SARS-CoV-2 infection alkalinizes the ERGIC and lysosomes through the viroporin activity of the viral envelope protein.

The coronavirus SARS-CoV-2, the agent of the deadly COVID-19 pandemic, is an enveloped virus propagating within the endocytic and secretory organelles of host mammalian cells. Enveloped viruses modify the ionic homeostasis of organelles to render their intra-luminal milieu permissive for viral entry, replication and egress. Here, we show that infection of Vero E6 cells with the delta variant of the SARS-CoV-2 alkalinizes the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) as well as lysosomes, mimicking the effect of inhibitors of vacuolar proton ATPases. We further show the envelope protein of SARS-CoV-2 accumulates in the ERGIC when expressed in mammalian cells and selectively dissipates the ERGIC pH. This viroporin action is prevented by mutations of Val25 but not Asn15 within the channel pore of the envelope (E) protein. We conclude that the envelope protein acts as a proton channel in the ERGIC to mitigate the acidity of this intermediate compartment. The altered pH homeostasis of the ERGIC likely contributes to the virus fitness and pathogenicity, making the E channel an attractive drug target for the treatment of COVID-19.

TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.

Mitochondrial Ca2+ ions are crucial regulators of bioenergetics and cell death pathways. Mitochondrial Ca2+ content and cytosolic Ca2+ homeostasis strictly depend on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+ /H+ exchanger (CHE). Originally identified as the mitochondrial K+ /H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identify TMBIM5/MICS1, the only mitochondrial member of the TMBIM family, and validate the physical interaction of TMBIM5 and LETM1. Cell-based and cell-free biochemical assays demonstrate the absence or greatly reduced Na+ -independent mitochondrial Ca2+ release in TMBIM5 knockout or pH-sensing site mutants, respectively, and pH-dependent Ca2+ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE, involved in setting and regulating the mitochondrial proton gradient. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.

Study on the Relationship Between ß2 Macroglobulin, Small Density, Low-density Lipoprotein and Carotid Plaque Instability after Acute Thrombolysis in Patients with Ischemic Stroke.

Objective: Study the relationship between ß2 microglobulin, small density, low-density lipoprotein and carotid plaque instability after acute thrombolysis in ischemic stroke patients (IS). Methods: 319 patients with acute cerebral infarction who were treated by thrombolysis in the Department of Neurology, Chongming Branch of Shanghai Xinhua Hospital from January 2017 to May 2022 were included retrospectively. All subjects have undergone a carotid artery ultrasound examination for plaque. According to the ultrasound results, the subjects were divided into plaque-free group (94 cases), a stable plaque group (38 cases) and an unstable plaque group (187 cases). Use an automatic blood biochemical analyzer to detect routine indicators. At the same time, compare the differences of risk factors and biochemical indicators among the groups according to the demographic data of the patient's previous hospitalization. To further evaluate the related risk factors of the instability of carotid plaque in patients through the multivariate logistic regression analysis, the odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Analysis the predictive value of ß2 microglobulin and small density low density lipoprotein on the instability of carotid plaque in I.S. patients after acute thrombolysis through subject work characteristic curve (ROC). Results: Among 319 patients, 187 had unstable plaque accounting for 58.6% and 38 had stable plaque accounting for 11.9%, according to the comparison of general clinical data. Lymphocyte, neutrophil ratio, triglyceride, T3, Hcy, ß2 microglobulin has statistical significance in the presence or absence of plaque. Lymphocytes, small dense low-density lipoprotein, ß2 microglobulin have statistical significance in the stability of plaque (P < .05). Total cholesterol, hypertension, ß2 microglobulin and small density low-density lipoprotein may be independent risk factors of carotid plaque instability through multivariate logistic regression analysis (P < .05). The area under ROC curve showed that ß2 microglobulin AUC: 0.6388, P < .05, small density low-density lipoprotein AUC: 0.6086, P < .05, combined diagnosis AUC: 0.6924, P < .05. Conclusion: ß2 microglobulin and density low-density lipoprotein are independent risk factors of carotid artery plaque instability in I.S. patients after acute thrombolysis. Moreover, the sensibility and differential of combined diagnosis are higher, which has certain predictive value for the instability of carotid plaque in such patients.

A randomized, double-blind, placebo-controlled study of Cistanche tubulosa and Ginkgo biloba extracts for the improvement of cognitive function in middle-aged and elderly people.

Mild cognitive impairment poses an increasing challenge to middle-aged and elderly populations. Traditional Chinese medicinal herbs like Cistanche tubulosa and Ginkgo biloba (CG) have been proposed as potential agents to improve cognitive and memory functions. A randomized controlled trial involving 100 Chinese middle-aged and elderly participants was conducted to investigate the potential synergistic effects of CG on cognitive function in individuals at risk of neurodegenerative diseases. Over 90 days, both CG group and placebo group received two tablets daily, with each pair of CG tablets containing 72 mg echinacoside and 27 mg flavonol glycosides. Cognitive functions were assessed using multiple scales and blood biomarkers were determined at baseline, Day 45, and Day 90. The CG group exhibited significant improvements in the scores of Mini-Mental State Examination (26.5 at baseline vs. 27.1 at Day 90, p < 0.001), Montreal Cognitive Assessment (23.4 at baseline vs. 25.3 at Day 90, p < 0.001), and World Health Organization Quality of Life (81.6 at baseline vs. 84.2 at Day 90, p < 0.001), all surpassing scores in placebo group. Notably, both the Cognitrax matrix test and the Wechsler Memory Scale-Revised demonstrated enhanced memory functions, including long-term and delayed memory, after CG intervention. Moreover, cognitive-related blood biomarkers, including total tau, pT181, pS199, pT231, pS396, and thyroid-stimulating hormone, significantly decreased, whereas triiodothyronine and free triiodothyronine significantly increased. No treatment-related adverse events were reported, and routine blood and urine tests remained stable. These findings indicated that CG supplementation could potentially serve as an effective supplementary solution for enhancing cognitive and memory functions.

The mammalian trafficking chaperone protein UNC93B1 maintains the ER calcium sensor STIM1 in a dimeric state primed for translocation to the ER cortex.

The stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum (ER) Ca2+ sensor that regulates the activity of Orai plasma membrane Ca2+ channels to mediate the store-operated Ca2+ entry pathway essential for immunity. Uncoordinated 93 homolog B1 (UNC93B1) is a multiple membrane-spanning ER protein that acts as a trafficking chaperone by guiding nucleic-acid sensing toll-like receptors to their respective endosomal signaling compartments. We previously showed that UNC93B1 interacts with STIM1 to promote antigen cross-presentation in dendritic cells, but the STIM1 binding site(s) and activation step(s) impacted by this interaction remained unknown. In this study, we show that UNC93B1 interacts with STIM1 in the ER lumen by binding to residues in close proximity to the transmembrane domain. Cysteine crosslinking in vivo showed that UNC93B1 binding promotes the zipping of transmembrane and proximal cytosolic helices within resting STIM1 dimers, priming STIM1 for translocation. In addition, we show that UNC93B1 deficiency reduces store-operated Ca2+ entry and STIM1-Orai1 interactions and targets STIM1 to lighter ER domains, whereas UNC93B1 expression accelerates the recruitment of STIM1 to cortical ER domains. We conclude that UNC93B1 therefore acts as a trafficking chaperone by maintaining the pool of resting STIM1 proteins in a state primed for activation, enabling their rapid translocation in an extended conformation to cortical ER signaling compartments.

α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis.

The α-arrestin domain containing protein 3 (ARRDC3) is a tumor suppressor in triple-negative breast carcinoma (TNBC), a highly metastatic subtype of breast cancer that lacks targeted therapies. Thus, understanding the mechanisms and targets of ARRDC3 in TNBC is important. ARRDC3 regulates trafficking of protease-activated receptor 1 (PAR1, also known as F2R), a G-protein-coupled receptor (GPCR) implicated in breast cancer metastasis. Loss of ARRDC3 causes overexpression of PAR1 and aberrant signaling. Moreover, dysregulation of GPCR-induced Hippo signaling is associated with breast cancer progression. However, the mechanisms responsible for Hippo dysregulation remain unknown. Here, we report that the Hippo pathway transcriptional co-activator TAZ (also known as WWTR1) is the major effector of GPCR signaling and is required for TNBC migration and invasion. Additionally, ARRDC3 suppresses PAR1-induced Hippo signaling via sequestration of TAZ, which occurs independently of ARRDC3-regulated PAR1 trafficking. The ARRDC3 C-terminal PPXY motifs and TAZ WW domain are crucial for this interaction and are required for suppression of TNBC migration and lung metastasis in vivo. These studies are the first to demonstrate a role for ARRDC3 in regulating GPCR-induced TAZ activity in TNBC and reveal multi-faceted tumor suppressor functions of ARRDC3. This article has an associated First Person interview with the first author of the paper.

Endovascular treatment over 24 hours after ischemic stroke onset: a single-center retrospective study.

PURPOSE: The aim of this study is to evaluate the safety and effectiveness of endovascular treatment (EVT) for acute ischemic stroke caused by large-vessel obstruction or stenosis (AIS-LVO/S) over 24 h after first AIS symptom recognition (FAISSR). METHODS: A total of 33 AIS-LVO/S cases with EVT over 24 h after FAISSR during the period from January 2019 to February 2022 in our hospital were divided into the 90d mRS ≤ 2 group [favorable outcome (FO) group] and 90d mRS > 2 group [unfavorable outcome (UFO) group] and retrospectively analyzed. RESULTS: The reperfusion was successfully established with EVT in 97% (32/33) of cases, and most (63.6%, 21/33) had 90d mRS ≤ 2 and only 36.4% (12/33) had 90d mRS > 2. Preoperative DWI-ASPECT and ASITN/SIR scores were significantly higher and NIHSS scores were significantly lower in the FO group than those in the UFO group (P < 0.05). In addition, the FAISSR to exacerbation time, FAISSR to groin puncture time, and FAISSR to reperfusion time were significantly longer, and the groin puncture to reperfusion time was significantly shorter in the FO group than those in the UFO group (P < 0.05), but there was no significant difference in the stroke exacerbation to groin puncture time (P > 0.05). The patients with cerebral infarction due to artery dissection had more favorable EVT outcomes, but the patients with posterior cerebral circulation infarction had very poor EVT outcomes. CONCLUSIONS: The FAISSR to groin puncture time over 24 h may not be a taboo for EVT and it may be safe and effective for AIS-LVO/S in anterior cerebral circulation, especially with lower preoperative NIHSS scores.

Basilar artery curvature increases the risk of posterior circulation infarction occurrence in patients without vertebrobasilar stenosis.

INTRODUCTION: Limited cross-sectional or case-control studies have identified the relationship between basilar artery (BA) curvature and posterior circulation infarction (PCI). This study aimed to identify the influence of BA curvature severity on the risk of PCI occurrence in patients without vertebrobasilar stenosis through a prospective cohort study. METHODS: In this study, we enrolled 171 patients with BA dolichosis but without vertebrobasilar stenosis. The BA geometric parameters were evaluated on MRA. The primary outcome was the occurrence of PCI, mainly referring to cerebellar and/or brainstem infarction. Cox proportional hazard models were used to detect possible predictors of PCI. RESULTS: Among them, 134 (78.4%) patients were diagnosed with BA curvature, including 124 with moderate curvature and 10 with prominent curvature. The defined PCI occurrence was observed in 32 (18.7%) patients with a median follow-up time of 45.6 months. Cox proportional hazard analysis showed that BA prominent curvature (HR = 6.09; 95% CI: 1.36-27.28; P = 0.018) significantly increased the risk of PCI occurrence, and bending length (BL) was also significantly associated with PCI occurrence, with the adjusted HR per 1-mm increase of BL of 1.09 (95% CI: 1.01-1.18; P = 0.040). In the subgroup analysis stratified by age, BA prominent curvature was highly associated with PCI occurrence in patients aged > 61 years (HR = 11.76; 95% CI: 1.21-113.90; P = 0.033). Additionally, good antiplatelet therapy adherence could significantly reduce the risk of PCI occurrence. CONCLUSION: BA curvature may increase the risk of PCI occurrence, especially in elderly patients with prominent curvature. Improving adherence to antiplatelet therapy can help reduce the risk of PCI occurrence.

Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila.

Hyccin/FAM126A mutations are linked to hypomyelination and congenital cataract disease (HCC), but whether and how Hyccin/FAM126A deficiency causes hypomyelination remains undetermined. This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila. Knockdown of Hyccin/FAM126A in glia reduced the enrichment of glial cells, disrupted axonal sheaths and visual ability in the visual system, and these defects could be fully rescued by overexpressing either human FAM126A or FAM126B, and partially rescued by overexpressing a plasma membrane-targeting recombinant mouse PI4KIIIα. Additionally, PI4KIIIα knockdown in glia phenocopied Hyccin/FAM126A knockdown, and this was partially rescued by overexpressing the recombinant PI4KIIIα, but not human FAM126A or FAM126B. This study establishes an animal model of HCC and indicates that Hyccin/FAM126A plays an essential role in glial enrichment and axonal sheath in a cell-autonomous manner in the visual system via controlling the expression and stabilization of the PI4KIIIα complex at the plasma membrane.

Potential proteomic alteration in the brain of Tg(SOD1*G93A)1Gur mice: A new pathogenesis insight of amyotrophic lateral sclerosis.

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. The recent studies have suggested that the protein abnormalities could play some important roles in ALS because several protein mutations were found in individuals with this disease. However, proteins that are currently known to be associated with ALS only explain the pathogenesis of this disease in a minority of cases, thus, further screening is needed to identify other ALS-related proteins. In this study, we systematically analyzed and compared the brain proteomic alterations between a mouse model of ALS, the Tg(SOD1*G93A)1Gur model, and wild-type mice using isobaric tags for relative and absolute quantitation (iTRAQ) as well as bioinformatics methods. The results revealed some significant up- and downregulated proteins at the different developmental stages in the ALS-like mice as well as the possibly related cellular components, molecular functions, biological processes, and pathways in the development of ALS. Our results identified some possible proteins that participate in the pathogenesis of ALS as well as the cellular components that are damaged by these proteins, we additionally identified the molecular functions, the biological processes, and the pathways of these proteins as well as the molecules that are associated with these pathways. This study represents an important preliminary investigation of the role of proteomic abnormalities in the pathogenesis of ALS, both in human patients and other animal models. We present some novel findings that may serve as a basis for further investigation of abnormal proteins that are involved in the pathogenesis of ALS.

Moving silicone oil particles in the ventricle: a case report and updated review.

BACKGROUND: The movement of intraventricular silicone oil observed in the supine position is extremely rare. Herein, we describe a patient who presented with dynamically moving silicone oil particles in the ventricle when changing position and provide an updated review of this phenomenon. CASE PRESENTATION: We report a case of a 70-year-old woman who presented with intraventricular hyperdensities that were occasionally found on brain computed tomography (CT). Initial nonenhanced brain CT demonstrated nondependent hyperdensities in the bilateral anterior horns of the lateral ventricles, the third ventricle, and the right suprasellar cistern, mimicking an intraventricular hemorrhage. Further brain magnetic resonance imaging (MRI) in the supine position revealed abnormal signals in the bilateral anterior horns of the lateral ventricles, the posterior horn of the right lateral ventricle, the third ventricle, the right suprasellar cistern, and the bilateral eyeballs, with isosignal intensities surrounded by low-signal chemical shift artifacts on T1-weighted imaging and variable signals (hypo- or hyperintensity) on T2-weighted imaging. The lesion in the anterior horn of the right ventricle largely moved to the posterior horn of the ipsilateral ventricle. The final craniocervical CT angiography showed that the lesion in the posterior horn had moved back to the anterior horn of the right lateral ventricle. These features were consistent with intraventricular silicone oil migration. The final spinal MRI did not demonstrate a migration of silicone oil into the spinal subarachnoid space. DISCUSSION AND CONCLUSIONS: This case report describes a dynamic process of silicone oil displacement in the supine position and provides a comprehensive imaging presentation. The moving pattern and a characteristic chemical shift artifact on MRI are key to the diagnosis and may help prevent unnecessary examinations or intervention.

NPM1 is a diagnostic and prognostic biomarker associated with the clinicopathological characteristics of gastric cancer.

NPM1 plays an important role in the occurrence and development of leukemia and various solid tumors. This study aimed to investigate the expression of NPM1 in gastric cancer (GC) and adjacent normal tissues, study the relationship between NPM1 expression and clinicopathological characteristics in GC patients, and explore the impact of NPM1 expression on the diagnosis and prognosis of GC. We used tissue microarray immunohistochemical analysis to examine the expression level of NPM1 in GC and adjacent tissues and analyzed the relationship between NPM1 expression, clinicopathological factors, and GC prognosis. Prognostic values of NPM1 mRNA were also investigated using an online database. qRT-PCR was used to detect the expression of NPM1 mRNA in cancer and adjacent tissues. According to microarray immunohistochemical analysis and qRT-PCR results, NPM1 had a high expression in all adjacent normal tissues. Microarray immunohistochemical analyses demonstrated that the NPM1 was lowly expressed in 75.5% of GC tissues but highly expressed in 24.5% of GC tissues. qRT-PCR results showed NPM1 mRNA low expression in most GC tissues. NPM1 high expression group was associated with a better overall survival rate and disease-free survival rate than the NPM1 low expression group (p<0.01). This result is consistent with that of the online database. The receiver operating characteristics curve showed that NPM1 was valuable in the diagnosis of GC. The assessment of NPM1 expression in GC samples may represent a useful tool for GC diagnosis and prognosis assessment.

Three-Stage Wiener-Process-Based Model for Remaining Useful Life Prediction of a Cutting Tool in High-Speed Milling.

Tool condition monitoring can be employed to ensure safe and full utilization of the cutting tool. Hence, remaining useful life (RUL) prediction of a cutting tool is an important issue for an effective high-speed milling process-monitoring system. However, it is difficult to establish a mechanism model for the life decreasing process owing to the different wear rates in various stages of cutting tool. This study proposes a three-stage Wiener-process-based degradation model for the cutting tool wear estimation and remaining useful life prediction. Tool wear stages classification and RUL prediction are jointly addressed in this work in order to take full advantage of Wiener process, as this three-stage Wiener process definitely constitutes to describe the degradation processes at different wear stages, based on which the overall useful life can be accurately obtained. The numerical results obtained using extensive experiment indicate that the proposed model can effectively predict the cutting tool's remaining useful life. Empirical comparisons show that the proposed model performs better than existing models in predicting the cutting tool RUL.

Publishing clinical prActice GuidelinEs (PAGE): Recommendations from editors and reviewers.

Transparency Ecosystem for Research and Journals in Medicine (TERM) working group summarized the essential recommendations that should be considered to review and publish a high-quality guideline. These recommendations from editors and reviewers included 10 components of essential requirements: systematic review of existing relevant guidelines, guideline registration, guideline protocol, stakeholders, conflicts of interest, clinical questions, systematic reviews, recommendation consensus, guideline reporting and external review. TERM working group abbreviates them as PAGE (essential requirements for Publishing clinical prActice GuidelinEs), and recommends guideline authors, editors, and peer reviewers to use them for high-quality guidelines.

Proteins Interacting with STIM1 and Store-Operated Ca2+ Entry.

The endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) interacts with ORAI Ca2+ channels at the plasma membrane to regulate immune and muscle cell function. The conformational changes underlying STIM1 activation, translocation, and ORAI1 trapping and gating, are stringently regulated by post-translational modifications and accessory proteins. Here, we review the recent progress in the identification and characterization of ER and cytosolic proteins interacting with STIM1 to control its activation and deactivation during store-operated Ca2+ entry (SOCE).

The glass-like structure of iron-nickel nanochains produced by the magnetic-field-induced reduction reaction with sodium borohydride.

Preparation and detailed structural characterization of iron-nickel wire-like nanochains with Fe0.75Ni0.25, Fe0.50Ni0.50, and Fe0.25Ni0.75 compositions are reported. The investigated nanomaterials were produced by the novel template-free magnetic-field-induced reduction reaction with NaBH4 as the reducing agent. It is demonstrated that this method leads to the formation of Fe-Ni nanochains composed of spherical nanoparticles with an average diameter of 50-70 nm and with a very high degree of atomic disorder manifested as the lack of clearly developed bcc and fcc phases, which are usually observed for nano- and polycrystalline Fe-Ni species. The recorded wide-angle X-ray scattering data for the obtained Fe-Ni nanochains exhibit a strong resemblance to those obtained for bulk metallic glasses. The atomic scale structure of the investigated nanochains has been studied using pair distribution function analysis of the recorded total scattering data. The best fits to the experimental pair distribution functions have been achieved assuming two-phase models of hcp and bcc networks with the size of coherently scattering regions of about 2.5 nm in diameter, for each Fe-Ni composition. The transmission electron microscopy images indicate that the glass-like bimetallic alloy cores are covered by amorphous oxide/hydroxide shells with their thickness ranging from 2 to 5 nm. Moreover, electron energy loss spectroscopy, X-ray photoelectron spectroscopy, and Mössbauer spectroscopy results confirm the core-shell structure of the Fe-Ni nanochains and the complex character of the shell layer which consists of several iron- and nickel-containing phases.

The early stages of caregiving: A qualitative study into the caregiving experiences of Asian family caregivers of persons with newly-diagnosed dementia.

In Asian societies, the responsibility of caring for persons with dementia often falls upon an immediate family member. However, little attention has been paid to the early stages of caregiving, as well as their transition into a more experienced caregiver. Thus, a qualitative descriptive study involving a purposive sample of 11 main family caregivers of a person with newly diagnosed dementia was recruited from a tertiary hospital in Singapore. Three themes emerged from the data analysis: (1) Suspicions to seeking confirmation of dementia, (2) Grappling with dementia diagnosis, and (3) Making adjustments for the future. Areas of needs and support identified during the early caregiving journey suggest the need for caregivers to be prepared for the practical and emotional challenges. Unique to the Asian culture, our findings put forth the advocacy of engaging persons with dementia in the discussions of their long-term care and options.

Demonstration of ohmic contact using ${{\rm MoO}_{\rm x}}/{\rm Al}$MoOx/Al on p-GaN and the proposal of a reflective electrode for AlGaN-based DUV-LEDs.

The ${{\rm MoO}_{\rm x}}/{\rm Al}$MoOx/Al electrode was designed and fabricated on p-GaN and sapphire with good ohmic behavior and decent deep ultraviolet (DUV) reflectivity, respectively. The influences of ${{\rm MoO}_{\rm x}}$MoOx thickness and annealing condition on the electrical and optical behaviors of the ${{\rm MoO}_{\rm x}}/{\rm Al}$MoOx/Al structure were investigated. Surface morphology of ${{\rm MoO}_{\rm x}}$MoOx with different thicknesses reveals a 3D growth mode. Partial decomposition of ${{\rm MoO}_{\rm x}}$MoOx was discovered, which helps in the formation of ohmic contact between ${{\rm MoO}_{\rm x}}$MoOx and Al. The potential for application in deep ultraviolet light-emitting-diodes (DUV-LEDs) has also been demonstrated.

Knockdown of ZFAS1 Inhibits Hippocampal Neurons Apoptosis and Autophagy by Activating the PI3K/AKT Pathway via Up-regulating miR-421 in Epilepsy.

Epilepsy is a common neurological disease. The dysregulated long noncoding RNAs (lncRNAs) are implicated in epileptogenesis. The aim of this research is to explore the role and mechanism of lncRNA zinc finger antisense 1 (ZFAS1) in status epilepticus (SE)-induced hippocampal neurons injury. SE mice model was established and primary hippocampal neurons were isolated. The expression levels of ZFAS1 and microRNA-421 (miR-421) were detected in hippocampus and hippocampal neurons via quantitative reverse transcription polymerase chain reaction. Hippocampal neurons viability, apoptosis and autophagy were analyzed via Cell Counting Kit-8, flow cytometry and western blot. The target relationship between ZFAS1 and miR-421 was analyzed via dual-luciferase reporter assay. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was blocked by LY294002 and related protein levels were detected via western blot. ZFAS1 expression was elevated in hippocampus and hippocampal neurons from SE mice. Knockdown of ZFAS1 increased SE hippocampal neurons viability and decreased apoptosis and autophagy. ZFAS1 could sponge miR-421. MiR-421 expression was declined in SE mice tissues and cells. Down-regulation of miR-421 abolished the suppressive effect of ZFAS1 knockdown on hippocampal neurons apoptosis and autophagy. Silencing of ZFAS1 induced activation of the PI3K/AKT pathway by up-regulating miR-421. Inhibition of the PI3K/AKT pathway reversed the effect of ZFAS1 knockdown on SE hippocampal neurons apoptosis and autophagy. Interference of ZFAS1 attenuated hippocampal neurons apoptosis and autophagy in SE by increasing miR-421 and activating the PI3K/AKT pathway, indicating a new mechanism for understanding the pathogenesis of SE.

Intrinsic properties of conservation-dissipation formalism of irreversible thermodynamics.

This paper proposes four fundamental requirements for establishing PDEs (partial differential equations) modelling irreversible processes. We show that the PDEs derived via the CDF (conservation-dissipation formalism) meet all the requirements. In doing so, we find useful constraints on the freedoms of CDF and point out that a shortcoming of the formalism can be remedied with the help of the Maxwell iteration. It is proved that the iteration preserves the gradient structure and strong dissipativeness of the CDF-based PDEs. A refined formulation of the second law of thermodynamics is given to characterize the strong dissipativeness, while the gradient structure corresponds to nonlinear Onsager relations. Further advantages and limitations of CDF will also be presented. This article is part of the theme issue 'Fundamental aspects of nonequilibrium thermodynamics'.