CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology.

Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind low-complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remain unclear. Here, we used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA "bait" oligonucleotides restore poly-GR-associated ribosomal deficits and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal dysfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms.

NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility.

A G4C2 hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. However, the relationship between FG nups and TDP-43 pathology remains elusive. Our studies show that nuclear depletion and cytoplasmic mislocalization of one FG nup, NUP62, is linked to TDP-43 mislocalization in C9-ALS/FTLD iPSC neurons. Poly-glycine arginine (GR) DPR accumulation initiates the formation of cytoplasmic RNA granules that recruit NUP62 and TDP-43. Cytoplasmic NUP62 and TDP-43 interactions promotes their insolubility and NUP62:TDP-43 inclusions are frequently found in C9orf72 ALS/FTLD as well as sporadic ALS/FTLD postmortem CNS tissue. Our findings indicate NUP62 cytoplasmic mislocalization contributes to TDP-43 proteinopathy in ALS/FTLD.

Evolution and Neural Network Prediction of CO2 Emissions in Weaned Piglet Farms.

This paper aims to study the evolution of CO2 concentrations and emissions on a conventional farm with weaned piglets between 6.9 and 17.0 kg live weight based on setpoint temperature, outdoor temperature, and ventilation flow. The experimental trial was conducted during one transition cycle. Generally, the ventilation flow increased with the reduction in setpoint temperature throughout the cycle, which caused a reduction in CO2 concentration and an increase in emissions. The mean CO2 concentration was 3.12 g m-3. Emissions of CO2 had a mean value of 2.21 mg s-1 per animal, which is equivalent to 0.195 mg s-1 kg-1. A potential function was used to describe the interaction between 10 min values of ventilation flow and CO2 concentrations, whereas a linear function was used to describe the interaction between 10 min values of ventilation flow and CO2 emissions, with r values of 0.82 and 0.85, respectively. Using such equations allowed for simple and direct quantification of emissions. Furthermore, two prediction models for CO2 emissions were developed using two neural networks (for 10 min and 60 min predictions), which reached r values of 0.63 and 0.56. These results are limited mainly by the size of the training period, as well as by the differences between the behavior of the series in the training stage and the testing stage.

Non-invasive devices for respiratory sound monitoring.

Respiratory diseases are leading causes of death and disability in the world. The recent COVID-19 pandemic is also affecting the respiratory system. Detecting and diagnosing respiratory diseases requires both medical professionals and the clinical environment. Most of the techniques used up to date were also invasive or expensive. Some research groups are developing hardware devices and techniques to make possible a non-invasive or even remote respiratory sound acquisition. These sounds are then processed and analysed for clinical, scientific, or educational purposes. We present the literature review of non-invasive sound acquisition devices and techniques. The results are about a huge number of digital tools, like microphones, wearables, or Internet of Thing devices, that can be used in this scope. Some interesting applications have been found. Some devices make easier the sound acquisition in a clinic environment, but others make possible daily monitoring outside that ambient. We aim to use some of these devices and include the non-invasive recorded respiratory sounds in a Digital Twin system for personalized health.

Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy.

Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function leading to alterations in the neurodevelopmental trajectory of patient iPSC-derived neurons.

Embedded system for non-obtrusive sleep apnea detection.

This document presents a new complete standalone system for a recognition of sleep apnea using signals from the pressure sensors placed under the mattress. The developed hardware part of the system is tuned to filter and to amplify the signal. Its software part performs more accurate signal filtering and identification of apnea events. The overall achieved accuracy of the recognition of apnea occurrence is 91%, with the average measured recognition delay of about 15 seconds, which confirms the suitability of the proposed method for future employment. The main aim of the presented approach is the support of the healthcare system with the cost-efficient tool for recognition of sleep apnea in the home environment.

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity.

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in C9orf72 (C9-HRE). While RNA and dipeptide repeats produced by C9-HRE disrupt nucleocytoplasmic transport, the proteins that become redistributed remain unknown. Here, we utilized subcellular fractionation coupled with tandem mass spectrometry and identified 126 proteins, enriched for protein translation and RNA metabolism pathways, which collectively drive a shift toward a more cytosolic proteome in C9-HRE cells. Among these was eRF1, which regulates translation termination and nonsense-mediated decay (NMD). eRF1 accumulates within elaborate nuclear envelope invaginations in patient induced pluripotent stem cell (iPSC) neurons and postmortem tissue and mediates a protective shift from protein translation to NMD-dependent mRNA degradation. Overexpression of eRF1 and the NMD driver UPF1 ameliorate C9-HRE toxicity in vivo. Our findings provide a resource for proteome-wide nucleocytoplasmic alterations across neurodegeneration-associated repeat expansion mutations and highlight eRF1 and NMD as therapeutic targets in C9orf72-associated ALS and/or FTD.

Recognition of Sleep/Wake States analyzing Heart Rate, Breathing and Movement Signals.

This document presents an algorithm for a non-obtrusive recognition of Sleep/Wake states using signals derived from ECG, respiration, and body movement captured while lying in a bed. As a core mathematical base of system data analytics, multinomial logistic regression techniques were chosen. Derived parameters of the three signals are used as the input for the proposed method. The overall achieved accuracy rate is 84% for Wake/Sleep stages, with Cohen's kappa value 0.46. The presented algorithm should support experts in analyzing sleep quality in more detail. The results confirm the potential of this method and disclose several ways for its improvement.

Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology.

The somatic DNA methylation (DNAme) landscape is established early in development but remains highly dynamic within focal regions that overlap with gene regulatory elements. The significance of these dynamic changes, particularly in the central nervous system, remains unresolved. Here, we utilize a powerful human embryonic stem cell differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNAme machinery. We quantitatively dissect the role of DNAme in directing somatic cell fate with high-resolution genome-wide bisulfite-, bulk-, and single-cell-RNA sequencing. We find defects in neuralization and MN differentiation in DNMT3A knockouts (KO) that can be rescued by the targeting of DNAme to key developmental loci using catalytically inactive dCas9. We also find decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a list of DNMT3A-regulated targets and a mechanistic link between de novo DNAme, cellular differentiation, and human MN function.

The complexity of the calretinin-expressing progenitors in the human cerebral cortex.

The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively. The calretinin-expressing (CalR(+)) cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR(+) interneurons originate in the caudal ganglionic eminence (CGE) from Gsx2(+) progenitors, but in humans it has been suggested that a subpopulation of CalR(+) cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ). The progenitors for cortically generated CalR(+) subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs) that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2(+) cells, not only in the ventral telencephalon (GE) as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR(+) neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh), an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR(+) cortical interneurons.

Inducing functional radial glia-like progenitors from cortical astrocyte cultures using micropatterned PMMA.

Radial glia cells (RGC) are multipotent progenitors that generate neurons and glia during CNS development, and which also served as substrate for neuronal migration. After a lesion, reactive glia are the main contributor to CNS regenerative blockage, although some reactive astrocytes are also able to de-differentiate in situ into radial glia-like cells (RGLC), providing beneficial effects in terms of CNS recovery. Thus, the identification of substrate properties that potentiate the ability of astrocytes to transform into RGLC in response to a lesion might help in the development of implantable devices that improve endogenous CNS regeneration. Here we demonstrate that functional RGLC can be induced from in vitro matured astrocytes by using a precisely-sized micropatterned PMMA grooved scaffold, without added soluble or substrate adsorbed biochemical factors. RGLC were extremely organized and aligned on 2 µm line patterned PMMA and, like their embryonic counterparts, express nestin, the neuron-glial progenitor marker Pax6, and also proliferate, generate different intermediate progenitors and support and direct axonal growth and neuronal migration. Our results suggest that the introduction of line patterns in the size range of the RGC processes in implantable scaffolds might mimic the topography of the embryonic neural stem cell niche, driving endogenous astrocytes into an RGLC phenotype, and thus favoring the regenerative response in situ.

Unitats de salut mediambiental pediàtriques / No disponible

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Hidrocefalia por ectasia de la arteria basilar / Hydrocephalus due to ectasia of basilar artery

Se presenta un paciente que tenía el cuadro clínico de la hidrocefalia crónica del adulto, producido por ectasia y elongación de la arteria basilar y que evolucionó satisfactoriamente con el tratamiento derivativo. Se revisa la literatura y la fisiopatología de esta afección (AU)

Convulsiones, trastornos mentales y tetania por hipocalcemia. Revisión a propósito de un caso / Convulsions, mental disorders and tetania due to hypocalcemia. Review for the purpose of one case

Se plantea que la hipocalcemia es una causa conocida de tetania y convulsiones. Existen muchas enfermedades que pueden causar hipocalcemia, pero el hipoparatiroidismo secundario a la ablación de estas glándulas en el desarrollo de operaciones del tiroides, es la causa más frecuente. Debido a que la hipocalcemia no es una causa frecuente de convulsiones, en muchas ocasiones no se sospecha y se cometen errores diagnósticos y terapéuticos. Se presenta el caso de una paciente que tenía trastornos mentales, tetania y convulsiones por hipocalcemia secundaria a un hipoparatiroidismo posquirúrgico, cuyas manifestaciones habían empeorado con los anticonvulsivantes y desaparecieron cpon tratamiento a base de calcio y vitamina D(AU)

Encefalopatía tóxica por procedimiento abortivo con rivanol. Presentación de un caso / Toxic encephalopathy due to abortive proceeding with rivanol

Se presenta una paciente de 17 años de edad, con antecendentes de sufrimiento perinatal, asma y retraso mental ligero, que en el segundo intento de un procedimiento abortivo con rivanol, presentó crisis convulsiva, estupor, excitación psicomotora y monoparesial braquial izquierda. El LCR fue hemorrágico y el EEG muy anormal, lento, generalizado, de bajo voltaje, con oleadas delta sudoperiódicas. El cuadro desapareció en el trasncurso de 7 días y se concluyó como una ncefalopatía tóxica por el rivanol (AU)

Traumatismo en el cuello como causa de oclusión aguda de la arteria central de la retina / Neck traumatism as cause of acute occlusion for central artery of the retina

Se ha descrito la oclusión de la arteria carótida interna y de las arterias vertebrales, entre otras causas, por traumatismos o manipulaciones del cuello; más raramente, se han comunicado casos en que los vasos ocluidos son parte de los sistemas vasculares a que ellas dan origen, como la arteria cerebral media, el tronco basilar y la cerebelosa porteroinferior. Se presenta el caso de un paciente que sufrió una oclusión aguda de la arteria central de la retina, secundaria a un traumatismo en la región lateral del cuello, con conservación de la visión central por la existencia de una arteria ciliorretiniana permeable, y su evolución a través de dos años. Se discuten aspectos fisiopatológicos y la importancia práctica que tiene para el oftalmólogo considerar este factor causal, así como mantener una estrecha relación con el neurólogo por las implicaciones que pueden tener estos traumatismos sobre el sistema nervioso central(AU)

Radiculoplexitis braquial aguda idiopática con neuritis craneal IX, X, XI y XII / Acute idiopathic brachial radiculoplexitis with IX, X, XI and XII cranial neuritis

Se estudia un paciente de 61 años de edad, con una radiculoplexitis braquial aguda idiopática con afectación del plexo braquial y de los pares craneales IX, X, XI, XII y probablemente del V, del lado derecho. En el electromiograma había signos de desnervación y desmielinización. Se discuten las características de la radiculoplexitis braquial aguda idiopática, serogénica y familiar. La afectación de pares craneales no ha sido informada previamente en esta entidad(AU)