Early Events Research Articles

Ancient Tsunami Records in the Viscous Remanent Magnetization of Reworked Boulders in the Kingdom of Tonga

AbstractThe movement history of boulders is crucial for the reconstruction of paleo‐tsunamis. We report findings from viscous remanent magnetization studies of the boulders on Tongatapu Island, aiming to reconstruct their reworkings. Two boulders exhibited viscous remanence, whereas two larger boulders lacked viscous components but exhibited stable remanence. Both the viscous and stable components deviated from the geomagnetic field direction. These observations indicate that: (a) the boulders with a viscous component were reworked before the latest event, which could have reworked all boulders, and (b) the magnitude of the latest event was larger than that of an earlier event. The reworked timing indicated that the event occurred between 3,000 years ago and the fifteenth century. The difference in the wave height required to move boulders on the eastern and western coasts suggests that the source of the earlier tsunami was likely an eruption due to volcanoes along the Tonga Ridge.

Prognostic role of gene variants in sudden cardiac death risk associated to paediatric hypertrophic cardiomyopathy

Abstract Introduction Genetic testing plays an important role in diagnosis of hypertrophic cardiomyopathy (HCM), being sarcomeric genes commonly involved, particularly MYBPC3. However, arrhythmic risk related to genotype remains unclear in adults and almost unexplored in children. Hence, current sudden cardiac death (SCD) risk calculators do not include genetic information. Purpose To analyse risk of arrhythmic events associated with causal variants in MYBPC3 respecting to other genes in a paediatric cohort with non-syndromic HCM from a cardiomyopathy referral centre. Methods This retrospective study included patients with non-syndromic HCM 0-18 years old between 2009-2022. Demographic, clinical, and genetic data were collected. Genetic variants pathogenicity followed American College of Medical Genetics criteria. A positive genetic test was considered if a likely pathogenic or pathogenic variant in HCM related genes was found. Considered outcomes were SCD or a major arrhythmic cardiac event (MACE) within 5 years follow-up: recovered SCD, appropriate ICD therapy, or sustained ventricular tachycardia. Some SCD-risk estimation models (in 5 years) as HCM Risk-SCD model for patients >=15 y.o and/or 55 kg, ESC Guidelines paediatric algorithm, and HCM Risk-Kids model were applied. Results 77 patients were diagnosed with non-syndromic HCM. A causal variant was found in 45/73 (62%). No significant differences in cardiac phenotype were found related to genes. 10/77 patients (13%) presented a MACE in 5 years follow-up. A positive genetic study was significantly associated with having an event (p=0.011). Most patients with a positive genetic test harboured MYBPC3 variants (21/45, 47%), however only 2 patients who suffered a MACE had a causal variant in MYBPC3. Those with causal variants in genes other than MYBPC3 presented more and earlier events (p=0.022). Risk of having a MACE during follow-up was higher when presenting causal variants in genes other than MYBPC3: Hazard Ratio 18.5 (95% CI 2.31, 148), p=0.006. Applying HCM Risk-SCD calculator, model had better predictive discrimination when variable "causal variant in gene other than MYBPC3" was added in multivariate analysis, with high-risk category >=6% (C-statistic =0.931 vs 0.844) and intermediate-risk category 4-6% (C-statistic =0.845 vs 0.514). Same occurred with ESC Guidelines algorithm, adding that variable to 2 risk factors category (C-statistic =0.881 vs 0.742) or 1 risk factor (C-statistic =0.844 vs 0.635). HCM Risk-Kids also improved its predictive discrimination adding the genetic value to high-risk category >=6% (C-statistic =0.896 vs 0.796) and intermediate-risk (C-statistic =0.821 vs 0.506). Conclusions Genotype may have prognostic value in SCD risk in HCM in children. Our results suggests that causal genetic variants in genes other than MYBPC3 can lead to higher risk of SCD. Genetic information might be considered for future models of arrhythmic risk in children with HCM.

Remembering change: Interdependence between change awareness and meaningful connection in achieving proactive facilitation.

Two experiments investigated proactive facilitation (PF) or proactive interference (PI) in the recall of recently learned targets, under conditions of assessing the detection and recollection of target changes across two learning phases (with A-B/A-D word pairs). Some changes established meaningful connections across the phases; others did not. Task instructions on the subsequent cued-recall test (Experiment 1) or during Phase 2 study (Experiment 2) guided participants (university students) to monitor and report the changes. Accuracy in cued recall conditionalized on measures of change awareness replicated previous findings in establishing conditions for PF and PI. However, PF was much reduced for unconnected materials. Moreover, when change recollection failed, PI occurred even under conditions of meaningful connections (Experiment 1). Discussion emphasizes this interdependence of meaningfulness of connections and change awareness in influencing whether and how memory for earlier events affects memory for more recent ones.

Activity-dependent synapse clustering underlies eye-specific competition in the developing retinogeniculate system.

Co-active synaptic connections are often spatially clustered to facilitate local dendritic computations underlying learning, memory, and basic sensory processing. In the mammalian visual system, retinal ganglion cell (RGC) axons converge to form clustered synaptic inputs that enable local signal integration in the dorsal lateral geniculate nucleus (dLGN) of the thalamus. While visual experience promotes retinogeniculate synapse clustering after eye-opening, the earliest events in cluster formation prior to visual experience are unknown. Here, using volumetric super-resolution single-molecule localization microscopy and eye-specific labeling of developing retinogeniculate synapses in mice, we show that synaptic clustering is eye-specific and activity-dependent during retinogeniculate refinement in the first postnatal week. We identified a subset of retinogeniculate synapses with multiple active zones that are surrounded by like-eye synapses and depleted of synapse clustering from the opposite eye. In mutant mice with disrupted spontaneous retinal wave activity, synapses with multiple active zones still form, but do not exhibit the synaptic clustering seen in controls. These results highlight a role for spontaneous retinal activity in regulating eye-specific synaptic clustering in circuits essential for visual perception and behavior.

Mechanics of reproductive differentiation in the land plants: a paradigm shift?

This article addresses the physical mechanics of gametogenesis in vascular plants. The earliest events that initiate reproductive differentiation in the land plants are not well understood. How are the few cells that initiate reproductive differentiation specified and how is that information translated into action at the cellular level? In this article I propose a physical mechanism that resolves the problem of spatial targeting without invoking dependence on diffusible morphogens or other external signals. I suggest that the initiation of archesporial differentiation can instead be attributed to the confluence of organ geometry, surficial topography, and the physical mechanics of sporangial growth, resulting in the spontaneous emergence of an isotropic singularity that locates and precipitates archesporial differentiation. In discussing the logic of single-cell target selection and the limits of stochastic molecular signaling I propose that the sporangium would be better understood as a pressurized stress-mechanical lens that focuses turgor-generated growth forces on a central location, generating a physical singularity that locates and specifies the cell or cells that become the archesporium and initiates their transition from somatic proliferation to reproductive differentiation.

Distinct copy number signatures between residual benign and transformed areas of carcinoma ex pleomorphic adenoma

The mechanisms involved with the pathogenesis of carcinoma ex pleomorphic adenoma (CXPA) seem to be associated with the accumulation of molecular alterations in the pleomorphic adenoma (PA). In this sense, using array-based comparative genomic hybridization (aCGH) a rare series of 27 cases of CXPA and 14 residual PA (rPA) adjacent to the transformation area, we investigated the profile of the copy number alterations (CNAs) comparing benign residual and transformed areas. The main findings were correlated with the histopathological classification by histologic subtype and degree of invasion. The distribution of losses (p = 0.187) and amplifications (p = 0.172) was not statistically different between rPA and CXPA. The number of gains was increased in the transformed areas compared to the benign residual areas (p = 0.005). PLAG1 gain was maintained along the malignant transformation, as it was observed in both residual PA and CXPA samples, likely being an earlier event during transformation. The amplification of GRB7 and ERBB2 may also be an initial step in the malignant transformation of PA to CXPA (salivary duct carcinoma subtype). Furthermore, the amplification of HMGA2 and RPSAP52 were the most prevalent alterations among the studied samples. It was noteworthy that amplified genes in the transformed areas of the tumors were enriched for biological processes related to immune signaling. In conclusion, our results underscored for the first-time crucial CNAs in CXPA, some of them shared with the residual benign area adjacent to the transformation site. These CNAs included PLAG1 gain, as well as amplification of GRB7, ERBB2, HMGA2, and RPSAP52.

Rapid drops of ocean temperatures in several shallow bays in Nova Scotia during a recent cold air outbreak

Abstract From February 3-5, 2023 Atlantic Canada experienced an extremecold Arctic air outbreak with high winds that set many local meteor-ological records, including wind chills as low as -47°C. The impacts of the cold air outbreak on ocean temperatures and ice formation are investigated using predictions from the Coastal Ice-Ocean Prediction System for the East Coast of Canada (CIOPS-E), developed by Environment and Climate Change Canada. Observations from moorings further inform the predictions. The analysis suggests that during the event, several shallow bays and coastal areas in Nova Scotia experienced significant, abrupt temperature decreases ranging from 1.0 to 3.9°C. Overall cooling estimated by the model was 2.3°C for nearshore locations where observations recorded an average temperature decrease of 3.0°C. On the other hand, at individual sites the difference between observed and modelled cooling was up to 2.4°C. This difference can be attributed partly to the fact that the model does not adequately resolve the coastline features of some of the nearshore mooring sites. In comparison, we also analyze another cold air outbreak that occurred on December 15-18, 2016, with wind chills as low as -37°C. The ocean temperatures changes associated with this earlier event saw decreases of 0.8 to 3.5°C, potentially contributing to an ongoing fish kill in St. Mary’s Bay (near the mouth of the Bay of Fundy) at the time. Keywords: Ocean temperature, Cold air outbreak, Ocean forecasting, Shallow bays, Nova Scotia

Impact of North Atlantic Tripole and Extratropical North Pacific Extreme SSTs on the 2023/24 El Niño

AbstractObservations revealed notable discrepancies in the 2023/24 El Niño compared to earlier events, despite registering moderate Niño3.4 index magnitudes. Essential indicators such as the westerly wind burst, thermocline zonal tilting, and eastward propagation of oceanic Kelvin waves were conspicuously weak, indicating a weak air‐sea coupled in contrast to past occurrences, the 2023/24 El Niño coincided with unusually high North Atlantic Tripole and extratropical North Pacific sea surface temperatures (SSTs). The elevated North Atlantic Tripole SST triggered a strong negative Pacific meridional mode and easterly anomalies in the equatorial western‐central Pacific. At the same time, the extratropical North Pacific SST induced a negative Pacific Decadal Oscillation‐like pattern. These anomalies potentially dampened SST‐wind coupling during the developmental stages of El Niño. The negative Pacific meridional mode distinguished the 2023/24 El Niño from previous events and substantially altered its local and remote influences.

Tsg101 UEV Interaction with Nedd4 HECT Relieves E3 Ligase Auto-Inhibition, Promoting HIV-1 Assembly and CA-SP1 Maturation Cleavage.

Tsg101, a component of the endosomal sorting complex required for transport (ESCRT), is responsible for recognition of events requiring the machinery, as signaled by cargo tagging with ubiquitin (Ub), and for recruitment of downstream acting subunits to the site. Although much is known about the latter function, little is known about its role in the earlier event. The N-terminal domain of Tsg101 is a structural homologue of Ub conjugases (E2 enzymes) and the protein associates with Ub ligases (E3 enzymes) that regulate several cellular processes including virus budding. A pocket in the domain recognizes a motif, PT/SAP, that permits its recruitment. PT/SAP disruption makes budding dependent on Nedd4L E3 ligases. Using HIV-1 encoding a PT/SAP mutation that makes budding Nedd4L-dependent, we identified as critical for rescue the residues in the catalytic (HECT) domain of the E3 enzyme that lie in proximity to sites in Tsg101 that bind Ub non-covalently. Mutation of these residues impaired rescue by Nedd4L but the same mutations had no apparent effect in the context of a Nedd4 isomer, Nedd4-2s, whose N-terminal (C2) domain is naturally truncated, precluding C2-HECT auto-inhibition. Surprisingly, like small molecules that disrupt Tsg101 Ub-binding, small molecules that interfered with Nedd4 substrate recognition arrested budding at an early stage, supporting the conclusion that Tsg101-Ub-Nedd4 interaction promotes enzyme activation and regulates Nedd4 signaling for viral egress. Tsg101 regulation of E3 ligases may underlie its broad ability to function as an effector in various cellular activities, including viral particle assembly and budding.

Oral and poster contributions for conferences: Some observations and recommendations

The recent 13th South American Symposium on Isotope Geology (SSAGI) in May 2024 in Buzios (Brazil) was an excellent conference, showcasing the current diversity and high standard of isotope geochemistry and geology at universities and research institutions across Latin America. Three days of oral and poster presentations provided a great forum for scientific and social exchange. This conference, however, also further supported observations made at earlier events that many oral and poster presentations by postgraduate students and docents alike suffer from a number of problems. There is ample scope for improvement, in the interest of more efficient information transfer and better exchange with colleagues. The main problem areas noted (e.g., overloading of powerpoint slides, and of posters, with diagrams and/or text; application of poor color, etc.) are discussed here, and suggestions are made how to avoid these issues and improve our scientific communication.

Two assumptions of the prior event rate ratio approach for controlling confounding can be evaluated by self-controlled case series and dynamic random intercept modeling

ObjectivesThe prior event rate ratio (PERR) is a recently developed approach for controlling confounding by measured and unmeasured covariates in real-world evidence research and observational studies. Despite its rising popularity in studies of safety and effectiveness of biopharmaceutical products, there is no guidance on how to empirically evaluate its model assumptions. We propose two methods to evaluate two of the assumptions required by the PERR, specifically, the assumptions that occurrence of outcome events does not alter the likelihood of receiving treatment, and that earlier event rate does not affect later event rate. Study Design and SettingWe propose using self-controlled case series (SCCS) and dynamic random intercept modeling (DRIM), respectively, to evaluate the two aforementioned assumptions. A nonmathematical introduction of the methods and their application to evaluate the assumptions are provided. We illustrate the evaluation with secondary analysis of deidentified data on pneumococcal vaccination and clinical pneumonia in The Gambia, West Africa. ResultsSCCS analysis of data on 12,901 vaccinated Gambian infants did not reject the assumption of clinical pneumonia episodes had no influence on the likelihood of pneumococcal vaccination. DRIM analysis of 14,325 infants with a total of 1719 episodes of clinical pneumonia did not reject the assumption of earlier episodes of clinical pneumonia had no influence on later incidence of the disease. ConclusionThe SCCS and DRIM methods can facilitate appropriate use of the PERR approach to control confounding. Plain Language SummaryThe prior event rate ratio is a promising approach for analysis of real-world data and observational studies. We propose two statistical methods to evaluate the validity of two assumptions it is based on. They can facilitate appropriate use of the prior even rate ratio.

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model.

Friedreich's ataxia (FRDA) is one of the most common hereditary ataxias. It is caused by a GAA repeat in the first intron of the FXN gene, which encodes an essential mitochondrial protein. Patients suffer from progressive motor dysfunction due to the degeneration of mechanoreceptive and proprioceptive neurons in dorsal root ganglia (DRG) and cerebellar dentate nucleus neurons, especially at early disease stages. Postmortem analyses of FRDA patients also indicate pathological changes in motor cortex including in the projection neurons that give rise to the cortical spinal tract (CST). Yet, it remains poorly understood how early in the disease cortical spinal neurons (CSNs) show these alterations, or whether CSN/CST pathology resembles the abnormalities observed in other tissues affected by FXN loss. To address these questions, we examined CSN driven motor behaviors and pathology in the YG8JR FRDA mouse model. We find that FRDA mice show impaired motor skills, exhibit significant reductions in CSN functional output, and, among other pathological changes, show abnormal mitochondrial distributions in CSN neurons and CST axonal tracts. Moreover, some of these alterations were observed as early as two months of age, suggesting that CSN/CST pathology may be an earlier event in FRDA disease than previously appreciated. These studies warrant a detailed mechanistic understanding of how FXN loss impacts CSN health and functionality.

Event Modification in EFL Learners’ Narration: A Case Study on Retelling Alibaba Story

Experiences of events of both direct and vicarious ones are perceived, organized, sequenced and represented in narrative text in coherent structure. An event consist of character, action and setting. The representation of the events in narration is realized in narrative discourse. The coherent text structure is used to narrate sequence of events in various discourse strategies. This structure is also used to understand a narrative texts. Narratives comprises of constituents and supplementary events. The constituent events are causal in the sense that earlier event contributes to the occurrence of the next event that keep the story moving forward. The supplementary events are not causal; they can be removed without disturbing continuance of the story. Supplementary events are responsible for the meaning and impact of the story. If the supplementary events are removed, the meaning and impact of the story decreases. This background leads the research to investigate event modification and find out narrative discourse used to convey the story. To collect the data, the students were assigned to listen to the story of Alibaba with forty thieves, having listened to the story, they are assigned to modify the story, and retold the modified story in written form. The data were analyzed by comparing the original and the modified story based on every aspect of story structure. The results show that the students’ story modification is limited to the modification of characters and supplementary events; constituent events and narrative discourse are retained; no modification was done to the two aspects. This leads to the conclusion that sequences of events are organized, understood and produced in a coherent structure.

Gomisin N rescues cognitive impairment of Alzheimer's disease by targeting GSK3β and activating Nrf2 signaling pathway

Oxidative stress is one of the earlier events causing neuronal dysfunction in Alzheimer's disease (AD). Gomisin N (GN), a lignin isolated from Schisandra chinensis, has anti-oxidative stress effects. There are currently no studies on the neuroprotective potential of GN in AD. In this study, two AD models were treated with GN for 8 weeks. The cognitive functions, amyloid deposition, and neuronal death were assessed. Additionally, the expressions of critical proteins in the GSK3β/Nrf2 signaling pathway were determined in vivo and in vitro. We showed that GN significantly upregulated the expressions of Nrf2, p-GSK3βSer9/GSK3β, NQO1 and HO-1 proteins in SHSY-5Y/APPswe cells after H2O2 injury, whereas the PI3K inhibitor LY294002 reversed the increase in the expressions of Nrf2, p-GSK3βSer9/GSK3β, NQO1 and HO-1 proteins induced by GN administration. In a further study, GN could significantly improve the learning and memory dysfunctions of the rat and mouse AD models, reduce the area of Aβ plaques in the hippocampus and cortex, and increase the number and function of neurons. Here, we first demonstrate the neuroprotective effects of GN on AD in vivo and in vitro. A possible mechanism by which GN prevents AD is proposed: GN significantly increased the expressions of Nrf2, p-GSK3Ser9/GSK3β and NQO1 proteins in the brain of AD animal models and promoted Nrf2 nuclear translocation, then activated Nrf2 downstream genes to combat oxidative stress in AD pathogenesis. GN might be a promising therapeutic agent for AD.

Sexual Assaults: A Pakistani Women and Sexual Harassments in Universities and Recent Scandal of Islamia University of Bahawalpur

Without a doubt, human beings are viewed more favorably by educational pedagogy as educated individuals than stupid ones. The educational system makes a distinction between humans and other animals and portrays humans as noble beings. In an Islamic climate where, serious scandals are occurring daily, it has become very challenging. According to Pakistani media, Islamia University, Bahawalpur, Pakistan reported 5500,5400 or maybe 400 obscene video records of dormitory ladies during the time of July 2023. The largest example of sexual exploitation in Pakistan to date is the one involving Islamia University. An earlier event of a such nature at Gomal University in Dera Ismail Khan resulted in the professor's honorable release. According to media reports, the vice chancellor of IUB was only forced to quit because to this incident. Although the Crime Bureau's assessment claims that there is no origin and not even one, chaos quickly spread throughout Pakistan.

Activation of Nrf2 inhibits atherosclerosis in ApoE−/− mice through suppressing endothelial cell inflammation and lipid peroxidation

BackgroundNuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. MethodsRNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE−/− mice, while EC-specific knockdown of Nrf2 was generated in Cdh5CreCas9floxed-stopApoE−/− mice. ResultsEndothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE−/− mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5CreCas9floxed-stopApoE−/− mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. ConclusionsUpon HCD feeding in ApoE−/− mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.

Impact of coseismic uplifting on relative sea level change in the Southern Adriatic during the past 4.500 years – New evidence from Dubrovnik epicentral area based on analysis of algal rims and tidal notches

The Southern Adriatic is recognized as one of the most seismically active regions of the Central Mediterranean. It hosted the strongest historically known and instrumentally recorded earthquakes in Croatia and Montenegro. We conducted a detailed study of algal rims and tidal notches along the Dubrovnik–Konavle coastal area, aimed to contribute in reconstruction of relative sea level (RSL) change, palaeoearthquakes and neotectonics during the last 4500 years. The RSL reconstruction based on high-resolution geochronology showed that the spatial variability of RSL change is largely controlled by local tectonics, leading generally to an alternation of periods of RSL rise and rapid falls caused by coseismic uplift events. During the interseismic periods RSL rose at rates from 1.03 to 0.7 mm/yr before AD, followed by a slowdown to ~0.43 mm/yr, and reaching ~1.3 mm/yr after 1850s. The only exception relates to a period of slow RSL drop probably related to the 3.2 ka cold event. Rapid RSL falls caused by coseismic uplift indicate the occurrence of several large-scale events during the 4th–6th centuries AD, the 800–1360 cal AD period, and in 1395, with hints of earlier events between 1395 cal BC and 565 cal AD. These instances correspond to either unknown or insufficiently documented earthquakes. Conversely, the earthquakes in 1520 and 1667 have been clearly identified. The most compelling evidence of coseismic uplift is associated with the 1667 Dubrovnik earthquake, with an estimated uplift of 40–60 ± 15 cm documented along 40 km of coastline. Analyses of multiple sites with the same high-resolution marker show that Holocene tectonic deformations vary along different fault segments with minimum uplift rates ranging from ~0.3 to ~0.9 mm/yr over ~1.5 ka. The main seismogenic source responsible for coseismic uplifts is attributed to the Dalmatian unit basal thrust and its NE-dipping splays at the Adria-Dinarides boundary.

Influence of clay content on repeated liquefaction resistance of sand using element test

Soil liquefaction is a major concern because of its potential to cause building collapse, roadbed settlement, and sand eruptions. Field investigations have shown that clayey sand, when liquefied during mainshock, may undergo multiple liquefaction events during the subsequent aftershocks. Although previous research has primarily focused on the initial liquefaction event in clayey sand, research on the mechanism responsible for repeated liquefaction is limited. Consequently, a series of cyclic triaxial experiments are conducted on sand with varying clay contents, and these samples are subjected to various earthquake sequences. The primary objective of this study is to evaluate the cyclic behavior of sandy soil with clay content and analyze its repeated liquefaction resistance under different load sequences. A comprehensive assessment is conducted to understand the evolution of the repeated liquefaction resistance. The test results indicate that clayey sand exhibits the lowest liquefaction resistance during the second liquefaction event. Repeated liquefaction is dominated by stress-induced anisotropy at earlier events and relative density at the final events.

Evaluating neural crest cell migration in a Col4a1 mutant mouse model of ocular anterior segment dysgenesis

The periocular mesenchyme (POM) is a transient migratory embryonic tissue derived from neural crest cells (NCCs) and paraxial mesoderm that gives rise to most of the structures in front of the eye. Morphogenetic defects of these structures can impair aqueous humor outflow, leading to elevated intraocular pressure and glaucoma. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause Gould syndrome – a multisystem disorder often characterized by variable cerebrovascular, ocular, renal, and neuromuscular manifestations. Approximately one-third of individuals with COL4A1 and COL4A2 mutations have ocular anterior segment dysgenesis (ASD), including congenital glaucoma resulting from abnormalities of POM-derived structures. POM differentiation has been a major focus of ASD research, but the underlying cellular mechanisms are still unclear. Moreover, earlier events including NCC migration and survival defects have been implicated in ASD; however, their roles are not as well understood. Vascular defects are among the most common consequences of COL4A1 and COL4A2 mutations and can influence NCC survival and migration. We therefore hypothesized that NCC migration might be impaired by COL4A1 and COL4A2 mutations. In this study, we used 3D confocal microscopy, gross morphology, and quantitative analyses to test NCC migration in Col4a1 mutant mice. We show that homozygous Col4a1 mutant embryos have severe embryonic growth retardation and lethality, and we identified a potential maternal effect on embryo development. Cerebrovascular defects in heterozygous Col4a1 mutant embryos were present as early as E9.0, showing abnormal cerebral vasculature plexus remodeling compared to controls. We detected abnormal NCC migration within the diencephalic stream and the POM in heterozygous Col4a1 mutants whereby mutant NCCs formed smaller diencephalic migratory streams and POMs. In these settings, migratory NCCs within the diencephalic stream and POM localize farther away from the developing vasculature. Our results show for the first time that Col4a1 mutations lead to cranial NCCs migratory defects in the context of early onset defective angiogenesis without affecting cell numbers, possibly impacting the relation between NCCs and the blood vessels during ASD development.

The Alzheimer's Disease Brain, Its Microvasculature, and NADPH Oxidase.

The deterioration of the brain's microvasculature, particularly in the hippocampus, appears to be a very early event in the development of Alzheimer's disease (AD), preceding even the deposition of amyloid-β. A damaged microvasculature reduces the supply of oxygen and glucose to this region and limits the production of energy, ATP. The damage may be a function of the rise with age in the expression and activity of NADPH oxidase (NOX) in these microvessels. This rise renders these vessels vulnerable to the effects of oxidative stress and inflammation. The rise in NOX activity with age is even more marked in the AD brain where an inverse correlation has been demonstrated between NOX activity and cognitive ability. Apocynin, a putative NOX inhibitor, has been shown to block the damaging effects of NOX activation. Apocynin acts as a strong scavenger of H2O2, and as a weak scavenger of superoxide. Like apocynin, sodium oxybate (SO) has also been shown to block the toxic effects of NOX activation. The application of SO generates NADPH and ATP. SO inhibits oxidative stress and maintains normal cerebral ATP levels under hypoxic conditions. Moreover, it acts epigenetically to attenuate the expression of NOX. SO may delay the onset and slow the progress of AD by suppling energy and maintaining an antioxidative environment in the brain throughout the night. The slow wave activity produced by SO may also activate the glymphatic system and promote the clearance of amyloid-β from the brain.