Frequenzstabile kontinuierliche Jodramanlaser gepumpt mit einem frequenzverdoppelten Nd:YAG-Laser

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Accelerated deep self-supervised ptycho-laminography for three-dimensional nanoscale imaging of integrated circuits

Three-dimensional inspection of nanostructures such as integrated circuits is important for security and reliability assurance. Two scanning operations are required: ptychographic to recover the complex transmissivity of the specimen; and rotation of the specimen to acquire multiple projections covering the 3D spatial frequency domain. Two types of rotational scanning are possible: tomographic and laminographic. For flat, extended samples, for which the full 180 degree coverage is not possible, the latter is preferable because it provides better coverage of the 3D spatial frequency domain compared to limited-angle tomography. It is also because the amount of attenuation through the sample is approximately the same for all projections. However, both techniques are time consuming because of extensive acquisition and computation time. Here, we demonstrate the acceleration of ptycho-laminographic reconstruction of integrated circuits with 16-times fewer angular samples and 4.67-times faster computation by using a physics-regularized deep self-supervised learning architecture. We check the fidelity of our reconstruction against a densely sampled reconstruction that uses full scanning and no learning. As already reported elsewhere [Zhou and Horstmeyer, Opt. Express, 28(9), pp. 12872-12896], we observe improvement of reconstruction quality even over the densely sampled reconstruction, due to the ability of the self-supervised learning kernel to fill the missing cone.Comment: 13 pages, 5 figures, 1 tabl

Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis

To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed by PEX2, which modulates ATGL levels through post-translational ubiquitination. We demonstrate the importance of this pathway for non-alcoholic fatty liver disease progression using genetic and pharmacological approaches to alter ROS levels in vivo, which can be utilized to increase hepatic ATGL levels and ameliorate hepatic steatosis. The discovery of this peroxisomal β-oxidation-mediated feedback mechanism, which is conserved in multiple organs, couples the functions of peroxisomes and lipid droplets and might serve as a new way to manipulate lipolysis to treat metabolic disorders

Metabolic reconstitution of germ-free mice by a gnotobiotic microbiota varies over the circadian cycle.

The capacity of the intestinal microbiota to degrade otherwise indigestible diet components is known to greatly improve the recovery of energy from food. This has led to the hypothesis that increased digestive efficiency may underlie the contribution of the microbiota to obesity. OligoMM12-colonized gnotobiotic mice have a consistently higher fat mass than germ-free (GF) or fully colonized counterparts. We therefore investigated their food intake, digestion efficiency, energy expenditure, and respiratory quotient using a novel isolator-housed metabolic cage system, which allows long-term measurements without contamination risk. This demonstrated that microbiota-released calories are perfectly balanced by decreased food intake in fully colonized versus gnotobiotic OligoMM12 and GF mice fed a standard chow diet, i.e., microbiota-released calories can in fact be well integrated into appetite control. We also observed no significant difference in energy expenditure after normalization by lean mass between the different microbiota groups, suggesting that cumulative small differences in energy balance, or altered energy storage, must underlie fat accumulation in OligoMM12 mice. Consistent with altered energy storage, major differences were observed in the type of respiratory substrates used in metabolism over the circadian cycle: In GF mice, the respiratory exchange ratio (RER) was consistently lower than that of fully colonized mice at all times of day, indicative of more reliance on fat and less on glucose metabolism. Intriguingly, the RER of OligoMM12-colonized gnotobiotic mice phenocopied fully colonized mice during the dark (active/eating) phase but phenocopied GF mice during the light (fasting/resting) phase. Further, OligoMM12-colonized mice showed a GF-like drop in liver glycogen storage during the light phase and both liver and plasma metabolomes of OligoMM12 mice clustered closely with GF mice. This implies the existence of microbiota functions that are required to maintain normal host metabolism during the resting/fasting phase of circadian cycle and which are absent in the OligoMM12 consortium

Melanoma Models for the Next Generation of Therapies

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies

Mechanical behaviour and formation process of silkworm silk gut

High performance silk fibers were produced directly from the silk glands of silkworms ("Bombyx mori") following an alternative route to natural spinning. This route is based on a traditional procedure that consists of soaking the silk glands in a vinegar solution and stretching them by hand leading to the so called silkworm guts. Here we present, to the authors’ best knowledge, the first comprehensive study on the formation, properties and microstructure of silkworm gut fibers. Comparison of the tensile properties and microstructural organization of the silkworm guts with those of naturally spun fibers allows gain of a deeper insight into the mechanisms that lead to the formation of the fiber, as well as the relationship between the microstructure and properties of these materials. In this regard, it is proved that an acidic environment and subsequent application of tensile stress in the range of 1000 kPa are sufficient conditions for the formation of a silk fiber

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Influencia del síndrome metabólico sobre el proceso de glicosilación aberrante en cáncer de próstata

Prostate cancer is the second most diagnosed neoplasic disease and the fifth cause of cancer death in men worldwide. In Argentina, is the second in incidence and the third cancer death cause in men. In spite of the fact that several genetic factors have been described influencing the development of this disease, non-heritable traits are also important risk factors. Evidence connect metabolic syndrome with an increased incidence and aggressiveness of prostate cancer; however, the molecular mechanisms mediating this connection are not completely clear.\nPreviously, we have described a possible explanation: C-terminal Binding Protein (CtBP1), a co-repressor of tumor suppressor genes that shows an increased activity in high energy conditions such as those found in metabolic syndrome. Based on an experimental model, we have shown that CtBP1 expression in mice with metabolic syndrome is associated with increased prostate tumor growth. Data from expression microarrays showed that CtBP1 hyperactivation, consequence of metabolic syndrome, modulates the expression of glycogenes related to the biosynthesis, degradation and recognition of glycans. This is relevant to the development of the disease, as aberrant glycosylation in cancer has been previoulsy described as an essential step in tumor development, but the biological mechanisms modulating the glycosylation profiles have not been completely characterized.\nConsidering all this, the goal of this Thesis was to study the influence of metabolic syndrome and CtBP1 on aberrant glycosylation in prostate cancer. Using prostate cancer PC3 cells genetically modified to overexpress/not to express CtBP1, we investigated the role of this protein in vitro. Furthermore, we evaluated the role of CtBP1 and metabolic syndrome in vivo, in xenotransplants of genetically modified PC3 lines overexpressing/not expressing CTBP1. Our results show that metabolic syndrome can modulate glycosylation profiles through influencing FUCA2/ALG13 expression, as well as MUC13 and MUC12 expression, both transmembrane membrane mucins; the latter was also influenced by CtBP1.\nIn summary, we have established a first step in understanding the connection between metabolic syndrome, CTBP1 and glycosylation in the development of prostate cancer.Fil: Klug, Manuel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, ArgentinaEl cáncer de próstata es el segundo tipo de cáncer más diagnosticado y la quinta causa de muerte por cáncer en hombres en el mundo. En la Argentina es el de mayor incidencia y ocupa el tercer lugar en mortalidad. Si bien existen factores genéticos que influyen el desarrollo tumoral, son los factores no heredables los que determinan la mayor parte de las variaciones en el riesgo de cáncer entre individuos y entre poblaciones. En particular, distintas evidencias asocian al síndrome metabólico o alguno de sus componentes con un incremento de la incidencia y la agresividad del cáncer de próstata. Sin embargo, aún no se conocen con claridad los mecanismos moleculares por los cuales el síndrome metabólico aumenta el riesgo de padecer cáncer de próstata.\nPreviamente encontramos una posible explicación para esta asociación: C-terminal Binding Protein (CtBP1), un co-represor de genes supresores tumorales que presenta mayor actividad en condiciones de alta energía como las encontradas en el síndrome metabólico. En base a un modelo experimental de síndrome metabólico, demostramos que la expresión de CtBP1 en animales con síndrome metabólico se asocia con un aumento en el crecimiento tumoral. Mediante microarreglos de expresión, determinamos que en este modelo murino la hiperactivación de CtBP1 como consecuencia de un síndrome metabólico modula la expresión algunos genes involucrados en la biosíntesis y/o modificación de la glicosilación, una modificación post-traduccional muy frecuente en glicoproteínas de superficie celular y/o secretadas. Esto es importante ya que la glicosilación aberrante fue descripta en cáncer hace más de 45 años y desde entonces se estudian y documentan cambios en los patrones de glicosilación que ocurren durante la transformación maligna y la progresión del cáncer, pero los mecanismos que regulan la glicosilación aberrante no están del todo esclarecidos.\nEn base a estos antecedentes, el objetivo de este trabajo fue investigar la influencia del síndrome metabólico y la proteína CtBP1 sobre la biosíntesis de glicoepítopes aberrantes en cáncer de próstata. Utilizando líneas celulares derivadas de PC3 con expresión modulada de CtBP1, investigamos el efecto de esta proteína en la expresión de un subgrupo de glicogenes seleccionados de acuerdo a nuestros resultados preliminares. Además investigamos el efecto de CtBP1 y el síndrome metabólico in vivo, en xenotransplantes generados en animales con síndrome metabólico o control por inyección de células tumorales de próstata con expresión modulada de CtBP1. Nuestros resultados demuestran que el síndrome metabólico puede alterar la glicosilación mediante la modulación de los genes FUCA2 y ALG13 y la expresión de mucinas de membrana, en particular MUC12 y MUC13. MUC12 demostró además ser regulado por CtBP1, dando un primer paso para la comprensión de la conexión entre cáncer de próstata, glicosilación, síndrome metabólico y CtBP1

Detection of fungal pathogens in viticulture by laser-induced fluorescence: Design studies on infected potted vines

We show stages of development and first results of our laser based stand-off detection system. Here, laser-induced fluorescence spectroscopy is tailored for remote detection of typical leaf-borne symptoms provoked by fungal pathogens and classification of causal agents