Sensitization Pathways in NIR-Emitting Yb(III) Complexes Bearing 0, +1, +2, or +3 Charges.

Yb(III) complexes of macrocyclic ligands based on 1,4,7,10-tetraazacyclododecane were synthesized. The ligands carried a carbostyril chromophore for Yb(III) sensitization, and carboxylate or carbamide donors for metal binding, forming complexes of 0, +1, +2, or +3 overall charge. The coordination geometry was little affected by the replacement of carboxylates with amides, as shown by paramagnetic 1H NMR spectroscopy. The Yb(III)/Yb(II) reduction potentials were dependent on the nature of the metal binding site, and the more positively charged complexes were easier to reduce. Carbostyril excitation resulted in Yb(III) luminescence in every complex. The residual carbostyril fluorescence quantum yields were smaller in complexes containing more reducible Yb(III) centers decreasing from 5.9% for uncharged complexes to 3.1-4.4% in +3 charged species, suggesting photoinduced electron transfer (PeT) from the antenna to the Yb(III). The relative Yb(III) luminescence quantum yields were identical within the experimental error, except for the +3 charged complex with fully methylated coordinating amides, which was the most intense Yb(III) emitter of the series in water. Quenching of the Yb(III) excited state by NH vibrations proved to limit Yb(III) emission. No clear improvement of the Yb(III) sensitization efficiency was shown upon faster PeT. This result can be explained by the concomitant sensitization of Yb(III) by phonon-assisted energy transfer (PAEnT) from the antenna triplet excited state, which was completely quenched in all of the Yb complexes. Depopulation of the triplet by PeT quenching of the donor singlet excited state would be compensated by the sensitizing nature of the PeT pathway, thus resulting in a constant overall sensitization efficiency across the series.

In Situ Rolling Circle Amplification Förster Resonance Energy Transfer (RCA-FRET) for Washing-Free Real-Time Single-Protein Imaging.

Fluorescence signal enhancement via isothermal nucleic acid amplification is an important approach for sensitive imaging of intra- or extracellular nucleic acid or protein biomarkers. Rolling circle amplification (RCA) is frequently applied for fluorescence in situ imaging but faces limitations concerning multiplexing, dynamic range, and the required multiple washing steps before imaging. Here, we show that Förster resonance energy transfer (FRET) between fluorescent dyes and between lanthanide (Ln) complexes and dyes that hybridize to ß-actin-specific RCA products in HaCaT cells can afford washing-free imaging of single ß-actin proteins. Proximity-dependent FRET could be monitored directly after or during (real-time monitoring) dye or Ln DNA probe incubation and could efficiently distinguish between photoluminescence from ß-actin-specific RCA and DNA probes freely diffusing in solution or nonspecifically attached to cells. Moreover, time-gated FRET imaging with the Ln-dye FRET pairs efficiently suppressed sample autofluorescence and improved the signal-to-background ratio. Our results present an important proof of concept of RCA-FRET imaging with a strong potential to advance in situ RCA toward easier sample preparation, higher-order multiplexing, autofluorescence-free detection, and increased dynamic range by real-time monitoring of in situ RCA.

Screening for the presence of scleroedema adultorum of Buschke in patients with diabetes mellitus: newly diagnosed patients had a high prevalence of dyslipidaemia.

BACKGROUND: Scleroedema adultorum of Buschke is a rare disorder characterized by fibromucinous thickening of the dermis that manifests mainly at the nape of the neck and on the upper back and shoulders. This study screened patients with diabetes mellitus for skin hardening caused by scleroedema adultorum of Buschke and characterized the clinical and laboratory findings in patients with newly identified cases, with a focus on lipid metabolism abnormalities and vascular complications. METHODS: Out of 113 consecutive patients with diabetes, 11 (9.7%) new scleroedema patients, all with type 2 diabetes, were found. Their clinical and laboratory data were compared to those of the rest of the screened patients and to those of a cohort of 15 patients with scleroedema and diabetes who were already being treated in a tertiary clinical centre at the University of Pécs. RESULTS: Higher proportions of patients with dyslipidaemia, hypertriglyceridemia (P < 0.05) and increased mean levels of non-high-density lipoprotein cholesterol (non-HDL-C) were found (P < 0.01) in both scleroedema groups than in the group without scleroedema. Stroke and venous thromboembolism (VTE) were more frequently found in the histories of both the newly identified scleroedema group (each 3/11; 27.3%) and the treated cohort (each 6/15; 40.0%) than in the group without scleroedema (6/102; 5.9% in cases of stroke P = 0.021, P < 0.001; and 14/102; 13.7%; P < 0.05 in cases of VTE, respectively). Based on binary logistic regression, a high non-HDL-C level (odds ratio (OD): 3.338, confidence interval (CI): 1.77-6.28; P < 0.001) and insulin treatment (OR 7.64, CI 1.9-29.3; P = 0.003) were independent predictors of scleroedema in patients with diabetes mellitus. CONCLUSIONS: Diabetes patients with scleroedema had more severe dyslipidaemia and higher occurrence of vascular complications compared to those without scleroedema. In addition to poorly controlled type 2 diabetes mellitus requiring insulin treatment, high non-HDL-C levels may be another contributing factor to the development of scleroedema. TRIAL REGISTRATION: NCT04335396 .

Coordination Environment-Controlled Photoinduced Electron Transfer Quenching in Luminescent Europium Complexes.

The quenching of sensitized Eu(III) luminescence by photoinduced electron transfer from the excited light-harvesting antenna to Eu(III) was investigated. A series of complexes incorporating different metal binding sites and thus having varying Eu(III)/Eu(II) reduction potentials were prepared. The complexes were fully characterized using a combination of single-crystal X-ray crystallography and paramagnetic 1H NMR spectroscopy, the results of which support the structural similarity of the complexes. The redox and photophysical behavior of the Eu(III) center and the light-harvesting antenna were studied using cyclic voltammetry and steady-state and time-resolved emission spectroscopy on the nanosecond and millisecond time scales. The contribution of photoinduced electron transfer to the overall reduction of the Eu(III) luminescence quantum yield was found to be comparable and, in many cases, larger than the quenching caused by well-established processes such as coupling to X-H oscillators. These results suggest that the elimination or mitigation of photoinduced electron transfer could substantially improve the emissive properties of the widely used Eu(III)-based emitters.

Obstructive sleep apnea and hypertriglyceridaemia share common genetic background: Results of a twin study.

Obstructive sleep apnea is associated with an increased risk of hypertension, diabetes and dyslipidaemia. Both obstructive sleep apnea and its comorbidities are at least partly heritable, suggesting a common genetic background. Our aim was to analyse the heritability of the relationship between obstructive sleep apnea and its comorbidities using a twin study. Forty-seven monozygotic and 22 dizygotic adult twin pairs recruited from the Hungarian Twin Registry (mean age 51 ± 15 years) attended an overnight diagnostic sleep study. A medical history was taken, blood pressure was measured, and blood samples were taken for fasting glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and lipoprotein (a). To evaluate the heritability of obstructive sleep apnea and its comorbidities bivariate analysis was performed with an adjustment for age, gender, body mass index (BMI) and smoking after false discovery rate correction and following exclusion of patients on lipid-lowering and antidiabetic medications. There was a significant correlation between indices of obstructive sleep apnea severity, such as the apnea-hypopnea index, oxygen desaturation index and percentage of sleep time spent with oxygen saturation below 90%, as well as blood pressure, serum triglyceride, lipoprotein (a) and glucose levels (all p < .05). The bivariate analysis revealed a common genetic background for the correlations between serum triglyceride and the oxygen desaturation index (r = .63, p = .03), as well as percentage of sleep time spent with oxygen saturation below 90% (r = .58, p = .03). None of the other correlations were significantly genetically or environmentally determined. This twin study demonstrates that the co-occurrence of obstructive sleep apnea with hypertriglyceridaemia has a genetic influence and heritable factors play an important role in the pathogenesis of dyslipidaemia in obstructive sleep apnea.

Eu(III) and Tb(III) Complexes of Octa- and Nonadentate Macrocyclic Ligands Carrying Azide, Alkyne, and Ester Reactive Groups.

Azide- and alkyne-functionalized bioconjugable luminescent lanthanide complexes are reported. Reactive handles were introduced into the complexes by the late-stage modification of a methylenecarboxylic acid antenna pendent group. Tb and Eu quantum yields (11-13% and 3.4-3.6%, respectively) were not greatly affected by the presence of the azide or the alkyne compared to the parent complex (ΦTb = 10%, ΦEu = 2.8%). Two avenues were explored for improving the luminescence of the lanthanide (Ln) complexes: (1) attaching the antenna through a tertiary amide linker and (2) replacing a monodentate carboxylate ligand with a bidentate pyridylcarboxylate donor, which yielded a nonadentate ligand that could saturate the lanthanide coordination sphere and eliminate the quenching metal-bound water molecule that was present in the octadentate complexes. The combination of both approaches yielded Eu and Tb emitters with 5.8% and 46% quantum yields. For the Eu complex, this value was the same as ΦEu in the octadentate parent complex. We attribute this to increased photoinduced electron transfer quenching in the nonadentate species, which compensates for the reduced O-H quenching.

Fast optical method for characterizing plasmonic nanoparticle adhesion on functionalized surfaces.

In this paper, a rapid optical method for characterizing plasmonic (gold) nanoparticle (AuNP) adhesion is presented. Two different methods were used for AuNP preparation: the well-known Turkevich method resulted in particles with negative surface charge; for preparing AuNPs with positive surface charge, stainless steel was used as reducing agent. The solid surface for adhesion was provided by a column packed with pristine or surface-modified glass beads. The size of the nanoparticles was studied by transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS); the surface charge of the components was determined by streaming potential measurements. The characterization of adhesion was performed in a flow system by UV-Vis spectroscopy. During the adhesion experiments, the role of the surface charge, the particle size, and the pH were studied, as well as the adhered amount of gold nanoparticles and the surface coverage values. The latter was estimated by theoretical calculations and defined by the quotient of the measured and the maximal adhered amount of nanoparticles, which could be determined by the cross-sectional area of the NPs and the specific surface area of the glass beads. The results are verified by the polarization reflectometric interference spectroscopy (PRIfS) method: silica nanoparticles with diameters of a few hundred (d~450) nanometers were immobilized on the surface of glass substrate by the Langmuir-Blodgett method, the surface was modified similar to the 3D (continuous flow packed column) system, and gold nanoparticles from different pH solutions were adhered during the measurements. These kinds of modified surfaces allow the investigation of biomolecule adsorption in the same reflectometric setup. Graphical abstract.

The human ABCB6 protein is the functional homologue of HMT-1 proteins mediating cadmium detoxification.

ABCB6 belongs to the family of ATP-binding cassette (ABC) transporters, which transport various molecules across extra- and intra-cellular membranes, bearing significant impact on human disease and pharmacology. Although mutations in the ABCB6 gene have been linked to a variety of pathophysiological conditions ranging from transfusion incompatibility to pigmentation defects, its precise cellular localization and function is not understood. In particular, the intracellular localization of ABCB6 has been a matter of debate, with conflicting reports suggesting mitochondrial or endolysosomal expression. ABCB6 shows significant sequence identity to HMT-1 (heavy metal tolerance factor 1) proteins, whose evolutionarily conserved role is to confer tolerance to heavy metals through the intracellular sequestration of metal complexes. Here, we show that the cadmium-sensitive phenotype of Schizosaccharomyces pombe and Caenorhabditis elegans strains defective for HMT-1 is rescued by the human ABCB6 protein. Overexpression of ABCB6 conferred tolerance to cadmium and As(III) (As2O3), but not to As(V) (Na2HAsO4), Sb(V), Hg(II), or Zn(II). Inactivating mutations of ABCB6 abolished vacuolar sequestration of cadmium, effectively suppressing the cadmium tolerance phenotype. Modulation of ABCB6 expression levels in human glioblastoma cells resulted in a concomitant change in cadmium sensitivity. Our findings reveal ABCB6 as a functional homologue of the HMT-1 proteins, linking endolysosomal ABCB6 to the highly conserved mechanism of intracellular cadmium detoxification.

Lanthanide(III) Complexes of Cyclen Triacetates and Triamides Bearing Tertiary Amide-Linked Antennae.

The coordination compounds of the trivalent lanthanide ions (Ln(III)) have unique photophysical properties. Ln(III) excitation is usually performed through a light-harvesting antenna. To enable Ln(III)-based emitters to reach their full potential, an understanding of how complex structure affects sensitization and quenching processes is necessary. Here, the role of the linker between the antenna and the metal binding fragment was studied. Four macrocyclic ligands carrying coumarin 2 or 4-methoxymethylcarbostyril sensitizing antennae linked to an octadentate macrocyclic ligand binding site were synthesized. Complexation with Ln(III) (Ln = La, Sm, Eu, Gd, Tb, Yb and Lu) yielded species with overall -1, 0, or +2 and +3-charge. Paramagnetic 1H NMR spectroscopy indicated subtle differences between the coumarin- and carbostyril-carrying Eu(III) and Yb(III) complexes. Cyclic voltammetry showed that the effect of the linker on the Eu(III)/Eu(II) apparent reduction potential was dependent on the electronic properties of the N-substituent. The Eu(III), Tb(III) and Sm(III) complexes were all luminescent. Coumarin-sensitized complexes were poorly emissive; photoinduced electron transfer was not a major quenching pathway in these species. These results show that seemingly similar emitters can undergo very different photophysical processes, and highlight the crucial role the linker can play.

Genetic influences on the onset of obstructive sleep apnoea and daytime sleepiness: a twin study.

BACKGROUND: Obstructive sleep apnoea (OSA) is one of the major sources of the excessive daily sleepiness, cognitive dysfunction, and it increases cardiovascular morbidity and mortality. Previous studies suggested a possible genetic influence, based on questionnaires but no objective genetic study was conducted to understand the exact variance underpinned by genetic factors. METHODS: Seventy-one Hungarian twin pairs involved from the Hungarian Twin Registry (48 monozygotic, MZ and 23 dizygotic, DZ pairs, mean age 51 ± 15 years) underwent overnight polysomnography (Somnoscreen Plus Tele PSG, Somnomedics GMBH, Germany). Apnoea hypopnea index (AHI), respiratory disturbance index (RDI) and oxygen desaturation index (ODI) were registered. Daytime sleepiness was measured with the Epworth Sleepiness Scale (ESS). Bivariate heritability analysis was applied. RESULTS: The prevalence of OSA was 41% in our study population. The heritability of the AHI, ODI and RDI ranged between 69% and 83%, while the OSA, defined by an AHI ≥5/h, was itself 73% heritable. The unshared environmental component explained the rest of the variance between 17% and 31%. Daytime sleepiness was mostly determined by the environment, and the variance was influenced in 34% by the additive genetic factors. These associations were present after additional adjustment for body mass index. CONCLUSION: OSA and the indices of OSA severity are heritable, while daytime sleepiness is mostly influenced by environmental factors. Further studies should elucidate whether close relatives of patients with OSA may benefit from early family risk based screening.