Low-Intensity Blast Induces Acute Glutamatergic Hyperexcitability in Mouse Hippocampus Leading to Long-Term Learning Deficits and Altered Expression of Proteins Involved in Synaptic Plasticity and Serine Protease Inhibitors

Neurocognitive consequences of blast-induced traumatic brain injury (bTBI) pose significant concerns for military service members and veterans with the majority of invisible injury. However, the underlying mechanism of such mild bTBI by low-intensity blast (LIB) exposure for long-term cognitive and mental deficits remains elusive. Our previous studies have shown that mice exposed to LIB result in nanoscale ultrastructural abnormalities in the absence of gross or apparent cellular damage in the brain. Here we tested the hypothesis that glutamatergic hyperexcitability may contribute to long-term learning deficits. Using brain slice electrophysiological recordings, we found an increase in averaged frequencies with a burst pattern of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal CA3 neurons in LIB-exposed mice at 1- and 7-days post injury, which was blocked by a specific NMDA receptor antagonist AP5. In addition, cognitive function assessed at 3-months post LIB exposure by automated home-cage monitoring showed deficits in dynamic patterns of discrimination learning and cognitive flexibility in LIB-exposed mice. Collected hippocampal tissue was further processed for quantitative global-proteomic analysis. Advanced data-independent acquisition for quantitative tandem mass spectrometry analysis identified altered expression of proteins involved in synaptic plasticity and serine protease inhibitors in LIB-exposed mice. Some were correlated with the ability of discrimination learning and cognitive flexibility. These findings show that acute glutamatergic hyperexcitability in the hippocampus induced by LIB may contribute to long-term cognitive dysfunction and protein alterations. Studies using this military-relevant mouse model of mild bTBI provide valuable insights into developing a potential therapeutic strategy to ameliorate hyperexcitability-modulated LIB injuries

Vulnerability to fuel price increases in the UK: A household level analysis

In highly motorised countries, some sectors of the population own and use cars despite struggling to afford their running costs, and so may be particularly vulnerable to motor fuel prices increases, whether market-led or policy-driven. This paper proposes a novel, disaggregated approach to investigating vulnerability to such increases at the household level. We propose a set of indicators of ‘car-related economic stress’ (CRES), based on individual household level expenditure data for the UK, to identify which low-income households spend disproportionately on running motor vehicles, and to assess the depth of their economic stress. By subsequently linking the dataset to local fuel price data, we are able to model the disaggregated price elasticities of car fuel demand. This provides us with an indicator of each households’ adaptive capacity to fuel price increases. The findings show that ‘Low-Income, High Cost’ households (LIHC) account for 9% of UK households and have distinct socio-demographic characteristics. Interestingly, they are characterised by very low responses to fuel price increases, which may cause them to compromise on other important areas of their household expenditures. Simulations suggest that a 20% increase in fuel prices would substantially increase the depth, but not the incidence of CRES. Overall, the study sheds light on a sector of the population with high levels of vulnerability to fuel price increases, owing to high exposure, high sensitivity and low adaptive capacity. This raises challenges for social, environmental and resilience policy in the transport sector

Potential triggering factors associated with aneurysmal subarachnoid hemorrhage: A large single‐center retrospective study

Abstract Controlling blood pressure levels is critical to preventing intracranial aneurysm rupture, and a summary review of induced rupture events allows better health education for patients. We retrospectively reviewed all medical records of consecutive patients with aneurysmal subarachnoid hemorrhage (aSAH) admitted to Beijing Tiantan Hospital from 2015 to 2020. We collected patients’ demographic information, aneurysm morphology, blood pressure level on admission, time to onset, and events at the time of aneurysm rupture to analyze the factors precipitating aneurysmal rupture. A total of 764 patients were enrolled for analysis, including 461 (60.3%) female patients and 303 (39.7%) male patients. The mean age of onset in this cohort was 55, and 465 (60.9%) patients had hypertension history. Autumn (245/764 [32.1%]) was the most frequent season for aneurysm rupture, and 07:00–12:59 (277/764 [36.3%]) was the most frequent time frame for aneurysm rupture. The five most prevalent events when aneurysm rupture happened were: (1) daily behaviors that may induce hypertension (181/764 [23.7%]), especially defecation or micturition (116/181 [64.1%]); (2) sporting (162/764 [21.2%]), especially high‐intensity sports (108/162 [66.7%]); (3) mood and mental factors (112/764 [14.7%]), especially arguing or quarreling (61/112 [54.5%]); (4) sudden postural changes (93/764 [12.2%]), especially getting up (69/93 [74.2%]); and (5) sleeping (72/764 [9.4%]). Patients should avoid behaviors that may cause fluctuations in blood pressure, including keeping warm during seasonal alternation, keeping their urine and defecation unobstructed, avoiding high intensity physical exercise, maintaining a happy mood, avoiding sudden postural changes, and should not bathe with too cold or too hot water

Signal Control Method for Through and Left-Turn Shared Lane by Setting Left-Turn Waiting Area at Signalized Intersections

This paper proposes a signal control method for the through and left-turn shared lanes at signalized intersections to solve traffic conflicts between left-turn vehicles and opposing through vehicles by setting left-turn waiting area (LWA). Delays and stops are weighted to form an integrated performance index (PI) in a vehicle-to-infrastructure cooperation system. The PI models pertaining to all vehicles are established based on the LWA intersection. In addition, an optimized method of signal timing parameters is constructed by minimizing the average PI. VISSIM simulation shows that the average PI decreases by 6.51% compared with the original layout and signal timing plan of the intersection, since the increased delay of the side-road left-turn vehicles is insufficient to offset the reduced delay of the side-road through vehicles after the improvement. The sensitivity analysis shows that the greater the traffic volume of the phase including the through and left-turn shared lanes, the higher the operation efficiency of the LWA intersection compared with the typical permitted phase intersection. When the left-turn vehicles of the shared lanes in each cycle are less than the stop spaces, the LWA intersection can effectively reduce the average PI of the shared lanes. Furthermore, the more the stop spaces in the LWA, the lower the average PI in the same traffic conditions

Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway

Combination of antiangiogenesis and immunotherapy may be an effective strategy for treatment of solid tumors. Our previous work reported that activation of CD137 signaling promotes intraplaque angiogenesis. A number of studies have demonstrated that vascular endothelial growth factor receptor 2 (VEGFR2) is a key target for angiogenesis. However, it is unknown whether CD137-mediated angiogenesis is related to VEGFR2. In this study, we investigated the effect of CD137 on the VEGFR2 expression and explored the underlying mechanisms of CD137-mediated angiogenesis. Knock-out of CD137 in ApoE-/- mice significantly decreased neovessel density in atherosclerotic plaques. CD137 silencing or inhibition attenuated endothelial cell (ECs) proliferation, migration, and tube formation. We found activation of CD137 signaling for increased VEGFR2 transcription and translation steadily. Moreover, CD137 signaling activated phosphorylated VEGFR2 (Tyr1175) and the downstream Akt/eNOS pathway, whereas neutralizing CD137 signaling weakened the activation of VEGFR2 and the downstream Akt/eNOS pathway. The aortic ring assay further demonstrated that CD137 signaling promoted ECc sprouting. Inhibition of VEGFR2 by siRNA or XL184 (cabozantinib) and inhibition of downstream signaling by LY294002 (inhibits AKT activation) and L-NAME (eNOS inhibitor) remarkably abolished proangiogenic effects of CD137 signaling both in vitro and ex vivo. In addition, the condition medium from CD137-activated ECs and vascular endothelial growth factor A (VEGFA) had similar effects on ECs that expressed high VEGFR2. Additionally, activating CD137 signaling promoted endothelial secretion of VEGFA, while blocking CD137 signaling attenuated VEGFA secretion. In conclusion, activation of CD137 signaling promoted sprouting angiogenesis by increased VEGFA secretion and the VEGFR2/Akt/eNOS pathway. These findings provide a basis for stabilizing intraplaque angiogenesis through VEGFR2 intervatioin, as well as cancer treatment via combination of CD137 agonists and specific VEGFR2 inhibitors

Study of myopia progression and risk factors in Hubei children aged 7–10 years using machine learning: a longitudinal cohort

Abstract Background To investigate the trend of refractive error among elementary school students in grades 1 to 3 in Hubei Province, analyze the relevant factors affecting myopia progression, and develop a model to predict myopia progression and the risk of developing high myopia in children. Methods Longitudinal study. Using a cluster-stratified sampling method, elementary school students in grades 1 to 3 (15,512 in total) from 17 cities in Hubei Province were included as study subjects. Visual acuity, cycloplegic autorefraction, and height and weight measurements were performed for three consecutive years from 2019 to 2021. Basic information about the students, parental myopia and education level, and the students’ behavioral habits of using the eyes were collected through questionnaires. Results The baseline refractive errors of children in grades 1 ~ 3 in Hubei Province in 2019 were 0.20 (0.11, 0.27)D, −0.14 (−0.21, 0.06)D, and − 0.29 (−0.37, −0.22)D, respectively, and the annual myopia progression was − 0.65 (−0.74, −0.63)D, −0.61 (−0.73, −0.59)D and − 0.59 (−0.64, −0.51)D, with the prevalence of myopia increasing from 17.56%, 20.9%, and 34.08% in 2019 to 24.16%, 32.24%, and 40.37% in 2021 (Χ2 = 63.29, P < 0.001). With growth, children’s refractive error moved toward myopia, and the quantity of myopic progression gradually diminished. (F = 291.04, P = 0.027). The myopia progression in boys was less than that in girls in the same grade (P < 0.001). The change in spherical equivalent refraction in myopic children was smaller than that in hyperopic and emmetropic children (F = 59.28, P < 0.001), in which the refractive change in mild myopia, moderate myopia, and high myopia children gradually increased (F = 73.12, P < 0.001). Large baseline refractive error, large body mass index, and high frequency of eating sweets were risk factors for myopia progression, while parental intervention and strong eye-care awareness were protective factors for delaying myopia progression. The nomogram graph predicted the probability of developing high myopia in children and found that baseline refraction had the greatest predictive value. Conclusion Myopia progression varies by age, sex, and myopia severity. Baseline refraction is the most important factor in predicting high myopia in childhood. we should focus on children with large baseline refraction or young age of onset of myopia in clinical myopia prevention and control

TNFα alters occludin and cerebral endothelial permeability: Role of p38MAPK

<div><p>Occludin is a key tight junction (TJ) protein in cerebral endothelial cells (CECs) playing an important role in modulating blood-brain barrier (BBB) functions. This protein (65kDa) has been shown to engage in many signaling pathways and phosphorylation by both tyrosine and threonine kinases. Despite yet unknown mechanisms, pro-inflammatory cytokines and endotoxin (lipopolysaccharides, LPS) may alter TJ proteins in CECs and BBB functions. Here we demonstrate the responses of occludin in an immortalized human cerebral endothelial cell line (hCMEC/D3) to stimulation by TNFα (10 ng/mL), IL-1β (10 ng/mL) and LPS (100 ng/mL). Exposing cells to TNFα resulted in a rapid and transient upward band-shift of occludin, suggesting of an increase in phosphorylation. Exposure to IL-1β produced significantly smaller effects and LPS produced almost no effects on occludin band-shift. TNFα also caused transient stimulation of p38MAPK and ERK1/2 in hCMEC/D3 cells, and the occludin band-shift induced by TNFα was suppressed by SB202190, an inhibitor for p38MAPK, and partly by U0126, the MEK1/2-ERK1/2 inhibitor. Cells treated with TNFα and IL-1β but not LPS for 24 h resulted in a significant (p < 0.001) decrease in the expression of occludin, and the decrease could be partially blocked by SB202190, the inhibitor for p38MAPK. Treatment with TNFα also altered cell morphology and enhanced permeability of the CEC layer as measured by the FITC-dextran assay and the trans-endothelial electrical resistances (TEER). However, treatment with SB202190 alone could not effectively reverse the TNFα -induced morphology changes or the enhanced permeability changes. These results suggest that despite effects of TNFα on p38MAPK-mediated occludin phosphorylation and expression, these changes are not sufficient to avert the TNFα-induced alterations on cell morphology and permeability.</p></div

Application of Quantitative Computed Tomographic Perfusion in the Prognostic Assessment of Patients with Aneurysmal Subarachnoid Hemorrhage Coexistent Intracranial Atherosclerotic Stenosis

The comorbidity of aneurysmal subarachnoid hemorrhage (aSAH) with intracranial atherosclerotic stenosis (ICAS) has been suggested to increase the risk of postoperative ischemic stroke. Logistic regression models were established to explore the association between computed tomography perfusion (CTP) parameters and 3-month neurological outcomes and delayed cerebral ischemia (DCI). Prognostic-related perfusion parameters were added to the existing prognostic prediction models to evaluate model performance improvement. Tmax > 4.0 s volume > 0 mL was significantly associated with 3-month unfavorable neurological outcomes after adjusting for potential confounders (OR 3.90, 95% CI 1.11–13.73), whereas the stenosis degree of ICAS was not. Although the cross-validated area under the curve (AUC) was similar after the addition of the Tmax > 4.0 s volume > 0 mL (SAHIT: p = 0.591; TAPS: p = 0.379), the continuous net reclassification index (cNRI) and integrated discrimination index (IDI) showed that the perfusion parameters significantly improved the performance of the two models (p 4.0 s volume > 0 mL is an independent factor of 3-month neurological outcomes. A quantitative assessment of cerebral perfusion may help accurately screen patients with poor outcomes due to the coexistence of aSAH and ICAS

Additional file 1 of Study of myopia progression and risk factors in Hubei children aged 7–10 years using machine learning: a longitudinal cohort

Supplementary Material

The oil vulnerability of commuter patterns: a case study from Yorkshire and the Humber, UK

Motorised transport infrastructure and increasingly specialised labour markets have resulted in energy intensive commuter patterns in many parts of the world. This is cause for concern due to the possibility of oil price shocks and the need to restrict the combustion of fossil fuels to minimise the chances of runaway climate change. The paper investigates methods to identify the spatial distribution and socio-demographic pro les of those who are vulnerable to high oil prices. It does this by use of four metrics of oil vulnerability which were developed using a spatial microsimulation model and applied to the case study region of Yorkshire and the Humber, UK. The metrics capture different aspects of vulnerability and highlight the importance of translating conceptual de nitions into practical metrics. The geographically aggregated results coincide with the literature: rural areas are associated with the highest levels of vulnerability. The individual level results indicate that vulnerability can be prevalent even in seemingly resilient areas. Ultimately, we conclude that the social and spatial distribution of oil vulnerability depends on how an energy-constrained future is envisioned. Creating localised metrics about the future is a challenging task fraught with danger but could, provided that these metrics are interpreted with su cient humility, aid the development of equitable policies to encourage resilience, as part of a worldwide transition away from fossil fuels