the patients undergoing these treatments are followed up. Our study sought to compare the characteristics and type of medical care received for chronic hepatitis C in patients with (PSY+ group) and without (PSY- group) psychiatric disorders using data from MDT meetings in the Alsace area of France collected from 2015 to 2019. All included patients were mono-infected and treated with DAAs in successive rounds between 2015 and 2019, as per recommendations from the French Hepatology Society. We compared the two groups (PSY+ and PSY-) based on 21 variables regarding the characteristics and medical care of hepatitis C. Psychiatric disorders were observed in 15% of patients. On multivariate analysis, a positive correlation was found between them and drug use (OR: 2.35; 95%CI: 1.40-3.98; p=0.001), excessive alcohol consumption (OR: 1.92; 95%CI: 0.98-3.69; p=0.05), smoking (OR: 1.81; 95%CI: 1.09-2.98; p=0.02), and incidence of drug interactions (OR: 3.94; 95%CI: 2.15-7.17; p

Hepatocellular carcinoma (HCC) is a major global health challenge with rising incidence. Despite the previous approval of several novel therapeutic approaches, HCC remains the second common cause of cancer-related death worldwide. The vast majority of HCCs arises in the context of chronic fibrotic liver diseases caused by viral or metabolic etiologies. In patients with advanced liver disease the risk of HCC persists even after viral cure or control of infection. Moreover, given the change in the lifestyle and increase of obesity and metabolic disorders, HCC incidence is predicted to drastically augment in the next decade. Early detection, improvement of the screening method in patient at-risk and development of chemopreventive strategies are therefore urgently needed to reduce HCC risk. This review summarizes the major challenges in the identification of patient at risk for HCC and the emergent strategies for HCC prevention to improve patients' outcome.Le carcinome hépatocellulaire (CHC) est un problème de santé mondial majeur dont l’incidence est en constante augmentation. Malgré l’approbation de plusieurs nouvelles approches thérapeutiques, le CHC demeure la deuxième cause de décès par cancer dans le monde. La grande majorité des CHC survient dans le contexte de maladies chroniques fibrotiques du foie causées par des étiologies virales ou métaboliques. Chez les patients présentant une maladie hépatique avancée, le risque de CHC persiste même après l’élimination du virus ou le contrôle de l’infection virale. En outre, compte tenu du changement de mode de vie et de l’augmentation de l’obésité et des troubles métaboliques, l’incidence du CHC devrait augmenter de façon spectaculaire au cours de la prochaine décennie. La détection précoce, l’amélioration des méthodes de dépistage chez les patients à risque et le développement de stratégies chimiopréventives sont donc nécessaires de toute urgence pour réduire le risque de CHC. Cette revue résume les principaux défis dans l’identification des patients à risque pour le CHC et les stratégies émergentes pour la prévention du CHC afin d’améliorer la prise en charge des patients.

Portal hypertension (PH) is one of the most severe complications of chronic liver diseases. It is defined as an increase in pressure in the portal venous system which results in a portosystemic gradient >5 mmHg. In the western world, cirrhosis is the most frequent cause of PH, mainly due to nonalcoholic fatty liver disease and alcoholic liver disease. Patients with PH have esophageal varices in 68-73% of cases, portal hypertensive gastropathy in 51-73% and hyperplastic polyps (HPs) in 0.9-2%. Recent studies have shown that HPs found in PH patients are different from classical HPs. They constitute a new entity called portal hypertensive polyps (PHPs). The main difference between sporadic HPs and PHP is the presence of larger and more numerous vascular capillaries in the lamina propria. The clinical course of PHPs is unknown. Their physiopathology seems different from HPs: the increased congestion caused by higher portal pressure in the stomach may induce capillaries proliferation and neoangiogenesis. PHPs may be responsible for symptoms, such as pyloric obstruction, iron deficiency and anemia. Their prevalence in portal hypertensive and cirrhotic patients is from 1% to 8%. PHPs can be single or numerous, in the antrum or the gastric corpus. Their size ranges from 2 to 3 cm. PHPs seem to disappear or shrink with the treatment of PH. They should be resected in case of symptom and if >10 mm, after Helicobacter pylori eradication if present. However, their recurrence is frequent (40-79%), thus surveillance endoscopy is mandatory, at the same time as esophageal varices.

Despite breakthroughs in antiviral therapies, chronic viral hepatitis B and C are still the major causes of liver fibrosis and hepatocellular carcinoma (HCC). Importantly, even in patients with controlled infection or viral cure, the cancer risk cannot be fully eliminated, highlighting a persisting oncogenic pressure imposed by epigenetic imprinting and advanced liver disease. Reliable and minimally invasive biomarkers for early fibrosis and for residual HCC risk in HCV-cured patients are urgently needed. Chronic infection with HBV and/or HCV dysregulates oncogenic and profibrogenic signaling within the host, also displayed in the secretion of soluble factors to the blood. The study of virus-dysregulated signaling pathways may, therefore, contribute to the identification of reliable minimally invasive biomarkers for the detection of patients at early-stage liver disease potentially complementing existing noninvasive methods in clinics. With a focus on virus-induced signaling events, this review provides an overview of candidate blood biomarkers for liver disease and HCC risk associated with chronic viral hepatitis and epigenetic viral footprints.

Photoelectron circular dichroism (PECD) is a fascinating phenomenon both from a fundamental science aspect but also due to its emerging role as a highly sensitive analytic tool for chiral recognition in the gas phase. PECD has been studied with single-photon as well as multi-photon ionization. The latter has been investigated in the short pulse limit with femtosecond laser pulses, where ionization can be thought of as an instantaneous process. In this contribution, we demonstrate that multiphoton PECD still can be observed when using an ultra-violet nanosecond pulse to ionize chiral showcase fenchone molecules. Compared to femtosecond ionization, the magnitude of PECD is similar, but the lifetime of intermediate molecular states imprints itself in the photoelectron spectra. Being able to use an industrial nanosecond laser to investigate PECD furthermore reduces the technical requirements to apply PECD in analytical chemistry.

This chapter studies the determinants of regional knowledge production in Europe discriminating by the phases of the EU-enlargement (as a proxy for the degree of economic development). For this purpose, we combine factorial analysis with a regression model based on a knowledge production function. Our results evidence that there are clearly differentiated patterns in the knowledge production function of European regions according to the time of entrance of their corresponding countries into the EU: the less developed regions are, the more important the role of the Universities and of the Public administration in their Innovation Systems is; in more developed regions, however, the leading role is taken over by the Regional economic environment, the Sophistication of the (technological) demand as well as by the availability of financing in the form of Venture capital. We conclude that policy actions aimed to drive innovation should carefully consider the relative stage of development of the specific regional innovation system.

We present a multidimensional spectroscopy approach based on strong-field coherent electronic excitation to elucidate intramolecular dynamics and unveil control mechanisms. Traditional 2D spectroscopy generally relies on weak-field interactions and the well-known control mechanism of spectral interference (SI) with its characteristic I n -scaling of transition probabilities (I, laser intensity; n, photonic order). For non-perturbative strong-field interactions, completely different scenarios become relevant. Especially, electronic coherences play a significant role to control the population dynamics and the bidirectional Stark shifts. To that end, we study the potassium dimer prototype both experimentally and with the help of quantum dynamics simulations. We employ two distinct types of shaped femtosecond laser pulses that induce either impulsive or adiabatic excitation of atoms and molecules – both directly related to coherent strong-field interaction.

This paper presents the first observation of two temporally separated regimes of nonlinear stimulated emission in a piece of laser-excited fused silica. The authors study temporal and energetic dependencies on excitation and amplification and show that one amplification regime is directly linked to the ultrafast formation of long-lived self-trapped excitons.

Photoelectron circular dichroism (PECD) is a highly sensitive enantiospecific spectroscopy for studying chiral molecules in the gas phase using either single-photon ionization or multiphoton ionization. In the short pulse limit investigated with femtosecond lasers, resonance-enhanced multiphoton ionization (REMPI) is rather instantaneous and typically occurs simultaneously via more than one vibrational or electronic intermediate state due to limited frequency resolution. In contrast, vibrational resolution in the REMPI spectrum can be achieved using nanosecond lasers. In this work, we follow the high-resolution approach using a tunable narrow-band nanosecond laser to measure REMPI-PECD through distinct vibrational levels in the intermediate 3s and 3p Rydberg states of fenchone. We observe the PECD to be essentially independent of the vibrational level. This behaviour of the chiral sensitivity may pave the way for enantiomer specific molecular identification in multi-component mixtures: one can specifically excite a sharp, vibrationally resolved transition of a distinct molecule to distinguish different chiral species in mixtures.

We present the observation of different regimes of nonlinear light amplification in optically excited sapphire and fused-silica via femtosecond imaging spectroscopy. We discuss possible mechanisms and implications of the novel understanding of light-matter interaction for current and future applications.

Physical review research 2(3), 033209 (2020). doi:10.1103/PhysRevResearch.2.033209, We show that the combination of two achiral components—an atomic or molecular target plus a circularly polarized photon—can yield chirally structured photoelectron angular distributions. For photoionization of CO, the angular distribution of carbon $K$-shell photoelectrons is chiral when the molecular axis is neither perpendicular nor (anti)parallel to the light propagation axis. In photo-double-ionization of He, the distribution of one electron is chiral if the other electron is oriented like the molecular axis in the former case and if the electrons are distinguishable by their energy. In both scenarios, the circularly polarized photon defines a plane with a sense of rotation and an additional axis is defined by the CO molecule or one electron. This is sufficient to establish an unambiguous coordinate frame of well-defined handedness. To produce a chirally structured electron angular distribution, such a coordinate frame is necessary but not sufficient. We show that additional electron-electron interaction or scattering processes are needed to create the chiral angular distribution., Published by APS, College Park, MD

The purpose of this article is to measure the efficiency of regional innovation systems (RIS) of the European Union (EU-14) between 2000 and 2010 based on the Data Envelopment Analysis. To measure the efficiency, we used 29 input variables synthesized in 5 factors or composite indicators. The output is reflected by patents and scientific publications. The results obtained highlight that only a few European RIS are situated on or near the efficiency frontier and most regions present very low efficiency levels. We detected a broad dispersion in terms of efficiency, although the tendency over time is a reduction of the dispersion reflecting a process of convergence. Moreover, the results reveal that an important possible cause of the inefficiencies is a problem of scale rather than technical inefficiency.

We present our observation of nonlinear light amplification under optical excitation of sapphire and fused silica via femtosecond imaging spectroscopy and discuss possible mechanisms and implications in the view of current and future applications.

Wide-bandgap dielectrics such as glasses or water are transparent at visible and infrared wavelengths. This changes when they are exposed to ultrashort and highly intense laser pulses. Different interaction mechanisms lead to the appearance of various transient nonlinear optical phenomena. Using these, the optical properties of dielectrics can be controlled from the transparent to the metal-like state. Here we expand this range by a yet unexplored mechanism in excited dielectrics: amplification. In a two-colour pump–probe experiment, we show that a 400 nm femtosecond laser pulse is coherently amplified inside an excited sapphire sample on a scale of a few micrometres. Simulations strongly support the proposed two-photon stimulated emission process, which is temporally and spatially controllable. Consequently, we expect applications in all fields that demand strongly localized amplification. Ultrashort high-intensity laser pulses change the properties of dielectrics in different ways. One unexpected outcome is light amplification in an excited dielectric, observed in a two-colour pump–probe experiment.