A novel four-dimensional prediction model of soil heavy metal pollution: Geographical explanations beyond artificial intelligence "black box".

The current artificial intelligence (AI)-based prediction approaches of soil pollutants are inadequate in estimating the geospatial source-sink processes and striking a balance between the interpretability and accuracy, resulting in poor spatial extrapolation and generalization. In this study, we developed and tested a geographically interpretable four-dimensional AI prediction model for soil heavy metal (Cd) contents (4DGISHM) in Shaoguan city of China from 2016 to 2030. The 4DGISHM approach characterized spatio-temporal changes in source-sink processes of soil Cd by estimating spatio-temporal patterns and the effects of drivers and their interactions of soil Cd at local to regional scales using TreeExplainer-based SHAP and parallel ensemble AI algorithms. The results demonstrate that the prediction model achieved MSE and R2 values of 0.012 and 0.938, respectively, at a spatial resolution of 1 km. The predicted areas exceeding the risk control values for soil Cd across Shaoguan from 2022 to 2030 increased by 22.92% at the baseline scenario. By 2030, enterprise and transportation emissions (SHAP values 0.23 and 0.12 mg/kg, respectively) were the major drivers. The influence of driver interactions on soil Cd was marginal. Our approach surpasses the limitations of the AI "black box" by integrating spatio-temporal source-sink explanation and accuracy. This advancement enables geographically precise prediction and control of soil pollutants.

PTPRN Serves as a Prognostic Biomarker and Correlated with Immune Infiltrates in Low Grade Glioma.

BACKGROUND: Glioma is one of the most common malignant tumors of the central nervous system. Immune infiltration of tumor microenvironment was associated with overall survival in low grade glioma (LGG). However, effects of Tyrosine phosphatase receptor type N (PTPRN) on the progress of LGG and its correlation with tumor infiltration are unclear. METHODS: Here, datasets of LGG were from The Cancer Genome Atlas (TCGA) and normal samples were from GTEx dataset. Gepia website and Human Protein Atlas (HPA) Database were used to analyze the mRNA and protein expression of PTPRN. We evaluated the influence of PTPRN on survival of LGG patients. MethSurv was used to explore the expression and prognostic patterns of single CpG methylation of PTPRN gene in LGG. The correlations between the clinical information and PTPRN expression were analyzed using logistic regression and Multivariate Cox regression. We also explored the correlation between PTPRN expression and cancer immune infiltration by TIMER. Gene set enrichment analysis (GSEA) was formed using TCGA RNA-seq datasets. RESULTS: PTPRN mRNA and protein expression decreased in LGG compared to normal brain tissue in TCGA and HPA database. Kaplan-Meier analysis showed that the high expression level of PTPRN correlated with a good overall survival (OS) of patients with LGG. The Multivariate Cox analysis demonstrated that PTPRN expression and other clinical-pathological factors (age, WHO grade, IDH status, and primary therapy outcome) significantly correlated with OS of LGG patients. The DNA methylation pattern of PTPRN with significant prognostic value were confirmed, including cg00672332, cg06971096, cg01382864, cg03970036, cg10140638, cg16166796, cg03545227, and cg25569248. Interestingly, PTPRN expression level significantly negatively correlated with infiltrating level of B cell, CD4+ T cells, Macrophages, Neutrophils, and DCs in LGG. Finally, GSEA showed that signaling pathways, mainly associated with tumor microenvironment and immune cells, were significantly enriched in PTPRN high expression. CONCLUSION: PTPRN is a potential biomarker and correlates with tumor immune infiltration in LGG.

Spatiotemporal Patterns of Spreading Depolarization and its Correlation with Brain Injury During the Acute Stage of Subarachnoid Hemorrhage in Mice.

OBJECTIVE: Spreading depolarization (SD) has been regarded as one cause of neuronal injury in subarachnoid hemorrhage (SAH). However, SD in the hyperacute phase of SAH is still unclear. The objective of this study was to detect real-time spatial-temporal patterns of SD, assess the effect of SD on cerebral blood flow, and test the relationship between SD and brain injury in the acute phase of SAH. METHODS: Twenty-eight mice were separated into two groups: 16 animals in the SAH group and 12 animals in the sham group. Experimental SAH was done with an endovascular filament perforation model. Changes in optical reflection were registered with intrinsic optical signal imaging (IOSI) after SAH. Spatial-temporal patterns of SDs were analyzed and brain injury including brain edema and infarction was tested. RESULTS: Totally, 117 SDs occurred after SAH. According to the hemodynamic response and duration, SDs could be classified into Type I (short SD), Type II (intermediate SD), and Type III (persistent SD). Most of SDs originated from the somatosensory and visual cortex. SDs demonstrated distinct spreading patterns. Moreover, the number and duration of SDs associated with brain water content (p < 0.05, p < 0.01). SDs, especially, persistent SDs associated with infarct volume in the hyperacute phase of SAH (p < 0.001, p < 0.001). CONCLUSION: Our results suggest that SD occurs with a high incidence during the acute stage of SAH in mice. And the lissencephalic mouse brain is capable of different SD propagation patterns. Additionally, SD may aggravate brain edema and induce brain infarction, contributing to early brain injury after SAH.

Minimally Invasive Surgery for Intracerebral and Intraventricular Hemorrhage.

Spontaneous intracerebral hemorrhage (ICH), especially related to intraventricular hemorrhage (IVH), is the most devastating type of stroke and is associated with high mortality and morbidity. Optimal management of ICH remains one of the most controversial areas of neurosurgery and no effective treatment exists for ICH. Studies comparing conventional surgical interventions with optimal medical management failed to show significant benefit. Recent exploration of minimally invasive surgery for ICH and IVH including catheter- and mechanical-based approaches has shown great promise. Early phase clinical trials have confirmed the safety and preliminary treatment effect of minimally invasive surgery for ICH and IVH. Pending efficacy data from phase III trials dealing with diverse minimally invasive techniques are likely to shape the treatment of ICH.

Loss of Kir6.1 facilitates peri-infarct depolarizations in focal cerebral ischemia.

OBJECTIVE: Peri-infarct depolarizations (PIDs) are spontaneous waves that propagate slowly across the penumbra region following stroke, contributing to secondary infarct growth and negatively affecting stroke outcomes. KATP channels are generally spread in the brain. Under conditions of ischemia and/or hypoxia, KATP channels play a cytoprotective role in neurons. However, it is still unknown whether KATP channels are involved in the initiation and propagation of PIDs. METHODS: The Kir6.1 knockout (Kir6.1-/-) mice, Kir6.2 knockout (Kir6.2-/-) mice, and wild-type C57Bl6 mice (n = 8) were used. The middle cerebral artery occlusion (MCAO) stroke model was made and PIDs were detected by an optical intrinsic signal (OIS) imaging system. RESULTS: Much more PIDs appeared in Kir6.1-/-mice than that in Kir6.2-/- and WT mice in both the first hour and 4 hours following MCAO (3.9 ± 0.7 vs. 1.5 ± 0.3, p < 0,05; 3.9 ± 0.7 vs. 1.9 ± 0.3, p < 0.05; 20.0 ± 2.5 vs. 10.4 ± 2.4, p < 0.05; 20.0 ± 2.5 vs. 11.3 ± 1.4, p < 0.05). Furthermore, the first PID occurred much earlier in Kir6.1-/- mice than that in Kir6.2-/- mice and WT mice (21.3 ± 2.1 min vs. 34.1 ± 4.8 min, p < 0.05; 21.3 ± 2.1 min vs. 38.8 ± 3.4 min, p < 0.01). No significant differences in other characteristics of PIDs including originating sites, duration time, propagation patterns, and velocity were detected. Additionally, the migration of originating sites was observed. CONCLUSION: This study shows that loss of Kir6.1, not Kir6.2 facilitates the induction of PIDs in focal cerebral ischemia, indicating that Kir6.1-forming channels in the brain may provide protection against PIDs.

Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice.

Transcription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

Loss of GFAP and Vimentin Does Not Affect Peri-Infarct Depolarizations after Focal Cerebral Ischemia.

Peri-infarct depolarization (PID), one kind of spreading depolarization, contributes to infarct volume enlargement after ischemic stroke. Astrocytes participate in PIDs by various mechanisms. The roles of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins in astrocytes, however, in PIDs induction and propagation remain unknown. Middle cerebral artery occlusion (MCAO) model was made in 9 GFAP-/-Vim-/- and 9 wild-type (WT) C57BL/6 mice. Using 4-wavelength optical intrinsic signal imaging (OIS), we identified PIDs as consistent, red and blue interaction waves in the cortical reflectance that slowly propagated peripherally from the origin site. Five propagation patterns of PIDs were observed after MCAO in mice, namely, latero-medial, medial-lateral, rostro-caudal, caudo-rostral, and collision. Additionally, the frequency, propagation velocity, and duration of PIDs between GFAP-/-Vim-/- and WT mice were not significantly different (p > 0.05). Furthermore, no significant difference was found in infarct volume and brain edema between the two groups. In conclusion, the 4-wavelength OIS system allows acquisition of high temporal-spatial resolution color images for analyzing temporal-spatial characteristics of PIDs in detail. GFAP and Vim in astrocytes are not involved in PIDs after MCAO in mice.

Spreading Depolarization during the Acute Stage of Experimental Subarachnoid Hemorrhage in Mice.

Spreading depolarization (SD) has been suggested as a pathomechanism for delayed cerebral ischemia after subarachnoid hemorrhage (SAH). However, the role of SD during the acute phase of SAH is still unclear. The objective of this study was to investigate (a) the occurrence of SD with intrinsic optical signal (IOS) imaging, (b) the effect of ketamine on SD, and (c) the resulting brain edema (brain water content (BWC)) during the acute stage of experimental SAH in mice. SAH was elicited by the endovascular filament perforation method. After SAH or sham operation, ketamine or saline, 30 mg/kg, was given every half hour. Changes in tissue light reflectance were recorded with IOS. BWC was measured during the acute stage. Overall, 199 SDs occurred in SAH groups and 33 SDs appeared in sham groups. These SDs displayed distinct originating and spreading patterns. Compared with saline, ketamine decreased SD spread and influenced the amplitude, duration, and speed of SD. However, the occurrence of SD was not prevented by ketamine. Moreover, ketamine did not reduce BWC after SAH. These results demonstrate that SD occurs with a high incidence during the acute stage of SAH. SDs are heterogeneous in incidence, origination, and propagation. It remains unclear whether ketamine effects on SD may be viewed as therapeutically beneficial after SAH.

Large field-of-view movement-compensated intrinsic optical signal imaging for the characterization of the haemodynamic response to spreading depolarizations in large gyrencephalic brains.

Haemodynamic responses to spreading depolarizations (SDs) have an important role during the development of secondary brain damage. Characterization of the haemodynamic responses in larger brains, however, is difficult due to movement artefacts. Intrinsic optical signal (IOS) imaging, laser speckle flowmetry (LSF) and electrocorticography were performed in different configurations in three groups of in total 18 swine. SDs were elicited by topical application of KCl or occurred spontaneously after middle cerebral artery occlusion. Movement artefacts in IOS were compensated by an elastic registration algorithm during post-processing. Using movement-compensated IOS, we were able to differentiate between four components of optical changes, corresponding closely with haemodynamic variations measured by LSF. Compared with ECoG and LSF, our setup provides higher spatial and temporal resolution, as well as a better signal-to-noise ratio. Using IOS alone, we could identify the different zones of infarction in a large gyrencephalic middle cerebral artery occlusion pig model. We strongly suggest movement-compensated IOS for the investigation of the role of haemodynamic responses to SDs during the development of secondary brain damage and in particular to examine the effect of potential therapeutic interventions in gyrencephalic brains.

Pharmacological modulation of spreading depolarizations.

Spreading depolarization (SD) is a wave of almost complete depolarization of the neuronal and glial cells. Nowadays there is sufficient evidence demonstrating its pathophysiological effect in migraine with aura, transient global amnesia, stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. In these cases, occurrence of SD has been associated with functional neuronal damage, neuronal necrosis, neurological degeneration, and poor clinical outcome. Animal models show that SD can be modulated by drugs that interfere with its initiation and propagation. There are many pharmacological targets that may help to suppress SD occurrence, such as Na⁺, K⁺, Cl⁻, and Ca²âº channels; Na⁺/K⁺ -ATPase; gap junctions; and ligand-based receptors, for example, adrenergic, serotonin, sigma-1, calcitonin gene-related peptide, GABAA, and glutamate receptors. In this regard, N-methyl-d-aspartate (NMDA) receptor blockers, in particular, ketamine, have shown promising results. Therefore, theoretically pharmacologic modulation of SD could help diminish its pathological effects.

The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex.

Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization that propagates across the cerebral cortex and has been implicated in the pathophysiology of brain injury states and migraine with aura. Analgesics and sedatives seem to have a significant effect on SD modulation. Studies have shown that ketamine, an NMDA receptor blocker, has the capacity to influence SD occurrence. The aim of this study was to analyze the dose-dependent effect of ketamine on SD susceptibility through electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging in a gyrencephalic brain. Ketamine in a low-dose infusion (2 mg/kg/h) decreases SD spread and had an effect on the amplitude of SD deflections, as well as on duration, and speed. Moreover, during ketamine infusion at this dose, there was a sustained decrease in the hyperemic response following SD. However, a high-dose infusion (4 mg/kg/h) of ketamine inhibited SD induction and expansion. Furthermore, a high-dose bolus (4 mg/kg), 1 min after stimulation, blocked SD propagation abruptly within 1-2 min, and hindered SD induction and expansion for the following 15-30 min. The results suggest that ketamine may be therapeutically beneficial in preventing SDs. Nonetheless, an adequate dosage and way of administration should be considered and established for human use.

Delayed cerebral ischemia after subarachnoid hemorrhage: from vascular spasm to cortical spreading depolarizations.

Non-traumatic subarachnoid hemorrhage (SAH) represents about 5 to 6% of the overall incidence of stroke and is associated with high morbidity and mortality. Despite the substantial research and clinical efforts, delayed cerebral ischemia (DCI) is still the major complication after SAH and represents an important factor for severe neurological deficits. Cerebral vasospasm (VSP) has been recognised for a long time as an important underlying pathophysiologic cause of DCI, but it is now clearer that the mechanisms underlying DCI are multifactorial. Among other pathomechanisms proposed, ischemia-producing cortical spreading depolarizations (CSDs) are likely to be involved in DCI development. Understanding the plethora of different pathophysiological derangements after SAH is very important for the development of new therapies, in order to abolish secondary ischemic brain injuries early-on and improve patients' outcome. In this review, we strive to summarise the mechanisms and therapeutic developments of DCI.

'Long' pressure reactivity index (L-PRx) as a measure of autoregulation correlates with outcome in traumatic brain injury patients.

BACKGROUND: Cerebral autoregulation and, consequently, cerebrovascular pressure reactivity, can be disturbed after traumatic brain injury (TBI). Continuous monitoring of autoregulation has shown its clinical importance as an independent predictor of neurological outcome. The cerebral pressure reactivity index (PRx) reflects that changes in seconds of cerebrovascular reactivity have prognostic significance. Using an alternative algorithm similar to PRx, we investigate whether the utilization of lower-frequency changes of the order of minutes of mean arterial blood pressure (MAP) and intracranial pressure (ICP) could have a prognostic value in TBI patients. MATERIALS AND METHODS: Head-injured patients requiring continued advanced multimodal monitoring, including hemodynamic, ICP and microdialysis (MD) monitoring, were analyzed retrospectively. A low-frequency sample pressure reactivity index (L-PRx) was calculated, using 20-min averages of MAP and ICP data as a linear Pearson's correlation. The mean values per patient were correlated to outcome at 6 months after injury. Differences of monitoring parameters between non-survivors and survivors were compared. RESULTS: A total of 29 patients (mean age 37.2 years, 26 males) suffering from TBI were monitored for a mean of 109.6 h (16-236 h, SD ± 60.4). Mean L-PRx was found to be of 0.1 (-0.2 to 0.6, SD ± 0.20), six patients presented impaired (>0.2) values. The averaged L-PRx correlated significantly with ICP (r = 0.467, p = 0.011) and 6-month outcome (r = -0.556, p = 0.002). Significant statistical differences were found in L-PRx, cerebral perfusion pressure (CPP), lactate, and lactate-pyruvate ratio when comparing patients who died (n = 5) and patients who survived. CONCLUSIONS: L-PRx correlates with the 6-month outcome in TBI patients. Very slow changes of MAP and ICP may contain important autoregulation information. L-PRx may be an alternative algorithm for the estimation of cerebral autoregulation and clinical prognosis.