Progress Report on pH-Influenced Photocatalysis for Active Motion

Living systems use catalysis to achieve chemical transformations to comply with their needs in terms of energy and building blocks. The pH is a powerful means to regulate such processes, which also influences synthetic systems. In fact, the pH sensitivity of artificial photocatalysts, such as bismuth vanadate, bears the strong potential of flexibly influencing both the motion pattern and the speed of catalytic microswimmers, but it has rarely been investigated to date. In this work, we first present a comprehensive view of the motion behavior of differently shaped bismuth vanadate microswimmers, discuss influences, such as shape, pH, and conductivity of the solutions, and find that the motion pattern of the swimmers switches between upright and horizontal at their point of zero charge. We then apply an immobilizable hydroxypyrene derivative to our substrates to locally influence the pH of the solution by excited-state proton transfer. We find that the motion pattern of our swimmers is strongly influenced by this functionalization and a third motion mode, called tumbling, is introduced. Taking other effects, such as an increased surface roughness of the modified substrates, into account, we critically discuss possible future developments

A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents

Systemic absorption and metabolism of drugs in the small intestine, metabolism by the liver as well as excretion by the kidney are key determinants of efficacy and safety for therapeutic candidates. However, these systemic responses of applied substances lack in most in vitro assays. In this study, a microphysiological system maintaining the functionality of four organs over 28 days in co-culture has been established at a minute but standardized microsystem scale. Preformed human intestine and skin models have been integrated into the four-organ-chip on standard cell culture inserts at a size 100000-fold smaller than their human counterpart organs. A 3D-based spheroid, equivalent to ten liver lobules, mimics liver function. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. A peristaltic on-chip micropump ensures pulsatile media flow interconnecting the four tissue culture compartments through microfluidic channels. A second microfluidic circuit ensures drainage of the fluid excreted through the kidney epithelial cell layer. This four-organ-chip system assures near to physiological fluid-to-tissue ratios. In-depth metabolic and gene analysis revealed the establishment of reproducible homeostasis among the co-cultures within two to four days, sustainable over at least 28 days independent of the individual human cell line or tissue donor background used for each organ equivalent. Lastly, 3D imaging two-photon microscopy visualised details of spatiotemporal segregation of the two microfluidic flows by proximal tubule epithelia. To our knowledge, this study is the first approach to establish a system for in vitro microfluidic ADME profiling and repeated dose systemic toxicity testing of drug candidates over 28 days.BMBF, 0315569, GO-Bio 3: Multi-Organ-Bioreaktoren für die prädiktive Substanztestung im Chipforma

Consequences of GMPPB deficiency for neuromuscular development and maintenance

Guanosine diphosphate-mannose pyrophosphorylase B (GMPPB) catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, which is required as a mannose donor for the biosynthesis of glycan structures necessary for proper cellular functions. Mutations in GMPPB have been associated with various neuromuscular disorders such as muscular dystrophy and myasthenic syndromes. Here, we report that GMPPB protein abundance increases during brain and skeletal muscle development, which is accompanied by an increase in overall protein mannosylation. To model the human disorder in mice, we generated heterozygous GMPPB KO mice using CIRSPR/Cas9. While we were able to obtain homozygous KO mice from heterozygous matings at the blastocyst stage, homozygous KO embryos were absent beyond embryonic day E8.5, suggesting that the homozygous loss of GMPPB results in early embryonic lethality. Since patients with GMPPB loss-of-function manifest with neuromuscular disorders, we investigated the role of GMPPB in vitro. Thereby, we found that the siRNA-mediated knockdown of Gmppb in either primary myoblasts or the myoblast cell line C2C12 impaired myoblast differentiation and resulted in myotube degeneration. siRNA-mediated knockdown of Gmppb also impaired the neuron-like differentiation of N2A cells. Taken together, our data highlight the essential role of GMPPB during development and differentiation, especially in myogenic and neuronal cell types

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Progress Report on pH-Influenced Photocatalysis for Active Motion

Living systems use catalysis to achieve chemical transformations to comply with their needs in terms of energy and building blocks. The pH is a powerful means to regulate such processes, which also influences synthetic systems. In fact, the pH sensitivity of artificial photocatalysts, such as bismuth vanadate, bears the strong potential of flexibly influencing both the motion pattern and the speed of catalytic microswimmers, but it has rarely been investigated to date. In this work, we first present a comprehensive view of the motion behavior of differently shaped bismuth vanadate microswimmers, discuss influences, such as shape, pH, and conductivity of the solutions, and find that the motion pattern of the swimmers switches between upright and horizontal at their point of zero charge. We then apply an immobilizable hydroxypyrene derivative to our substrates to locally influence the pH of the solution by excited-state proton transfer. We find that the motion pattern of our swimmers is strongly influenced by this functionalization and a third motion mode, called tumbling, is introduced. Taking other effects, such as an increased surface roughness of the modified substrates, into account, we critically discuss possible future developments

Open-label study of the efficacy and safety of intravenous ferric carboxymaltose in pregnant women with restless legs syndrome

OBJECTIVE: The objective of this study was to test the efficacy and safety of intravenous ferric carboxymaltose (FCM) in pregnant women with restless legs syndrome (RLS) and iron deficiency or anemia. The open-label pilot study (exploratory) was performed at the University Hospital of Zürich and the Neurocenter of Southern Switzerland (Lugano). PATIENT AND METHODS: Nineteen women in the third trimester of pregnancy with moderate-to-severe RLS and serum ferritin levels <35 µg/l or hemoglobin (Hb) < 11.0 g/dl were included in the study. RLS was graded according to the International Restless Legs Syndrome (IRLS) Study Group rating scale. All participants had a score of ≥20 or had RLS ≥3 times/week. Based on the Hb levels, 500 or 700 mg of FCM was administered over 20 min. The primary end point was a ≥ 50% reduction in the mean IRLS score one week after FCM infusion. The secondary end points included periodic limb movements (PLMs; assessed using nocturnal foot actigraphy), sleep quality (assessed using the Pittsburgh Sleep Quality Index), and safety. RESULTS: The IRLS score decreased from 23 ± 7 (baseline) to 13 ± 7 (P <0.01), whereas the PLM index decreased from 35 ± 26 (baseline) to 25 ± 20 (P <0.001). Significant improvement in sleep quality was also reported (P <0.029), and treatment was well tolerated. Three serious adverse events were reported, but they were considered unrelated to treatment. CONCLUSIONS: These data provide promising evidence on the safety and efficacy of FCM for moderate-to-severe RLS in pregnant women with iron deficiency or anemia. Therefore, a future placebo-controlled study is warranted

Differences in Clinical Presentations of Omicron Infections with the Lineages BA.2 and BA.5 in Mecklenburg-Western Pomerania, Germany, between April and July 2022

Knowledge on differences in the severity and symptoms of infections with the SARS-CoV-2 Omicron variants BA.2 (Pango lineage B.1.529.2) and BA.5 (Pango lineage B.1.529.5) is still scarce. We investigated epidemiological data available from the public health authorities in Mecklenburg-Western Pomerania, Northeast Germany, between April and July 2022 retrospectively. Comparative analyses revealed significant differences between recorded symptoms of BA.2 and BA.5 infected individuals and found strong correlations of associations between symptoms. In particular, the symptoms ‘chills or sweating’, ‘freeze’ and ‘runny nose’ were more frequently reported in BA.2 infections. In contrast, ‘other clinical symptoms’ appeared more frequently in Omicron infections with BA.5. However, the results obtained in this study provide no evidence that BA.5 has a higher pathogenicity or causes a more severe course of infection than BA.2. To our knowledge, this is the first report on clinical differences between the current Omicron variants BA.2 and BA.5 using public health data. Our study highlights the value of timely investigations of data collected by public health authorities to gather detailed information on the clinical presentation of different SARS-CoV-2 subvariants at an early stage

Simultaneous evaluation of anti-EGFR-induced tumour and adverse skin effects in a microfluidic human 3D co-culture model

Abstract Antibody therapies targeting the epithelial growth factor receptor (EGFR) are being increasingly applied in cancer therapy. However, increased tumour containment correlates proportionally with the severity of well-known adverse events in skin. The prediction of the latter is not currently possible in conventional in vitro systems and limited in existing laboratory animal models. Here we established a repeated dose “safficacy” test assay for the simultaneous generation of safety and efficacy data. Therefore, a commercially available multi-organ chip platform connecting two organ culture compartments was adapted for the microfluidic co-culture of human H292 lung cancer microtissues and human full-thickness skin equivalents. Repeated dose treatment of the anti-EGFR-antibody cetuximab showed an increased pro-apoptotic related gene expression in the tumour microtissues. Simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated, demonstrating crucial inhibitory effects on the physiological skin cell turnover. Furthermore, antibody exposure modulated the release of CXCL8 and CXCL10, reflecting the pattern changes seen in antibody-treated patients. The combination of a metastatic tumour environment with a miniaturized healthy organotypic human skin equivalent make this “safficacy” assay an ideal tool for evaluation of the therapeutic index of EGFR inhibitors and other promising oncology candidates