Focal Events Research Articles

C-Src-induced vascular malformations require localised matrix degradation at focal adhesions.

Endothelial cells lining the blood vessel wall communicate intricately with the surrounding extracellular matrix, translating mechanical cues into biochemical signals. Moreover, vessels require the capability to enzymatically degrade the matrix surrounding them, to facilitate vascular expansion. c-Src plays a key role in blood vessel growth, with its loss in the endothelium reducing vessel sprouting and focal adhesion signalling. Here, we show that constitutive activation of c-Src in endothelial cells results in rapid vascular expansion, operating independently of growth factor stimulation or fluid shear stress forces. This is driven by an increase in focal adhesion signalling and size, with enhancement of localised secretion of matrix metalloproteinases responsible for extracellular matrix remodelling. Inhibition of matrix metalloproteinase activity results in a robust rescue of the vascular expansion elicited by heightened c-Src activity. This supports the premise that moderating focal adhesion-related events and matrix degradation can counteract abnormal vascular expansion, with implications for pathologies driven by unusual vascular morphologies.

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Neuroprotective effects of VCE-004.8 in a rat model of neonatal stroke

BackgroundCurrently there is no effective treatment for neonatal stroke, an acute neurologic syndrome with sequelae, due to focal ischemic, thrombotic, or hemorrhagic event occurring in the perinatal period. VCE-004.8, an aminoquinone exhibiting activity on CB2 and PPARγ receptors, is neuroprotective in adult mice models of acute and chronic brain damaging conditions. We hereby aimed to study VCE-004.8 neuroprotection in a rat model of neonatal stroke. Methods7-day-old (P7) Wistar rats of both sexes were submitted to Middle Cerebral Artery Occlusion (MCAO), receiving i.p. 30 min after vehicle (MCAO + VEH) or VCE-004.8 5 mg/kg (MCAO + VCE). Non-occluded rats served as controls (SHAM). MCAO consequences were assessed at P14 by MRI, histological (TUNEL staining), biochemical (lactate/n-acetyl aspartate ratio by 1H-NMR spectroscopy) and motor studies (grasp test), and at P37 assessing myelination (MBP signal), hemiparesis and hyperlocomotion. Effects of VCE-004.8 on excitotoxicity (glutamate/n-acetyl aspartate, 1H-NMR), oxidative stress (protein nitrosylation, Oxyblot) and neuroinflammation (Toll-like receptor 4 and TNFa expression, Western blot) were assessed at P14. Therapeutic window was assessed by delaying drug administration for 12 or 18 h. ResultsPost-MCAO administration of VCE-004.8 reduced the volume of infarct and histological and biochemical brain damage, reducing hyperlocomotion, restoring motor performance and preserving myelination, in a manner linked to the modulation of excitotoxicity, oxidative stress and neuroinflammation. VCE-004.8 was still effective being administered 12–18 h post-insult. ConclusionsThese data suggest that this drug could be effective for the treatment of stroke in newborns.

Transient deficit in acute stroke: a case of musical hallucinations

We reported a case of a 62-year-old female patient affected by musical hallucinations (MHs) as a transient symptom after an ischemic stroke in the right middle cerebral artery. CT scan showed widespread cortical and subcortical hypodensity associated with moderate hemorrhage involving the lentiform nucleus, insular cortex, and caudate nucleus. The patient had no history of psychiatric disorders, hearing defects, or epilepsy. MHs appeared one week after the stroke and spontaneously vanished 10 days after their onset. From our perspective, the early activation of MHs after unilateral brain injury, and their timing of resolution, can be explained according to the “interhemispheric imbalance theory”. According to this theory, in the minutes or weeks following the onset of a focal cerebrovascular event, a series of changes in global brain connectivity occur leading to a temporary imbalance in interhemispheric excitation.

Genomic analysis of primary epithelial neoplasms of the seminal vesicle identifies a subset of mucinous cystic tumours driven by KRAS mutations.

Carcinomas of the seminal vesicle are exceedingly rare, with a limited number of cases described in the literature. Reported cases span a relatively wide morphological spectrum, and their genomic features remain unexplored. In this study, we interrogated five primary epithelial neoplasms of the seminal vesicle using a targeted DNA sequencing platform (OncoPanel, 447 genes). The tumours included one adenocarcinoma with intestinal phenotype presenting after external beam radiation (for prostatic adenocarcinoma), one carcinoma with Müllerian-type clear cell phenotype, two mucinous tumours resembling low-grade mucinous neoplasms of the appendix (LAMN) and one mucinous cystadenoma. The post-radiation mucinous adenocarcinoma had genomic findings consistent with bi-allelic inactivation of TP53, as well as multiple copy-number changes with regional and chromosomal arm-level copy-number losses. The Müllerian-type clear cell carcinoma exhibited a complex copy-number profile with numerous regional and arm-level copy-number changes, as well as focal amplification events, including copy-number gain of 8q and amplification of a region within 20q13. Both low-grade mucinous tumours resembling LAMN harboured hot-spot gain-of-function KRAS variants (p.G12V and p.G13D) as the only genomic alteration. No genomic alterations were detected inthe lesion diagnosed as mucinous cystadenoma. Our results suggest that primary low-grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain-of-function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparablephenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.

Therapeutic strategies and outcomes in neuropsychiatric systemic lupus erythematosus: an international multicentre retrospective study.

The management of neuropsychiatric systemic lupus erythematosus (NPSLE) poses considerable challenges due to limited clinical trials. Therapeutic decisions are customized based on suspected pathogenic mechanisms and symptoms severity. This study aimed to investigate therapeutic strategies and disease outcome for patients with NPSLE experiencing their first neuropsychiatric (NP) manifestation. This retrospective cohort study defined NP events according to the American College of Rheumatology case definition, categorizing them into three clusters: central/diffuse, central/focal and peripheral. Clinical judgment and a validated attribution algorithm were used for NP event attribution. Data included demographic variables, SLE disease activity index, cumulative organ damage, and NP manifestation treatments. The clinical outcome of all NP events was determined by a physician seven-point Likert scale. Predictors of clinical improvement/resolution were investigated in a multivariable logistic regression analysis. The analysis included 350 events. Immunosuppressants and corticosteroids were more frequently initiated/escalated for SLE-attributed central diffuse or focal NP manifestations. At 12 months of follow-up, 64% of patients showed a clinical improvement in NP manifestations. Focal central events and SLE-attributed manifestations correlated with higher rates of clinical improvement. Patients with NP manifestations attributed to SLE according to clinical judgment and treated with immunosuppressants had a significantly higher probability of achieving clinical response (OR 2.55, 95%CI 1.06-6.41, P = 0.04). Age at diagnosis and focal central events emerged as additional response predictors. NP manifestations attributed to SLE by clinical judgment and treated with immunosuppressants demonstrated improved 12-month outcomes. This underscores the importance of accurate attribution and timely diagnosis of NPSLE.

Abstract WMP14: Cerebrospinal Fluid Beta-Amyloid Concentration and MRI Manifestations of Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with reduced cerebrospinal fluid (CSF) levels of the beta-amyloid (Aβ) 40- and 42-amino acid species, thought to reflect the burden of vascular Aβ deposition in the brain. Little is known regarding the association of CSF Aβ reduction with specific MRI manifestations of CAA. Methods: We identified 31 patients with CAA per Boston criteria v2.0 (1 definite, 27 probable, and 3 possible), who underwent CSF sampling for measurement of Aβ42, total tau (t-tau), and phospho-tau (p-tau) as part of their evaluation with ADmark (Athena Diagnostics). We assessed the following MRI manifestations of CAA while blinded to CSF biomarkers: the presence of cortical superficial siderosis (cSS), number of lobar cerebral microbleeds (CMBs), pattern and severity of white matter hyperintensities (WMH), and number of enlarged perivascular spaces in centrum semiovale (CSO-EPVS). Results: Median age of presentation was 69 years (range 56-89). Out of 31 patients, 19 were female (61.3%), 20 (64.5%) presented with cognitive impairment, 9 (29%) with intracerebral hemorrhage, and 2 (6.5%) with transient focal neurologic events. Mean (±SD) CSF Aβ42 concentration in our cohort was 359.3±126.7 pg/ml, substantially reduced relative to that reported in healthy controls. MRI manifestations associated with reduced Aβ42 without altered tau were presence of cSS (310±136 vs. 406±101, p=0.03) and higher burden of CSO-EPVS (307±101 vs. 431±127, p=0.005). Patients presented with cognitive impairment had higher tau levels (t-tau: 551±320 vs. 317±141, p=0.03; p-tau: 75.7±39.8 vs. 49.2±22.4, p=0.05) without altered Aβ42. Similar results were obtained when patients with possible CAA were excluded. Discussion: Our results suggest that presence of cSS and higher burden of CSO-EPVS are associated with lower Aβ42 concentration in CSF, potentially reflecting higher overall burden of vascular Aβ deposition in the brain. We found that higher tau concentrations in CSF are associated with cognitive impairment, presumably reflecting concomitant Alzheimer’s disease pathology. These results help inform interpretation of this clinically accessible test in practice and suggest potential mechanisms for specific CAA-related pathologies.

Identifying factors influencing local governments' adoption of comprehensive smoke-free policies: an event history analysis based on panel data from 36 key cities in China (2013-2021).

The issue of tobacco control remains a significant concern for public health worldwide. In recent years, remarkable progress has been made toward adopting smoke-free measures in indoor public places. Although China has yet to introduce a national regulation, specifically for smoke-free public places, more than a dozen cities have successively approved and implemented comprehensive smoke-free regulations. Different cities in China have diverse attitudes and behaviors toward smoke-free policies; however, the reasons for these policy differences and the influencing factors have not received sufficient attention and research. On the basis of the multiple streams framework, this study selects 36 key Chinese cities as research samples and uses a directed dyad-year event history analysis method to analyze the factors influencing the implementation of comprehensive smoke-free policies in cities. Results show that the adoption of such policies is positively influenced by scientific evidence, focal events, media coverage, institutional foundations, economic comparisons, and the influence of health departments and of tobacco control groups. By contrast, policy adoption is negatively affected by the differences in administrative levels, central policy signals, and the influence of the tobacco industry. This study contributes to understanding the internal logic behind local governments' adoption of comprehensive smoke-free policies, offering insights for further advocacy at the city and national levels in China and providing experiences that can promote the global tobacco control movement.

Mechanisms of microglial responses to injury related focal ATP events

Mechanisms of microglial responses to injury related focal ATP events

Turkish-Israeli relations under AKP rule

ABSTRACT Turkey was the first Muslim state to recognise Israel in 1949. While Israeli-Turkish relations have been characterised by ups and downs, mainly due to the Palestinian issue, they reached an all-time low under the Justice and Development Party (AKP) rule. Yet, it was not until 2009 that bilateral relations started to deteriorate. Operation Cast Lead marked a turning point in bilateral relations, followed by a series of crisis: the ‘One Minute crisis’, the ‘Lower Sofa crisis’, and the Mavi Marmara flotilla crisis. With both sides’ agreement to restore full diplomatic relations following Israel’s President Isaac Herzog’s visit to Turkey in March 2022, the normalisation process in bilateral relations gained pace, only to go into a swift decline yet again following the outbreak of the Gaza war in October 2023. This article analyses the focal events and dynamics that led to the deterioration and normalisation of bilateral relations under the AKP’s rule. It shows that in addition to the Palestinian issue, the AKP’s foreign policy vision and both states’ divergent security interests created a conducive environment for the deterioration of bilateral relations.

What are we really teaching? The implications of including phonics instruction in Group Guided Reading

Background: In the context of the ongoing crisis in early reading literacy in South Africa, this article gives insight into teacher practices which reduce learners’ opportunities to read continuous text for meaning.Aim: This ethnographic study investigated the microcosm of teacher practices in well-resourced environments.Setting: A purposive sample was drawn of three Grade One teachers in former Model C primary schools for intensive investigation of their literacy teaching practices. A pilot study established that a literacy teaching event resembling Group Guided Reading was attended every day by every learner in these classrooms and therefore provided the focal event in the research.Method: Micro-ethnographic classroom observations, with accompanying video recordings and transcriptions were the primary data sources. Interviews provided narrative and descriptive data. Data were analysed by means of qualitative content analysis and discourse analysis.Results: Findings suggested that the introduction of flashcards and texts designed for phonics practice into a methodology designed to promote reading for meaning has a cumulative impact on the time teachers spend on discussion, modelling comprehension strategies and silent reading. Potentially this limits learners to only one of the four roles of a reader, that is, a reader as code breaker.Conclusion: Findings caution against teachers making changes to the requirements of explicit teaching methodologies. The aims of Group Guided Reading are not achievable when phonics instruction reduces engagement with continuous text.Contribution: This article, by critiquing a practice, encourages teachers and teacher educators to consider the balance between whole-language and phonics-based approaches.

Genomic tools for comparative conservation genetics among three recently diverged stag beetles (Lucanus, Lucanidae)

Abstract We are witnessing a rapid decline in global biodiversity. International protocols and local conservation laws have been installed to counter such an unprecedent rate of decline. However, quantitatively evaluating how much biodiversity has been lost due to climatic and anthropogenic effects and how much biodiversity has been restored due to conservation efforts remains challenging. We applied a comparative conservation genomic approach to statistically and quantitatively address these questions using three geographical taxa from a stag beetle species complex. We found that the three sky‐island taxa formed three independently evolving units without detectable post‐divergence gene flow; furthermore, the three taxa, which have been divergent from each other since the mid‐Pleistocene, have experienced episodes of demographic decline in the past. More importantly, even though idiosyncratic anthropogenic exploitations have been hypothesised to impact the recent demographic history (<100 years) differently, we found a shared pattern of continuous decline in effective population size among the three geographical taxa. We argue that future empirical studies should include more taxa, in addition to the focal species, that may or may not be affected by the focal historical events to avoid making biased conservation plans.

Phase Gradient Divergence for the Quantitative Detection of Focal Activation Events During Cardiac Fibrillation

PurposeAtrial fibrillation is the most common arrhythmia. Spiral wave and focal activation (FA) are known to play an important mechanistic role in the generation, sustenance, and termination of tachyarrhythmia. However, to date no quantitative method of detecting FA under complex excitations has yet been established.MethodsIn this study, we propose such a detection method of FA by calculating the divergence of the spatial gradient of a phase map, which identifies the phase of the excitation cycle at each point of the heart as derived from measurement signals. Next, to verify the accuracy of the proposed method, we conducted a membrane potential measurement experiment using an excised porcine heart (n = 1).ResultsBy comparing the conventional and proposed methods for 126 instances of FA, we found that the proposed method showed improved detection accuracy, with precision, sensitivity, and F-measure values of 0.45, 0.84, and 0.58, while conventional method showed 0.04, 0.26, and 0.08, respectively.ConclusionThe proposed method, which uses the divergence of the phase gradient to predict FA, shows potential to suppress false positives that are observed in the conventional method, and it can more accurately detect FA than conventional methods.

초점사건 이후의 정책변동에 관한 연구

This study analyzes policy changes in response to COVID-19. Following the discovery of the first domestic case on January 20, 2020, the infectious disease crisis alert was raised from “watch” to “caution” to “warning”. This study classifies COVID-19 as a focal event and uses Birkland's ERPL model to analyze the process of policy agendization and policy change after the event. The results of the analysis show that, first, the focal event significantly increased the number of media reports at each stage of the epidemic crisis warning. Second, collective mobilization took place through the formation of the National Assembly Special Committee on COVID-19, the Health and Welfare Committee, and government expert group meetings. Third, the Special Committee as well as the standing committee discussed some proposals. Finally, some amendments were passed by the National Assembly. In conclusion, this study found that media coverage of the focal event of COVID-19 had a significant impact on policy changes.

Cancer aneuploidies are shaped primarily by effects on tumour fitness.

Aneuploidies-whole-chromosome or whole-arm imbalances-are the most prevalent alteration in cancer genomes1,2. However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events1,2. Here we developed a method, BISCUT, that identifies loci subject to fitness advantages or disadvantages by interrogating length distributions of telomere- or centromere-bounded copy-number events. These loci were significantly enriched for known cancer driver genes, including genes not detected through analysis of focal copy-number events, and were often lineage specific. BISCUT identified the helicase-encoding gene WRN as a haploinsufficient tumour-suppressor gene on chromosome 8p, which is supported by several lines of evidence. We also formally quantified the role of selection and mechanical biases in driving aneuploidy, finding that rates of arm-level copy-number alterations are most highly correlated with their effects on cellular fitness1,2. These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis.

Definition and characteristic features of a ‘cultural flashpoint’: a case study of Exploring Masculinities, a controversial gender and education programme in Ireland

ABSTRACT The concept ‘cultural flashpoint’ (CF) has not been fully defined or described. The authors test this concept through the prism of a controversial gender-focused Irish school programme, Exploring Masculinities (EM). Adopting an instrumental case study methodology, they use media content analysis to develop a temporal trajectory of the CF, describe its shape, explicit and implied contentious themes, and its process. They identify characteristic features of a cultural flashpoint: (i) a focal issue, event and/or object; (ii) conflict; (iii) bounded time period; (iv) the involvement of exo- and multi-sectoral individuals and groups; (v) randomness, opaqueness and conflation among its expressions; and (vi) broadly cultural and not confined to its sector of origin. They offer a definition of a CF and suggest it as a conceptual device for identifying, analysing and understanding contestation about educational (and other) change occurring in the context of wider and more long-standing cultural, social and political movements.

Protocolo de tratamiento del brote de esclerosis múltiple

Multiple sclerosis relapses consist of symptoms and signs caused by a new focal or multifocal inflammatory event in the central nervous system and must be distinguished from pseudo-relapses, related to the reappearance of residual symptoms from previous attacks, often in the context of fever or infection. Treating the relapse will hasten short-term recovery but will not modify the prognosis in the long-term. There are no differences between using high-dose oral or parenteral corticosteroids, but follow-up with a tapered oral regimen is not recommended. Mild symptoms (eg, localized sensory symptoms) can be managed on an outpatient basis or left untreated, but corticosteroid therapy is advised for disabling symptoms (eg, optic neuritis, ataxia, ophthalmoplegia, paresis). In the case of severe relapses and in the absence of a response to corticosteroids in the first week, a low threshold is advised so as to indicate plasma exchange, even if the diagnosis of the demyelinating syndrome is not fully established.

ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

BackgroundLiquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution.MethodsTo interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity.ResultsSCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour.ConclusionsThis work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.

Text recognition and analysis of network public opinion focus events of a major epidemic: a case study of "COVID-19" in Sina Microblogs.

Identifying and analyzing the public's opinion of focal events during a major epidemic can help the government grasp the vicissitudes of network public opinion in a timely manner and provide the appropriate responses. Taking the COVID-19 epidemic as an example, this study begins by using Python-selenium to capture the original text and comment data related to COVID-19 from Sina Microblog's CCTV News from Jan. 19, 2020, to Feb. 20, 2020. The study subsequently uses a manual interpretation method to classify the Weibo content and analyzes the shifting focus phenomena of network public opinion based on the moving average method. Next, the study uses an enhances TF-IDF to extract keywords from the Weibo comment and uses the keywords to construct a word co-occurrence network. The results show that during the epidemic, the network public opinion focus shifted significantly over time. With the progression of the epidemic, the focus of network public opinion diversified, and various categories stabilized. Compared to simple keyword and text classification recognition focus problems, the proposed model, which is highly accurate, identified multiple network public opinion focus problems and described the core contradictions of the different focus problems.

Blowing out a candle from a distance with high amplitude time reversal

Time reversal is a technique that allows the focusing of sound from a source to a remote location causing an impulsive focusing event. Using more sources and other amplitude-increasing techniques, the focusing of audible sound can reach over 200 dB peak. This can extinguish the flame on a single candle without affecting nearby lit candles. Most methods used to extinguish a flame using sound involve the nearfield and nonlinear airflow effects. Because time reversal focusing can occur far from the sources, the mechanism is different. Using high-speed video footage of the focal event, we can see the finer details of this millisecond scale focus interacting with the flame. Measuring the sound field during the focus event at and near the focal location also sheds light on the mechanism. So far, it has been seen that the focus pushes the flame outward, separating the plasma from its fuel source. The known formation of shock waves provides a possible explanation. Further research is being done to explore the cause of the extinguishing of the flame. This talk will show that not only is it possible to focus high amplitude sound waves but targeted flows of air as well.