RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.

TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.

Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis.

Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact of TTBK1 inhibition in diseases like Alzheimer's disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 knockout in iPSCs, confirming a role for TTBK2 in ciliogenesis.

In Situ Spectroelectrochemical-Conductance Measurements as an Efficient Tool for the Evaluation of Charge Trapping in Conducting Polymers.

In situ UV-vis-NIR spectroelectrochemistry has been intensively used to evaluate the electronic transitions during the charging/discharging process of π-conjugated polymers. However, the type of charge carrier and the mechanisms of their transport, remains still a point of discussion. Herein, the coupling between UV-vis-NIR spectroscopy and in situ electrochemical-conductance measurements is proposed to compare the doping process of three different thiophene-based conducting polymers. The simultaneous monitoring of electrical and absorption properties, associated with low energy electronic transitions characteristic for polarons and bipolarons, was achieved. In addition, this method allows evaluating the reversible charge trapping mechanism of poly-3,4-o-xylendioxythiophene (PXDOT), caused by the formation of σ-dimers, making it a very useful tool to determine relevant physicochemical properties of conductive materials.

Generation of an induced pluripotent stem cell line (UNCCi002-A) from a healthy donor using a non-integration system to study Cerebral Cavernous Malformation (CCM).

The generation of induced pluripotent stem cells (iPSCs) from healthy individuals is an invaluable resource as reference control in disease modeling and drug discovery. This paper details the reprogramming of peripheral blood mononuclear cells (PBMCs) isolated from a healthy 27 years-old male using non-integration technology. The derived iPSCs displayed typical pluripotent stem cell morphology, the capacity to differentiate into the three germ layers, and normal karyotype. This iPSC line will be used as a reference control to study the Cerebral Cavernous Malformation disease mechanism.

Organic Electrochemical Transistors (OECTs) Toward Flexible and Wearable Bioelectronics.

Organic electronics have emerged as a fascinating area of research and technology in the past two decades and are anticipated to replace classic inorganic semiconductors in many applications. Research on organic light-emitting diodes, organic photovoltaics, and organic thin-film transistors is already in an advanced stage, and the derived devices are commercially available. A more recent case is the organic electrochemical transistors (OECTs), whose core component is a conductive polymer in contact with ions and solvent molecules of an electrolyte, thus allowing it to simultaneously regulate electron and ion transport. OECTs are very effective in ion-to-electron transduction and sensor signal amplification. The use of synthetically tunable, biocompatible, and depositable organic materials in OECTs makes them specially interesting for biological applications and printable devices. In this review, we provide an overview of the history of OECTs, their physical characterization, and their operation mechanism. We analyze OECT performance improvements obtained by geometry design and active material selection (i.e., conductive polymers and small molecules) and conclude with their broad range of applications from biological sensors to wearable devices.

Design of Potassium-Selective Mixed Ion/Electron Conducting Polymers.

An approach providing cation-selective poly-(3,4-ethylenedioxythiophene)(PEDOT):polyelectrolyte-mixed conductors is presented in this communication based on the structural modification of this ambivalent (ionic and electronic conductive) polymer complex. First, an 18-crown-6 moiety is integrated into the styrene sulfonate monomer structure as a specific metal cation scavenger particularly targeting K+ versus Na+ detection. This newly functionalized monomer is characterized by 1 H NMR titration to evaluate the ion selectivity. Aqueous PEDOT dispersion inks containing the polymeric ion-selective moieties are designed and their electrical and electrochemical properties analyzed. These biocompatible inks are the first proof-of-concept step towards ion selectivity in view of their interfacing with biological cells and microorgans of interest in the field of biosensors and physiology.

Systemic Lupus Erythematosus and Its Association with Hemophagocytic Syndrome as an Initial Manifestation.

Introduction: Hemophagocytic syndrome (HS) is a potentially fatal hyperinflammatory condition characterized by excessive activation of macrophages and T cells. Systemic lupus erythematosus (SLE) is an autoimmune condition that predisposes to HS. The appearance of SLE and HS is rare. Clinical case: A 16-year-old male presented with fever for one month and lymphadenopathy prior to admission. During evaluation, the patient accumulated 10 points required by EULAR/ACR 2019 for classifying the condition as SLE. Hemophagocytosis was observed in the bone marrow aspirate. The diagnosis of HS secondary to SLE was concluded. Under treatment with intravenous methylprednisolone and mycophenolic acid, symptoms improved and the patient was subsequently discharged. Discussion: The most typical findings of HS include fever, hepatosplenomegaly, and cytopenias, with lymphadenopathy being the least common. The characteristics of SLE and HS are very similar, making it difficult to differentiate between these two entities. Conclusion: Although HS is not one of the frequent manifestations of SLE, a high suspicion of its possible association with SLE must be maintained for timely treatment.

Synthesis of Carboxyl-EDOT as a Versatile Addition and Additive to PEDOT:PSS.

Two-step synthesis of EDOT (3,4-ethylenedioxythiophene) derivate bearing a carboxylic acid group (carboxyl-EDOT) is presented. This reactive monomer has been copolymerized with EDOT to afford PEDOT copolymers. Thanks to the most common additives usually added to the PEDOT:PSS dispersion, ethylene glycol and 4-dodecylbenzenesulfonic acid (DBSA), the carboxylic acid has been used to cross-link the material via esterification reactions. This result offers the possibility to produce a polymer network without adding any cross-linking agent. Furthermore, the short synthetic pathway of carboxyl-EDOT offers the possibility to incorporate new functionality either in EDOT monomer or in PEDOT materials with a reasonable chemical effort and background.

Simultaneous monitoring of single cell and of micro-organ activity by PEDOT:PSS covered multi-electrode arrays.

Continuous and long-term monitoring of cellular and micro-organ activity is required for new insights into physiology and novel technologies such as Organs-on-Chip. Moreover, recent advances in stem cell technology and especially in the field of diabetes call for non-invasive approaches in quality testing of the large quantities of surrogate pancreatic islets to be generated. Electrical activity of such a micro-organ results in single cell action potentials (APs) of high frequency and in low frequency changes in local field potentials (slow potentials or SPs), reflecting coupled cell activity and overall organ physiology. Each of them is indicative of different physiological stages in islet activation. Action potentials in islets are of small amplitude and very difficult to detect. The use of PEDOT:PSS to coat metal electrodes is expected to reduce noise and results in a frequency-dependent change in impedance, as shown here. Whereas detection of high-frequency APs improves, low frequency SPs are less well detected which is, however, an acceptable trade off in view of the strong amplitude of SPs. Using a dedicated software, recorded APs and SPs can be automatically diagnosed and analyzed. Concomitant capture of the two signals will considerably increase the diagnostic power of monitoring islets and islet surrogates in fundamental research as well as drug screening or the use of islets as biosensors.

Tratamiento con rituximab para la trombocitopenia secundaria a lupus eritematoso sistémico / Treatment with rituximab for thrombocytopenia due to systemic lupus erythematosus

En algunos casos la trombocitopenia secundaria a lupus eritematoso sistémico (LES) no responde al tratamiento convencional. En los últimos años se ha reportado que el rituximab es una alternativa para estos pacientes. Objetivo Evaluar la respuesta de la trombocitopenia (T) secundaria a LES con el uso de rituximab y determinar el tiempo que se mantiene el efecto libre de recaída. Material y métodos Se revisaron los expedientes de los pacientes con diagnóstico de LES con T que recibieron tratamiento con rituximab (2g) para conocer la proporción de pacientes que lograron remisión completa (RC): definida como una cuenta plaquetaria >100.000/mm3; remisión parcial (RP): cuenta plaquetaria entre 50.000 y 100.000/mm3 y los no respondedores (NR); así como el tiempo que se mantiene el paciente sin recaída. Resultados Se aplicaron 16 tratamientos en 13 pacientes, en una paciente 3 y en otra 2 ciclos. Fueron 12 mujeres y 1 hombre con edad media de 28±9 años y tiempo medio de duración del LES de 68±44 meses, con una cuenta media plaquetaria de 38.000±29.000. En 14 tratamientos (87%) se logró RC después de 5±2 semanas y 2 pacientes (12.5%) fueron NR. Una de ellas murió por hemorragia masiva. El tiempo medio de respuesta sin recaída fue de 15,6±6 meses. Tres pacientes perdieron el seguimiento y 3 murieron de infecciones. Conclusiones El rituximab es una alternativa de tratamiento en pacientes con T secundaria a LES (AU)

Some patients with thrombocytopenia due SLE fail to respond to conventional therapies. Rituximab has been reported to be an alternative for patient treatment. Objective To evaluate the response of thrombocytopenia due to Systemic Lupus Erythematosus to the use of Rituximab and patient relapse time at our hospital. Patients and methods We analyzed patients with SLE than received a 2 gram rituximab treatment for thrombocytopenia. We analyzed the rate of patients that achieved complete remission (CR), defined as a platelet count over 100mil/mm3, partial remission (PR) described as platelets within 50–100mil/mm3 and no response (NR) if platelets remained unchanged and the time the remission was sustained.Results16 treatments were applied to 13 patients, aged 28±9 years of age and SLE mean duration time of 68±44 months with a mean platelet count of 38±29mil. In 14 treatments (87%) remission was achieved after 5±2 weeks where 2 patients (12.5%) were non respondent. One of them died due to a massive hemorrhage. The mean response time without relapse was 15.6±6 months. Follow up of three patients was not possible and 3 other died due to infections. Conclusions Rituximab is an alternative for treatment of thrombocytopenia due to Systemic Lupus Erythematosus (AU)

[Treatment with rituximab for thrombocytopenia due to systemic lupus erythematosus]. / Tratamiento con rituximab para la trombocitopenia secundaria a lupus eritematoso sistémico.

UNLABELLED: Some patients with thrombocytopenia due SLE fail to respond to conventional therapies. Rituximab has been reported to be an alternative for patient treatment. OBJECTIVE: To evaluate the response of thrombocytopenia due to Systemic Lupus Erythematosus to the use of Rituximab and patient relapse time at our hospital. PATIENTS AND METHODS: We analyzed patients with SLE than received a 2 gram rituximab treatment for thrombocytopenia. We analyzed the rate of patients that achieved complete remission (CR), defined as a platelet count over 100mil/mm(3), partial remission (PR) described as platelets within 50-100mil/mm(3) and no response (NR) if platelets remained unchanged and the time the remission was sustained. RESULTS: 16 treatments were applied to 13 patients, aged 28±9 years of age and SLE mean duration time of 68±44 months with a mean platelet count of 38±29mil. In 14 treatments (87%) remission was achieved after 5±2 weeks where 2 patients (12.5%) were non respondent. One of them died due to a massive hemorrhage. The mean response time without relapse was 15.6±6 months. Follow up of three patients was not possible and 3 other died due to infections. CONCLUSIONS: Rituximab is an alternative for treatment of thrombocytopenia due to Systemic Lupus Erythematosus.