Narrow Time Window Research Articles

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors

Cerebral malaria (CM) is a severe neurological condition caused by Plasmodium falciparum. Disruption of the brain-blood barrier (BBB) is a key pathological event leading to brain edema and vascular leakage in both humans and in the mouse model of CM. Interactions of brain endothelial cells with infected red blood cells (iRBCs) and with circulating inflammatory mediators and immune cells contribute to BBB dysfunction in CM. Adjunctive therapies for CM aim at preserving the BBB to prevent neurologic deficits. Experimental animal and cellular models are essential to develop new therapeutic strategies. However, in mice, the disease develops rapidly, which offers a very narrow time window for testing the therapeutic potential of drugs acting in the BBB. Here, we establish a brain endothelial cell barrier whose disturbance can be monitored by several parameters. Using this system, we found that incubation with iRBCs and with extracellular particles (EPs) released by iRBCs changes endothelial cell morphology, decreases the tight junction protein zonula occludens-1 (ZO-1), increases the gene expression of the intercellular adhesion molecule 1 (ICAM-1), and induces a significant reduction in transendothelial electrical resistance (TEER) with increased permeability. We propose this in vitro experimental setup as a straightforward tool to investigate molecular interactions and pathways causing endothelial barrier dysfunction and to test compounds that may target BBB and be effective against CM. A pre-selection of the effective compounds that strengthen the resistance of the brain endothelial cell barrier to Plasmodium-induced blood factors in vitro may increase the likelihood of their efficacy in preclinical disease mouse models of CM and in subsequent clinical trials with patients.

Perspective insights into hydrogels and nanomaterials for ischemic stroke.

Ischemic stroke (IS) is a neurological disorder prevalent worldwide with a high disability and mortality rate. In the clinic setting, tissue plasminogen activator (tPA) and thrombectomy could restore blood flow of the occlusion region and improve the outcomes of IS patients; however, these therapies are restricted by a narrow time window. Although several preclinical trials have revealed the molecular and cellular mechanisms underlying infarct lesions, the translatability of most findings is unsatisfactory, which contributes to the emergence of new biomaterials, such as hydrogels and nanomaterials, for the treatment of IS. Biomaterials function as structural scaffolds or are combined with other compounds to release therapeutic drugs. Biomaterial-mediated drug delivery approaches could optimize the therapeutic effects based on their brain-targeting property, biocompatibility, and functionality. This review summarizes the advances in biomaterials in the last several years, aiming to discuss the therapeutic potential of new biomaterials from the bench to bedside. The promising prospects of new biomaterials indicate the possibility of an organic combination between materialogy and medicine, which is a novel field under exploration.

Sinning in the Rain: Weather Shocks, Church Attendance, and Crime

AbstractThis paper provides evidence of the causal effect of church attendance on petty crime by using quasi-random variation in the number of Sundays when it precipitated at the specific time of most religious services. Using a novel strategy, I find a narrow time window when most individuals attend church. Based on a panel between 1980 and 2016, I find that one more Sunday with precipitation at the time of church increases yearly drug-related, alcohol-related, and white-collar crimes. I do not find an effect for violent or property crimes. These effects are driven by more religious counties. Previous evidence showing negative effects of church attendance on the demand for alcohol and drugs is consistent with a demand-driven interpretation of the results presented.

The new target population of stroke awareness campaign: Kindergarten students

<p>&nbsp;Thrombolysis and/or thrombectomy have been proven effective in the treatment of acute ischemic stroke. Due to the narrow time window, the number of patients suitable for these treatments is low. The main limitation is the pre-hospital stage, few people call an ambulance in time. The delay may be caused by the population&rsquo;s insufficient health knowledge, but also by the loneliness and isolation of the population most prone to stroke. Among the latter, there are many grandparents who spend considerable time with their grandchildren. This gave rise to the idea of educating even younger children about the symptoms of a stroke, enabling them to call an ambulance if necessary. To this end, we adapted the Angels Initiative project previously tested in Greece. The Hungarian pilot study Budapest District XII. took place in district kindergartens. The Angels&rsquo; original role-playing program could not be implemented due to the COVID epidemic, so the necessity called for a new, Hungarian version: the online &ldquo;Stroke Ovi&rdquo; program. We introduced this in several stages, and in the third we also carried out an impact study.</p>. <p>&nbsp;We adapted the Angels Initiative&rsquo;s international program and its Hungarian translation to our program. We prepared the original, live role-playing form, with a parent meeting in the selected &ldquo;test kindergarten&rdquo;. Due to the uncertainly lingering impact of the COVID epidemic, we reevaluated our plan, using the Hungarian storybook and take-home workbook created in the meantime, we developed our own online version in several kindergartens in Budapest. We held 10 and then 25 minute sessions a week for 5 weeks. In the third educational cycle, which always targets new groups, we already examined the impact of the program by taking pre- and post-tests, in which not only the children but also their parents participated. In addition to neurologists and kindergarten teachers, we also included psychologists and speech therapists in our work, because we believed that in a social environment that includes parents and children, results can only be achieved through multidisciplinary cooperation.</p>. <p>&nbsp;In the third cycle of the program, tests were taken before (pre-test) and after (post-test) among children and their parents. We only took into account those answers where we received an evaluable answer in the survey before and after the program. Our most important results: 1. there was no negative change in any question, so it was not the case that the total score of any question in the pre-test was higher than in the post-test. 2. The children learned that not only adults can call the ambulance. 3. Before the program, all children were already aware that if &ldquo;someone is very ill&rdquo;, the ambulance should be called. 4. Among the questions about stroke symptoms, it is important that hemiparesis, facial paresis and speech/language disorder are clear symptoms for children. Based on the parental questionnaires, the knowledge of the adults can be judged to be very good. The same number of correct answers were received during the pre-test and the post-test, on the basis of which we could not calculate a transfer effect. However, it is important that the parents considered the program useful, motivating and important for the children, so cooperation can be expected in the future.</p>. <p>The Hungarian &ldquo;Stroke Ovi&rdquo; program has so far proven to be clearly effective. This was proven by the impact assessments even if, instead of the original role-playing game, we implemented it &ldquo;only&rdquo; online due to the COVID epidemic. This constraint also forced and created a new &ldquo;Hungarian version&rdquo;. Despite the small number of samples caused by the circumstances, we consider this positive effect to be measurable. However, as the main result and evidence, we evaluated the children&rsquo;s reaction, which took shape in spontaneous drawings and displayed professional values in addition to positive emotional reactions, such as the drawing of ambulances, the recurring representation of the 112 number. With the involvement of the media, we think online education is also a good option in the series of stroke campaigns, but we think the original role-playing form is really effective. At the same time, we can see that the application of the new method requires great caution due to the education of developing children. For this reason, results can only be achieved through social and multidisciplinary cooperation involving neurologists, psychologists, kindergarten teachers, and parents.</p>.

Combining mathematical model for HRV mapping and machine learning to predict sudden cardiac death

Sudden cardiac death, a prominent cause of mortality, often occurs within a narrow time window of less than an hour. This study introduces a novel methodology with the aim of early prediction of sudden cardiac death. The proposed approach involves the extraction of diverse features from the ECG signal, including the calculation of angles between two vectors, the computation of triangle areas formed by consecutive points, the determination of the shortest distance to a 450 line, and their combinations. Additionally, a thresholding technique is proposed to identify the risk period and predict the occurrence of sudden death. To assess the performance of the algorithm, data from the MIT-BH Holter database were utilized. The results obtained demonstrate that the angle feature achieves an average sensitivity of 93.75% with five false alarms, the area feature achieves an average sensitivity of 88.75% with nine false alarms, the shortest distance feature achieves an average sensitivity of 86.25% with 12 false alarms, and the combined feature achieves an average sensitivity of 96.25% with three false alarms. Remarkably, unlike existing methodologies in the literature, this method exhibits high accuracy in predicting the development of the risk of sudden cardiac death (SCD) even up to 30 min prior to onset. As a consequence, it plays a critical role in diagnosing patients' conditions and facilitating timely interventions. Moreover, the results confirm the feasibility of predicting cardiac arrest solely based on geometric features derived from variations in heart rate variability (HRV) dynamics.

Upregulation of miRNA-200c during Disease Progression in COVID-19 Patients.

The COVID-19 pandemic has caused more than 6 million deaths worldwide since its first outbreak in December 2019 and continues to be a major health problem. Several studies have established that the infection by SARS-CoV-2 can be categorized in a viremic, acute and recovery or severe phase. Hyperinflammation during the acute pneumonia phase is a major cause of severe disease progression and death. Treatment of COVID-19 with directly acting antivirals is limited within a narrow window of time between first clinical symptoms and the hyperinflammatory response. Therefore, early initiation of treatment is crucial to assure optimal health care for patients. Molecular diagnostic biomarkers represent a potent tool to predict the course of disease and thus to assess the optimal treatment regimen and time point. Here, we investigated miRNA-200c as a potential marker for the prediction of the severity of COVID-19 to preventively initiate and personalize therapeutic interventions in the future. We found that miRNA-200c correlates with the severity of disease. With retrospective analysis, however, there is no correlation with prognosis at the time of hospitalization. Our study provides the basis for further evaluation of miRNA-200c as a predictive biomarker for the progress of COVID-19.

Aspects of xenobiotics and their receptors in stroke

AbstractStroke is devastating and the second leading cause of disability and death worldwide. The pathophysiology of stroke is intricate involving oxidative stress, ionic imbalance, and excitotoxicity leading to cell death. The current therapeutic strategies for ischemic stroke primarily aim to restore cerebral blood flow by removing clots using intravenous thrombolysis and mechanical thrombectomy. However, hemorrhagic stroke requires different therapeutic interventions, where intravenous thrombolysis worsens the persistent condition. Nevertheless, the present treatment strategies do not provide effective neuroprotection as they have limitations such as narrow time window, specialized clinics and personnel, and higher expense. Therefore, studies on novel therapeutic strategies that can render neuroprotection over an extended time with minimum adverse effects are solicited. Xenobiotics are agents that are foreign to the biological system but can regulate their metabolism by binding to different xenobiotic receptors (XRs) to produce toxic substances. Modulation of XRs in different preclinical studies have shown benefits in the stroke outcome. Therefore, targeting XRs may be a future therapeutic strategy for stroke intervention. The present review briefly discusses various implications of xenobiotics and their receptors to evolve as a potential therapeutic target for prospective use as an adjunctive therapy for stroke.

Identification of immunogenic cell death-related gene classification patterns and immune infiltration characterization in ischemic stroke based on machine learning.

Ischemic stroke (IS) accounts for more than 80% of strokes and is one of the leading causes of death and disability in the world. Due to the narrow time window for treatment and the frequent occurrence of severe bleeding, patients benefit less from early intravenous thrombolytic drug therapy. Therefore, there is an urgent need to explore the molecular mechanisms poststroke to drive the development of new therapeutic approaches. Immunogenic cell death (ICD) is a type of regulatory cell death (RCD) that is sufficient to activate the adaptive immune response of immunocompetent hosts. Although there is growing evidence that ICD regulation of immune responses and immune responses plays an important role in the development of IS, the role of ICD in the pathogenesis of IS has rarely been explored. In this study, we systematically evaluated ICD-related genes in IS. The expression profiles of ICD-related genes in IS and normal control samples were systematically explored. We conducted consensus clustering, immune infiltration analysis, and functional enrichment analysis of IS samples using ICD differentially expressed genes. The results showed that IS patients could be classified into two clusters and that the immune infiltration profile was altered in different clusters. In addition, we performed machine learning to screen nine signature genes that can be used to predict the occurrence of disease. We also constructed nomogram models based on the nine risk genes (CASP1, CASP8, ENTPD1, FOXP3, HSP90AA1, IFNA1, IL1R1, MYD88, and NT5E) and explored the immune infiltration correlation, gene-miRNA, and gene-TF regulatory network of the nine risk genes. Our study may provide a valuable reference for further elucidation of the pathogenesis of IS and provide directions for drug screening, personalized therapy, and immunotherapy for IS.

A Prediction Model for Rapid Identification of Ischemic Stroke: Application of Serum Soluble Corin.

Rapid identification is critical for ischemic stroke due to the very narrow therapeutic time window. The objective of this study was to construct a diagnostic model for the rapid identification of ischemic stroke. A mixture population constituted of patients with ischemic stroke (n = 481), patients with hemorrhagic stroke (n = 116), and healthy individuals from communities (n = 2498) were randomly resampled into training (n = 1547, mean age: 55 years, 44% males) and testing (n = 1548, mean age: 54 years, 43% males) samples. Serum corin was assayed using commercial ELISA kits. Potential risk factors including age, sex, education level, cigarette smoking, alcohol consumption, obesity, blood pressure, lipids, glucose, and medical history were obtained as candidate predictors. The diagnostic model of ischemic stroke was developed using a backward stepwise logistic regression model in the training sample and validated in the testing sample. The final diagnostic model included age, sex, cigarette smoking, family history of stroke, history of hypertension, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, fasting glucose, and serum corin. The diagnostic model exhibited good discrimination in both training (AUC: 0.910, 95% CI: 0.884-0.936) and testing (AUC: 0.907, 95% CI: 0.881-0.934) samples. Calibration curves showed good concordance between the observed and predicted probability of ischemic stroke in both samples (all P>0.05). We developed a simple diagnostic model with routinely available variables to assist rapid identification of ischemic stroke. The effectiveness and efficiency of this model warranted further investigation.

Is bank resilience affected by unconventional monetary policy in the Euro area?

This paper examines whether euro area unconventional monetary policies have influenced the overall resilience of the banking industry. We proxy bank resilience with a Z-score measure that reflects the size of banks’ loss-absorbing buffers. We employ two alternative strategies to construct instruments that allow us to identify the effect of monetary policy in this context. First, within a two-stage least squares framework, we rely on ECB balance sheet data to capture the effect of the broad array of programmes used by the ECB to implement quantitative easing, while we control for the effect of conventional and negative, or very low, interest rate policy. Second, relying on high-frequency identification methods on narrow time windows around ECB policy announcements, we compute three factors reflecting different types of monetary policy surprises and examine their impact on bank resilience. With both methodologies we find that loosening the monetary policy stance through UMPs had an overall positive impact on euro-area banks’ shock absorbing buffers. The first approach, the only one that allows us to consider the level of interest rates, suggests that such effect is moderated when policy rates approach and breach the nominal zero-lower bound. The second strategy, which allows us to analyse forward guidance surprises, indicates that looser forward guidance has a positive impact on resilience. Balance sheet easing policies also seem to enhance resilience in the full sample, according to both strategies. The results are heterogeneous across subsamples, with contrasts between banks headquartered in core countries of the euro area vis-à-vis banks in the periphery of the euro-area. The contours of this heterogeneity differ in both methodologies and shows that balance sheet easing policies is detrimental for euro-area periphery banks. We also study the differential impact of monetary policy tools on banks, depending on their specific business model and their strength (i.e., their position within the distribution of loss-absorbing buffers); and the timing and persistence of monetary policy effects, which also varies with policy tools and jurisdictions.

Point-of-Care Assessment of Direct Oral Anticoagulation in Acute Ischemic Stroke: Protocol for a Prospective Observational Diagnostic Accuracy Study.

Treatment of ischemic stroke with recombinant tissue plasminogen activator for intravenous thrombolysis (IVT) must be delivered within a narrow time window after symptom onset. This effective hyperacute treatment can be administered after ruling out active anticoagulation with direct oral anticoagulants (DOACs). Whenever this is impractical, e.g., due to aphasia, plasmatic DOAC levels are measured with a consequent delay in the IVT decision-making process ranging from 30 to 60 minutes of time. This study will test the hypothesis that hyperacute point-of-care assessment of clotting time in the patient's whole blood has sufficient diagnostic accuracy to determine immediately whether stroke patients are pretreated with DOAC. This will be a prospective single-center diagnostic accuracy study in 1,850 consecutive acute ischemic stroke patients at a tertiary stroke center in Saxony, Germany. Presence of active anticoagulation with DOAC will be determined by point-of-care quantification of clotting time via whole blood viscoelastic testing (ClotPro) using Russell venom viper and ecarin assay compared with high-performance liquid chromatography-tandem mass spectrometry as the reference standard. Viscoelastic point-of-care assessment of clotting time in whole blood might improve swift delivery of time-sensitive hyperacute treatment with IVT in stroke patients.

Immediate protein expression from exogenous mRNAs in embryonic brain

mRNA vaccines for SARS-CoV-2 have been widely used and saving millions of people in the world. How efficiently proteins are produced from exogenous mRNAs in the embryonic brain, however, is less known. Here we show that protein expression occurs highly efficiently in neural stem cells, in a very narrow time window after mRNA electroporation in the embryonic mouse brain, where plasmids have been successfully transfected. Protein expression is detected 1 h and 12 h after the electroporation of mRNAs and plasmids, respectively. The delivery of exogenous mRNAs may be useful for not only vaccines but also functional analysis in the brain.

Discovery, Chemistry, and Preclinical Development of Pritelivir, a Novel Treatment Option for Acyclovir-Resistant Herpes Simplex Virus Infections.

When the nucleoside analogue acyclovir was introduced in the early 1980s, it presented a game-changing treatment modality for herpes simplex virus infections. Since then, work has been ongoing to improve the weaknesses that have now been identified: a narrow time window for therapeutic success, resistance in immunocompromised patients, little influence on frequency of recurrences, relatively fast elimination, and poor bioavailability. The present Drug Annotation focuses on the helicase-primase inhibitor pritelivir currently in development for the treatment of acyclovir-resistant HSV infections and describes how a change of the molecular target (from viral DNA polymerase to the HSV helicase-primase complex) afforded improvement of the shortcomings of nucleoside analogs. Details are presented for the discovery process leading to the final drug candidate, the pivotal preclinical studies on mechanism of action and efficacy, and on how ongoing clinical research has been able to translate preclinical promises into clinical use.

A review of helochelydrid shell material from late Albian to early Cenomanian greensands of Southern England, United Kingdom.

A number of helochelydrid turtle shell remains were recovered over the course of the 19th century from mid-Cretaceous sediments throughout Southern England, including the poorly figured and described types of Trachydermochelys phlyctaenus from the Cambridge Greensand of Cambridgeshire, Plastremys lata from the Upper Greensand of the Isle of Wight, and "Trachydermochelys" rutteri from the Melbury Sandstone of Dorset. A review of stratigraphic provenience suggests that all material originates from late Late Aptian portions of the Upper Greensand or early Early Cenomanian portions of the West Melbury Marly Chalk Formation, a relatively narrow time window geologically speaking. As described, Trachydermochelys phlyctaenus is a problematic taxon, because the most plausible type series is a chimera that includes two helochelydrid morphotypes in addition to protostegid remains. This conundrum is resolved through the designation of a lectotype. A review of all historic material confirms the presence of three English taxa distinct from Helochelydra danubina, a coeval taxon named from Germany. At least four helochelydrid taxa, therefore, occurred in western Europe during the Early to Late Cretaceous transition.

Monetary Policy and Liquidity Constraints: Evidence from the Euro Area

We quantify the relationship between the response of output to monetary policy shocks and the share of liquidity-constrained households. We do so in the context of the euro area, using a Local Projections Instrumental Variables estimation. We construct an instrument for changes in interest rates from changes in overnight indexed swap rates in a narrow time window around ECB announcements. Monetary policy shocks have heterogeneous effects on output across countries. Using micro data, we show that the elasticity of output to monetary policy shocks is larger in countries that have a larger fraction of households that are liquidity constrained. (JEL E23, E43, E52, F33, F45, G51)

Pine caterpillar occurrence modeling using satellite spring phenology and meteorological variables

Outbreaks of leaf-feeding Lepidopteran insects substantially weaken the quality of forest trees and strongly affect the ecosystem functions of plant photosynthesis and carbon uptake. The narrow phenological time window of leaf out about ten days, during which Lepidopteran larvae feed on high nutrient newly flushed leaves, may change the insect community and outbreak dynamics by determining the survival rate of larvae. The Chinese pine Caterpillar (Dendrolimus tabulaeformis Tsai et Liu) infestation of the northern Chinese pine (Pinus tabulaeformis) forest in China is a major concern, and accurately modeling the day of insect occurrence (DIO) in the spring remains challenging. With continuous in-situ observed insect activities of 20 plots and satellite and meteorological observations from 1983 to 2014, we found a strong synchronization (r = 0.54, p = 0.001) between the satellite-based vegetation spring phenology, i.e. the green-up day (GUD), and DIO of the pine caterpillar over time. We used partial least squares regression and ridge regression models, and identified that monthly preseason air temperature, wind speed, specific humidity, and downward radiation were key environmental cues that awakened the overwintering pine caterpillars. After removing the collinearity of multiple variables, we showed that the dimensionality reduction-based regression models substantially improved the accuracy of DIO modeling than commonly used models, such as interval and degree-day models. In particular, including GUD significantly enhanced the predictive strength of the models increasing the coefficient of determination (R 2) by 17.1% and consequently a decrease of 16.5% in the root mean square error. We further showed that evapotranspiration changed the environmental moisture content, which indirectly affected the activities of insects. Our results revealed a useful linkage between spring leaf development and insect occurrence, and therefore are of great importance for the large-scale monitoring of pest outbreaks with future remote sensing observations.

A Dilp8-dependent time window ensures tissue size adjustment in Drosophila.

The control of organ size mainly relies on precise autonomous growth programs. However, organ development is subject to random variations, called developmental noise, best revealed by the fluctuating asymmetry observed between bilateral organs. The developmental mechanisms ensuring bilateral symmetry in organ size are mostly unknown. In Drosophila, null mutations for the relaxin-like hormone Dilp8 increase wing fluctuating asymmetry, suggesting that Dilp8 plays a role in buffering developmental noise. Here we show that size adjustment of the wing primordia involves a peak of dilp8 expression that takes place sharply at the end of juvenile growth. Wing size adjustment relies on a cross-organ communication involving the epidermis as the source of Dilp8. We identify ecdysone signaling as both the trigger for epidermal dilp8 expression and its downstream target in the wing primordia, thereby establishing reciprocal hormonal feedback as a systemic mechanism, which controls organ size and bilateral symmetry in a narrow developmental time window.

O-Glycoproteomic analysis of engineered heavily glycosylated fusion proteins using nanoHILIC-MS

Recombinant protein engineering design affects therapeutic properties including protein efficacy, safety, and immunogenicity. Importantly, glycosylation modulates glycoprotein therapeutic pharmacokinetics, pharmacodynamics, and effector functions. Furthermore, the development of fusion proteins requires in-depth characterization of the protein integrity and its glycosylation to evaluate their critical quality attributes. Fc-fusion proteins can be modified by complex glycosylation on the active peptide, the fragment crystallizable (Fc) domain, and the linker peptides. Moreover, the type of glycosylation and the glycan distribution at a given glycosite depend on the host cell line and the expression system conditions that significantly impact safety and efficacy. Because of the inherent heterogeneity of glycosylation, it is necessary to assign glycan structural detail for glycoprotein quality control. Using conventional reversed-phase LC–MS methods, the different glycoforms at a given glycosite elute over a narrow retention time window, and glycopeptide ionization is suppressed by co-eluting non-modified peptides. To overcome this drawback, we used nanoHILIC-MS to characterize the complex glycosylation of UTI-Fc, a fusion protein that greatly increases the half-life of ulinastatin. By this methodology, we identified and characterized ulinastatin glycopeptides at the Fc domain and linker peptide. The results described herein demonstrate the advantages of nanoHILIC-MS to elucidate glycan features on glycotherapeutics that fail to be detected using traditional reversed-phase glycoproteomics.

Temporal origin of mouse claustrum and development of its cortical projections.

The claustrum is known for its extensive connectivity with many other forebrain regions, but its elongated shape and deep location have made further study difficult. We have sought to understand when mouse claustrum neurons are born, where they are located in developing brains, and when they develop their widespread connections to the cortex. We established that a well-characterized parvalbumin plexus, which identifies the claustrum in adults, is only present from postnatal day (P) 21. A myeloarchitectonic outline of the claustrum can be derived from a triangular fiber arrangement from P15. A dense patch of Nurr1+ cells is present at its core and is already evident at birth. Bromodeoxyuridine birth dating of forebrain progenitors reveals that the majority of claustrum neurons are born during a narrow time window centered on embryonic day 12.5, which is later than the adjacent subplate and endopiriform nucleus. Retrograde tracing revealed that claustrum projections to anterior cingulate (ACA) and retrosplenial cortex (RSP) follow distinct developmental trajectories. Claustrum-ACA connectivity matures rapidly and reaches adult-like innervation density by P10, whereas claustrum-RSP innervation emerges later over a protracted time window. This work establishes the timeline of claustrum development and provides a framework for understanding how the claustrum is built and develops its unique connectivity.

Tissue Rotation of the Xenopus Anterior-Posterior Neural Axis Reveals Profound but Transient Plasticity at the Mid-Gastrula Stage.

The establishment of anterior–posterior (AP) regional identity is an essential step in the appropriate development of the vertebrate central nervous system. An important aspect of AP neural axis formation is the inherent plasticity that allows developing cells to respond to and recover from the various perturbations that embryos continually face during the course of development. While the mechanisms governing the regionalization of the nervous system have been extensively studied, relatively less is known about the nature and limits of early neural plasticity of the anterior–posterior neural axis. This study aims to characterize the degree of neural axis plasticity in Xenopus laevis by investigating the response of embryos to a 180-degree rotation of their AP neural axis during gastrula stages by assessing the expression of regional marker genes using in situ hybridization. Our results reveal the presence of a narrow window of time between the mid- and late gastrula stage, during which embryos are able undergo significant recovery following a 180-degree rotation of their neural axis and eventually express appropriate regional marker genes including Otx, Engrailed, and Krox. By the late gastrula stage, embryos show misregulation of regional marker genes following neural axis rotation, suggesting that this profound axial plasticity is a transient phenomenon that is lost by late gastrula stages.