Decision uncertainty in multiobjective optimization

In many real-world optimization problems, a solution cannot be realized in practice exactly as computed, e.g., it may be impossible to produce a board of exactly 3.546~mm width. Whenever computed solutions are not realized exactly but in a perturbed way, we speak of decision uncertainty. We study decision uncertainty in multiobjective optimization problems and we propose the concept decision robust efficiency for evaluating the robustness of a solution in this case. Therefore, we address decision uncertainty within the framework of set-valued maps. First, we prove that convexity and continuity are preserved by the resulting set-valued mappings. Second, we obtain specific results for particular classes of objective functions that are relevant for solving the set-valued problem. We furthermore prove that decision robust efficient solutions can be found by solving a deterministic problem in case of linear objective functions. We also investigate the relationship of the proposed concept to other concepts in the literature

Electron Diffraction of Water in No Man's Land

A generally accepted understanding of the anomalous properties of water will only emerge if it becomes possible to systematically characterize water in the deeply supercooled regime, from where the anomalies appear to emanate. This has largely remained elusive because water crystallizes rapidly between 160 K and 232 K. Here, we present an experimental approach to rapidly prepare deeply supercooled water at a well-defined temperature and probe it with electron diffraction before crystallization occurs. We show that as water is cooled from room temperature to cryogenic temperature, its structure evolves smoothly, approaching that of amorphous ice just below 200 K. Our experiments narrow down the range of possible explanations of the origin for the water anomalies and open up new avenues for studying supercooled water

Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome

Background Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS. Methods Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment. Results Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP. Conclusions Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected

Identification of PARP-1, Histone H1 and SIRT-1 as new regulators of breast cancer-related aromatase promoter I.3/II

Paracrine interactions between malignant estrogen receptor positive (ER+) breast cancer cells and breast adipose fibroblasts (BAFs) stimulate estrogen biosynthesis by aromatase in BAFs. In breast cancer, mainly the cAMP-responsive promoter I.3/II-region mediates excessive aromatase expression. A rare single nucleotide variant (SNV) in this promoter region, which caused 70% reduction in promoter activity, was utilized for the identification of novel regulators of aromatase expression. To this end, normal and mutant promoter activities were measured in luciferase reporter gene assays. DNA-binding proteins were captured by DNA-affinity and identified by mass spectrometry. The DNA binding of proteins was analyzed using electrophoretic mobility shift assays, immunoprecipitation-based in vitro binding assays and by chromatin immunoprecipitation in BAFs in vivo. Protein expression and parylation were analyzed by western blotting. Aromatase activities and RNA-expression were measured in BAFs. Functional consequences of poly (ADP-ribose) polymerase-1 (PARP-1) knock-out, rescue or overexpression, respectively, were analyzed in murine embryonic fibroblasts (MEFs) and the 3T3-L1 cell model. In summary, PARP-1 and histone H1 (H1) were identified as critical regulators of aromatase expression. PARP-1-binding to the SNV-region was crucial for aromatase promoter activation. PARP-1 parylated H1 and competed with H1 for DNA-binding, thereby inhibiting its gene silencing action. In MEFs (PARP-1 knock-out and wild-type) and BAFs, PARP-1-mediated induction of the aromatase promoter showed bi-phasic dose responses in overexpression and inhibitor experiments, respectively. The HDAC-inhibitors butyrate, panobinostat and selisistat enhanced promoter I.3/II-mediated gene expression dependent on PARP-1-activity. Forskolin stimulation of BAFs increased promoter I.3/II-occupancy by PARP-1, whereas SIRT-1 competed with PARP-1 for DNA binding but independently activated the promoter I.3/II. Consistently, the inhibition of both PARP-1 and SIRT-1 increased the NAD+/NADH-ratio in BAFs. This suggests that cellular NAD+/NADH ratios control the complex interactions of PARP-1, H1 and SIRT-1 and regulate the interplay of parylation and acetylation/de-acetylation events with low NAD+/NADH ratios (reverse Warburg effect), promoting PARP-1 activation and estrogen synthesis in BAFs. Therefore, PARP-1 inhibitors could be useful in the treatment of estrogen-dependent breast cancers

Wingless-related integration site (WNT) signaling is activated during the inflammatory response upon cardiac surgery: A translational study

ObjectiveCardiac surgery and the use of cardiopulmonary bypass initiate a systemic inflammatory response. Wingless-related integration site (WNT) signaling is part of the innate immunity and has been attributed a major role in the regulation of inflammation. In preclinical research, WNT-5a may sustain an inflammatory response and cause endothelial dysfunction. Our aim was to investigate WNT signaling after cardiac surgery and its association with postoperative inflammation (Clinicaltrials.gov, NCT04058496).MethodsIn this prospective, single-center, observational study, 64 consecutive patients for coronary artery bypass grafting (CABG) ± valve surgery were assigned into three groups: off-pump CABG (n = 28), on-pump CABG (n = 16) and combined valve-CABG surgery (n = 20). Blood samples were acquired before surgery, at intensive care unit (ICU) admission and 4, 8, and 48 h thereafter. Plasma concentrations of WNT-5a and its antagonists Secreted frizzled-related protein 1 (sFRP-1), Secreted frizzled-related protein 5 (sFRP-5), and WNT inhibitory factor 1 (WIF-1) were determined by enzyme-linked immunosorbent assay. In addition, plasma concentrations of six inflammatory cytokines were measured by multiplex immunoassay. Parameters were analyzed for evolution of plasma concentration over time, interactions, intergroup differences, and association with clinical outcome parameters.ResultsAt baseline, WNT-5a, sFRP-1, and WIF-1 were present in a minimal concentration, while sFRP-5 was elevated. A higher baseline value of WNT-5a, sFRP-5, and WIF-1 resulted in higher subsequent values of the respective parameter. At ICU admission, WNT-5a and sFRP-5 reached their maximum and minimum value, respectively. WIF-1 decreased over time and was lowest 8 h after surgery. sFRP-1 changed minimally over time. While WNT-5a returned to the baseline within 48 h, sFRP-5 and WIF-1 did not reach their baseline value at 48 h. Of the investigated WNT system components, only WIF-1 partially reflected the severity of surgery. WNT-5a and WIF-1 had an impact on postoperative fluid balance and noradrenaline requirement.ConclusionWNT-5a, sFRP-5, and WIF-1 are part of the systemic inflammatory response after cardiac surgery. WNT-5a peaks immediately after cardiac surgery and returns to baseline within 48 h, presumably modulated by its antagonist sFRP-5. Based on this translational study, WNT-5a antagonism may be further investigated to assess potentially beneficial effects in patients with a dysregulated inflammation after cardiac surgery

Are changes in physical activity during COVID-19 associated with mental health among Danish university students?

AimsThe benefits associated with being physical active on mental health is well-established, but little is known on how rapid changes in physical activity are associated with mental health. This study investigated the association between changes in physical activity and mental health among Danish university students during the first COVID-19 lockdown.MethodsOnline survey data were collected among 2,280 university students at the University of Southern Denmark and University of Copenhagen in May–June 2020 as part the “COVID-19 International Student Well-being Study.” Multiple linear regressions were used to analyze associations between changes in physical activity and mental health (depression and stress scores) adjusted for potential socio-economic confounders.ResultsDuring the first COVID-19 lockdown, 40% decreased their moderate and 44% their vigorous physical activity, while 16% increased their moderate and 13% their vigorous physical activity. Overall, students with a stable physical activity level had the lowest mean depressive and stress scores. Adjusted analyses showed that a decrease in vigorous and moderate physical activity level was significantly associated with a higher depression score (mean difference (vigorous): 1.36, p < 0.001 and mean difference (moderate): 1.55, p < 0.001). A decrease in vigorous physical activity and an increase in moderate physical activity was associated with a 1-point increase in the PSS-4 stress score (p < 0.001).ConclusionA substantial proportion of students changed their physical activity level during lockdown. Our findings emphasize the importance of staying physically active during COVID-19 lockdown. This knowledge might be important for relevant health authorities to bridle post-pandemic mental health challenges

Влияние исходного состава углеродных пресс - композиций на внутреннюю и внешнюю поверхность получаемых из них таблеток

Исследование влияния наличия в исходных для прессования углеродных смесях связующих веществ, их свойств и количества, на размеры внутренней и внешней поверхности получающихся из них таблеток.Investigation of the effect of the presence of binders in the initial compression mixtures of carbon mixtures, their properties and quantities, on the dimensions of the inner and outer surfaces of the tablets obtained from them

Lasing in cuprous iodide microwires

We report on the observation of lasing in cuprous iodide (CuI) microwires. A vapor-phase transport growth procedure was used to synthesize CuI microwires with low defect concentration. The crystal structure of single microwires was determined to be of zincblende-type. The high optical quality of single microwires is indicated by the observed series of excitonic emission lines as well as by the formation of gain under optical excitation. Lasing of triangular whispering-gallery modes in single microwires is demonstrated for fs- and ns-excitation from cryogenic temperatures up to 200 K. Timeresolved micro-photoluminescence studies reveal the dynamics of the laser process on the time scale of several picoseconds

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.publishedVersio

Intussuscepção jejunoileal dupla em um cão

Intussuscepção é uma afecção digestiva relativamente comum na clínica veterinária. Caracteriza-se pela invaginação de um segmento intestinal em outro adjacente, de maneira anterógrada ou retrógrada. No presente estudo descreve-se um caso de intussuscepção jejunoileal dupla em um cão. Os sinais clínicos são inespecíficos e incluem vômito, dor abdominal, fezes mucóides e sanguinolentas e pela existência de massa abdominal palpável. O diagnóstico se dá pelos sinais clínicos e exames complementares, como radiografias e ultra-sonografia. Através de celiotomia mediana ventral foi empregada técnica de enteroanastomose término-terminal para tratamento da afecção em questão. Um segmento de aproximadamente 80 cm do intestino delgado foi ressectado. Radiografias contrastadas pós-operatórias realizadas ao redor do vigésimo dia de evolução cirúrgica evidenciaram o trânsito intestinal normal no sítio anastomosado. O ganho de peso demonstrado pelo animal e a ausência de qualquer alteração de origem gastrintestinal confirmaram o sucesso do tratamento instituído