A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.

OBJECTIVE: X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development. METHODS: We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice. RESULTS: Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity. INTERPRETATION: Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2024.

Long chain capsaicin analogues synthetized by CALB-CLEAs show cytotoxicity on glioblastoma cell lines.

Glioblastoma is one of the most lethal tumors, displaying striking cellular heterogeneity and drug resistance. The prognosis of patients suffering from glioblastoma after 5 years is only 5%. In the present work, capsaicin analogues bearing modifications on the acyl chain with long-chain fatty acids showed promising anti-tumoral activity by its cytotoxicity on U-87 and U-138 glioblastoma multiforme cells. The capsaicin analogues were enzymatically synthetized with cross-linked enzyme aggregates of lipase B from Candida antarctica (CALB). The catalytic performance of recombinant CALB-CLEAs was compared to their immobilized form on a hydrophobic support. After 72 h of reaction, the synthesis of capsaicin analogues from linoleic acid, docosahexaenoic acid, and punicic acid achieved a maximum conversion of 69.7, 8.3 and 30.3% with CALB-CLEAs, respectively. Similar values were obtained with commercial CALB, with conversion yields of 58.3, 24.2 and 22% for capsaicin analogues from linoleic acid, DHA and punicic acid, respectively. Olvanil and dohevanil had a significant cytotoxic effect on both U-87 and U-138 glioblastoma cells. Irrespective of the immobilization form, CALB is an efficient biocatalyst for the synthesis of anti-tumoral capsaicin derivatives. KEY POINTS: • This is the first report concerning the enzymatic synthesis of capsaicin analogues from docosahexaenoic acid and punicic acid with CALB-CLEAs. • The viability U-87 and U-138 glioblastoma cells was significantly affected after incubation with olvanil and dohevanil. • Capsaicin analogues from fatty acids obtained by CALB-CLEAs are promising candidates for therapeutic use as cytotoxic agents in glioblastoma cancer cells.

JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net/) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups. In this 9th release, we expanded the CORE collection with 341 new profiles (148 for plants, 101 for vertebrates, 85 for urochordates, and 7 for insects), which corresponds to a 19% expansion over the previous release. We added 298 new profiles to the Unvalidated collection when no orthogonal evidence was found in the literature. All the profiles were clustered to provide familial binding profiles for each taxonomic group. Moreover, we revised the structural classification of DNA binding domains to consider plant-specific TFs. This release introduces word clouds to represent the scientific knowledge associated with each TF. We updated the genome tracks of TFBSs predicted with JASPAR profiles in eight organisms; the human and mouse TFBS predictions can be visualized as native tracks in the UCSC Genome Browser. Finally, we provide a new tool to perform JASPAR TFBS enrichment analysis in user-provided genomic regions. All the data is accessible through the JASPAR website, its associated RESTful API, the R/Bioconductor data package, and a new Python package, pyJASPAR, that facilitates serverless access to the data.

Chitosan-Hydroxycinnamic Acids Conjugates: Emerging Biomaterials with Rising Applications in Biomedicine.

Over the past thirty years, research has shown the huge potential of chitosan in biomedical applications such as drug delivery, tissue engineering and regeneration, cancer therapy, and antimicrobial treatments, among others. One of the major advantages of this interesting polysaccharide is its modifiability, which facilitates its use in tailor-made applications. In this way, the molecular structure of chitosan has been conjugated with multiple molecules to modify its mechanical, biological, or chemical properties. Here, we review the conjugation of chitosan with some bioactive molecules: hydroxycinnamic acids (HCAs); since these derivatives have been probed to enhance some of the biological effects of chitosan and to fine-tune its characteristics for its application in the biomedical field. First, the main characteristics of chitosan and HCAs are presented; then, the currently employed conjugation strategies between chitosan and HCAs are described; and, finally, the studied biomedical applications of these derivatives are discussed to present their limitations and advantages, which could lead to proximal therapeutic uses.

Intranasal Administration of Undifferentiated Oligodendrocyte Lineage Cells as a Potential Approach to Deliver Oligodendrocyte Precursor Cells into Brain.

Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination; these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs; as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.

Recombinant Erythropoietin Provides Protection against Renal Fibrosis in Adenine-Induced Chronic Kidney Disease.

Chronic kidney disease (CKD) causes anemia by renal damage. In CKD, the kidney is submitted to hypoxia, persistent inflammation, leading to fibrosis and permanent loss of renal function. Human recombinant erythropoietin (rEPO) has been widely used to treat CKD-associated anemia and is known to possess organ-protective properties that are independent from its well-established hematopoietic effects. Nonhematopoietic effects of EPO are mediated by an alternative receptor that is proposed to consist of a heterocomplex between the erythropoietin receptor (EPOR) and the beta common receptor (ßcR). The present study explored the effects of rEPO to prevent renal fibrosis in adenine-induced chronic kidney disease (Ad-CKD) and their association with the expression of the heterodimer EPOR/ßcR. Male Wistar rats were randomized to control group (CTL), adenine-fed rats (Ad-CKD), and Ad-CKD with treatment of rEPO (1050 IU/kg, once weekly for 4 weeks). Ad-CKD rats exhibited anemia, uremia, decreased renal function, increased infiltration of inflammatory cells, tubular atrophy, and fibrosis. rEPO treatment not only corrected anemia but reduced uremia and partially improved renal function as well. In addition, we observed that rEPO diminishes tubular injury, prevents fibrosis deposition, and induces the EPOR/ßcR heteroreceptor. The findings may explain the extrahematopoietic effects of rEPO in CKD and provide new strategies for the treatment of renal fibrosis in CKD.

Underlying domains of anxiety trait in a Costa Rican sample: preliminary results.

BACKGROUND: Imprecision of the psychiatric phenotype might partially explain the failure of genetic research to identify genes that contribute to susceptibility of anxiety disorders. Previous research concluded two underlying constructs, worry and rumination, might explain anxiety sub-syndromic symptoms in Costa Rican patients with history of mania. The goal of the current study is to explore the presence of latent constructs for quantitative anxiety in a group of subjects with a wide diagnostic phenotype and non-affected individuals. METHODS: We conducted an exploratory factor analysis of anxiety trait in 709 subjects. Our sample was comprised by 419 subjects with psychiatric disorders and 290 non-affected individuals. We used principal factors extraction method with squared multiple correlations of the STAI (trait subscale). RESULTS: We found the following preliminary results: a three-factor solution with a good simple structure and statistical adequacy was obtained with a KMO of 0.92 (>0.6) and Bartlett's Test of Sphericity of 5644,44 (p<0.05). The STAI items were grouped into three factors: anxiety-absent, worry and rumination based on the characteristics of the symptoms. CONCLUSION: Two underlying constructs, worry and rumination may explain anxiety sub-syndromic symptoms in Costa Rican subjects. Our proposed underlying structure of subsyndromal anxiety in individuals should be considered as an important factor in defining better phenotypic characterizations on a broader diagnostic concept. Worry and rumination as a phenotypic characterization may assist in genotyping; however, its predictive value on actual illness outcome still requires more research. The Genome-Wide QTL analysis for anxiety trait in the same sample is ongoing.

Comparison of the in vivo and in vitro genotoxicity of glyphosate isopropylamine salt in three different organisms.

There is considerable controversy with regard to the genotoxicity of glyphosate, with some reports stating that this compound is non-toxic for fish, birds and mammals. In this work, we used the comet assay to examine the genotoxicity of glyphosate isopropylamine (0.7, 7, 70 and 700 µM) in human lymphocytes, erythrocytes of Oreochromis niloticus and staminal nuclei of Tradescantia (4430) in vitro and in vivo. Cells, nuclei and fish that had and had not been exposed to 5 mM N-nitrosodiethylamine (NDEA) were used as positive and negative controls, respectively. Significant (p < 0.01) genetic damage was observed in vivo and in vitro in all cell types and organisms tested. Human lymphocytes and Tradescantia hairs showed lower genetic damage in vivo compared to in vitro, possibly because of efficient metabolization of the herbicide. In O. niloticus erythrocytes, significant (p < 0.001) genotoxicity was observed at ≥ 7 µM, whereas in vitro, glyphosphate was genotoxic in human lymphocytes and Tradescantia hairs at ≥ 0.7 µM. These results indicate that glyphosate is genotoxic in the cells and organisms studied at concentrations of 0.7-7 µM.

Early Animal Origin of BACE1 APP/Aß Proteolytic Function.

Alzheimer's disease is characterized, in part, by the accumulation of ß-amyloid (Aß) in the brain. Aß is produced via the proteolysis of APP by BACE1 and γ-secretase. Since BACE1 is the rate-limiting enzyme in the production of Aß, and a target for therapeutics, it is of interest to know when its proteolytic function evolved and for what purpose. Here, we take a functional evolutionary approach to show that BACE1 likely evolved from a gene duplication event near the base of the animal clade and that BACE1 APP/Aß proteolytic function evolved during early animal diversification, hundreds of millions of years before the evolution of the APP/Aß substrate. Our examination of BACE1 APP/Aß proteolytic function includes cnidarians, ctenophores, and choanoflagellates. The most basal BACE1 ortholog is found in cnidarians, while ctenophores, placozoa, and choanoflagellates have genes equally orthologous to BACE1 and BACE2. BACE1 from a cnidarian (Hydra) can cleave APP to release Aß, pushing back the date of the origin of its function to near the origin of animals. We tested more divergent BACE1/2 genes from a ctenophore (Mnemiopsis) and a choanoflagellate (Monosiga), and neither has this activity. These findings indicate that the specific proteolytic function of BACE1 evolved during the very earliest diversification of animals, most likely after a gene-duplication event.

Docosahexaenoic Acid (DHA), Vitamin D3, and Probiotics Supplementation Improve Memory, Glial Reactivity, and Oxidative Stress Biomarkers in an Aluminum-Induced Cognitive Impairment Rat Model.

Globally, the rise in neurodegenerative issues in tandem with shifts in lifestyle and aging population has prompted a search for effective interventions. Nutraceutical compounds have emerged as promising agents for addressing these challenges. This 60-day study on an aluminum-induced cognitive impairment rat model assessed three compounds and their combinations: probiotics (Prob, Lactobacillus plantarum [5 × 1010 CFU/day], and Lactobacillus acidophilus [5 × 1010 CFU/day]), docosahexaenoic acid (DHA, 23.8 mg/day), and vitamin D3 (VD3, 150 IU/day). Behavioral outcomes were evaluated by using the Morris water maze and novel object recognition tests. Glial activation was assessed through immunofluorescence analysis of GFAP/Iba1, and oxidative stress markers in brain tissue were determined by measuring the levels of Malondialdehyde (MDA) and Superoxide dismutase (SOD). The results demonstrated a progressive improvement in the learning and memory capacity. The aluminum group exhibited the poorest performance in the behavioral test, enhanced GFAP/Iba1 activation, and elevated levels of oxidative stress markers. Conversely, the DHA + Prob + VD3 treatment demonstrated the best performance in the Morris water maze. The combination of DHA + Prob + VD3 exhibited superior performance in the Morris water maze, accompanied by reduced levels of GFAP/Iba1 activation in DG/CA1 brain regions. Furthermore, DHA + Prob supplementation showed lower GFAP/Iba1 activation in the CA3 region and enhanced antioxidant activity. In summary, supplementing various nutraceutical combinations, including DHA, VD3, and Prob, displayed notable benefits against aluminum-induced cognitive impairment. These benefits encompassed memory enhancement, diminished MDA concentration, increased SOD activity, and reduced glial activation, as indicated by GFAP/Iba1 markers.

Thermosensitive chitosan-based hydrogel: A vehicle for overcoming the limitations of nose-to-brain cell therapy.

Cell therapy is a promising strategy for treating neurological pathologies but requires invasive methods to bypass the blood-brain barrier restrictions. The nose-to-brain route has been presented as a direct and less invasive alternative to access the brain. The primary limitations of this route are low retention in the olfactory epithelium and poor cell survival in the harsh conditions of the nasal cavity. Thus, using chitosan-based hydrogel as a vehicle is proposed in this work to overcome the limitations of nose-to-brain cell administration. The hydrogel's design was driven to achieve gelification in response to body temperature and a mucosa-interacting chemical structure biocompatible with cells. The hydrogel showed a < 30 min gelation time at 37 °C and >95 % biocompatibility with 2D and 3D cultures of mesenchymal stromal cells. Additionally, the viability, stability, and migration capacity of oligodendrocyte precursor cells (OPCs) within the hydrogel were maintained in vitro for up to 72 h. After the intranasal administration of the OPCs-containing hydrogel, histological analysis showed the presence of viable cells in the nasal cavity for up to 72 h post-administration in healthy athymic mice. These results demonstrate the hydrogel's capacity to increase the residence time in the nasal cavity while providing the cells with a favorable environment for their viability. This study presents for the first time the use of thermosensitive hydrogels in nose-to-brain cell therapy, opening the possibility of increasing the delivery efficiency in future approaches in translational medicine. STATEMENT OF SIGNIFICANCE: This work highlights the potential of biomaterials, specifically hydrogels, in improving the effectiveness of cell therapy administered through the nose. The nose-to-brain route has been suggested as a non-invasive way to directly access the brain. However, delivering stem cells through this route poses a challenge since their viability must be preserved and cells can be swept away by nasal mucus. Earlier attempts at intranasal cell therapy have shown low efficiency, but still hold promise to the future. The hydrogels designed for this study can provide stem cells with a biocompatible environment and adhesion to the nasal atrium, easing the successful migration of viable cells to the brain.

Imaging spectrum of non-neoplastic and neoplastic conditions of the duodenum: a pictorial review.

Given its crucial location at the crossroads of the gastrointestinal tract, the hepatobiliary system and the splanchnic vessels, the duodenum can be affected by a wide spectrum of abnormalities. Computed tomography and magnetic resonance imaging, in conjunction with endoscopy, are often performed to evaluate these conditions, and several duodenal pathologies can be identified on fluoroscopic studies. Since many conditions affecting this organ are asymptomatic, the role of imaging cannot be overemphasized. In this article we will review the imaging features of many conditions affecting the duodenum, focusing on cross-sectional imaging studies, including congenital malformations, such as annular pancreas and intestinal malrotation; vascular pathologies, such as superior mesenteric artery syndrome; inflammatory and infectious conditions; trauma; neoplasms and iatrogenic complications. Because of the complexity of the duodenum, familiarity with the duodenal anatomy and physiology as well as the imaging features of the plethora of conditions affecting this organ is crucial to differentiate those conditions that could be managed medically from the ones that require intervention.

A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis.

Objective: We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues. Background: ALD is caused by mutations in the gene ABCD1 encoding a peroxisomal transporter. More than half of males with an ABCD1 mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the Abcd1-null mouse. Methods: We generated a cALD phenotype in 8-week-old, male Abcd1-null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employed in vivo MRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue. Results: MRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue. Interpretation: This novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination.

In Vitro Antiviral Activity of Nordihydroguaiaretic Acid against SARS-CoV-2.

The coronavirus infectious disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been spreading rapidly worldwide, creating a pandemic. This article describes the evaluation of the antiviral activity of nordihydroguaiaretic acid (NDGA), a molecule found in Creosote bush (Larrea tridentata) leaves, against SARS-CoV-2 in vitro. A 35 µM concentration of NDGA was not toxic to Vero cells and exhibited a remarkable inhibitory effect on the SARS-CoV-2 cytopathic effect, viral plaque formation, RNA replication, and expression of the SARS-CoV-2 spike glycoprotein. The 50% effective concentration for NDGA was as low as 16.97 µM. Our results show that NDGA could be a promising therapeutic candidate against SARS-CoV-2.

Mesenchymal Stem Cell-Based Therapies in the Post-Acute Neurological COVID Syndrome: Current Landscape and Opportunities.

One of the main concerns related to SARS-CoV-2 infection is the symptoms that could be developed by survivors, known as long COVID, a syndrome characterized by persistent symptoms beyond the acute phase of the infection. This syndrome has emerged as a complex and debilitating condition with a diverse range of manifestations affecting multiple organ systems. It is increasingly recognized for affecting the Central Nervous System, in which one of the most prevalent manifestations is cognitive impairment. The search for effective therapeutic interventions has led to growing interest in Mesenchymal Stem Cell (MSC)-based therapies due to their immunomodulatory, anti-inflammatory, and tissue regenerative properties. This review provides a comprehensive analysis of the current understanding and potential applications of MSC-based interventions in the context of post-acute neurological COVID-19 syndrome, exploring the underlying mechanisms by which MSCs exert their effects on neuroinflammation, neuroprotection, and neural tissue repair. Moreover, we discuss the challenges and considerations specific to employing MSC-based therapies, including optimal delivery methods, and functional treatment enhancements.

Curcumin protects against the oxidative damage induced by the pesticide parathion in the hippocampus of the rat brain.

UNLABELLED: One of the main concerns regarding organophosphate pesticides (OP) is their possible toxic effects. Doses that do not produce acute toxicity are capable of altering the structure and biochemistry of different tissues and organs by production of reactive oxygen species (ROS). Curcumin (CUR) is the main substance in Curcuma longa (Zingiberacea) rhizome that has strong antioxidant activity. However, the neuroprotective properties of curcumin against oxidative stress induced by prolonged exposure to parathion (PAR) is not clear. OBJECTIVE: The present work evaluated the protective effect of curcumin against the oxidative damage induced in the rat hippocampus by the OP PAR. METHODS: Forty female Wistar rats were distributed in four groups as follows: exposed to PAR by inhalation (PAR group); pre-treated with CUR and then exposed to PAR by inhalation, (CUR + PAR group); exposed to environmental air and treated with CUR in the food (CUR group); and exposed to environmental air (the control group). At the end of the handling process, the concentration of erythrocyte cholinesterase was monitored, as indicator of PAR intoxication and lipoperoxidation, immunohistochemistry for astrocytes, and activated microglia and apoptosis was determined in the hippocampus. RESULTS: In the present study, we show that the administration of CUR (200 mg/kg body weight) significantly diminished the oxidative damage in the hippocampus of rats exposed to the OP PAR. DISCUSSION: These data suggest that CUR may be an alternative to prevent neurodegenerative damage after pesticide exposure.

PSEN1 c.1292C<A Variant and Early-Onset Alzheimer's Disease: A Scoping Review.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive loss of cognitive function, with ß-amyloid plaques and neurofibrillary tangles being its major pathological findings. Although the disease mainly affects the elderly, c. 5-10% of the cases are due to PSEN1, PSEN2, and APP mutations, principally associated with an early onset of the disease. The A413E (rs63750083) PSEN1 variant, identified in 2001, is associated with early-onset Alzheimer's disease (EOAD). Although there is scant knowledge about the disease's clinical manifestations and particular features, significant clinical heterogeneity was reported, with a high incidence of spastic paraparesis (SP), language impairments, and psychiatric and motor manifestations. This scoping review aims to synthesize findings related to the A431E variant of PSEN1. In the search, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the guidelines proposed by Arksey and O'Malley. We searched and identified 247 studies including the A431E variant of PSEN1 from 2001 to 2021 in five databases and one search engine. After the removal of duplicates, and apply inclusion criteria, 42 studies were finally included. We considered a narrative synthesis with a qualitative approach for the analysis of the data. Given the study sample conformation, we divided the results into those carried out only with participants carrying A431E (seven studies), subjects with PSEN variants (11 studies), and variants associated with EOAD in PSEN1, PSEN2, and APP (24 studies). The resulting synthesis indicates most studies involve Mexican and Mexican-American participants in preclinical stages. The articles analyzed included carrier characteristics in categories such as genetics, clinical, imaging techniques, neuropsychology, neuropathology, and biomarkers. Some studies also considered family members' beliefs and caregivers' experiences. Heterogeneity in both the studies found and carrier samples of EOAD-related gene variants does not allow for the generalization of the findings. Future research should focus on reporting data on the progression of carrier characteristics through time and reporting results independently or comparing them across variants.

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation.

Cardiovascular diseases are the leading cause of mortality and reduced quality of life globally. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a personalized platform to study inherited heart diseases, drug-induced cardiac toxicity, and cardiac regenerative therapy. However, the immaturity of CMs obtained by current strategies is a major hurdle in utilizing hiPSC-CMs at their fullest potential. Here, the major findings and limitations of current maturation methodologies to enhance the utility of hiPSC-CMs in the battle against a major source of morbidity and mortality are reviewed. The most recent knowledge of the potential signaling pathways involved in the transition of fetal to adult CMs are assimilated. In particular, we take a deeper look on role of nutrient sensing signaling pathways and the potential role of cap-independent translation mediated by the modulation of mTOR pathway in the regulation of cardiac gap junctions and other yet to be identified aspects of CM maturation. Moreover, a relatively unexplored perspective on how our knowledge on the effects of preterm birth on cardiovascular development can be actually utilized to enhance the current understanding of CM maturation is examined. Furthermore, the interaction between the evolving neonatal human heart and brown adipose tissue as the major source of neonatal thermogenesis and its endocrine function on CM development is another discussed topic which is worthy of future investigation. Finally, the current knowledge regarding transcriptional mediators of CM maturation is still limited. The recent studies have produced the groundwork to better understand CM maturation in terms of providing some of the key factors involved in maturation and development of metrics for assessment of maturation which proves essential for future studies on in vitro PSC-CMs maturation.

[Latex allergy: therapeutic options]. / Alergia al látex: opciones terapéuticas.

Latex allergy is a major problem worldwide due to both the severity of the symptomatology it produces and the risk groups that are exposed to it. Complete avoidance is difficult, if not impossible, due to its ubiquity. Natural rubber latex (NRL) is a natural polymer that is released by the Hevea brasiliensis (Hev b) tree, which functions as a protective sealant. It is currently used for the manufacture of health-care products such as tube caps, pistons, masks, and cannulas. The purpose of this review is to highlight the epidemiological, clinical, and diagnostic aspects of NRL allergy, and to conduct a review of the literature on its management through a bibliographic search of articles in databases such as PubMed, Cochrane, UpToDate, and Google Scholar, up to September 2021. About 121 articles were reviewed, of which 76 were used as a reference. We concluded that latex allergy is an entity for which its treatment, even nowadays, is avoidance, despite having a worldwide prevalence of 4.3 % and representing a surgical complication in about 20 % of surgeries with an anaphylactic reaction and a mortality rate that can reach 9 %. The only treatment that could modify the evolution of this disease is immunotherapy, but there are no standardized extracts yet and it has not been possible to determine the safest and most effective way to apply it.

La alergia al látex es un problema importante en el mundo debido a la gravedad de la sintomatología que produce y a los grupos de riesgo expuestos. La evitación completa es difícil, casi imposible, dada su ubicuidad. El látex de caucho natural (LCN) es un polímero secretado por el árbol Hevea brasiliensis (Hev b), que funciona como sellador protector. Actualmente se usa para fabricar productos para el cuidado de la salud como tapones para tubos, pistones, mascarillas y cánulas. El objetivo de esta revisión es resaltar los aspectos epidemiológicos, clínicos y diagnósticos de la alergia al LCN, y realizar una revisión de la literatura sobre su manejo, mediante una búsqueda bibliográfica de artículos en bases de datos como PubMed, Cochrane, UpToDate y Google Académico, hasta septiembre del 2021. Se revisaron aproximadamente 121 artículos, de los cuales se utilizaron 76 como referencia. Concluimos que la alergia al látex es una entidad cuyo tratamiento aún hoy en día es la evitación, a pesar de tener una prevalencia mundial de 4.3 % y representar una complicación quirúrgica de cerca de 20 % de las cirugías con una reacción anafiláctica y una mortalidad que puede llegar a 9 %. El único tratamiento que podría modificar la evolución de esta enfermedad es la inmunoterapia, pero aún no se cuenta con extractos estandarizados y no se ha podido determinar la vía más segura y efectiva.

Exosomes and Biomaterials: In Search of a New Therapeutic Strategy for Multiple Sclerosis.

Current efforts to find novel treatments that counteract multiple sclerosis (MS) have pointed toward immunomodulation and remyelination. Currently, cell therapy has shown promising potential to achieve this purpose. However, disadvantages such as poor survival, differentiation, and integration into the target tissue have limited its application. A series of recent studies have focused on the cell secretome, showing it to provide the most benefits of cell therapy. Exosomes are a key component of the cell secretome, participating in the transfer of bioactive molecules. These nano-sized vesicles offer many therapeutical advantages, such as the capacity to cross the blood-brain barrier, an enrichable cargo, and a customizable membrane. Moreover, integrating of biomaterials into exosome therapy could lead to new tissue-specific therapeutic strategies. In this work, the use of exosomes and their integration with biomaterials is presented as a novel strategy in the treatment of MS.