RNA-assisted sequestration of RNA-binding proteins by cytoplasmic inclusions of the C-terminal 35-kDa fragment of TDP-43.

TDP-43 (also known as TARDBP) is a nuclear splicing factor functioning in pre-mRNA processing. Its C-terminal 35-kDa fragment (TDP-35) forms inclusions or aggregates in cytoplasm, and sequesters full-length TDP-43 into the inclusions through binding with RNA. We extended the research to investigate whether TDP-35 inclusions sequester other RNA-binding proteins (RBPs) and how RNA-binding specificity has a role in this sequestration process. We have characterized T-cell restricted intracellular antigen-1 (TIA1) and other RBPs that can be sequestered into the TDP-35 inclusions through specific RNA binding, and found that this sequestration leads to the dysfunction of TIA1 in maturation of target pre-mRNA. Moreover, we directly visualized the dynamic sequestration of TDP-43 by the cytoplasmic TDP-35 inclusions by live-cell imaging. Our results demonstrate that TDP-35 sequesters some specific RBPs and this sequestration is assisted by binding with RNA in a sequence-specific manner. This study provides further evidence in supporting the hijacking hypothesis for RNA-assisted sequestration and will be beneficial to further understanding of the TDP-43 proteinopathies.

Increased risk of dementia differs across cardiovascular diseases and types of dementia - Data from a nationwide study.

AIMS: Dementia is a major health problem. Cardiovascular diseases (CVD) and risk factors are associated with incident dementia. However, whether there is an association among CVD, Alzheimer's disease (AD) and vascular dementia (VD) at the population level remains unclear. METHODS: We analysed the association between CVD (heart failure [HF], atrial fibrillation [AF], myocardial infarction [MI], peripheral arterial disease, stroke and transient ischemic attack) and the incidence of dementia using nationwide FinnGen data of 218,192 individuals. The last follow-up information on dementia was available from October 2021. RESULTS: The age at the end of the follow-up was 61.7 ± 17.1 years, and 53% were women. Overall, we observed 9701 (4.4%) dementia, 6323 (2.9%) AD and 1918 (0.7%) VD cases. Individuals with CVD had a higher risk of developing dementia than unexposed individuals. In the multivariable-adjusted Cox models, stroke was most strongly associated with dementia (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.6-1.8). CVD was more strongly associated with VD than with AD. Individuals with HF and MI had an increased risk of AD (HF: HR 1.11, 95% CI 1.04-1.19; MI: HR 1.10, 95% CI 1.02-1.18). AF was associated with VD (HR 1.58, 95% CI 1.42-1.77), but not with AD (HR 1.03, 95% CI 0.97-1.09). Clinical characteristics, such as diabetes, smoking and alcohol abuse, were associated with both types of dementia. CONCLUSION: All major CVDs were associated with an increased risk of developing dementia, particularly VD. Therefore, CVD onset should prompt an assessment of cognitive decline and possible preventive measures.

Ti─O─C Bonding at 2D Heterointerfaces of 3D Composites for Fast Sodium Ion Storage at High Mass Loading Level.

3D composite electrodes have shown extraordinary promise as high mass loading electrode materials for sodium ion batteries (SIBs). However, they usually show poor rate performance due to the sluggish Na+ kinetics at the heterointerfaces of the composites. Here, a 3D MXene-reduced holey graphene oxide (MXene-RHGO) composite electrode with Ti─O─C bonding at 2D heterointerfaces of MXene and RHGO is developed. Density functional theory (DFT) calculations reveal the built-in electric fields (BIEFs) are enhanced by the formation of bridged interfacial Ti─O─C bonding, that lead to not only faster diffusion of Na+ at the heterointerfaces but also faster adsorption and migration of Na+ on the MXene surfaces. As a result, the 3D composite electrodes show impressive properties for fast Na+ storage. Under high current density of 10 mA cm-2, the 3D MXene-RHGO composite electrodes with high mass loading of 10 mg cm-2 achieve a strikingly high and stable areal capacity of 3 mAh cm-2, which is same as commercial LIBs and greatly exceeds that of most reported SIBs electrode materials. The work shows that rationally designed bonding at the heterointerfaces represents an effective strategy for promoting high mass loading 3D composites electrode materials forward toward practical SIBs applications.

Physical activity modification following a Transient Ischemic Attack in individuals with diabetes.

BACKGROUND: Individuals with diabetes exhibit a higher risk of cardiovascular disease and mortality compared to healthy individuals. Following a transient ischemic attack (TIA) the risk of stroke and death increase further. Physical activity engagement after a TIA is an effective way of secondary prevention. However, there's a lack of research on how individuals with diabetes modify physical activity levels and how these adjustments impact survival post-TIA. This study aimed to determine the extent to which individuals with diabetes alter their physical activity levels following a TIA and to assess the impact of these changes on mortality. METHODS: This was a nationwide longitudinal study, employing data from national registers in Sweden spanning from 01/01/2003 to 31/12/2019. Data were collected 2 years retro- and prospectively of TIA occurrence, in individuals with diabetes. Individuals were grouped based on decreasing, remaining, or increasing physical activity levels after the TIA. Cox proportional hazards models were fitted to evaluate the adjusted relationship between change in physical activity and all-cause, cardiovascular, and non-cardiovascular mortality. RESULTS: The final study sample consisted of 4.219 individuals (mean age 72.9 years, 59.4% males). Among them, 35.8% decreased, 37.5% kept steady, and 26.8% increased their physical activity after the TIA. A subsequent stroke occurred in 6.7%, 6.4%, and 6.1% of individuals, while death occurred in 6.3%, 7.3%, and 3.7% of individuals, respectively. In adjusted analyses, participants who increased their physical activity had a 45% lower risk for all-cause mortality and a 68% lower risk for cardiovascular mortality, compared to those who decreased their physical activity. CONCLUSIONS: Positive change in physical activity following a ΤΙΑ was associated with a reduced risk of mortality. Increased engagement in physical activity should be promoted after TIA, thereby actively supporting individuals with diabetes in achieving improved health outcomes.

Clopidogrel with indobufen or aspirin in minor ischemic stroke or high-risk transient ischemic attack: a randomized controlled clinical study.

BACKGROUND: Ischemic stroke and transient ischemic attack (TIA) are the most prevalent cerebrovascular diseases. The conventional antiplatelet drugs are associated with an inherent bleeding risk, while indobufen is a new antiplatelet drug and has the similar mechanism of antiplatelet aggregation as aspirin with more safety profile. However, there have been no studies evaluating the combination therapy of indobufen and clopidogrel for antiplatelet therapy in cerebrovascular diseases. OBJECTIVE: The CARMIA study aims to investigate the effectiveness and safety of a new dual antiplatelet therapy consisting of indobufen and clopidogrel comparing with the conventional dual antiplatelet therapy consisting of aspirin and clopidogrel in patients with minor ischemic stroke or high-risk TIA. METHODS: An open-label randomized controlled clinical trial was conducted at a clinical center. We randomly assigned patients who had experienced a minor stroke or transient ischemic attack (TIA) within 72 h of onset, or within 1 month if they had intracranial stenosis (IS), to receive either indobufen 100 mg twice daily or aspirin 100 mg once daily for 21 days. For patients with IS, the treatment duration was extended to 3 months. All patients received a loading dose of 300 mg clopidogrel orally on the first day, followed by 75 mg once daily from the second day to 1 year. We collected prospective data using paper-based case report forms, and followed up on enrolled patients was conducted to assess the incidence of recurrent ischemic stroke or TIA, mRS score, NIHSS (National Institutes of Health Stroke Scale) score, and any bleeding events occurring within 3 month after onset. RESULTS: We enrolled 202 patients diagnosed with ischemic stroke or transient ischemic attack. After applying the criteria, 182 patients were eligible for data analysis. Endpoint events (recurrence of ischemic stroke/TIA, myocardial infarction, or death) were observed in 6 patients (6.5%) receiving aspirin and clopidogrel, including 4 (4.3%) with stroke recurrence, 1 (1.1%) with TIA recurrence, and 1 (1%) with death. In contrast, no endpoint events were reported in the indobufen and clopidogrel group (P = 0.029). The group of patients receiving indobufen and clopidogrel exhibited significantly lower modified Rankin Scale (mRS) score. (scores range from 0 to 6, with higher scores indicating more severe disability) compared to the aspirin and clopidogrel group (common odds ratio 3.629, 95% CI 1.874-7.036, P < 0.0001). Although the improvement rate of NIHSS score in the indobufen and clopidogrel group was higher than that in the aspirin and clopidogrel group, the difference was not statistically significant (P > 0.05). Bleeding events were observed in 8 patients (8.6%) receiving aspirin and clopidogrel, including 4 (4.3%) with skin bleeding, 2 (2.2%) with gingival bleeding, 1 (1.1%) with gastrointestinal bleeding, and 1 (1.1%) with urinary system bleeding. On the other hand, only 1 patient (1.1%) in the indobufen and clopidogrel group experienced skin bleeding (P = 0.035). CONCLUSION: The combination of indobufen and clopidogrel has shown non-inferior and potentially superior effectiveness and safety compared to aspirin combined with clopidogrel in patients with minor ischemic stroke and high-risk TIA in the CARMIA study (registered under chictr.org.cn with registration number ChiCTR2100043087 in 01/02/2021).

Unravelling stress granules in the deep cold: Characterisation of TIA-1 gene sequence in Antarctic fish species.

Stress granules (SGs) are cytoplasmic foci lacking membranes, comprising non-translating messenger ribonucleoproteins, translational initiation factors, and additional proteins. Their formation is crucial for rapidly modulating gene expression in response to adverse environmental conditions, such as pollution and infections. Limited research has focused on investigating the molecular components of SGs in fish, with minimal exploration in Antarctic fish. This study characterises for the first time the transcript sequences of one key protein component of SGs, TIA-1 (T-cell intracellular antigen 1), in two Antarctic endemic fish species, i.e. Trematomus bernacchii and Chionodraco hamatus. The mRNA-binding protein TIA-1 acts as a post-transcriptional regulator of gene expression and its aggregation leads to the formation of SGs in response to cellular damage. The in vitro and bioinformatic analyses of the TIA-1 gene sequences of these two species highlighted interesting peculiarities, which include the transcription of alternatively spliced isoforms unique to the notothenioid lineage, potentially unlocking further insights into their unique adaptations to extreme environmental conditions. This is the first study to analyze tia-1 expression levels in different tissues of Antarctic fish species. Our key findings indicate that the TIA-1 gene is expressed at particularly high levels in the liver and spleen of C. hamatus, as well as in the heart and skeletal muscle of T. bernacchii. This suggests that those tissues play a significant role in the stress response mechanisms of the studied species. This study provides novel insights into the molecular adaptations of Antarctic fish, highlighting the potential importance of TIA-1 in their response to environmental stressors. The unique features of TIA-1 identified in these species may offer broader implications for understanding how Antarctic fish regulate gene transcriptions in their extreme environments.

Quantitative proteomics reveals pregnancy prognosis signature of polycystic ovary syndrome women based on machine learning.

OBJECTIVE: We aimed to screen and construct a predictive model for pregnancy loss in polycystic ovary syndrome (PCOS) patients through machine learning methods. METHODS: We obtained the endometrial samples from 33 PCOS patients and 7 healthy controls at the Reproductive Center of the Second Hospital of Lanzhou University from September 2019 to September 2020. Liquid chromatography tandem mass spectrometry (LCMS/MS) was conducted to identify the differentially expressed proteins (DEPs) of the two groups. Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to analyze the related pathways and functions of the DEPs. Then, we used machine learning methods to screen the feature proteins. Multivariate Cox regression analysis was also conducted to establish the prognostic models. The performance of the prognostic model was then evaluated by the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). In addition, the Bootstrap method was conducted to verify the generalization ability of the model. Finally, linear correlation analysis was performed to figure out the correlation between the feature proteins and clinical data. RESULTS: Four hundred and fifty DEPs in PCOS and controls were screened out, and we obtained some pathways and functions. A prognostic model for the pregnancy loss of PCOS was established, which has good discrimination and generalization ability based on two feature proteins (TIA1, COL5A1). Strong correlation between clinical data and proteins were identified to predict the reproductive outcome in PCOS. CONCLUSION: The model based on the TIA1 and COL5A1 protein could effectively predict the occurrence of pregnancy loss in PCOS patients and provide a good theoretical foundation for subsequent research.

Association of Impedance Aggregometry-Measured Platelet Aggregation With Thromboembolic Events in Patients Who Undergo Carotid Endarterectomy: A Pilot Study.

OBJECTIVES: The aim of the current study was to assess the relationship among thrombin receptor activator peptide 6 (TRAP test), adenosine-5'-diphosphate (ADP test), arachidonic acid (ASPI test), and stroke/transient ischemic attack (TIA), using the multiple electrode aggregometry (Multiplate) in patients undergoing carotid thromboendarterectomy (CEA). DESIGN: A retrospective study. SETTING: Vascular surgery operating rooms of a university hospital. PARTICIPANTS: One hundred thirty-one out of 474 patients undergoing CEA between November 2020 and October 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A preoperative blood sample of all enrolled patients was analyzed using the Multiplate analyzer. Receiver operating characteristics curves, were generated to test the ability of TRAP, ADP, and ASPI in discriminating perioperative thromboembolic stroke/TIA. A logistic LASSO regression model was used to identify factors independently associated with stroke/TIA. Eight patients experienced a perioperative stroke/TIA. Although all the platelet functional assays showed excellent predictive performance, an ADP value exceeding 72 U showed the highest specificity (87%) and sensitivity (68%) in discriminating patients who had a perioperative thromboembolic stroke/TIA, with a negative predictive value of 99% and a positive predictive value of 15%. After LASSO regression, an ADP >72 U and the need for a shunt during CEA were the only 2 variables independently associated with perioperative stroke/TIA. CONCLUSION: Because the ADP test was independently associated with perioperative stroke/TIA, the assessment of platelet reactivity using Multiplate may offer potential utility in monitoring patients undergoing CEA.

'There are things I have learned the hard way' Patient experiences on lasting challenges 4 months after Transient Ischemic Attack: A qualitative study.

BACKGROUND: Fatigue, depression, anxiety and cognitive difficulties are reported by 1/3 of patients following transient ischemic attack (TIA). AIMS: To explore the timeline and how the diagnosis impacts individuals experiencing lasting challenges after TIA. Furthermore, to identify what they believed facilitated return to everyday life. DESIGN: Qualitative exploratory study with a phenomenological-hermeneutic approach. METHODS: Individual semi-structured interviews and thematic analysis. RESULTS: Fifteen patients were included. Four themes were identified; (1) 'They say it is transient - no, not for me' where all participants described lasting challenges emphasizing invalidating fatigue and impaired social participation, (2) 'I am a changed person; how does this impact my future?' which reflects altered identity and elevated alertness to symptoms, (3) 'Time has been my ally and new perspectives have evolved' where most participants described improvement over time and a few considered the diagnosis a wake-up call to change lifestyle. Lastly (4) 'What would have helped me recover?' which unfolds that close, trustful relations influence positively. In addition, the system often failed to support. Participants described pressure to return to work and lack of trust and negative experiences when involving their general practitioner. CONCLUSIONS: During the 4 months since diagnosis, participants experienced limitations impacting physical, psychological and social domains. They felt uninformed that lasting challenges could affect them. Different coping strategies were activated, and participants with close, supportive relations managed better. A pressure to return to work and a lack of trust in the general practitioner affected their recovery negatively. Overall, return to everyday life after TIA was considered stressful and appropriate support lacking. RELEVANCE TO CLINICAL PRACTICE: To be able to support patients with challenges following TIA, we as healthcare professionals need to understand the identified impact and life changing circumstances. Currently the system seemingly is not able to provide timely, sufficient and competent support. IMPACT (ADDRESSING): WHAT PROBLEM DID THE STUDY ADDRESS?: We know from the literature that up to 1/3 of patients following transient ischemic attack experience lasting challenges measured on a variety of questionnaires. This is paradoxical to a diagnosis defined by focal neurological symptoms that resolve within 24 h. It is unknown how patients with lasting challenges experience the timeline from diagnosis and until 4 months after, how the diagnosis impacts the lives of these individuals, and what they believe as beneficial in returning to their everyday life. WHAT WERE THE MAIN FINDINGS?: These participants with self-reported lasting challenges experienced substantial impacts on physical, psychological and social domains. Further, they felt alone with their struggles and when in need of support from the healthcare system, it failed to provide this. A pressure to return to work and a lack of trust in the general practitioner affected return to everyday life negatively, whereas close and supportive relations facilitated positively. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: This study will have an impact on the healthcare professionals that provide support and the (limited) follow-up services to patients after TIA. These healthcare professionals are often specialized nurses who need to know what these patients experience and need in order to act upon their struggles and provide timely support. REPORTING METHOD: The Standards of Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: Patients with TIA was involved in planning this study. They participated in a panel to plan a prospective observational cohort study and emphasized the importance of exploring the subjective perspectives of impact and prognosis for those patients struggling in a longer term (through qualitative interviews).

Troponin levels in transient ischemic attack and ischemic stroke: does "transient" in your brain mean "better" for your heart?

PURPOSE: Transient ischemic attack (TIA) is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction. In this type of ischemic event, there are no data about a possible cardiac injury tested with troponin. After a stroke, it is well established the cardiac involvement due to a neuro-inflammatory response (recently defined as Stroke Heart Syndrome). The aim of this study is to compare the troponin elevation after a stroke with the troponin elevation after a TIA. MATERIALS AND METHODS: This is a retrospective, single center study on 565 patients (73 TIAs, 492 stroke). We collected demographic characteristics, cardiovascular risk factors, cardiac data such as troponin, NT-proBNP, left atrial dilatation, etiology of the ischemic event (TOAST classification). RESULTS: We compare IS and TIA for each TOAST subtype. In all groups no substantial differences were found in demographic and past medical history (p > 0.05). However, the maximum troponin level reached were significantly lower in TIAs than IS (p < 0.05), except in lacunar etiology were troponin elevation was low also in IS group. We found a trend in favor to IS in the rise and fall troponin elevation over 30% in all the TOAST subgroups, but only in the cryptogenic etiology the difference was significant. About the others cardiac markers of injury, a significant higher rate of elevated NT-proBNP was found in the IS cohort. CONCLUSIONS: Troponin level after TIAs is significantly lower than after IS. Troponin elevation after an ischemic event may be more relevant in patients with higher NT-proBNP levels and older age. More studies are needed to better understand the pathophysiology of this phenomenon after an ischemic event.