Editorial: Protein post-translational modifications in the nervous system: from development to disease and ageing.

PTMs are crucial for biological processes contributing to healthy organ function. Protein post-translational modifications (PTMs), such as phosphorylation (P), acetylation (Ac), SUMOylation (SUMO), S-nitrosylation (Nitro), ubiquitination (Ub) and glycosylation (Glyco), affect a wide range of cellular and biological functions as depicted in this cartoon. Perturbations lead to severe consequences for the normal function of the brain and other organs, such as muscle.

Unlocking Spanish pear genetic diversity: strategies for construction of a national core collection.

Spanish pear germplasm collections are crucial for preservation, research, and breeding efforts. However, genetic diversity and structure is unknown at national level. A coordinated national project analyzed 1251 accessions from 7 Spanish pear collections using an internationally recognized set of 14 SSRs to enhance the utilization of these collections.

Blockade of brain alkaline phosphatase efficiently reduces amyloid-β plaque burden and associated cognitive impairment.

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. Three new drugs for AD based on monoclonal antibodies against the amyloid-β peptide (Aβ) have recently been approved because they favor the reduction of the burden of senile plaque in the AD patient's brain. Nonetheless, both drugs have very limited applicability and benefits and show several side effects.

Protective effects of PDGF-AB/BB against cellular senescence in human intervertebral disc.

Cellular senescence, characterized by a permanent state of cell cycle arrest and a secretory phenotype contributing to inflammation and tissue deterioration, has emerged as a target for age-related interventions. Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism.

Inhibition of KDM2/7 Promotes Notochordal Differentiation of hiPSCs.

Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal diseases. Therefore, adult somatic cells reprogrammed into human induced pluripotent stem cells (hiPSCs) represent an attractive cell source for the derivation of notochordal-like cells (NCs) as a first step towards the development of a regenerative therapy for IDD.

Paving the Path for Sustainable and Responsible Off-Label Use of Pharmaceutical Products in Europe.

Off-label use of pharmaceuticals involves a wide array of aspects ranging from legal and regulatory ones to clinical to safety considerations. Access to off-label therapies is particularly relevant question for patients in areas of unmet medical need. Simultaneously, off-label use also triggers wider considerations relating to social and economic sustainability of health care systems and access to health.

Differential efficacy of two small molecule PHLPP inhibitors to promote nucleus Pulposus cell health.

Background: Intervertebral disc (IVD) degeneration is associated with chronic back pain. We previously demonstrated that the phosphatase pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1 was positively correlated with IVD degeneration and its deficiency decelerated IVD degeneration in both mouse IVDs and human nucleus pulposus (NP) cells. Small molecule PHLPP inhibitors may offer a translatable method to alleviate IVD degeneration.

PEGylation Strategy for Improving the Pharmacokinetic and Antitumoral Activity of the IL-2 No-alpha Mutein.

Background: In a previous work, an IL-2Rβγ biased mutant derived from human IL-2 and called IL-2noα, was designed and developed. Greater antitumor effects and lower toxicity were observed compared to native IL-2. Nevertheless, mutein has some disadvantages, such as a very short half-life of about 9-12 min, propensity for aggregation, and solubility problems.

pH-sensing G protein-coupled orphan receptor is expressed in human cartilage and correlates with degradation of extracellular matrix during OA progression.

Background: Osteoarthritis (OA) is a debilitating joints disease affecting millions of people worldwide. As OA progresses, chondrocytes experience heightened catabolic activity, often accompanied by alterations in the extracellular environment's osmolarity and acidity. Nevertheless, the precise mechanism by which chondrocytes perceive and respond to acidic stress remains unknown.

Efficient Differentiation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Mesenchymal Progenitors Into Adipocytes and Osteoblasts.

Human induced pluripotent stem cells (hiPSCs) hold immense promise in regenerative medicine as they can differentiate into various cell lineages, including adipocytes, osteoblasts, and chondrocytes. Precisely guiding hiPSC-derived mesenchymal progenitor cells (iMSCs) towards specific differentiation pathways is crucial for harnessing their therapeutic potential in tissue engineering, disease modeling, and regenerative therapies. To achieve this, we present a comprehensive and reproducible protocol for effectively differentiating iMSCs into adipocytes and osteoblasts.

Differentiation of Human Induced Pluripotent Stem Cells (iPSCs)-derived Mesenchymal Progenitors into Chondrocytes.

Induced pluripotent stem cells (iPSCs) generated from human sources are valuable tools for studying skeletal development and diseases, as well as for potential use in regenerative medicine for skeletal tissues such as articular cartilage. To successfully differentiate human iPSCs into functional chondrocytes, it is essential to establish efficient and reproducible strategies that closely mimic the physiological chondrogenic differentiation process. Here, we describe a simple and efficient protocol for differentiation of human iPSCs into chondrocytes via generation of an intermediate population of mesenchymal progenitors.

Validation of the knowledge evaluation questionnaire of the cardiopulmonary resuscitation training program in high school students.

There is an urgent need for generalized training in cardiopulmonary resuscitation (CPR) techniques, starting with secondary education. Validated instruments for assessing the efficacy of such interventions are not yet available. This study aimed to validate an evaluation questionnaire of a CPR training program for high school students, to analyze the levels of readability, difficulty, reliability, and content validity, as well as the fit the purpose for which they were designed, the trait they are intended to measure.

TNAP and P2X7R: New Plasma Biomarkers for Alzheimer's Disease.

Over the last few years, intense research efforts have been made to anticipate or improve the diagnosis of Alzheimer's disease by detecting blood biomarkers. However, the most promising blood biomarkers identified to date have some limitations, most of them related to the techniques required for their detection. Hence, new blood biomarkers should be identified to improve the diagnosis of AD, better discriminate between AD and mild cognitive impairment (MCI) and identify cognitively unimpaired (CU) older individuals at risk for progression to AD.

P2X7 receptor inhibition ameliorates ubiquitin-proteasome system dysfunction associated with Alzheimer's disease.

Background: Over recent years, increasing evidence suggests a causal relationship between neurofibrillary tangles (NFTs) formation, the main histopathological hallmark of tauopathies, including Alzheimer's disease (AD), and the ubiquitin-proteasome system (UPS) dysfunction detected in these patients. Nevertheless, the mechanisms underlying UPS failure and the factors involved remain poorly understood. Given that AD and tauopathies are associated with chronic neuroinflammation, here, we explore if ATP, one of the danger-associated molecules patterns (DAMPs) associated with neuroinflammation, impacts on AD-associated UPS dysfunction.

Diadenosine pentaphosphate regulates dendrite growth and number in cultured hippocampal neurons.

During the establishment of neuronal circuits, axons and dendrites grow and branch to establish specific synaptic connections. This complex process is highly regulated by positive and negative extracellular cues guiding the axons and dendrites. Our group was pioneer in describing that one of these signals are the extracellular purines.

Dynamic Association of ESCRT-II Proteins with ESCRT-I and ESCRT-III Complexes during Phagocytosis of .

By their active movement and voraux phagocytosis, the trophozoites of constitute an excellent system to investigate the dynamics of the Endosomal Sorting Complex Required for Transport (ESCRT) protein interactions through phagocytosis. Here, we studied the proteins forming the ESCRT-II complex and their relationship with other phagocytosis-involved molecules. Bioinformatics analysis predicted that EhVps22, EhVps25, and EhVps36 are orthologues of the ESCRT-II protein families.

Differential chondrogenic differentiation between iPSC derived from healthy and OA cartilage is associated with changes in epigenetic regulation and metabolic transcriptomic signatures.

Induced pluripotent stem cells (iPSCs) are potential cell sources for regenerative medicine. The iPSCs exhibit a preference for lineage differentiation to the donor cell type indicating the existence of memory of origin. Although the intrinsic effect of the donor cell type on differentiation of iPSCs is well recognized, whether disease-specific factors of donor cells influence the differentiation capacity of iPSC remains unknown.

PHLPP1 deficiency protects against age-related intervertebral disc degeneration.

Background: Intervertebral disc (IVD) degeneration is strongly associated with low back pain and is highly prevalent in the elderly population. Hallmarks of IVD degeneration include cell loss and extracellular matrix degradation. The PH domain leucine-rich-repeats protein phosphatase (PHLPP1) is highly expressed in diseased cartilaginous tissues where it is linked to extracellular matrix degradation.

Purinergic Signalling and Inflammation-Related Diseases.

While acute inflammation is widely accepted as an important response mechanism of cells against tissue injury, sustained inflammatory processes are increasingly recognized as one of the main contributors to numerous diseases, including central-nervous system (CNS)-related and non-CNS-related diseases such as depression, neurodegenerative diseases, type 2 diabetes, hypertension, cardiovascular diseases, chronic kidney disease, osteoporosis, and cancer [...

Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults.

Background: SOBERANA 02 has been evaluated in phase I and IIa studies comparing homologous versus heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety, and reactogenicity of SOBERANA 02 in a two- or three-dose heterologous scheme in adults.

Method: Phase IIb was a parallel, multicenter, adaptive, double-blind, randomized, and placebo-controlled trial.

Sexually Dimorphic Increases in Bone Mass Following Tissue-specific Overexpression of Runx1 in Osteoclast Precursors.

Many metabolic bone diseases arise as a result excessive osteoclastic bone resorption, which has motivated efforts to identify new molecular targets that can inhibit the formation or activity of these bone-resorbing cells. Mounting evidence indicates that the transcription factor Runx1 acts as a transcriptional repressor of osteoclast formation. Prior studies using a conditional knockout approach suggested that Runx1 in osteoclast precursors acts as an inhibitor of osteoclastogenesis; however, the effects of upregulation of Runx1 on osteoclast formation remain unknown.

Studying the Role of P2X7 Receptor in Axonal Growth Using In Utero Electroporation Technique.

The nervous system is formed by a complex network of neuronal connections. During development, neurons elongate their axons through highly stereotyped anatomical pathways to form precise connections. Defects in these mechanisms are related with neurological disorders.

Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related Repeat Expansion Carriers.

The GGGGCC (G4C2) repeat expansion in is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulated DNA damage response and the generation of reactive oxygen species (ROS) have been postulated as major drivers of toxicity in pathogenesis. Telomeres are tandem-repeated nucleotide sequences that are located at the end of chromosomes and protect them from degradation.

Safety and immunogenicity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous scheme: Open label phase I and phase IIa clinical trials.

Background: SOBERANA 02 is a COVID-19 vaccine based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid (TT). SOBERANA Plus antigen is dimeric-RBD. Here we report safety and immunogenicity from phase I and IIa clinical trials using two-doses of SOBERANA 02 and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols.