Metal-Organic Bichromophore Lowers the Upconversion Excitation Power Threshold and Promotes UV Photoreactions.

Sensitized triplet-triplet annihilation upconversion is a promising strategy to use visible light for chemical reactions requiring the energy input of UV photons. This strategy avoids unsafe ultraviolet light sources and can mitigate photo-damage and provide access to reactions, for which filter effects hamper direct UV excitation. Here, we report a new approach to make blue-to-UV upconversion more amenable to photochemical applications. The tethering of a naphthalene unit to a cyclometalated iridium(III) complex yields a bichromophore with a high triplet energy (2.68 eV) and a naphthalene-based triplet reservoir featuring a lifetime of 72.1 µs, roughly a factor of 20 longer than the photoactive excited state of the parent iridium(III) complex. In combination with three different annihilators, consistently lower thresholds for the blue-to-UV upconversion to crossover from a quadratic into a linear excitation power dependence regime were observed with the bichromophore compared to the parent iridium(III) complex. The upconversion system composed of the bichromophore and the 2,5-diphenyloxazole annihilator is sufficiently robust under long-term blue irradiation to continuously provide a high-energy singlet-excited state that can drive chemical reactions normally requiring UV light. Both photoredox and energy transfer catalyses were feasible using this concept, including the reductive N-O bond cleavage of Weinreb amides, a C-C coupling reaction based on reductive aryl debromination, and two Paternò-Büchi [2 + 2] cycloaddition reactions. Our work seems relevant in the context of developing new strategies for driving energetically demanding photochemistry with low-energy input light.

A hard pill to swallow? Parental health shocks and children's mental health.

Based on comprehensive administrative health record data from Austria, this study examines how children's mental health responds to a severe parental health shock. To account for the endogeneity of a serious parental illness, our sample is restricted to children who experience the health shock of a parent at some point in time and we exploit the timing of shocks in a dynamic DID setting. We find a positive causal effect of parental health shocks on children's mental health care utilization. Affected children have higher medical attendance for the treatment of mental illnesses, consume more psychotropic drugs, and are more likely to be hospitalized with mental and behavioral disorders. A significant increase in the utilization of antidepressants, anxiolytics, and sedatives can be observed for older children, girls and children with a white-collar family background. Our findings have important policy implications for children's access to psychotherapies and mental health care after experiencing a traumatic household event.

Shedding Light on the Oxidizing Properties of Spin-Flip Excited States in a CrIII Polypyridine Complex and Their Use in Photoredox Catalysis.

The photoredox activity of well-known RuII complexes stems from metal-to-ligand charge transfer (MLCT) excited states, in which a ligand-based electron can initiate chemical reductions and a metal-centered hole can trigger oxidations. CrIII polypyridines show similar photoredox properties, although they have fundamentally different electronic structures. Their photoactive excited state is of spin-flip nature, differing from the electronic ground state merely by a change of one electron spin, but with otherwise identical d-orbital occupancy. We find that the driving-force dependence for photoinduced electron transfer from 10 different donors to a spin-flip excited state of a CrIII complex is very similar to that for a RuII polypyridine, and thereby validate the concept of estimating the redox potential of d3 spin-flip excited states in analogous manner as for the MLCT states of d6 compounds. Building on this insight, we use our CrIII complex for photocatalytic reactions not previously explored with this compound class, including the aerobic bromination of methoxyaryls, oxygenation of 1,1,2,2-tetraphenylethylene, aerobic hydroxylation of arylboronic acids, and the vinylation of N-phenyl pyrrolidine. This work contributes to understanding the fundamental photochemical properties of first-row transition-metal complexes in comparison to well-explored precious-metal-based photocatalysts.

High Triplet Energy Iridium(III) Isocyanoborato Complex for Photochemical Upconversion, Photoredox and Energy Transfer Catalysis.

Cyclometalated Ir(III) complexes are often chosen as catalysts for challenging photoredox and triplet-triplet-energy-transfer (TTET) catalyzed reactions, and they are of interest for upconversion into the ultraviolet spectral range. However, the triplet energies of commonly employed Ir(III) photosensitizers are typically limited to values around 2.5-2.75 eV. Here, we report on a new Ir(III) luminophore, with an unusually high triplet energy near 3.0 eV owing to the modification of a previously reported Ir(III) complex with isocyanoborato ligands. Compared to a nonborylated cyanido precursor complex, the introduction of B(C6F5)3 units in the second coordination sphere results in substantially improved photophysical properties, in particular a high luminescence quantum yield (0.87) and a long excited-state lifetime (13.0 µs), in addition to the high triplet energy. These favorable properties (including good long-term photostability) facilitate exceptionally challenging organic triplet photoreactions and (sensitized) triplet-triplet annihilation upconversion to a fluorescent singlet excited state beyond 4 eV, unusually deep in the ultraviolet region. The new Ir(III) complex photocatalyzes a sigmatropic shift and [2 + 2] cycloaddition reactions that are unattainable with common transition metal-based photosensitizers. In the presence of a sacrificial electron donor, it furthermore is applicable to demanding photoreductions, including dehalogenations, detosylations, and the degradation of a lignin model substrate. Our study demonstrates how rational ligand design of transition-metal complexes (including underexplored second coordination sphere effects) can be used to enhance their photophysical properties and thereby broaden their application potential in solar energy conversion and synthetic photochemistry.

Severe disease exacerbation after mRNA COVID-19 vaccination unmasks suspected multiple sclerosis as neuromyelitis optica spectrum disorder: a case report.

BACKGROUND: Since the beginning of the COVID-19 pandemic and development of new vaccines, the issue of post-vaccination exacerbation or manifestation of demyelinating central nervous system (CNS) disorders has gained increasing attention. CASE PRESENTATION: We present a case of a 68-year-old woman previously diagnosed with multiple sclerosis (MS) since the 1980s who suffered a rapidly progressive severe sensorimotor paraparesis with loss of bladder and bowel control due to an acute longitudinal extensive transverse myelitis (LETM) after immunization with the mRNA Pfizer-BioNTech COVID-19 vaccine. Detection of Aquaporin-4-antibodies (AQP4) in both serum and CSF led to diagnosis of AQP4-antibody positive neuromyelitis optica spectrum disorder (NMOSD). Treatment with intravenous corticosteroids and plasmapheresis led to a slight improvement of the patient's symptoms. CONCLUSIONS: Pathogenic mechanisms of post-vaccination occurrence of NMOSD are still unknown. However, cases like this should make aware of rare neurological disorders manifesting after vaccination and potentially contribute to improvement of management of vaccinating patients with inflammatory CNS disorders in the future. So far two cases of AQP4-antibody positive NMOSD have been reported in association with viral vector COVID-19 vaccines. To our knowledge, we report the first case of AQP4-antibody positive NMOSD after immunization with an mRNA COVID-19-vaccine.

Aryl dechlorination and defluorination with an organic super-photoreductant.

Direct excitation of the commercially available super-electron donor tetrakis(dimethylamino)ethylene (TDAE) with light-emitting diodes at 440 or 390 nm provides a stoichiometric reductant that is able to reduce aryl chlorides and fluorides. The method is very simple and requires only TDAE, substrate, and solvent at room temperature. The photoactive excited state of TDAE has a lifetime of 17.3 ns in cyclohexane at room temperature and an oxidation potential of ca.-3.4 V vs. SCE. This makes TDAE one of the strongest photoreductants able to operate on the basis of single excitation with visible photons. Direct substrate activation occurs in benzene, but acetone is reduced by photoexcited TDAE and substrate reduction takes place by a previously unexplored solvent radical anion mechanism. Our work shows that solvent can have a leveling effect on the photochemically available redox power, reminiscent of the pH-leveling effect that solvent has in acid-base chemistry.

Multi-Photon Excitation in Photoredox Catalysis: Concepts, Applications, Methods.

The energy of visible photons and the accessible redox potentials of common photocatalysts set thermodynamic limits to photochemical reactions that can be driven by traditional visible-light irradiation. UV excitation can be damaging and induce side reactions, hence visible or even near-IR light is usually preferable. Thus, photochemistry currently faces two divergent challenges, namely the desire to perform ever more thermodynamically demanding reactions with increasingly lower photon energies. The pooling of two low-energy photons can address both challenges simultaneously, and whilst multi-photon spectroscopy is well established, synthetic photoredox chemistry has only recently started to exploit multi-photon processes on the preparative scale. Herein, we have a critical look at currently developed reactions and mechanistic concepts, discuss pertinent experimental methods, and provide an outlook into possible future developments of this rapidly emerging area.

Long-Lived, Strongly Emissive, and Highly Reducing Excited States in Mo(0) Complexes with Chelating Isocyanides.

Newly discovered tris(diisocyanide)molybdenum(0) complexes are Earth-abundant isoelectronic analogues of the well-known class of [Ru(α-diimine)3]2+ compounds with long-lived 3MLCT (metal-to-ligand charge transfer) excited states that lead to rich photophysics and photochemistry. Depending on ligand design, luminescence quantum yields up to 0.20 and microsecond excited state lifetimes are achieved in solution at room temperature, both significantly better than those for [Ru(2,2'-bipyridine)3]2+. The excited Mo(0) complexes can induce chemical reactions that are thermodynamically too demanding for common precious metal-based photosensitizers, including the widely employed fac-[Ir(2-phenylpyridine)3] complex, as demonstrated on a series of light-driven aryl-aryl coupling reactions. The most robust Mo(0) complex exhibits stable photoluminescence and remains photoactive after continuous irradiation exceeding 2 months. Our comprehensive optical spectroscopic and photochemical study shows that Mo(0) complexes with diisocyanide chelate ligands constitute a new family of luminophores and photosensitizers, which is complementary to precious metal-based 4d6 and 5d6 complexes and represents an alternative to nonemissive Fe(II) compounds. This is relevant in the greater context of sustainable photophysics and photochemistry, as well as for possible applications in lighting, sensing, and catalysis.

Coulomb interactions for mediator-enhanced sensitized triplet-triplet annihilation upconversion in solution.

Sensitized triplet-triplet annihilation upconversion offers an attractive possibility to replace a high-energy photon by two photons with lower energy through the combination of a light-harvesting triplet sensitizer and an annihilator for the formation of a fluorescent singlet state. Typically, high annihilator concentrations are required to achieve an efficient initial energy transfer and as a direct consequence the most highly energetic emission is often not detectable due to intrinsic reabsorption by the annihilator itself. Herein, we demonstrate that the addition of a charge-adapted mediator drastically improves the energy transfer efficiency at low annihilator concentrations via an energy transfer cascade. Inspired by molecular dyads and recent developments in nanocrystal-sensitized upconversion, our system exploits a concept to minimize intrinsic filter effects, while boosting the upconversion quantum yield in solution. A sensitizer-annihilator combination consisting of a ruthenium-based complex and 9,10-diphenylanthracene (DPA) is explored as model system and a sulfonated pyrene serves as mediator. The impact of opposite charges between sensitizer and mediator - to induce coulombic attraction and subsequently result in accelerated energy transfer rate constants - is analyzed in detail by different spectroscopic methods. Ion pairing and the resulting static energy transfer in both directions is a minor process, resulting in an improved overall performance. Finally, the more intense upconverted emission in the presence of the mediator is used to drive two catalytic photoreactions in a two-chamber setup, illustrating the advantages of our approach, in particular for photoreactions requiring oxygen that would interfere with the upconversion system.

Red Light-Based Dual Photoredox Strategy Resembling the Z-Scheme of Natural Photosynthesis.

Photoredox catalysis typically relies on the use of single chromophores, whereas strategies, in which two different light absorbers are combined, are rare. In photosystems I and II of green plants, the two separate chromophores P680 and P700 both absorb light independently of one another, and then their excitation energy is combined in the so-called Z-scheme, to drive an overall reaction that is thermodynamically very demanding. Here, we adapt this concept to perform photoredox reactions on organic substrates with the combined energy input of two red photons instead of blue or UV light. Specifically, a CuI bis(α-diimine) complex in combination with in situ formed 9,10-dicyanoanthracenyl radical anion in the presence of excess diisopropylethylamine catalyzes ca. 50 dehalogenation and detosylation reactions. This dual photoredox approach seems useful because red light is less damaging and has a greater penetration depth than blue or UV radiation. UV-vis transient absorption spectroscopy reveals that the subtle change in solvent from acetonitrile to acetone induces a changeover in the reaction mechanism, involving either a dominant photoinduced electron transfer or a dominant triplet-triplet energy transfer pathway. Our study illustrates the mechanistic complexity in systems operating under multiphotonic excitation conditions, and it provides insights into how the competition between desirable and unwanted reaction steps can become more controllable.

Sensitizer-controlled photochemical reactivity via upconversion of red light.

By combining the energy input from two red photons, chemical reactions that would normally require blue or ultraviolet irradiation become accessible. Key advantages of this biphotonic excitation strategy are that red light usually penetrates deeper into complex reaction mixtures and causes less photo-damage than direct illumination in the blue or ultraviolet. Here, we demonstrate that the primary light-absorber of a dual photocatalytic system comprised of a transition metal-based photosensitizer and an organic co-catalyst can completely alter the reaction outcome. Photochemical reductions are achieved with a copper(i) complex in the presence of a sacrificial electron donor, whereas oxidative substrate activation occurs with an osmium(ii) photosensitizer. Based on time-resolved laser spectroscopy, this changeover in photochemical reactivity is due to different underlying biphotonic mechanisms. Following triplet energy transfer from the osmium(ii) photosensitizer to 9,10-dicyanoanthracene (DCA) and subsequent triplet-triplet annihilation upconversion, the fluorescent singlet excited state of DCA triggers oxidative substrate activation, which initiates the cis to trans isomerization of an olefin, a [2 + 2] cycloaddition, an aryl ether to ester rearrangement, and a Newman-Kwart rearrangement. This oxidative substrate activation stands in contrast to the reactivity with a copper(i) photosensitizer, where photoinduced electron transfer generates the DCA radical anion, which upon further excitation triggers reductive dehalogenations and detosylations. Our study provides the proof-of-concept for controlling the outcome of a red-light driven biphotonic reaction by altering the photosensitizer, and this seems relevant in the greater context of tailoring photochemical reactivities.

Sensitization-initiated electron transfer via upconversion: mechanism and photocatalytic applications.

Sensitization-initiated electron transfer (SenI-ET) describes a recently discovered photoredox strategy that relies on two consecutive light absorption events, triggering a sequence of energy and electron transfer steps. The cumulative energy input from two visible photons gives access to thermodynamically demanding reactions, which would be unattainable by single excitation with visible light. For this reason, SenI-ET has become a very useful strategy in synthetic photochemistry, but the mechanism has been difficult to clarify due to its complexity. We demonstrate that SenI-ET can operate via sensitized triplet-triplet annihilation upconversion, and we provide the first direct spectroscopic evidence for the catalytically active species. In our system comprised of fac-[Ir(ppy)3] as a light absorber, 2,7-di-tert-butylpyrene as an annihilator, and N,N-dimethylaniline as a sacrificial reductant, all photochemical reaction steps proceed with remarkable rates and efficiencies, and this system is furthermore suitable for photocatalytic aryl dehalogenations, pinacol couplings and detosylation reactions. The insights presented here are relevant for the further rational development of photoredox processes based on multi-photon excitation, and they could have important implications in the greater contexts of synthetic photochemistry and solar energy conversion.

KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549).

Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyrosine kinase inhibitors (TKIs), but patients develop inevitably a resistance against these drugs. On the other hand, KCa3.1 channels contribute to NSCLC progression so that elevated KCa3.1 expression is a strong predictor of poor NSCLC patient prognosis. The present study tests whether blocking KCa3.1 channels increases the sensitivity of NSCLC cells towards the EGFR TKI erlotinib and overcomes drug resistance. mRNA expression of KCa3.1 channels in erlotinib-sensitive and -resistant NSCLC cells was analysed in datasets from Gene expression omnibus (GEO) and ArrayExpress. We assessed proliferation and migration of NSCLC cells. These (live cell-imaging) experiments were complemented by patch clamp experiments and Western blot analyses. We identified three out of four datasets comparing erlotinib-sensitive and -resistant NSCLC cells which revealed an altered expression of KCa3.1 mRNA in erlotinib-resistant NSCLC cells. Therefore, we evaluated the combined effect of erlotinib and the KCa3.1 channel inhibition with sencapoc. Erlotinib elicits a dose-dependent inhibition of migration and proliferation of NSCLC cells. The simultaneous application of the KCa3.1 channel blocker senicapoc increases the sensitivity towards a low dose of erlotinib (300 nmol/L) which by itself has no effect on migration and proliferation. Partial erlotinib resistance can be overcome by KCa3.1 channel blockade. The sensitivity towards erlotinib as well as the potentiating effect of KCa3.1 blockade is further increased by mimicking hypoxia. Our results suggest that KCa3.1 channel blockade may constitute a therapeutic concept for treating NSCLC and overcome EGFR TKI resistance. We propose that this is due to complementary mechanisms of action of both blockers.

Case Report: A Spinal Ischemic Lesion in a 24-Year-Old Patient With Fabry Disease.

Background: While cerebral lesions are common in Fabry disease (FD), spinal lesions have not been described, and their presence was suggested to be indicative of multiple sclerosis. Here, we present a FD patient with histopathological confirmed spinal ischemic stroke. Case presentation: A patient with genetically and biochemically diagnosed FD and characteristic manifestations (acroparesthesia, angiokeratomas, hypohidrosis, microalbuminuria, myocardial hypertrophy) presented with paraplegia, loss of all sensory modalities below Th9, and loss of bowel and bladder function. While cranial MRI was inconspicuous, spinal MRI showed a T2 hyperintense, non-contrast-enhancing lesion of the thoracic spinal cord. Lumbar puncture revealed mild pleocytosis, increased total protein and lactate levels, decreased glucose ratio, and negative oligoclonal bands. Rheumatic, neoplastic, and infectious disorders were excluded. The patient received intravenous and intrathecal methylprednisolone, plasmapheresis, intravenous immunoglobulins, and cyclophosphamide without clinical improvement. A biopsy of the thoracic lesion was performed. A histopathological examination revealed necrotic tissue consistent with spinal cord ischemia. Diagnostic work-up for stroke etiology clarification was not conspicuous. Two years onward, the patient suffered from a pontine infarction and a transient ischemic attack. Conclusion: The current case highlights the possible occurrence of spinal ischemic lesions in FD. Thus, the diagnosis of FD should not be prematurely discarded in the presence of spinal lesions.

KCa3.1 channel inhibition leads to an ICAM-1 dependent increase of cell-cell adhesion between A549 lung cancer and HMEC-1 endothelial cells.

Early metastasis leads to poor prognosis of lung cancer patients, whose 5-year survival rate is only 15%. We could recently show that the Ca2+ sensitive K+ channel KCa3.1 promotes aggressive behavior of non-small cell lung cancer (NSCLC) cells and that it can serve as a prognostic marker in NSCLC. Since NSCLC patients die of metastases, we investigated whether KCa3.1 channels contribute to poor patient prognosis by regulating distinct steps of the metastatic cascade. We investigated the extravasation of NSCLC cells and focused on their adhesion to endothelial cells and on transendothelial migration. We quantified the adhesion forces between NSCLC cells and endothelial cells by applying single cell force spectroscopy, and we monitored transendothelial migration using live-cell imaging. Inhibition of KCa3.1 channels with senicapoc or KCa3.1 silencing increases the adhesion force of A549 lung cancer cells to human microvascular endothelial cells (HMEC-1). Western blotting, immunofluorescence staining and biotinylation assays indicate that the elevated adhesion force is due to increased expression of ICAM-1 in both cell lines when KCa3.1 channels are downregulated. Consistent with this interpretation, an anti-ICAM-1 blocking antibody abolishes the KCa3.1-dependent increase in adhesion. Senicapoc inhibits transendothelial migration of A549 cells by 50%. Selectively silencing KCa3.1 channels in either NSCLC or endothelial cells reveals that transendothelial migration depends predominantly on endothelial KCa3.1 channels. In conclusion, our findings disclose a novel function of KCa3.1 channels in cancer. KCa3.1 channels regulate ICAM-1 dependent cell-cell adhesion between endothelial and cancer cells that affects the transmigration step of the metastatic cascade.

Early intestinal changes following abdominal radiotherapy comparison of endpoints.

PURPOSE: To compare tests for intestinal function with clinical scores after abdominal irradiation. PATIENTS AND METHODS: At the Department of Radiotherapy, Erfurt, Germany, intestinal changes were studied in 91 patients receiving abdominal radiotherapy between 1992 and 1996. Conventional fractionation (1.8-2 Gy per fraction, total doses 30.6-62.5 Gy) was applied. Before and at weekly intervals during radiotherapy, the clinical response was scored according to RTOG/EORTC for the upper and lower gastrointestinal (GI) tract. Resorption tests for vitamin B(12) and D-xylose were performed before the onset and immediately after treatment. RESULTS: The clinical response displayed a well-defined dose-effect relationship with grade 1 effects in 5% and 50% of the patients at about 10 Gy and 50 Gy, respectively. For grade 2 reactions, 5%- and 50%-effective doses were 20-30 Gy and 60-80 Gy. Effects in the upper and lower GI tract were highly correlated. Changes in body weight did not show a correlation with other clinical symptoms. Changes in resorption also displayed a significant dose effect. However, no correlation was found with the clinical symptoms in the individual patient. CONCLUSION: In the present study, the clinical manifestation of intestinal side effects according to RTOG/EORTC criteria was reflected by neither the vitamin B(12) nor by the D-xylose resorption test. Hence, these tests cannot be regarded as useful for objective quantitation of intestinal radiation injury.