Nonpathogenic E. coli engineered to surface display cytokines as a new platform for immunotherapy.

Given the safety, tumor tropism, and ease of genetic manipulation in non-pathogenic Escherichia coli (E. coli), we designed a novel approach to deliver biologics to overcome poor trafficking and exhaustion of immune cells in the tumor microenvironment, via the surface display of key immune-activating cytokines on the outer membrane of E. coli K-12 DH5α. Bacteria expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and NK cell-dependent immune responses leading to dramatic tumor control, extending survival, and curing a significant proportion of immune-competent mice with colorectal carcinoma and melanoma. The engineered bacteria demonstrated tumor tropism, while the abscopal and recall responses suggested epitope spreading and induction of immunologic memory. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting CAR NK cells and safely enhanced their trafficking into the tumors, leading to improved control and survival in xenograft mice bearing mesothelioma tumor cells, otherwise resistant to NK cells. Gene expression analysis of the bacteria-primed CAR NK cells showed enhanced TNFα signaling via NFkB and upregulation of multiple activation markers. Our novel live bacteria-based immunotherapeutic platform safely and effectively induces potent anti-tumor responses in otherwise hard-to-treat solid tumors, motivating further evaluation of this approach in the clinic.

SDF-1/CXCR4 axis participants in the pathophysiology of adult patients with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) is characterized by an abundance of moyamoya vessels; however, the precise mechanism driving the spontaneous angiogenesis of these compensatory vessels remains unclear. Previous research has established a link between the stromal cell-derived factor-1 (SDF-1)/ CXC receptor 4 (CXCR4) axis and angiogenesis under hypoxic conditions. Nevertheless, the alterations in this axis within the cerebrospinal fluid, arachnoid membranes and vascular tissue of MMD patients have not been fully investigated. METHODS: Our study enrolled 66 adult MMD patients and 61 patients with atherosclerotic vascular disease (ACVD). We investigated the SDF-1 concentration in cerebrospinal fluid (CSF) and CXCR4 expression level on the arachnoid membranes and vascular tissue. We utilized enzyme-linked immunosorbent assay and immunohistochemistr. Additionally, we cultured and stimulated human brain microvascular endothelial cells (HBMECs) and smooth muscle cells (SMCs) under oxygen and glucose deprivation (OGD) conditions followed by reoxygenation, to examine any changes in the SDF-1/CXCR4 axis. RESULTS: The results demonstrated an elevation in the level of SDF-1 in CSF among MMD patients compared to those with ACVD. Moreover, the expression of CXCR4 in arachnoid membranes and vascular tissue showed a similar trend. Furthermore, the content of CXCR4 in HBMECs and SMCs increased with the duration of ischemia and hypoxia. However, it was observed that the expression of CXCR4 decreased at OGD/R 24h compared to OGD 24h. The temporal pattern of SDF-1 expression in HBMECs and SMCs mirrored that of CXCR4 expression. CONCLUSION: These findings indicate a critical role for the SDF-1/CXCR4 axis in the angiogenesis of moyamoya disease.

ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.

Protein homeostasis is fundamental to the development of tumors. Ribosome-associated quality-control (RQC) is able to add alanine and threonine to the stagnant polypeptide chain C-terminal (CAT-tail) when protein translation is hindered, while Ankyrin repeat and zinc-finger domain-containing-protein 1 (ANKZF1) can counteract the formation of the CAT-tail, preventing the aggregation of polypeptide chains. In particular, ANKZF1 plays an important role in maintaining mitochondrial protein homeostasis by mitochondrial RQC (mitoRQC) after translation stagnation of precursor proteins targeting mitochondria. However, the role of ANKZF1 in glioblastoma is unclear. Therefore, the current study was aimed to investigate the effects of ANKZF1 in glioblastoma cells and a nude mouse glioblastoma xenograft model. Here, we reported that knockdown of ANKZF1 in glioblastoma cells resulted in the accumulation of CAT-tail in mitochondria, leading to the activated mitochondrial unfolded protein response (UPRmt) and inhibits glioblastoma malignant progression. Excessive CAT-tail sequestered mitochondrial chaperones HSP60, mtHSP70 and proteases LONP1 as well as mitochondrial respiratory chain subunits ND1, Cytb, mtCO2 and ATP6, leading to mitochondrial oxidative phosphorylation dysfunction, membrane potential impairment, and mitochondrial apoptotic pathway activation. Our study highlights ANKZF1 as a valuable target for glioblastoma intervention and provides an innovative insight for the treatment of glioblastoma through the regulating of mitochondrial protein homeostasis.

Arabidopsis calcineurin B-like-interacting protein kinase 8 and its functional homolog in tomato negatively regulates ABA-mediated stomatal movement and drought tolerance.

Stomatal movement is critical for water transpiration, gas exchange, and responses to biotic stresses. Abscisic acid (ABA) induces stomatal closure to prevent water loss during drought. We report that Arabidopsis CIPK8 negatively regulates ABA-mediated stomatal closure and drought tolerance. CIPK8 is highly enriched in guard cells and transcriptionally induced by ABA. Functional loss of CIPK8 results in hypersensitive stomatal closure to ABA and enhanced drought tolerance. Guard cell-specific downregulation of CIPK8 mimics the phenotype of cipk8 whereas guard cell-specific expression of a constitutive active CIPK8 (CIPK8CA) has an opposite effect, suggesting a cell autonomous activity of CIPK8. CIPK8 physically interacts with CBL1 and CBL9. Functional loss of CBL1 and CBL9 mimics ABA-hypersensitive stomatal closure of cipk8 whereas abolishes the effect of CIPK8CA, indicating that CIPK8 and CBL1/CBL9 form a genetic module in ABA-responsive stomatal movement. SlCIPK7, the functional homolog of CIPK8 in tomato (Solanum lycopersicum), plays a similar role in ABA-responsive stomatal movement. Genomic editing of SlCIPK7 results in more drought-tolerant tomato, making it a good candidate for germplasm improvement.

Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment. We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt. METHODS: Western blot analysis, aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression. RESULTS: The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo. CONCLUSIONS: We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.

Downregulation of Nrp1 transcription promotes blood-brain barrier disruption following experimental cerebral ischemia-reperfusion.

Disruption of the blood-brain barrier (BBB) following cerebral ischemia-reperfusion injury (CIRI) is a major factor in the pathophysiology of stroke. Endothelial cell-cell communication is essential for maintaining BBB integrity. By analyzing GSE227651 data, we found that a decrease in endothelial cell-cell communication mediated by Sema3/Nrp1 may be due to the downregulation of Nrp1 transcription, which could contribute to BBB breakdown after CIRI. We confirmed this hypothesis by using western blot analysis to show a reduction in Nrp1 protein levels in penumbra endothelial cells after CIRI in mice. We then overexpressed Nrp1 specifically in brain endothelial cells using adeno-associated virus in mice. Furthermore, Nrp1 overexpression had a protective effect on BBB integrity, as evidenced by a decrease in IgG and albumin leakage caused by CIRI in mice. Finally, we found that Nrp1 overexpression also reduced brain cell death and neurological deficits induced by cerebral ischemia-reperfusion in mice. Our findings suggest that Nrp1 downregulation may be a key factor in the breakdown of endothelial cell-cell communication and subsequent BBB disruption following CIRI. Targeting Nrp1-mediated pathways may be a promising approach for mitigating BBB damage and alleviating neurological consequences in stroke patients.

Engineered Bacillus subtilis as oral probiotics to target circulating lactic acid.

Lactic acid or lactate, a key byproduct of anaerobic glycolysis, plays pivotal roles in routine metabolism. An increase in lactic acid is observed in various pathological conditions such as cancer, diabetes, genetic mitochondrial disease, and aging. While several groups have proposed small molecule inhibitors to reduce circulating lactic acid, there are few clinically relevant ways to manage acute or chronic elevations in lactic acid in patients. In addition, recent evidence suggests that lactic acid exchanges between the gut, blood, and peripheral tissues, and professional marathon runners harbor specific gut microbial species that more efficiently metabolize lactic acid. Inspired by these findings, this work sought to engineer probiotic B. subtilis strains to express lactate oxidase that could increase circulating lactic acid catabolism after delivery to the gut. After optimization, oral administration of engineered B. subtilis to the gut of mice reduced the elevation in blood lactic acid levels after exogenous lactic acid challenge without affecting normal gut microbiota composition, inflammation or liver enzymes. Taken together, through the oral delivery of engineered probiotics to the gastrointestinal tract, our proof-of-concept study offers a new opportunity to therapeutically target diseases where blood lactic acid is elevated, and provides a new approach to "knocking down" metabolites to help understand the roles of metabolites in host physiological and pathological processes.

Resection of ruptured aneurysm associated with bilateral anomalous posterior inferior cerebellar anastomotic arteries: case report and review of literature.

Introduction: Aneurysms on the posterior inferior cerebellar artery (PICA) may not be the major part of intracranial aneurysm. Especially, an aneurysm located on the bilateral posterior inferior cerebellar anastomotic artery has abnormal anatomical characteristics in the vessel wall and then causes stroke including subarachnoid hemorrhage. This case report explores the direct resection of a ruptured aneurysm associated with the bilateral anomalous anastomotic artery of PICA. Methods: The case report discusses a 53-year-old woman who suffered from sudden severe headache and vomiting for more than 3 h admitted to our hospital. Emergency computed tomography (CT) revealed subarachnoid hemorrhage (SAH) in the third and fourth ventricles. Preoperative 3 Dimensions-digital subtraction angiography (3-D DSA) indicated a ruptured aneurysm located on the bilateral posterior inferior cerebellar anastomotic artery. Postoperative pathological findings indicated the characteristics of parent artery PICA and control aneurysm. The authors performed an overview of PICA aneurysms with anomalous variation in the Pubmed, Web of Science, and Medline databases. The search was until 1 August 2023. Related terms "posterior inferior cerebellar artery" And "aneurysm" AND "anatomical variants" were used to search the review. The reasons for anomalous variation anastomosis between bilateral PICAs were analyzed. Results: The aneurysm was resected successfully. Post-operative 3-D DSA revealed the disappearance of the aneurysm. The vessel wall of anastomotic PICA showed neovascularized hyperplasia, abnormal arrangement of smooth muscle, CD31+ endothelial cells, and SMA+ smooth muscle cells. In contrast, when it came to aneurysm, the wall at the location of the fracture thinned, which could be used to explain that the local nodular protrusion was formed and CD31+ endothelial cells existed. No neurological deficits were found at her 1-year follow-up visit (mRS score of 0). Conclusion: Direct resection of ruptured aneurysm associated with bilateral anomalous posterior inferior cerebellar anastomotic arteries was an effective treatment and careful consideration of the anatomical characteristics concerning the interesting aneurysm and the variant PICA was critical for sate treatment. Also, the literature on the lesion was reviewed.

APE1 regulates mitochondrial DNA damage repair after experimental subarachnoid haemorrhage in vivo and in vitro.

BACKGROUND: Subarachnoid haemorrhage (SAH) can result in a highly unfavourable prognosis. In recent years, the study of SAH has focused on early brain injury (EBI), which is a crucial progress that contributes to adverse prognosis. SAH can lead to various complications, including mitochondrial dysfunction and DNA damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein with multifaceted functionality integral to DNA repair and redox signalling. However, the role of APE1 in mitochondrial DNA damage repair after SAH is still unclear. METHODS: Our study involved an in vivo endovascular perforation model in rats and an in vitro neuron oxyhaemoglobin intervention. Then, the effects of APE1 on mitochondrial DNA damage repair were analysed by western blot, immunofluorescence, quantitative real-time PCR, mitochondrial bioenergetics measurement and neurobehavioural experiments. RESULTS: We found that the level of APE1 decreased while the mitochondria DNA damage and neuronal death increased in a rat model of SAH. Overexpression of APE1 improved short-term and long-term behavioural impairment in rats after SAH. In vitro, after primary neurons exposed to oxyhaemoglobin, APE1 expression significantly decreased along with increased mitochondrial DNA damage, a reduction in the subunit of respiratory chain complex levels and subsequent respiratory chain dysfunction. Overexpression of APE1 relieved energy metabolism disorders in the mitochondrial of neurons and reduced neuronal apoptosis. CONCLUSION: In conclusion, APE1 is involved in EBI after SAH by affecting mitochondrial apoptosis via the mitochondrial respiratory chain. APE1 may potentially play a vital role in the EBI stage after SAH, making it a critical target for treatment.

Correlation of event-related potentials N170 with dysfunctional attitudes in patients with major depressive disorder.

BACKGROUND: Cognitive impairment frequently accompanies first-episode major depressive disorder (MDD) in patients. Early detection and intervention for cognitive impairment can enhance the quality of life for individuals with depressive disorders. Impaired emotion recognition may serve as an initial manifestation of cognitive impairment in these patients. This study examines the characteristics of event-related potentials N170 and dysfunctional attitudinal questionnaire total scores, as well as each factor and their correlation, revealing characteristic electroencephalogram (EEG) changes associated with cognitive impairment in first-episode MDD patients. METHOD: A total of 88 patients experiencing first-episode MDD and 29 healthy volunteers from the same period participated in the study. They underwent event-related potential N170 measures to assess mood recognition function, the 17-item Hamilton depression scale (HAMD-17) to evaluate the severity of depressive disorder, and the Dysfunctional Attitudes Scales(DAS) to appraise cognitive function. RESULT: The dysfunctional attitude questionnaire's total score and each factor score were higher in the MDD group compared to the healthy control (HC) group. The MDD group exhibited lower amplitudes than the HC group at CZ, PZ, POZ, P7, PO7, P8, and PO8 electrode points. A correlation was identified between the P7 and PO7 electrode points of the event-related potential N170 and cognitive function. LIMITATION: This study solely considered neutral face emotional stimuli and did not account for depressive disorder subtypes. CONCLUSION: Differences were observed between the MDD and HC groups in cognitive function and N170 amplitude in the central brain region (CZ, PZ, POZ), left posterior temporal region (P7), left occipitotemporal region (PO7), right posterior temporal region (P8), and right occipitotemporal region (PO8). Additionally, a correlation was found between N170 latency in the left posterior temporal region of the brain (P7) and the left occipitotemporal region (PO7) with cognitive function.

Armcx1 attenuates secondary brain injury in an experimental traumatic brain injury model in male mice by alleviating mitochondrial dysfunction and neuronal cell death.

Armcx1 is highly expressed in the brain and is located in the mitochondrial outer membrane of neurons, where it mediates mitochondrial transport. Mitochondrial transport promotes the removal of damaged mitochondria and the replenishment of healthy mitochondria, which is essential for neuronal survival after traumatic brain injury (TBI). This study investigated the role of Armcx1 and its potential regulator(s) in secondary brain injury (SBI) after TBI. An in vivo TBI model was established in male C57BL/6 mice via controlled cortical impact (CCI). Adeno-associated viruses (AAVs) with Armcx1 overexpression and knockdown were constructed and administered to mice via stereotactic cortical injection. Exogenous miR-223-3p mimic or inhibitor was transfected into cultured cortical neurons, which were then scratched to simulate TBI in vitro. It was found that Armcx1 expression decreased significantly, while miR-223-3p levels increased markedly in peri-lesion tissues after TBI. The overexpression of Armcx1 significantly reduced TBI-induced neurological dysfunction, neuronal cell death, mitochondrial dysfunction, and axonal injury, while the knockdown of Armcx1 had the opposite effect. Armcx1 was potentially a direct target of miR-223-3p. The miR-223-3p mimic obviously reduced the Armcx1 protein level, while the miR-223-3p inhibitor had the opposite effect. Finally, the miR-223-3p inhibitor dramatically improved mitochondrial membrane potential (MMP) and increased the total length of the neurites without affecting branching numbers. In summary, our results suggest that the decreased expression of Armcx1 protein in neurons after experimental TBI aggravates secondary brain injury, which may be regulated by miR-223-3p. Therefore, this study provides a potential therapeutic approach for treating TBI.

Immune regulation in neurovascular units after traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Survivors may experience movement disorders, memory loss, and cognitive deficits. However, there is a lack of understanding of the pathophysiology of TBI-mediated neuroinflammation and neurodegeneration. The immune regulation process of TBI involves changes in the peripheral and central nervous system (CNS) immunity, and intracranial blood vessels are essential communication centers. The neurovascular unit (NVU) is responsible for coupling blood flow with brain activity, and comprises endothelial cells, pericytes, astrocyte end-feet, and vast regulatory nerve terminals. A stable NVU is the basis for normal brain function. The concept of the NVU emphasizes that cell-cell interactions between different types of cells are essential for maintaining brain homeostasis. Previous studies have explored the effects of immune system changes after TBI. The NVU can help us further understand the immune regulation process. Herein, we enumerate the paradoxes of primary immune activation and chronic immunosuppression. We describe the changes in immune cells, cytokines/chemokines, and neuroinflammation after TBI. The post-immunomodulatory changes in NVU components are discussed, and research exploring immune changes in the NVU pattern is also described. Finally, we summarize immune regulation therapies and drugs after TBI. Therapies and drugs that focus on immune regulation have shown great potential for neuroprotection. These findings will help us further understand the pathological processes after TBI.

Molecular mechanism of FBXW7-mediated ubiquitination modification in nasopharyngeal carcinoma cell proliferation in vitro and in vivo.

OBJECTIVES: Nasopharyngeal carcinoma (NPC) is a type of keratinizing squamous cell malignancy. Ubiquitination, a common protein posttranslational modification, participates in cancer development. This study sought to investigate the mechanism of F-box and WD repeat domain containing 7 (FBXW7) in NPC cell proliferation in vivo and in vitro. METHODS: FBXW7, Homeobox A10 (HOXA10), and bone morphogenetic protein-2 (BMP2) expression levels in NPC tissues and cells were detected by RT-qPCR and Western blotting. Cell proliferation was assessed by cell counting kit-8 and colony formation assays. The binding of FBXW7 to HOXA10 and HOXA10 ubiquitination level were detected via co-immunoprecipitation and ubiquitination assay. Cells were treated with MG132 (the proteasome inhibitor), followed by the determination of HOXA10 ubiquitination and protein levels. The binding of HOXA10 to BMP2 was testified via dual-luciferase and chromatin immunoprecipitation assays. Collaborative experiments were performed to confirm the role of HOXA10 or BMP2 in FBXW7-mediated NPC cell proliferation. Xenograft tumor assay was performed to confirm the role of FBXW7/HOXA10/BMP2 in vivo. RESULTS: FBXW7 was under-expressed, while HOXA10 and BMP2 were up-expressed in NPC tissues and cells. FBXW7 overexpression restricted NPC cell proliferation. Mechanically, FBXW7 bound to HOXA10 to promote ubiquitination-based degradation of HOXA10 and further reduced the binding of HOXA10 to the BMP2 promoter and inhibited BMP2 transcription. Overexpression of HOXA10 or BMP2 attenuated the role of FBXW7 overexpression in inhibiting NPC cell proliferation. FBXW7 overexpression reduced Ki67 positive rate and repressed tumor growth. CONCLUSION: FBXW7 overexpression promoted HOXA10 ubiquitination-based degradation and further inhibited BMP2 transcription, consequently restricting NPC cell proliferation in vitro and in vivo.

The effect of tamsulosin in postoperative urinary retention: a meta-analysis of randomized controlled trials.

Tamsulosin is a therapeutic drug of alpha-adrenergic antagonists. Previous randomized controlled trials and retrospective analyses have proved the efficacy of tamsulosin on many urinary system diseases. However, there is still a conflict about whether tamsulosin could prevent postoperative urinary retention (POUR). This meta-analysis aims to probe into the efficacy of tamsulosin for preventing POUR versus placebo. We searched MEDLINE, EMBASE, and Cochrane Library from December 31, 1999 to April 30, 2022, for randomized controlled trials (RCTs). Studies that were not RCTs or without negative controls were excluded. Cochrane Collaboration harmonized criteria were used to assess the risk of bias in included studies. Revman (version 5.3) software was invited to synthesize the results. We performed subgroup analyses to explore the factors that could influence tamsulosin's efficacy in POUR prevention. Our meta-analysis pooled 13 RCTs with 2163 patients. We concluded that tamsulosin brought about a significant reduction in the risk of POUR versus placebo (13.54% vs 20.88% for tamsulosin vs placebo, RR = 0.63, 95% CI 0.47 to 0.84, P = 0.002). Tamsulosin could significantly reduce the risk of POUR in abdominal (11.52% vs 20.25% for tamsulosin vs placebo, RR = 0.52, 95% CI 0.31 to 0.88, P = 0.02) and female pelvic surgery (15.57% vs 31.50% for tamsulosin vs placebo, RR = 0.51, 95% CI 0.31 to 0.82, P = 0.006) but not in spinal surgery (13.45% vs 12.75% for tamsulosin vs placebo, RR = 1.07, 95% CI 0.72 to 1.60, P = 0.73) and lower limb surgery (21.43% vs 33.33% for tamsulosin vs placebo, RR = 0.64, 95% CI 0.35 to 1.14, P = 0.13). The preventive effect of postoperative (17.70% vs 33.93% for tamsulosin vs placebo, RR = 0.53, 95% CI 0.33 to 0.85, P = 0.008) and postoperative with preoperative tamsulosin (13.96% vs 23.44% for tamsulosin vs placebo, RR = 0.64, 95% CI 0.43 to 0.93, P = 0.02) on POUR were significantly better than preoperative management (11.95% vs 14.63% for tamsulosin vs placebo, RR = 0.62, 95% CI 0.23 to 1.65, P = 0.34). Postoperative catheter placement appears to have a negative impact on the POUR-preventive effect of tamsulosin. (9.37% vs 16.46% for tamsulosin vs placebo, RR = 0.51, 95% CI 0.31 to 0.83, P = 0.007) Tamsulosin showed significantly effect on POUR prevention in patients during spinal (15.07% vs 26.51% for tamsulosin vs placebo, RR = 0.52, 95% CI 0.31 to 0.90, P = 0.02) and epidural anesthesia (12.50% vs 29.79% for tamsulosin vs placebo, RR = 0.42, 95% CI 0.18 to 1.00, P = 0.05) but not in general anesthesia (12.40% vs 18.52% for tamsulosin vs placebo, RR = 0.68, 95% CI 0.45 to 1.03, P = 0.07). Tamsulosin shows better outcomes for preventing POUR than placebo. Besides, tamsulosin showed a different effect on POUR prevention in the various surgical sites, anesthesia, medication management, and catheter use. However, our conclusions still have some limitations due to the lack of evidence.

Peroxiredoxin-3 plays a neuroprotective role in early brain injury after experimental subarachnoid hemorrhage in rats.

Subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke, is a neurological emergency associated with a high morbidity and mortality rate. After SAH, early brain injury (EBI) is the leading cause of poor prognosis in SAH patients. Peroxiredoxins (PRDXs) are a family of sulphhydryl-dependent peroxidases. Peroxiredoxin-3 (PRDX3) is mainly located in the mitochondria of neurons, which can remove hydrogen peroxide (H2O2); however, the effect of PRDX3 on EBI after SAH remains unclear. In this study, an endovascular perforation model was used to mimic SAH in Sprague Dawley rats in vivo. The results revealed that after SAH, PRDX3 levels decreased in the neurons. PRDX3 overexpression by neuron-specific adeno-associated viruses upregulated PRDX3 levels. Furthermore, PRDX3 overexpression improved long- and short-term behavioral outcomes and alleviated neuronal impairment in rats. Nissl staining revealed that the upregulation of PRDX3 promoted cortical neuron survival. PRDX3 overexpression decreased the H2O2 content and downregulated caspase-9 expression. In conclusion, PRDX3 participates in neuronal protection by inhibiting the neuronal mitochondria-mediated death pathway; PRDX3 may be an important target for EBI intervention after SAH.

Data-Independent Acquisition-Based Serum Proteomic Profiling of Adult Moyamoya Disease Patients Reveals the Potential Pathogenesis of Vascular Changes.

Moyamoya disease (MMD) is a chronic cerebrovascular disease with unknown etiology. The pathogenesis of vascular changes remains unclear. Ischemic and hemorrhagic adult MMD patients and healthy volunteers were enrolled to collect serum for data-independent acquisition (DIA)-based proteomic analysis and ELISA validation. DIA serum proteomic revealed that apolipoprotein C-I (APOC1), apolipoprotein D (APOD), and apolipoprotein A-IV (APOA4) were decreased. The reductases glutathione S-transferase omega-1 (GSTO1) and peptidyl-prolyl cis-trans isomerase A (PPIA) were upregulated, and ADAMTS-like protein 4 (ADAMTSL4) was downregulated in both ischemic and hemorrhagic MMD. Afamin (AFM) and transforming growth factor-beta-induced protein ig-h3 (TGFBI) increased in ischemic patients but decreased in hemorrhagic patients. Serum ELISA results confirmed that APOA4, APOC1, and APOD were decreased compared to controls. Then, we retrospectively analyzed biochemical indexes of 200 MMD patients. A total of 54 enrolled MMD patients showed decreased total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-c). APOA4, APOC1, and APOD were vital factors in the HDL decrease in MMD patients. Lipoprotein dysfunction in MMD patients is involved in MMD. Intimal thickening by enhanced adhesion, middle layer vascular smooth muscle cell migration, and decreased lipid antioxidant function represented by HDL are potential pathogeneses of vascular changes in MMD.

Spatial Distribution Characteristics and Influencing Factors of Traditional Villages on the Tibetan Plateau in China.

The Tibetan Plateau is one of the world's most extreme habitats and one of the most challenging ecosystems on the planet. Many multi-ethnic traditional villages have developed on the plateau over its long history, and are an essential component of human settlement. It is critical to research them, and it is also significant for China's goals to make the Tibetan Plateau a distinctive ethnic cultural preservation site and a world tourist destination. While there have been limited studies focusing on villages in the entire Tibetan Plateau area, as a result, we aim to expand the field of research on the regional study of traditional villages and make progress in research throughout the Tibetan Plateau. The question addressed in this study is what the current characteristics of the distribution of traditional villages on the Tibetan Plateau are, and we attempt to propose suggestions for the preservation of traditional villages according to the distribution characteristics. Methods such as the closest neighbor index, kernel density estimates, and spatial autocorrelation analysis are used to investigate the characteristics of the spatial distribution of traditional Chinese villages on the Tibetan Plateau, as well as regression analysis of the factors that control this distribution. The findings indicate that traditional villages are unevenly distributed over the plateau, with fewer villages in the northwest and more in the southeast, showing an agglomeration type of distribution. The village distribution on provincial and municipal is uneven with a large step difference. Tibetans make up the majority of the population in the villages, but other ethnic groups are present at the margins of the plateau. The distribution of traditional villages shows "big scattered, small gather" characteristics, and one core cluster (the Hehuang Valley area of Qinghai Province) and five high-density areas (the western Sichuan Plateau; the Three Parallel Rivers area of Yunnan Province; the Yarlung Zangbo, Nyangqu, and Lhasa rivers (YZN) area of Tibet Province; the Yushu area of Qinghai Province; and the Gannan area of Gansu and Sichuan province). The natural environment has the strongest influence on the distribution of traditional villages, followed by human impacts, especially concerning the distribution of single and multi-ethnic villages, and socioeconomic factors, which have multiple influences.

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs.

Glioma is characterized as the most aggressive brain tumor that occurred in the central nervous system. The circadian rhythm is an essential cyclic change system generated by the endogenous circadian clock. Current studies found that the circadian clock affects glioma pathophysiology. It is still controversial whether the circadian rhythm disruption is a cause or an effect of tumorigenesis. This review discussed the association between cell cycle and circadian clock and provided a prominent molecular theoretical basis for tumor therapy. We illustrated the external factors affecting the circadian clock including thermodynamics, hypoxia, post-translation, and microRNA, while the internal characteristics concerning the circadian clock in glioma involve stemness, metabolism, radiotherapy sensitivity, and chemotherapy sensitivity. We also summarized the molecular pathways and the therapeutic drugs involved in the glioma circadian rhythm. There are still many questions in this field waiting for further investigation. The results of glioma chronotherapy in sensitizing radiation therapy and chemotherapy have shown great therapeutic potential in improving clinical outcomes. These findings will help us further understand the characteristics of glioma pathophysiology.

Intermittent theta-burst stimulation with physical exercise improves poststroke motor function: A systemic review and meta-analysis.

Background: Intermittent theta-burst stimulation (iTBS) is an optimized rTMS modality that could modulate the excitability of neural structures. Several studies have been conducted to investigate the efficacy of iTBS in improving the motor function of stroke patients. However, the specific role of iTBS in motor function recovery after stroke is unclear. Hence, in our study, we performed a meta-analysis to investigate the efficacy of iTBS for the motor function improvement of stroke patients. Methods: MEDLINE, Embase, and Cochrane Library were searched until May 2022 for randomized controlled trials (RCTs). Results: Thirteen RCTs with 334 patients were finally included in our study. The primary endpoints were the Fugl-Meyer assessment scale (FMA) and Motor Assessment Scale (MAS) change from baseline. We found that iTBS led to a significant reduction in FMA score (P = 0.002) but not in MAS score (P = 0.24) compared with the sham group. Moreover, standard 600-pulse stimulation showed a better effect on motor function improvement than the sham group (P = 0.004), however, 1200-pulse iTBS showed no effect on motor function improvement after stroke (P = 0.23). The effect of iTBS for improving motor function only exists in chronic stroke patients (P = 0.02) but not in subacute patients (P = 0.27). Conclusion: This study supports that iTBS has good efficacy for improving motor function in stroke patients. Therefore, standard 600-pulse stimulation iTBS therapy is proper management and treatment for chronic stroke.

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice.

The infiltration of blood components into the brain parenchyma through the lymphoid system is an important cause of subarachnoid hemorrhage injury. AQP4, a water channel protein located at the astrocyte foot, has been reported to regulate blood-brain barrier integrity, and its polarization is disrupted after SAH. Neuronal ferroptosis is involved in subarachnoid hemorrhage- (SAH-) induced brain injury, but the inducing factors are not completely clear. Transferrin is one of the inducing factors of ferroptosis. This study is aimed at researching the role and mechanism of AQP4 in brain injury after subarachnoid hemorrhage in mice. An experimental mouse SAH model was established by endovascular perforation. An AAV vector encoding AQP4 with a GFAP-specific promoter was administered to mice to achieve specific overexpression of AQP4 in astrocytes. PI staining, Fer-1 intervention, and transmission electron microscopy were used to detect neuronal ferroptosis, and dextran (40 kD) leakage was used to detect BBB integrity. Western blot analysis of perfused brain tissue protein samples was used to detect transferrin infiltration. First, neuronal ferroptosis 24 h after SAH was observed by PI staining and Fer-1 intervention. Second, a significant increase in transferrin infiltration was found in the brain parenchyma 24 h after SAH modeling, while transferrin content was positively correlated with neuronal ferroptosis. Then, we observed that AQP4 overexpression effectively improved AQP depolarization and BBB injury induced by SAH and significantly reduced transferrin infiltration and neuronal ferroptosis after SAH. Finally, we found that AQP4 overexpression could effectively improve the neurobehavioral ability of SAH mice, and the neurobehavioral ability was negatively correlated with transferrin brain content. Taken together, these data indicate that overexpression of AQP4 in the mouse brain can effectively improve post-SAH neuronal ferroptosis and brain injury, at least partly by inhibiting transferrin infiltration into the brain parenchyma in the glymphatic system.