NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific ...role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK−/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics. In line with this we found that NIK-deficient T cells were hampered in phosphorylation of Zap70, LAT, AKT, ERK1/2 and PLCγ upon TCR engagement. Hence, our data disclose a hitherto unknown function of NIK in T-cell priming and differentiation.
•NIK deficiency in T cells results in impaired generation of effector T-cells and subsequent resistance to EAE induction.•NIK is important for Treg development but not for their maintenance.•NIK is a posttranscriptional regulator in activated T cells.•NIK affects expression of proteins involved in the immunological synapse formation and F-actin dynamics.•NIK plays a crucial role in initial events of activated TCR signaling cascade.
Atomic-level defects in van der Waals (vdW) materials are essential building blocks for quantum technologies and quantum sensing applications. The layered magnetic semiconductor CrSBr is an ...outstanding candidate for exploring optically active defects because of a direct gap, in addition to a rich magnetic phase diagram, including a recently hypothesized defect-induced magnetic order at low temperature. Here, we show optically active defects in CrSBr that are probes of the local magnetic environment. We observe a spectrally narrow (1 meV) defect emission in CrSBr that is correlated with both the bulk magnetic order and an additional low-temperature, defect-induced magnetic order. We elucidate the origin of this magnetic order in the context of local and nonlocal exchange coupling effects. Our work establishes vdW magnets like CrSBr as an exceptional platform to optically study defects that are correlated with the magnetic lattice. We anticipate that controlled defect creation allows for tailor-made complex magnetic textures and phases with direct optical access.
We implement a multi-color laser engine with silicon nitride photonic integrated circuit technology, that combines four fluorophore excitation wavelengths (405 nm, 488 nm, 561 nm, 640 nm) and splits ...them with variable attenuation among two output fibers used for different microscope imaging modalities. With the help of photonic integrated circuit technology, the volume of the multi-color laser engine's optics is reduced by two orders of magnitude compared to its commercially available discrete optics counterpart. Light multiplexing is implemented by means of a directional coupler based device and variable optical attenuation as well as fiber switching with thermally actuated Mach-Zehnder interferometers. Total insertion losses from lasers to output fibers are in the order of 6 dB at 488 nm, 561 nm, and 640 nm. Higher insertion losses at 405 nm can be further improved on. In addition to the system level results, spectrally resolved performance has been characterized for each of the developed devices.
Abstract
Die Flüssigkeitsmaldistribution in Füllkörperschüttungen wird experimentell in einer Ø1,2‐m‐Kolonne unter Variation der Versuchs‐ und Betriebsparameter – Füllkörper, Packungshöhe, ...Flüssigkeitsverteiler, Berieselungsdichte und Gasbelastung – untersucht. Eingesetzt werden Füllkörper vom Typ Raflux Ring 35‐5 und 50‐5 Metall, RVT Metall Sattel Ring 70‐5 und Hiflow® Ring 50‐6 Kunststoff. Die grafische Darstellung in Form von Verteilspektren und die weiterführende Auswertung anhand eines Maldistributionsfaktors geben Aufschluss über den Einfluss der verschiedenen Parameter auf die Maldistribution.
Abstract
Investigations on liquid maldistribution in random packings are conducted in a Ø1.2 m packed column at varying experimental and operating parameters – type of packing, packing height, liquid distributor, liquid load, and gas load. Used types of packing are metal Raflux‐Rings 35‐5 and 50‐5, RVT Metal Saddle Rings 70‐5 and plastic Hiflow®‐Rings 50‐6. Graphical presentation in form of distribution spectra and further evaluation by means of a maldistribution factor provide insight into the influence of different parameters on maldistribution.
Seroconversion rates after COVID-19 vaccination are significantly lower in kidney transplant recipients compared to healthy cohorts. Adaptive immunization strategies are needed to protect these ...patients from COVID-19. In this prospective observational cohort study, we enrolled 76 kidney transplant recipients with no seroresponse after at least three COVID-19 vaccinations to receive an additional mRNA-1273 vaccination (full dose, 100 μg). Mycophenolic acid was withdrawn in 43 selected patients 5–7 days prior to vaccination and remained paused for 4 additional weeks after vaccination. SARS-CoV-2-specific antibodies and neutralization of the delta and omicron variants were determined using a live-virus assay 4 weeks after vaccination. In patients with temporary mycophenolic acid withdrawal, donor-specific anti-HLA antibodies and donor-derived cell-free DNA were monitored before withdrawal and at follow-up. SARS-CoV-2 specific antibodies significantly increased in kidney transplant recipients after additional COVID-19 vaccination. The effect was most pronounced in individuals in whom mycophenolic acid was withdrawn during vaccination. Higher SARS-CoV-2 specific antibody titers were associated with better neutralization of SARS-CoV-2 delta and omicron variants. In patients with short-term withdrawal of mycophenolic acid, graft function and donor-derived cell-free DNA remained stable. No acute rejection episode occurred during short-term follow-up. However, resurgence of prior anti-HLA donor-specific antibodies was detected in 7 patients.
Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs ...such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity.
We performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 95% CI 2.12-9.23; p (trend)<0.001; p (corrected) = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies.
Our results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.
Seroconversion rates following infection and vaccination are lower in dialysis patients compared to healthy controls. There is an urgent need for the characterization of humoral responses and success ...of a single-dose SARS-CoV-2 vaccination in previously infected dialysis patients. We performed a dual-center cohort study comparing three different groups: 25 unvaccinated hemodialysis patients after PCR-confirmed COVID-19 (Group 1), 43 hemodialysis patients after two-time BNT162b2 vaccination without prior SARS-CoV-2 infection (Group 2), and 13 single-dose vaccinated hemodialysis patients with prior SARS-CoV-2 infection (Group 3). Group 3 consists of seven patients from Group 1 and 6 additional patients with sera only available after single-dose vaccination. Anti-S1 IgG, neutralizing antibodies, and antibodies against various SARS-CoV-2 protein epitopes were measured 3 weeks after the first and 3 weeks after the second vaccination in patients without prior SARS-CoV-2 infection, 6 weeks after the onset of COVID-19 in unvaccinated patients, and 3 weeks after single-dose vaccination in patients with prior SARS-CoV-2 infection, respectively. Unvaccinated patients after COVID-19 showed a significantly higher neutralizing antibody capacity than two-time vaccinated patients without prior COVID-19 median (IQR) percent inhibition 88.0 (71.5-95.5) vs. 50.7 (26.4-81.0);
= 0.018. After one single vaccine dose, previously infected individuals generated 15- to 34-fold higher levels of anti-S1 IgG than age- and dialysis vintage-matched unvaccinated patients after infection or two-time vaccinated patients without prior SARS-CoV-2 infection with a median (IQR) index of 274 (151-791) compared to 18 (8-41) and 8 (1-21) (for both
< 0.001). With a median (IQR) percent inhibition of 97.6 (97.2-98.9), the neutralizing capacity of SARS-CoV-2 antibodies was significantly higher in single-dose vaccinated patients with prior SARS-CoV-2 infection compared to other groups (for both
< 0.01). Bead-based analysis showed high antibody reactivity against various SARS-CoV-2 spike protein epitopes after single-dose vaccination in previously infected patients. In conclusion, single-dose vaccination in previously infected dialysis patients induced a strong and broad antibody reactivity against various SARS-CoV-2 spike protein epitopes with high neutralizing capacity.
Loss given default in SME leasing Kaposty, Florian; Klein, Philipp; Löderbusch, Matthias ...
Review of managerial science,
07/2022, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Leasing provides a fundamental source of firm funding, especially for small and medium-sized enterprises. A crucial difference from loans and bonds is that the lessor retains ownership rights of the ...leased asset during the lease term. This facilitates the asset utilization and work-out process and leads to higher liquidation proceeds. Hence, previous findings on the loan and bond loss given default (LGD) are not transferable to the leasing industry. Our analysis is based on a very granular data set covering a great variety of information on the lessee, the leased asset, as well as contractual and transactional characteristics. We examine novel LGD determinants such as an external credit rating, the lessee's limited liability, and the number of leased assets and collaterals. Moreover, new results on previously explored factors question earlier findings, for example, on the lease contract type. Most importantly, as proposed by Miller and Töws (J Bank Finance 91:189–201, 2018), we analyze two different LGDs, one based on the asset utilization proceeds, the other on repayments. Our results clearly indicate the crucial importance of this separation when analyzing the drivers of the leasing LGD in detail because several determinants affect these LGDs in different ways. Our study assists both lessors and regulators in assessing the effective risk of lease contracts and enables lessors to enhance their risk management and work-out processes.
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