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Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To better understand the consequences on the cellular phenotype and pathophysiology of neurogenetic diseases associated with defective mitochondrial dynamics, we have compared the fibroblasts phenotypes of (i) patients carrying pathogenic variants in genes involved in mitochondrial dynamics such as DRP1 (also known as DNM1L), GDAP1, OPA1, and MFN2, and (ii) patients carrying mutated genes that their dysfunction affects mitochondria or induces a mitochondrial phenotype, but that are not directly involved in mitochondrial dynamic network, such as FXN (encoding frataxin, located in the mitochondrial matrix), MED13 (hyperfission phenotype), and CHKB (enlarged mitochondria phenotype). We identified mitochondrial network alterations in all patients' fibroblasts except for CHKBQ198*/Q198*. Functionally, all fibroblasts showed mitochondrial oxidative stress, without membrane potential abnormalities. The lysosomal area and distribution were abnormal in GDAP1(W67L/W67L), DRP1(K75E/+), OPA1(F570L/+), and FXNR165C/GAA fibroblasts. These lysosomal alterations correlated with mitochondria-lysosome membrane contact sites (MCSs) defects in GDAP1(W67L/W67L) exclusively. The study of mitochondrial contacts in all samples further revealed a significant decrease in MFN2(R104W/+) fibroblasts. GDAP1 and MFN2 are outer mitochondrial membrane (OMM) proteins and both are related to Charcot-Marie Tooth neuropathy. Here we identified their constitutive interaction as well as MFN2 interaction with LAMP-1. Therefore MFN2 is a new mitochondria-lysosome MCSs protein. Interestingly, GDAP1(W67L/W67L) and MFN2(R104W/+) fibroblasts carry pathogenic changes that occur in their catalytic domains thus suggesting a functional role of GDAP1 and MFN2 in mitochondria-lysosome MCSs. Finally, we observed starvation-induced autophagy alterations in DRP1(K75E/+), GDAP1(W67L/W67L), OPA1(F570L/+), MFN2(R104W/+), and CHKBQ198*/Q198* fibroblasts. These genes are related to mitochondrial membrane structure or lipid composition, which would associate the OMM with starvation-induced autophagy. In conclusion, the study of mitochondrial dynamics and mitochondria-lysosome axis in a group of patients with different neurogenetic diseases has deciphered common and unique cellular phenotypes of degrading and non-degrading pathways that shed light on pathophysiological events, new biomarkers and pharmacological targets for these disorders.

Mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT) neuropathy. GDAP1 is an atypical glutathione S-transferase (GST) of the outer mitochondrial membrane and the mitochondrial membrane contacts with the endoplasmic reticulum (MAMs). Here, we investigate the role of this GST in the autophagic flux and the membrane contact sites (MCSs) between mitochondria and lysosomes in the cellular pathophysiology of GDAP1 deficiency. We demonstrate that GDAP1 participates in basal autophagy and that its depletion affects LC3 and PI3P biology in autophagosome biogenesis and membrane trafficking from MAMs. GDAP1 also contributes to the maturation of lysosome by interacting with PYKfyve kinase, a pH-dependent master lysosomal regulator. GDAP1 deficiency causes giant lysosomes with hydrolytic activity, a delay in the autophagic lysosome reformation, and TFEB activation. Notably, we found that GDAP1 interacts with LAMP-1, which supports that GDAP1-LAMP-1 is a new tethering pair of mitochondria and lysosome membrane contacts. We observed mitochondria-lysosome MCSs in soma and axons of cultured mouse embryonic motor neurons and human neuroblastoma cells. GDAP1 deficiency reduces the MCSs between these organelles, causes mitochondrial network abnormalities, and decreases levels of cellular glutathione (GSH). The supply of GSH-MEE suffices to rescue the lysosome membranes and the defects of the mitochondrial network, but not the interorganelle MCSs nor early autophagic events. Overall, we show that GDAP1 enables the proper function of mitochondrial MCSs in both degradative and nondegradative pathways, which could explain primary insults in GDAP1-related CMT pathophysiology, and highlights new redox-sensitive targets in axonopathies where mitochondria and lysosomes are involved.

Voltage-controlled magnetism, where magnetic properties are controlled via an applied electricfield instead of current, could represent a significant increase in energy savings in future magnetically actuateddevices. Practically, however, this approach faces several important obstacles, such as thickness limitations inelectrically charged metallic films, mechanical failure in strain-mediated piezoelectric/magnetostrictive devices,and a lack of room-temperature multiferroics. Voltage-driven ionic motion (magneto-ionics) may provide a pathforward by avoiding many of these drawbacks, in addition to its own interesting magnetoelectric phenomena.Nevertheless, translating magneto-ionics into real world devices requires significant improvements in magneto-ionic rates, cyclability, and magnetization. Here, we report on the development of magneto-ionics in single-layer, semiconducting transition metal oxides and nitrides, and the subsequent enhancements in theirperformance. We first present electrolyte-gated and defect-mediated O transport in single-layer, paramagneticCo O at room temperature (i.e. without thermal assistance), which allows voltage-controlled magneticswitching (referred to here as ON-OFF ferromagnetism: Fig. 1) via internal reduction/oxidation processes .Negative bias partially reduces Co O to Co, resulting in films with Co- and O-rich areas (ferromagnetism: ON).Positive bias re-oxidizes Co back to Co O (paramagnetism: OFF). We show that the bias-induced motion of Ois caused by mixed vacancy clusters, with O motion promoted at grain boundaries and assisted by thedevelopment of O-rich diffusion channels. The generated ferromagnetism is shown to be stable, and easilyerased by sufficient positive bias. This voltage-induced process is demonstrated to be compositionally,structurally, and magnetically reversible and self-contained, as no oxygen reservoir besides Co O is needed.We then show that room-temperature magneto-ionic effects in electrolyte-gated paramagnetic Co O films canbe significantly increased, both in terms of generated magnetization (6 times larger) and speed (35 timesfaster), if the electric field is applied using an electrochemical capacitor configuration (utilizing an underlyingconducting buffer layer: Fig. 2) instead of electric-double-layer transistor-like configuration (placing the electriccontacts at the side of the semiconductor) . In addition to gains in speed, magnetization measurements showa marked increase in the squareness ratio and a decrease in the switching field distribution of the hysteresisloops in Co O biased in the capacitor configuration, the result of the formation of more uniform ferromagneticregions. These results are attributed to the uniform electric field applied throughout the film, as confirmed byCOMSOL simulations. As the measured films are quite thick, further miniaturization promises even greatermagneto-ionic rates. We then demonstrate room-temperature voltage-driven nitrogen magneto-ionics (i.e., Ntransport) by electrolyte-gating of a CoN film . Nitrogen magneto-ionics in CoN is compared to oxygenmagneto-ionics in Co O , in films using an electrochemical capacitor configuration. Both materials are shownto be nanocrystalline (face-centered cubic structure), and show reversible voltage-driven ON-OFFferromagnetism (Fig. 1). Nitrogen transport is found to occur uniformly throughout the film, creating a plane-wave-like migration front, without assistance of diffusion channels. Nitrogen magneto-ionics also requires lowerthreshold voltages and exhibits enhanced rates and cyclability, due to the combination of a lower criticalelectric field required to overcome the energy barrier for ion diffusion and the lower electronegativity of nitrogenwith respect to oxygen, consistent with ab initio calculations contrasting N vs. O motion in cobalt stacks. Theseresults place nitrogen magneto-ionics as a robust alternative for efficient voltage-driven effects and, along withoxygen magneto-ionics, may enable the use of magneto-ionics in devices that require endurance and moderate speeds of operation, such as brain-inspired/stochastic computing or magnetic micro-electro-mechanical systems. References: [1] A. Quintana, E. Menéndez, M. O. Liedke et al., ACS Nano, Vol. 12, p. 10291 (2018) [2] J. de Rojas, A. Quintana, A. Lopeandía et al., Advanced Functional Materials, Vol. 30, p. 2003704 (2020) [3] J. de Rojas, A. Quintana, A. Lopeandía et al., Nature Communications, Vol. 11, p. 5871 (2020) KEYWORDS: magneto-ionics, voltage-controlled magnetism, oxygen, nitrogen. IMAGE CAPTION: Fig. 1. Hysteresis loops (M vs. H) of as-prepared, negatively-biased, and positively-biased CoN films atmagneto-ionic activation voltages. Fig. 2. A schematic of the electrochemical capacitor configuration used to bias cobalt-oxide (Co O ) andcobalt-nitride (CoN) films.

Charcot-Marie-Tooth (CMT) disease is a neuropathy that lacks effective therapy. CMT patients show degeneration of peripheral nerves, leading to muscle weakness and loss of proprioception. Loss of mitochondrial oxidative phosphorylation proteins and enzymes of the antioxidant response accompany degeneration of nerves in skin biopsies of CMT patients. Herein, we followed a drug-repurposing approach to find drugs in a Food and Drug Administration-approved library that could prevent development of CMT disease in the Gdap1-null mouse model. We found that the antibiotic florfenicol is a mitochondrial uncoupler that prevents the production of reactive oxygen species and activates respiration in human GDAP1-knockdown neuroblastoma cells and in dorsal root ganglion neurons of Gdap1-null mice. Treatment of CMT-affected Gdap1-null mice with florfenicol has no beneficial effect in the course of the disease. However, administration of florfenicol, or the antioxidant MitoQ, to pre-symptomatic GDAP1-null mice prevented weight gain and ameliorated the motor coordination deficiencies that developed in the Gdap1-null mice. Interestingly, both florfenicol and MitoQ halted the decay in mitochondrial and redox proteins in sciatic nerves of Gdap1-null mice, supporting that oxidative damage is implicated in the etiology of the neuropathy. These findings support the development of clinical trials for translation of these drugs for treatment of CMT patients.

Introducción y objetivos La cistectomía radical con derivación urinaria asociada a linfadenectomía pélvica ampliada continúa siendo el tratamiento de elección en el cáncer vesical musculoinvasivo. Un 64% de los pacientes presentan complicaciones postoperatorias, siendo la infección urinaria responsable en un 20-40% de los casos. El objetivo del presente proyecto es valorar la tasa de infección urinaria como causa de reingreso tras cistectomía, e identificar factores protectores y predisponentes de infección urinaria en nuestro medio. Por último, conocer los resultados obtenidos al aplicar el protocolo de profilaxis antibiótica tras la retirada de los catéteres ureterales. Material y métodos Estudio descriptivo retrospectivo de pacientes cistectomizados en el Servicio de Urología del Hospital Clínico Universitario desde enero de 2012 hasta diciembre de 2018. Desde octubre de 2017, de forma estandarizada, a todo paciente se le aplica un protocolo de prevención de infección del tracto urinario (ITU) tras la retirada de catéteres. Resultados La ITU es responsable del 54, 7% de los reingresos, siendo un 55, 1% de estos por causa de una ITU tras la retirada de los catéteres ureterales. El 9, 5% de los pacientes con profilaxis presenta ITU tras la retirada, frente a un 10, 6% en el grupo de pacientes sin profilaxis. El paciente que reingresa por ITU tras la retirada tiene un tiempo de catéteres medio de 24, 3 ± 7, 2 días, frente a los 24, 5 ± 7, 4 días en el grupo sin ITU (p = 0, 847). Conclusiones El tipo de derivación urinaria empleada no guarda relación con la tasa de infección urinaria. El modelo de regresión no identifica la profilaxis antibiótica, ni tampoco el tiempo de catéteres, como factores independientes de ITU tras la retirada de los catéteres. Introduction and objectives: Radical cystectomy with urinary diversion associated with extended pelvic lymphadenectomy continues to be the treatment of choice in muscle invasive bladder cancer. Sixty-four percent of patients submitted to this procedure present postoperative complications, with urinary infection being responsible in 20-40% of cases. The aim of this project is to assess the rate of urinary infection as a cause of re-admission after cystectomy, and to identify protective and predisposing factors for urinary infection in our environment. Finally, we will evaluate the outcomes after the establishment of a prophylactic antibiotic protocol after removal of ureteral catheters. Material and methods: Retrospective descriptive study of cystectomized patients in the Urology Service of the Hospital Clínico Universitario of Zaragoza, from January 2012 to December 2018. A urinary tract infection (UTI) prevention protocol after catheter removal is established for all patients since October 2017. Results: UTI is responsible for 54.7% of readmissions, with 55.1% of these being due to UTI after removal of ureteral catheters. Of the patients who received with prophylaxis, 9.5% presented UTIs after withdrawal, compared to 10.6% in the group of patients without prophylaxis. The patient who is re-admitted for UTI after withdrawal has a mean catheter time of 24.3 ± 7.2 days, compared to 24.5 ± 7.4 days for patients in the group without UTI (P =.847). Conclusions: The type of urinary diversion performed is not related to the rate of urinary infection. The regression model does not identify antibiotic prophylaxis, nor catheter time, as independent factors of UTI after catheter removal.

Magneto‐ionics, understood as voltage‐driven ion transport in magnetic materials, has largely relied on controlled migration of oxygen ions. Here, we demonstrate room‐temperature voltagedriven nitrogen transport (i.e., nitrogen magneto‐ionics) by electrolyte‐gating of a CoN film. Nitrogen magneto‐ionics in CoN is compared to oxygen magneto‐ionics in Co3O4. Both materials are nanocrystalline (face‐centered‐cubic structure) and show reversible voltage‐driven ON‐OFF ferromagnetism. In contrast to oxygen, nitrogen transport occurs uniformly creating a plane‐wavelike migration front, without assistance of diffusion channels. Remarkably, nitrogen magnetoionics requires lower threshold voltages and exhibits enhanced rates and cyclability. This is due to the lower activation energy for ion diffusion and the lower electronegativity of nitrogen compared to oxygen. These results may open new avenues in applications such as brain‐inspired computing or iontronics in general.

In August 2009, Typhoon Morakot caused a record-breaking rainfall in Taiwan. The heavy rainfall triggered thousands of landslides, in particular in the central-southern part of the island. Large landslides can block rivers and can lead to the formation of landslide-dammed lakes. Cascading hazards like floods and debris flows after landslide dam breaches pose a high risk for people and infrastructure downstream. Thus, better knowledge about landslides that significantly impact the channel system and about the resulting landslide-dammed lakes are key elements for assessing the direct and indirect hazards caused by the moving mass. The main objectives of this study are 1) to develop an object-based image analysis (OBIA) approach for semi-automated detection of landslides that caused the formation of landslide-dammed lakes and 2) to monitor the evolution of landslide-dammed lakes based on Landsat imagery. For landslide and lake mapping, primarily spectral indices and contextual information were used. By integrating morphological and hydrological parameters derived from a digital elevation model (DEM) into the OBIA framework, we automatically identified landslide-dammed lakes, and the landslides that likely caused the formation of those lakes, due to the input of large amounts of debris into the channel system. The proposed approach can be adapted to other remote sensing platforms and can be used to monitor the evolution of landslide-dammed lakes and triggering landslides at regional scale after typhoon and heavy rainstorm events within an efficient time range after suitable remote sensing data has been provided. (VLID)4590414

Very rare polymorphisms in the human VRK1 (vaccinia-related kinase 1) gene have been identified in complex neuromotor phenotypes associated to spinal muscular atrophy (SMA), pontocerebellar hypoplasia (PCH), microcephaly, amyotrophic lateral sclerosis (ALS) and distal motor neuron dysfunctions. The mechanisms by which these VRK1 variant proteins contribute to the pathogenesis of these neurological syndromes are unknown. The syndromes are manifested when both of these rare VRK1 polymorphic alleles are implicated, either in homozygosis or compound heterozygosis. In this report, to identify the common underlying pathogenic mechanism of VRK1 polymorphisms, we have studied all human VRK1 variants identified in these neurological phenotypes from a biochemical point of view by molecular modeling, protein stability and kinase activity assays. Molecular modelling predicted that VRK1 variant proteins are either unstable or have an altered kinase activity. The stability and kinase activity of VRK1 pathogenic variants detected two groups. One composed by variants with a reduced protein stability: R133C, R358X, L195V, G135R and R321C. The other group includes VRK1variants with a reduced kinase activity tested on several substrates: histones H3 and H2AX, p53, c-Jun, coilin and 53BP1, a DNA repair protein. VRK1 variants with reduced kinase activity are H119R, R133C, G135R, V236M, R321C and R358X. The common underlying effect of VRK1 pathogenic variants with reduced protein stability or kinase activity is a functional insufficiency of VRK1 in patients with neuromotor developmental syndromes. The G135 variant cause a defective formation of 53BP1 foci in response to DNA damage, and loss Cajal bodies assembled on coilin.

On July 7, 2018, a large landslide occurred at the eastern slope of the Fagraskógarfjall Mountain in Hítardalur valley in West Iceland. The landslide dammed the river, led to the formation of a lake and, consequently, to a change in the river course. The main focus of this research is to develop a knowledge-based expert system using an object-based image analysis (OBIA) approach for identifying morphology changes caused by the Hítardalur landslide. We use synthetic aperture radar (SAR) and optical remote sensing data, in particular from Sentinel-1/2 for detection of the landslide and its effects on the river system. We extracted and classified the landslide area, the landslide-dammed lake, other lakes and the river course using intensity information from S1 and spectral information from S2 in the object-based framework. Future research will focus on further developing this approach to support mapping and monitoring of the spatio-temporal dynamics of surface morphology in an object-based framework by combining SAR and optical data. The results can reveal details on the applicability of different remote sensing data for the spatio-temporal investigation of landslides, landslide-induced river course changes and lake formation and lead to a better understanding of the impact of large landslides on river systems. (VLID)4590381