Hyperglycemia as a Risk Factor of Ischemic Stroke

Diabetes is considered a major risk factor for stroke and is associated with worsened stroke outcomes. Here, we discuss and summarize the mechanisms that have been associated with the increased risk of stroke due to the hyperglycemia in diabetes mellitus. In diabetic stroke models, hyperglycemia exaggerates the following damaging processes: acidosis, accumulation of reactive oxygen species/reactive nitrogen, inflammation and mitochondrial dysfunction. Understanding the mechanism of diabetes acting as a stroke risk factor will definitely assist to reveal issues related to drug metabolism and toxicity in diabetic stroke. In addition, it is suggested that future studies may focus on the mechanisms mediating blood-brain barrier and astrocytes dysfunction under hyperglycemic stroke.This research was supported in part by a grant from the National Institutes of Health (R01NS058807) and a Kansas University Center for Research startup fund

Hypothalamic Menin Regulates Systemic Aging and Cognitive Decline

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline

Hypoxia-inducible factor 1 contributes to N-acetylcysteine’s protection in stroke

Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC’s neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC’s neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant’s neuroprotection in ischemic stroke

Back to ABCs: Clustering Alphabetically, Rather than Semantically, EnhancesVocabulary Learning

Optimizing the study of vocabulary words for high-stakes tests such as the SAT or GRE prep can beproblematic, given that many words are semantically,orthographically, or phonologically confusable. Companiesmarketing test preparation programs make multiplerecommendations, such as clustering words on some basis,but little research has been carried out to examine what thatbasis should be. Across two experiments, we compare theefficacy of different types of clustering—categorical,alphabetical, and confusable--for the learning ofsemantically related words (Experiment 1) and confusablewords (Experiment 2). We demonstrate that, in contrastto most learners’ intuitions, an alphabetical sequence yieldssuperior learning

The Future of Cognitive Strategy-enhanced Persuasive Dialogue Agents: New Perspectives and Trends

Persuasion, as one of the crucial abilities in human communication, has garnered extensive attention from researchers within the field of intelligent dialogue systems. We humans tend to persuade others to change their viewpoints, attitudes or behaviors through conversations in various scenarios (e.g., persuasion for social good, arguing in online platforms). Developing dialogue agents that can persuade others to accept certain standpoints is essential to achieving truly intelligent and anthropomorphic dialogue system. Benefiting from the substantial progress of Large Language Models (LLMs), dialogue agents have acquired an exceptional capability in context understanding and response generation. However, as a typical and complicated cognitive psychological system, persuasive dialogue agents also require knowledge from the domain of cognitive psychology to attain a level of human-like persuasion. Consequently, the cognitive strategy-enhanced persuasive dialogue agent (defined as CogAgent), which incorporates cognitive strategies to achieve persuasive targets through conversation, has become a predominant research paradigm. To depict the research trends of CogAgent, in this paper, we first present several fundamental cognitive psychology theories and give the formalized definition of three typical cognitive strategies, including the persuasion strategy, the topic path planning strategy, and the argument structure prediction strategy. Then we propose a new system architecture by incorporating the formalized definition to lay the foundation of CogAgent. Representative works are detailed and investigated according to the combined cognitive strategy, followed by the summary of authoritative benchmarks and evaluation metrics. Finally, we summarize our insights on open issues and future directions of CogAgent for upcoming researchers.Comment: 36 pages, 6 figure

The RANK/RANKL/OPG system and tumor bone metastasis: Potential mechanisms and therapeutic strategies

With the markedly increased diagnosis and incidence of cancer in the population, tumor bone metastasis has become a frequent event in tumor patients. Healthy bone integrity is maintained by a delicate balance between bone formation and bone resorption. Unfortunately, many tumors, such as prostate and breast, often metastasize to the bone, and the alterations to the bone homeostasis can particularly favor tumor homing and consequent osteolytic or osteoblastic lesions. Receptor activator of NF-κB ligand (RANKL), its receptor RANK, and osteoprotegerin (OPG) are involved in the regulation of the activation, differentiation, and survival of osteoclasts, which play critical roles in bone metastasis formation. High rates of osteoclastic bone resorption significantly increase fracture risk, cause severe bone pain, and contribute to homing tumor cells in bone and bone marrow. Consequently, suppression of the RANK/RANKL/OPG system and osteoclastic activity can not only ameliorate bone resorption but may also prevent tumor bone metastases. This review summarizes the important role of the RANK/RANKL/OPG system and osteoclasts in bone homeostasis and its effect on tumor bone metastasis and discusses therapeutic strategies based on RANKL inhibition

Therapeutics of Charcot neuroarthropathy and pharmacological mechanisms: A bone metabolism perspective

Charcot neuroarthropathy (CN) is a chronic, destructive, and painless damage of the skeletal system that affects the life quality of patients. CN, with an unclear mechanism, is characterized with invasive destruction of bones and a serious abnormality of bone metabolism. Unfortunately, development of an effective prevention and treatment strategy for CN is still a great challenge. Of note, recent studies providing an insight into the molecular mechanisms of bone metabolism and homeostasis have propelled development of novel CN therapeutic strategies. Therefore, this review aims to shed light on the pathogenesis, diagnosis, and treatment of CN. In particular, we highlight the eminent role of the osteoprotegerin (OPG)-receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL) system in the development of CN. Furthermore, we summarize and discuss the diagnostic biomarkers of CN as well as the potential pharmacological mechanisms of current treatment regimens from the perspective of bone metabolism. We believe that this review will enhance the current state of knowledge on the diagnosis, prevention, and therapeutic efficacy of CN

Simulation of future global warming scenarios in rice paddies with an open-field warming facility

To simulate expected future global warming, hexagonal arrays of infrared heaters have previously been used to warm open-field canopies of upland crops such as wheat. Through the use of concrete-anchored posts, improved software, overhead wires, extensive grounding, and monitoring with a thermal camera, the technology was safely and reliably extended to paddy rice fields. The system maintained canopy temperature increases within 0.5°C of daytime and nighttime set-point differences of 1.3 and 2.7°C 67% of the time

Epigenetic regulation of autophagy in neuroinflammation and synaptic plasticity

Autophagy is a conserved cellular mechanism that enables the degradation and recycling of cellular organelles and proteins via the lysosomal pathway. In neurodevelopment and maintenance of neuronal homeostasis, autophagy is required to regulate presynaptic functions, synapse remodeling, and synaptic plasticity. Deficiency of autophagy has been shown to underlie the synaptic and behavioral deficits of many neurological diseases such as autism, psychiatric diseases, and neurodegenerative disorders. Recent evidence reveals that dysregulated autophagy plays an important role in the initiation and progression of neuroinflammation, a common pathological feature in many neurological disorders leading to defective synaptic morphology and plasticity. In this review, we will discuss the regulation of autophagy and its effects on synapses and neuroinflammation, with emphasis on how autophagy is regulated by epigenetic mechanisms under healthy and diseased conditions

Prognostic value of the FUT family in acute myeloid leukemia

Genetic abnormalities are more frequently viewed as prognostic markers in acute myeloid leukemia (AML) in recent years. Fucosylation, catalyzed by fucosyltransferases (FUTs), is a post-translational modification that widely exists in cancer cells. However, the expression and clinical implication of the FUT family (FUT1-11) in AML has not been investigated. From the Cancer Genome Atlas database, a total of 155 AML patients with complete clinical characteristics and FUT1-11 expression data were included in our study. In patients who received chemotherapy alone showed that high expression levels of FUT3, FUT6, and FUT7 had adverse effects on event-free survival (EFS) and overall survival (OS) (all P <0.05), whereas high FUT4 expression had favorable effects on EFS and OS (all P <0.01). However, in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) group, we only found a significant difference in EFS between the high and low FUT3 expression subgroups (P = 0.047), while other FUT members had no effect on survival. Multivariate analysis confirmed that high FUT4 expression was an independent favorable prognostic factor for both EFS (HR = 0.423, P = 0.001) and OS (HR = 0.398, P <0.001), whereas high FUT6 expression was an independent risk factor for both EFS (HR = 1.871, P = 0.017) and OS (HR = 1.729, P = 0.028) in patients who received chemotherapy alone. Moreover, we found that patients with low FUT4 and high FUT6 expressions had the shortest EFS and OS (P <0.05). Our study suggests that high expressions of FUT3/6/7 predict poor prognosis, high FUT4 expression indicates good prognosis in AML; FUT6 and FUT4 have the best prognosticating profile among them, but their effects could be neutralized by allo-HSCT