Dominant ACO2 mutations are a frequent cause of isolated optic atrophy.

Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells

Emerging Themes and Future Directions of Multi-Sector Nexus Research and Implementation

Water, energy, and food are all essential components of human societies. Collectively, their respective resource systems are interconnected in what is called the “nexus”. There is growing consensus that a holistic understanding of the interdependencies and trade-offs between these sectors and other related systems is critical to solving many of the global challenges they present. While nexus research has grown exponentially since 2011, there is no unified, overarching approach, and the implementation of concepts remains hampered by the lack of clear case studies. Here, we present the results of a collaborative thought exercise involving 75 scientists and summarize them into 10 key recommendations covering: the most critical nexus issues of today, emerging themes, and where future efforts should be directed. We conclude that a nexus community of practice to promote open communication among researchers, to maintain and share standardized datasets, and to develop applied case studies will facilitate transparent comparisons of models and encourage the adoption of nexus approaches in practice

Emerging Themes and Future Directions of Multi-Sector Nexus Research and Implementation

Water, energy, and food are all essential components of human societies. Collectively, their respective resource systems are interconnected in what is called the “nexus”. There is growing consensus that a holistic understanding of the interdependencies and trade-offs between these sectors and other related systems is critical to solving many of the global challenges they present. While nexus research has grown exponentially since 2011, there is no unified, overarching approach, and the implementation of concepts remains hampered by the lack of clear case studies. Here, we present the results of a collaborative thought exercise involving 75 scientists and summarize them into 10 key recommendations covering: the most critical nexus issues of today, emerging themes, and where future efforts should be directed. We conclude that a nexus community of practice to promote open communication among researchers, to maintain and share standardized datasets, and to develop applied case studies will facilitate transparent comparisons of models and encourage the adoption of nexus approaches in practice

Autofluorescence of lipofuscin and melanin in the retinal pigment epithelium in patients with hereditary retinal degeneration

GesamtdissertationBei 70 Patienten mit hereditären Netzhautdegenerationen (adulte vitelliforme Makuladystrophie (n=3), Morbus Best (2), Morbus Stargardt (14), Retinitis pigmentosa (31), Makuladystrophie (5), Zapfen-Stäbchendystrophie (12), Choroideremie (2), Malattia leventinese (1)) wurden Fundusautofluoreszenz (FAF) und Nah-Infrarot Autofluoreszenz (NIA) Images mit dem HRA 2 Scanning Laser Ophthalmoskop aufgenommen. FAF zeigt die Verteilung von Lipofuszin im retinalen Pigmentepithel, wohingegen NIA vorwiegend die Verteilung von Melanin zeigt, den beiden wichtigsten Fluorophoren des retinalen Pigmentepithels. Die Patienten-Images wurden mit Images von gesunden Normalpersonen verglichen. FAF und NIA Images wurden bezüglich der Intensität der Autofluoreszenz, der Läsiongröße und des Läsionsmusters verglichen. Bei allen 70 Patienten zeigten FAF und NIA Images pathologische Veränderungen verglichen mit den gesunden Probanden. FAF und NIA zeigten unterschiedliche Läsionsmuster. In 57,1% war die Läsionsgröße größer in der NIA verglichen mit der FAF, in 39,2 % zeigten die Läsionen die gleiche Größe und in 2 % waren die Läsionen kleiner. Bei Morbus Stargardt, Retinitis pigmentosa und Zapfen-Stäbchendystrophie konnten spezifische NIA Läsionsmuster in einen zentralen und einen peripheren Typ differenziert werden. Der Nachweis von Fehlen oder Vorhandensein von Melanin und Lipofuszin in verschiedenen Arealen des retinalen Pigmentepithels kann das Verständnis für die pathophysiologischen Veränderungen bei Netzhautdegenerationen verbessern.In 70 patients with hereditary retinal degenerations (adult vitelliform macular dystrophy (n=3), Best disease (2), Stargardt disease (14), retinitis pigmentosa (31), macular dystrophy (5), cone-rod dystrophy (12), choroideremia (2), Malattia leventinese (1)) fundus autofluorescence (FAF) and near infrared autofluorescence (NIA) images were obtained with the HRA 2 scanning laser ophthalmoscope. FAF shows the distribution of lipofuscin in the retinal pigment epithelium, whereas NIA shows predominantly the distribution of melanin, the two most important fluorophors of the retinal pigment epithelium. The patient s images were compared with images obtained from healthy subjects. FAF and NIA images were compared for intensity of autofluorescence, lesion size and lesion pattern. In all 70 cases FAF and NIA images showed pathological changes compared to the normal group. FAF and NIA changes showed different patterns. In 57.1% lesion size was larger in NIA compared to FAF, in 39.2 % lesions had the same size and in 2% lesions were smaller. In Stargardt disease, retinitis pigmentosa and cone-rod dystrophy specific NIA patterns for the disease could be divided in a central and more peripheral type. Showing the presence or absence of melanin and lipofuscin in the different areas of the retinal pigment epithelium can improve understanding of the pathophysiological changes in retina degenerations

Wide-field optical coherence tomography in ABCA4-associated inherited retinal dystrophies

Aim: With a need to expand the monitoring options in therapeutic clinical trials, we evaluated the additional information provided by wide-field optical coherence tomography (W-OCT) compared to conventional macular volume scan OCT (M-OCT) in ABCA4 gene-associated inherited retinal dystrophies (ABCA4-IRD).Methods: A consecutive series of 52 ABCA4-IRD patients (mean age at last examination: 35.9 years, range 8.8-68.7 years) was examined between 2015 and 2021. Ophthalmologic examination included clinical examination, M-OCT [20 × 20 degree field (6.2 mm × 6.2 mm)], W-OCT [55 × 25 degree field (16.1 mm × 7.3 mm)], multicolor reflectance photography, fundus (FAF), and near-infrared autofluorescence (NIA) in macular and wide-field mode. Molecular genetic testing to confirm the clinical phenotype was performed in all patients.Results: In 37/52 (71.2%) of patients W-OCT revealed alterations of the outer retinal layers beyond the area covered by M-OCT at their last examination. In 15 patients, lesions were located within the area covered by M-OCT. Lesions beyond M-OCT consisted of subretinal material (31/37), as well as patches (18/37) or large continuous areas (3/37) of photoreceptor and retinal pigment epithelial dystrophy. In one patient, W-OCT identified peripheral lesions that were not detectable in wide-field FAF and NIA. In 48/52 patients, two causative mutations in the ABCA4 gene were identified, while the remaining four patients carried one pathogenic ABCA4 variant.Conclusion: W-OCT as well as wide-field FAF and NIA document lesions in the retinal mid- and far periphery in the majority of ABCA4-IRD patients and provide means for detailed analysis of progression and future treatment planning and monitoring

Group VIA phospholipase A2 deficiency in mice chronically fed with high-fat-diet attenuates hepatic steatosis by correcting a defect of phospholipid remodeling

A defect of hepatic remodeling of phospholipids (PL) is seen in non-alcoholic fatty liver disease and steatohepatitis (NASH) indicating pivotal role of PL metabolism in this disease. The deletion of group VIA calcium independent phospholipase A2 (iPla2 beta) protects ob/ob mice from hepatic steatosis (BBAIip 1861, 2016, 440-461), however its role in high-fat diet (HFD)-induced NASH is still elusive. Here, wild-type and iPla2 beta-null mice were subjected to chronic feeding with HFD for 6 months. We showed that protection was observed in iPla2 beta-null mice with an attenuation of diet-induced body and liver-weight gains, liver enzymes, serum free fatty acids as well as hepatic TG and steatosis scores. iPla2 beta deficiency under HFD attenuated the levels of 1-stearoyl lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and lysophosphatidylinositol (LPI) as well as elevation of hepatic arachidonate, arachidonate-containing cholesterol esters and prostaglandin E-2. More importantly, this deficiency rescued a defect in PL remodeling and attenuated the ratio of saturated and unsaturated PL. The protection by iPla2 beta deficiency was not observed during short-term HFD feeding of 3 or 5 weeks which showed no PL remodeling defect. In addition to PC/PE, this deficiency reversed the suppression of PC/PI and PE/PI among monounsaturated PL. However, this deficiency did not modulate hepatic PL contents and PL ratios in ER fractions, ER stress, fibrosis, and inflammation markers. Hence, iPla2 beta inactivation protected mice against hepatic steatosis and obesity during chronic dietary NASH by correcting PL remodeling defect and PI composition relative to PC and PE

Biochemical and structural insights into Carbonic Anhydrase XII/Fab6A10 complex.

6A10 is a CA XII inhibitory monoclonal antibody, which was demonstrated to reduce the growth of cancer cells in vitro and in a xenograft model of lung cancer. It was also shown to enhance chemosensitivity of multiresistant cancer cell lines and to significantly reduce the number of lung metastases in combination with doxorubicin in mice carrying human triple-negative breast cancer xenografts. Starting from these data, we report here on the development of the 6A10 antigen-binding fragment (Fab), termed Fab6A10, and its functional, biochemical, and structural characterization. In vitro binding and inhibition assays demonstrated that Fab6A10 selectively binds and inhibits CA XII, whereas immunohistochemistry experiments highlighted its capability to stain malignant glioma cells in contrast to the surrounding brain tissue. Finally, the crystallographic structure of CA XII/Fab6A10 complex provided insights into the inhibition mechanism of Fab6A10, showing that upon binding, it obstructs the substrate access to the enzyme active site and interacts with CA XII His64 freezing it in its out conformation. Altogether, these data indicate Fab6A10 as a new promising therapeutic tool against cancer