Clinical and genetic features of GATOR1 complex-associated epilepsy.

OBJECTIVES: To analyse the prevalence of pathogenic variants in DEPDC5, NPRL2 and NPRL3 that encode the GATOR1 (GTPase-activating protein towards the Rags 1) complex, a modulator in the mammalian target of rapamycin (mTOR) pathway, and to define the characteristics of GATOR1-associated epilepsy. METHODS: Clinical details and whole-exome sequencing data of 170 novel probands with lesional or non-lesional epilepsy were retrieved. Candidate variants in GATOR1 genes were verified by Sanger sequencing, and cosegregate analysis was performed. The pathogenicity of variants and their effect on mTOR signalling were investigated. RESULTS: Two novel frameshift variants and one recurrent nonsense variant were detected in DEPDC5, with a prevalence of 1.8% (3 out of 170) in the whole cohort and 3.1% (3 out of 97) in focal epilepsies. These variants cosegregated in pedigrees with epilepsy, respectively. Rare missense variants in NPRL2 and NPRL3 did not segregate with epilepsy in families, respectively. Epileptic phenotypes of 21 patients with DEPDC5 variants showed focal seizures with non-lesional variable foci that were predominantly sleep-related, with a median onset age of 10 years (range 1-30). Seizure outcome was variable. About 24% of patients were drug-resistant, and seizure attacks were absent in 33% of variant carriers. Of 13 patients who experienced seizures, 54% tended to resolve spontaneously. Functional assessments showed that the three variants affected DEPDC5 expression. These loss-of-function (LoF) variants affected the DEPDC5-dependent inhibition of mTOR. CONCLUSIONS: Patients carrying DEPDC5-LoF variants might show a high prevalence of focal seizures with a dynamic phenotype, indicating reduced penetrance and self-resolving features. The associated epilepsy was caused by loss of inhibition of the mTOR pathway. The pathogenicity of missense variants in GATOR1 genes should be cautiously evaluated.

Progressive multifocal leukoencephalopathy and peripheral neuropathy in a patient with Good's syndrome.

Good's syndrome (GS) is an immunodeficiency characterized by thymoma, hypogammaglobulinemia, and impaired T-cell function. Progressive multifocal encephalopathy (PML), an infection caused by JC virus (JCV), usually occurs in patients infected with human immunodeficiency virus (HIV), or in patients on treatment with immunosuppressive or immunomodulatory drugs. There were few reports of PML due to GS, especially with the comorbidity of peripheral neuropathy. We describe a case of an uncommon presentation of PML and peripheral neuropathy in a male who presented with blurred vision, cognitive changes, limb weakness, and numbness over a 4-month period due to GS. To the best of our knowledge, this is the first report of PML and peripheral neuropathy due to GS. This case aims to highlight that it is necessary to consider the possibility of PML due to GS in patients with thymoma and intracranial lesions, and we should focus not only on opportunistic infections of the central nervous system, such as PML, but also on peripheral neuropathy.

Scalp-HFO indexes are biomarkers for the lateralization and localization of the epileptogenic zone in preoperative assessment.

During the noninvasive evaluation phase for refractory epilepsy, the localization of the epileptogenic zone (EZ) is essential for the surgical protocols. Confirmation of laterality is required when the preoperative evaluation limits the EZ to bilateral anterior temporal lobes or bilateral frontal lobes. High-frequency oscillations (HFOs) are considered to be promising biological markers for the EZ. However, a large number of studies on HFOs stem from intracranial research. There were few quantitative measures for scalp HFOs, so we proposed a new method to quantify and analyze scalp HFOs. This method was called the "scalp-HFO index" (HI) and calculated in both the EZ and non-EZ. The calculation was based on the numbers and spectral power of scalp HFOs automatically detected. We labeled the brain lobes involved in the EZ as regions of interest (ROIs). The HIs based on the ripple numbers (n-HI) and spectral power (s-HI) were significantly higher in the ROI than in the contra-ROI (P = 0.012, P = 0.003), indicating that HIs contributed to the lateralization of EZ. The sensitivity and specificity of n-HI for the localization of the EZ were 90% and 79.58%, respectively, suggesting that n-HI was valuable in localizing the EZ. HI may contribute to the implantation strategy of invasive electrodes. However, few scalp HFOs were recorded when the EZ was located in the medial cortex region.NEW & NOTEWORTHY We proposed the scalp-high-frequency oscillation (HFO) index (HI) as a quantitative assessment method for scalp HFOs to locate the epileptogenic zone (EZ). Our results showed that the HI in regions of interest (ROIs) was significantly higher than in contra-ROIs. Sensitivity and specificity of HI based on ripple rates (n-HI) for EZ localization were 90% and 79.58%, respectively. If the n-HI of the brain region was >1.35, it was more likely to be an epileptogenic region. Clinical application of HIs as an indicator may facilitate localization of the EZ.

Overexpression of BMP4 protects retinal ganglion cells in a mouse model of experimental glaucoma.

PURPOSE: Activation of bone morphogenetic protein (BMP) 4 signaling promotes the survival of retinal ganglion cell (RGC) after acute injury. Chordin-like 1 (CHRDL1) is an endogenous BMP antagonist. In this study, we researched whether CHRDL1 was involved in BMP4 signaling and regulation of RGC degeneration in a mouse model of glaucoma. METHODS: Magnetic microbeads were intracameral injected to induce experimental glaucoma in a mouse model. A recombinant adeno-associated virus (rAAV) system was designed for overexpression of BMP4 or CHRDL1 in mouse retina. Immunohistochemistry and hematoxylin-eosin (HE) stains were performed to identify changes in retinal morphology. Electroretinogram (ERG) recordings were used to assess changes in visual function. RESULTS: The mRNA expression levels of Bmp4 and its downstream BMPRIa, small mothers against decapentaplegic 1 (Smad1), were significantly upregulated in retinas with glaucoma. RGC survival was significantly enhanced in the beads + AAV-BMP4 group and significantly reduced in the beads + AAV-CHRDL1 group, compared with the beads + AAV-EGFP group. Similar results were observed in retinal explant culture in vitro. Consistent with these findings, the photopic negative response (PhNR)responses in ERG, which indicate RGC function, were restored in mice overexpressing BMP4, whereas a-wave and b-wave responses were not. Activation of CHRLD1 inhibited Smad1/5/8 phosphorylation and exacerbated RGC damage. The expression of Glial fibrillary acidic protein (GFAP) was decreased significantly in beads + AAV-BMP4 group. CONCLUSIONS: BMP4 promoted RGC survival and visual function in an experimental glaucoma model. Activation of CHRDL1 exaggerated RGC degeneration by inhibiting the BMP4/Smad1/5/8 pathway. The mechanism of BMP4/Smad1/5/8 pathway may be related to the inhibition of glial cell activation. Our studies suggested that BMP4 and CHRLD1 might serve as therapeutic targets in glaucoma.

A concordance study determining language dominance between navigated transcranial magnetic stimulation and the Wada test in patients with drug-resistant epilepsy.

OBJECTIVE: It remains unclear whether transcranial magnetic stimulation (TMS) can replace the Wada test to determine language hemisphere dominance (HD). Using the Wada test as the gold standard, this study aimed to investigate the accuracy of navigated TMS (nTMS) in determining language HD. METHODS: This study enrolled nine right-handed patients with drug-resistant epilepsy. We hypothesized that application of nTMS to language-related areas of the language-dominant hemisphere would induce positive manifestation of language dysfunction (LD). To test our hypothesis, the patients were instructed to perform a visual object-naming task while nTMS was applied to the anterior (e.g., Broca's area) and posterior (e.g., Wernicke's area) regions, which are closely related to language processing. The Wada test result was used as the gold standard, and the diagnostic value of nTMS was assessed using the Kappa consistency test. RESULTS: The nTMS-induced LD positive rate for the bilateral anterior language areas (85.7%) was higher than that for the posterior language areas (57.1%). There was high consistency between nTMS stimulation of the left anterior and posterior language areas and the Wada test results for determining language HD. In contrast, the consistency of stimulation of the right anterior and posterior transfer sites was moderate (Kappa value = 0.545, P = 0.171) and low, respectively. For the latter, no statistical calculation was performed because stimulation of the right posterior speech area was negative in all patients compared with the Wada test results. CONCLUSIONS: Our findings revealed that using nTMS to stimulate language-related left anterior and posterior areas could predict language HD with high accuracy. When the stimulation performance of these areas is positive, nTMS and the Wada test are equally accurate. Observing only negative performance may indicate that language HD has been transferred to the right side.

A cell-permeable peptide inhibitor of p55PIK signaling alleviates ocular inflammation in mouse models of uveitis.

PURPOSE: Previously we developed TAT-N24 as a synthetic cell-permeable peptide inhibitor of p55PIK signaling and demonstrated its anti-inflammatory effects. This study aimed to evaluate the potential of TAT-N24 as a new agent for the treatment of ocular inflammatory diseases. METHODS: The endotoxin-induced uveitis (EIU) model was established by intravitreal injection of lipopolysaccharide (LPS) in BALB/c mice and experimental autoimmune uveitis (EAU) model was established by subcutaneous injection of a peptide spanning amino acid residues 161-180 of interphotoreceptor retinoid binding protein (IRBP161-180) with complete Freund's adjuvant (CFA) in B10.RIII mice. TAT-N24 was topically administered in EIU model and intraperitoneally administered in EAU model. The severity levels of uveitis were assessed by clinical and histopathological scores. The mRNA levels of inflammatory cytokines in iris-ciliary body (ICB) and retina were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein levels of inflammatory factors were determined by ELISA or Western blotting. RESULTS: The results showed that TAT-N24 alleviated clinical signs, decreased inflammatory cell infiltration and the expression of inflammatory cytokines in both EIU and EAU models. Furthermore, protein levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in aqueous humor and mRNA and protein levels of NF-κB p65 in the ICB significantly decreased in EIU model. In EAU model, TAT-N24 application induced a significant decrease of IFN-gamma (IFN-γ) and interleukin-17 (IL-17) in the retina, which were secreted by Th1 and Th17 cells, respectively. CONCLUSION: In conclusion, TAT-N24 suppressed intraocular inflammation in both EIU and EAU models, and the anti-inflammatory effects were mediated by suppressing the expression of inflammatory cytokines by PI3K/NF-κB signaling pathway. TAT-N24 could be potential candidate for the treatment of ocular inflammatory diseases.

Assessment of cerebral low-frequency oscillations in patients with retinal vein occlusion: a preliminary functional MRI study.

BACKGROUND: There is increasing evidence that patients with retinal vein occlusion exhibit cerebral vascular changes and are at an increased risk of stroke. However, it remains unknown whether patients with retinal vein occlusion exhibit changes in intrinsic brain activity. PURPOSE: This study investigated intrinsic brain activity changes in patients with retinal vein occlusion by assessing the amplitude of low-frequency fluctuations. MATERIAL AND METHODS: Forty-five patients with retinal vein occlusion (22 men, 23 women, mean age 56.55 ± 6.97 years) and 43 healthy controls (13 men, 30 women; mean age 53.53 ± 8.19 years) closely matched in age, sex, and education level underwent resting-state MRI scans. The amplitude of low-frequency fluctuation method was used to compare intrinsic brain activity between the two groups. RESULTS: Compared with healthy controls, patients with retinal vein occlusion exhibited significantly lower amplitude of low-frequency fluctuation values in the left middle occipital gyrus, right middle occipital gyrus, and right calcarine. However, patients with retinal vein occlusion showed significantly higher amplitude of low-frequency fluctuations in the bilateral cerebellum 6, right hippocampus, left insula, and left fusiform (voxel-level P < 0.01, Gaussian random field correction, cluster-level P < 0.05). CONCLUSION: Our results demonstrated that patients with retinal vein occlusion showed abnormal spontaneous neural activities in the visual cortices, cerebellum, and Papez circuit, which might indicate impaired vision, cognition, and emotional function in patients with retinal vein occlusion. These findings offer important insights into the neural mechanism of retinal vein occlusion.

Large-Scale Neuronal Network Dysfunction in Diabetic Retinopathy.

Diabetic retinopathy (DR) patients are at an increased risk of cognitive decline and dementia. There is accumulating evidence that specific functional and structural architecture changes in the brain are related to cognitive impairment in DR patients. However, little is known regarding whether the functional architecture of resting-state networks (RSNs) changes in DR patients. The purpose of this study was to investigate the intranetwork functional connectivity (FC) and functional network connectivity (FNC) of RSN changes in DR patients using independent component analysis (ICA). Thirty-four DR patients (18 men and 16 women; mean age, 53.53 ± 8.67 years) and 38 nondiabetic healthy controls (HCs) (15 men and 23 women; mean age, 48.63 ± 11.83 years), closely matched for age, sex, and education, underwent resting-state magnetic resonance imaging scans. ICA was applied to extract the nine RSNs. Then, two-sample t-tests were conducted to investigate different intranetwork FCs within nine RSNs between the two groups. The FNC toolbox was used to assess interactions among RSNs. Pearson correlation analysis was conducted to explore the relationship between intranetwork FCs and clinical variables in the DR group. A receiver operating characteristic (ROC) curve was conducted to assess the ability of the intranetwork FCs of RSNs in discriminating between the two groups. Compared to the HC group, DR patients showed significant decreased intranetwork FCs within the basal ganglia network (BGN), visual network (VN), ventral default mode network (vDMN), right executive control network (rECN), salience network (SN), left executive control network (lECN), auditory network (AN), and dorsal default mode network (dDMN). In addition, FNC analysis showed increased VN-BGN, VN-vDMN, VN-dDMN, vDMN-lECN, SN-BGN, lECN-dDMN, and AN-BGN FNCs in the DR group, relative to the HC group. Furthermore, altered intranetwork FCs of RSNs were significantly correlated with the glycosylated hemoglobin (HbA1c) level in DR patients. A ROC curve showed that these specific intranetwork FCs of RSNs discriminated between the two groups with a high degree of sensitivity and specificity. Our study highlighted that DR patients had widespread deficits in both low-level perceptual and higher-order cognitive networks. Our results offer important insights into the neural mechanisms of visual loss and cognitive decline in DR patients.

The neuroprotective effects of novel estrogen receptor GPER1 in mouse retinal ganglion cell degeneration.

PURPOSE: To investigate the potential protective effect of novel G protein coupled estrogen receptor (GPER1) against the neurotoxicity induced by NMDA in the mouse retina. METHODS: We induce retinal ganglion cells (RGCs) toxic injury through intravitreal injection of NMDA or acute ocular hypertension (AOH) induced by anterior chamber infusion with saline. Endogenous ligand 17-ß-estradiol (E2), GPER1 agonist (G-1), and E2 with GPER1 antagonist (G-15) or classic estrogen receptor α and ß (ERα and ERß) antagonist tamoxifen (TAM) were subcutaneous administered before NMDA to identify the possible involved receptors. Immunofluorescence staining was performed to explore the survival of RGCs and Müller cell gliosis. TUNEL staining was used to evaluate the RGC apoptosis. The involved molecular pathway was detected via antibody array expression profiling. RESULTS: Activation of estrogen receptor by E2 or G-1 could significantly rescue the RGCs injury in NMDA administration. The protective effect was carried exclusively by GPER1 activation. E2 application can still mimicked the protective function when estrogen receptor α and ß (ERα and ERß) blocked by tamoxifen (TAM), while the effects was blocked by GPER1 antagonist G-15. Moreover, the TUNEL positive RGCs and GFAP expression level were both attenuated in G-1 application and the effects could be reversed by G-15. In addition, application of the PI3K/Akt antagonist LY294002 counteracted the effect of G-1. And a number of apoptosis regulatory factors decreased dramatically in the G-1 group, including Bad, Caspase 3, Caspase 7, Smad2, P-53 and TAK1. Also, similar protective effect of G-1 was spotted in acute ocular hypertension (AOH) model. CONCLUSION: Estrogen played a protective role via a novel estrogen receptor, GPER1, instead of classical receptors ERα or ERß. Activation of GPER1 attenuated RGCs apoptosis and Müller cells gliosis, indicating GPER1 as a potential treatment target in RGCs degeneration diseases.

A Novel CNGA1 Gene Mutation (c.G622A) of Autosomal Recessive Retinitis Pigmentosa Leads to the CNGA1 Protein Reduction on Membrane.

CNGA1 encodes a membrane protein on rod photoreceptor related to phototransduction. The present study was to identify a novel mutation of CNGA1 associated with autosomal recessive retinitis pigmentosa by using next generation sequencing of a Chinese family. Next generation sequencing and Sanger sequencing has identified a compound heterozygous mutation in CNGA1 gene, c0.472 del C (reported) and c0.829G>A (novel mutation, same as c0.622G>A according to NM_000087.3) of the proband. SIFT and Polyphen-2 predicted the CNGA1 G622A site to be possibly deleterious. Evolutionary conservation analysis of amino acid residues showed this aspartic acid is highly conserved between species, and protein structure prediction by I-TASSER server indicated that the D208N mutation induced a large disappear of interactions between S2 and S4. Flag-tagged CNGA1 and mutant G622A cDNA were generated and inserted into pCIG-eGFP vectors. Transfection of human embryonic kidney 293T cells was performed with lipofectamine. Interestingly, western blot and immunofluorescence results indicated that the expression of mutant CNGA1 (D208N) decreased significantly, especially on the membrane of transfected HEK293T cells. The novel variant c0.622G>A (p. D208N) in this study enriched the CNGA1 mutation spectrum. Besides, this mutant was predicted "possibly damaging" due to bioinformatics analysis and validated by laboratorial experiments. Our study suggests that this mutation lead to the CNGA1 protein reduction from the cell membrane.

Inhibitory effects of low decibel infrasound on the cardiac fibroblasts and the involved mechanism.

INTRODUCTION: Infrasound is a mechanical vibration wave with frequency between 0.0001 and 20 Hz. It has been established that infrasound of 120 dB or stronger is dangerous to humans. However, the biological effects of low decibel infrasound are largely unknown. The purpose of this study was to investigate the effects of low decibel infrasound on the cardiac fibroblasts. MATERIALS AND METHODS: The cardiac fibroblasts were isolated and cultured from Sprague-Dawley rats. The cultured cells were assigned into the following four groups: control group, angiotensin II (Ang II) group, infrasound group, and Ang II+infrasound group. The cell proliferation and collagen synthesis rates were evaluated by means of [3H]-thymidine and [3H]-proline incorporation, respectively. The levels of TGF-ß were determined by enzyme-linked immunosorbent assay. Moreover, RNAi approaches were used for the analysis of the biological functions of miR-29a, and the phosphorylation status of Smad3 was detected using western blotting analysis. RESULTS: The results showed that low decibel infrasound significantly alleviated Ang II-induced enhancement of cell proliferation and collagen synthesis. DISCUSSION: Compared with the control, Ang II markedly decreased the expression of miR-29a levels and increased the secretion of TGF-ß and phosphorylation of Smad3, which was partly reversed by the treatment with low decibel infrasound. Importantly, knockdown of miR-29a diminished the effects of infrasound on the cardiac fibroblasts. In conclusion, low decibel infrasound inhibits Ang II-stimulated cardiac fibroblasts via miR-29a targeting TGF-ß/Smad3 signaling.

Identification of Key lncRNAs in Gout Under Copper Death and Iron Death Mechanisms: A Study Based on ceRNA Network Analysis and Random Forest Algorithm.

This study focused on identifying potential key lncRNAs associated with gout under the mechanisms of copper death and iron death through ceRNA network analysis and Random Forest (RF) algorithm, which aimed to provide new insights into the molecular mechanisms of gout, and potential molecular targets for future therapeutic strategies of gout. Initially, we conducted an in-depth bioinformatics analysis of gout microarray chips to screen the key cuproptosis-related genes (CRGs) and key ferroptosis-related genes (FRGs). Using these data, we constructed a key ceRNA network for gout. Finally, key lncRNAs associated with gout were identified through the RF algorithm combined with ROC curves, and validated using the Comparative Toxicogenomics Database (CTD). We successfully identified NLRP3, LIPT1, and DBT as key CRGs associated with gout, and G6PD, PRKAA1, LIG3, PHF21A, KLF2, PGRMC1, JUN, PANX2, and AR as key FRGs associated with gout. The key ceRNA network identified four downregulated key lncRNAs (SEPSECS-AS1, LINC01054, REV3L-IT1, and ZNF883) along with three downregulated mRNAs (DBT, AR, and PRKAA1) based on the ceRNA theory. According to CTD validation inference scores and biological functions of target mRNAs, we identified a potential gout-associated lncRNA ZNF883/hsa-miR-539-5p/PRKAA1 regulatory axis. This study identified the key lncRNA ZNF883 in the context of copper death and iron death mechanisms related to gout for the first time through the application of ceRNA network analysis and the RF algorithm, thereby filling a research gap in this field and providing new insights into the molecular mechanisms of gout. We further found that lncRNA ZNF883 might function in gout patients by regulating PRKAA1, the mechanism of which was potentially related to uric acid reabsorption in the proximal renal tubules and inflammation regulation. The proposed lncRNA ZNF883/hsa-miR-539-5p/PRKAA1 regulatory axis might represent a potential RNA regulatory pathway for controlling the progression of gout disease. This discovery offered new molecular targets for the treatment of gout, and had significant implications for future therapeutic strategies in managing the gout.

Interplay between obesity and aging on myocardial geometry and function: Role of leptin-STAT3-stress signaling.

BACKGROUND: Uncorrected obesity facilitates premature aging and cardiovascular anomalies. This study examined the interaction between obesity and aging on cardiac remodeling and contractile function. METHODS: Cardiac echocardiographic geometry, function, morphology, intracellular Ca2+ handling, oxidative stress (DHE fluorescence), STAT3 and stress signaling were evaluated in young (3-mo) and old (12- and 18-mo) lean and leptin deficient ob/ob obese mice. Cardiomyocytes from young and old lean and ob/ob mice were treated with leptin (1 nM) for 4 h in vitro prior to assessment of mechanical and biochemical properties. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obese mice at young and old age were evaluated for comparison. RESULTS: Our results displayed reduced survival in ob/ob mice. Obesity but less likely older age dampened echocardiographic, geometric, cardiomyocyte function and intracellular Ca2+ properties, elevated O2- and p47phox NADPH oxidase levels with a more pronounced geometric change at older age. Immunoblot analysis revealed elevated p47phox NADPH oxidase and dampened phosphorylation of STAT3, with a more pronounced response in old ob/ob mice, the effects were restored by leptin. Obesity and aging inhibited phosphorylation of Akt, eNOS, AMPK, and p38 while promoting phosphorylation of JNK and IκB. Leptin reconciled cardiomyocyte dysfunction, O2- yield, p47phox upregulation, STAT3 dephosphorylation and stress signaling in ob/ob mice although its action on stress signaling cascades were lost at old age. High fat diet-induced and db/db obesity displayed aging-associated cardiomyocyte anomalies reminiscent of ob/ob model albeit lost leptin response. CONCLUSIONS: Our data suggest disparate age-associated obesity response in cardiac remodeling and contractile dysfunction due to phosphorylation of Akt, eNOS and stress signaling-related oxidative stress.

Empagliflozin attenuates trastuzumab-induced cardiotoxicity through suppression of DNA damage and ferroptosis.

Trastuzumab (TZM) is commonly used for target therapy in breast cancer patients with high HER2 although the cardiotoxicity restricts its clinical usage. DNA damage and ferroptosis are implicated in anti-tumor drug cardiotoxicity. Given the emerging use of SGLT2 inhibitors in clinical cardiology, this study evaluated the impact of SGLT2 inhibitor Empagliflozin on TZM-induced cardiotoxicity, and mechanism involved with a focus on DNA damage and ferroptosis. Adult C57BL/6 mice were challenged with TZM (10 mg/kg/week, i.p.) or saline for six weeks. A cohort of mice received Empagliflozin (10 mg/kg, i.p.) at the same time. Myocardial function, morphology, ultrastructure, mitochondrial integrity, oxidative stress, DNA damage and various cell death domains were evaluated in TZM-challenged mice with or without Empagliflozin treatment. Our data revealed that TZM challenge overtly increased levels of serum LDH and troponin I, promoted adverse myocardial remodeling (increased heart weight, chamber size, cardiomyocyte area and interstitial fibrosis), contractile dysfunction and intracellular Ca2+ mishandling, oxidative stress, lipid peroxidation, mitochondrial ultrastructural damage, DNA damage, apoptosis and ferroptosis, the effects of which were greatly attenuated or mitigated by Empagliflozin with little effects from Empagliflozin itself. In vitro study indicated that induction of DNA damage mimicked TZM-induced lipid peroxidation and cardiomyocyte contractile dysfunction while the ferroptosis inducer erastin mitigated Empagliflozin-offered protection against lipid peroxidation and cardiomyocyte dysfunction (but not DNA damage). Likewise, in vivo and in vitro inhibition of ferroptosis recapitulated Empagliflozin-offered cardioprotection against TZM exposure. Taken together, these data demonstrated that Empagliflozin may be possible candidate drug for TZM cardiotoxicity likely through a DNA damage-ferroptosis-mediated mechanism.

Dynamic evolution of the anterior cingulate-insula network during seizures.

OBJECTIVES: In physiological situations, the anterior cingulate cortex (ACC) and anterior insular cortex (AIC) are prone to coactivation. The functional connectivity and interaction between ACC and AIC in the context of epilepsy remain unclear. This study aimed to investigate the dynamic coupling between these two brain regions during seizures. METHODS: Patients who underwent stereoelectroencephalography (SEEG) recording were included in this study. The SEEG data were visually inspected and quantitatively analyzed. The narrowband oscillations and aperiodic components at seizure onset were parameterized. The frequency-specific non-linear correlation analysis was applied to the functional connectivity. The excitation/inhibition ratio (E:I ratio) reflected by the aperiodic slope was performed to evaluate the excitability. RESULTS: Twenty patients were included in the study, with 10 diagnosed with anterior cingulate epilepsy and 10 with anterior insular epilepsy. In both types of epilepsy, the correlation coefficient (h2 ) between the ACC and AIC at seizure onset exhibited a significantly higher value than that during interictal and preictal periods (p < 0.05). The direction index (D) showed a significant increase at seizure onset, serving as an indicator for the direction of information flow between these two brain regions with up to 90% accuracy. The E:I ratio increased significantly at seizure onset, with the seizure-onset zone (SOZ) demonstrating a more pronounced increase compared to non-SOZ (p < 0.05). For seizures originating from AIC, the E:I ratio was significantly higher in the AIC than in the ACC (p = 0.0364). CONCLUSIONS: In the context of epilepsy, the ACC and AIC are dynamically coupled during seizures. The functional connectivity and excitability exhibit a significant increase at seizure onset. By analyzing connectivity and excitability, the SOZ in ACC and AIC can be identified. The direction index (D) serves as an indicator for the direction of information flow from SOZ to non-SOZ. Notably, the excitability of SOZ changes more significantly than that of non-SOZ.

The characteristics and alteration of peripheral immune function in patients with multiple system atrophy.

Objective: Multiple system atrophy (MSA) is a degenerative disease. Immune dysfunction found to play a crucial role in the pathogenesis of this disease in the literature, while the characteristics of peripheral immune function remain unclear. This study aimed to investigate the characteristics and alterations of peripheral immune function in patients with MSA. Methods: A case-control study was conducted between January 2021 to December 2022 at SanBo Brain Hospital, Capital Medical University, Beijing, China. A total of 74 participants were recruited, including 47 MSA patients and 27 non-MSA participants. Peripheral blood samples were collected from each participant. A total of 29 types of immune cells were measured using the flow cytometry analysis technology. Single-factor analysis and multiple-factor analysis (multiple linear regression models) were performed to determine the differences and risk factors in immune cells between the MSA and non-MSA groups. Results: Alterations of the count or percentage of CD19+ B lymphocytes and CD3-CD56+ B lymphocytes in MSA patients were found in this study. The reductions of the count and percentage of CD19+ B lymphocytes were still robust after adjusting for variables of age, gender, body mass index, albumin, and hemoglobin. Furthermore, the reductions in the count and percentage of CD19+ B lymphocytes in the MSA patients were more significant in women and individuals aged 60 years old or above than in the non-MSA participants. Conclusion: Our findings suggested that MSA patients may be influenced by B lymphocytes, particularly CD19+ cells. Therefore, the reductions in immune cells should be considered in the diagnosis and treatment of MSA. Further studies are warranted to confirm and expand upon these findings.

Diagnostic value of aldosterone to renin ratio calculated by plasma renin activity or plasma renin concentration in primary aldosteronism: a meta-analysis.

BACKGROUND: Since the diagnostic value of aldosterone to renin ratio (ARR) calculated by plasma renin concentration (PRC) or plasma renin activity (PRA) is still inconclusive, we conducted a meta-analysis by systematically reviewing relevant literature to explore the difference in the diagnostic efficacy of ARR calculated by PRC or PRA, so as to provide guidance for clinical diagnosis. METHODS: We searched PubMed, Embase, and Cochrane Library from the establishment of the database to March 2021. We included studies that report the true positive, false positive, true negative, and false negative values for the diagnosis of primary aldosteronism, and we excluded duplicate publications, research without full text, incomplete information, or inability to conduct data extraction, animal experiments, reviews, and systematic reviews. STATA 15.1 was used to analyze the data. RESULTS: The pooled results showed that ARR (plasma aldosterone concentration [PAC]/PRC) had a sensitivity of 0.82 (95% confidence interval [CI]: 0.78-0.86), a specificity of 0.94 (95% CI: 0.92-0.95), a positive-likelihood ratio (LR) of 12.77 (95% CI: 7.04-23.73), a negative LR of 0.11 (95% CI: 0.07-0.17), and symmetric area under the curve (SAUC) of 0.982, respectively. Furthermore, the diagnostic odds ratio (DOR) of ARR (PAC/PRC) was 180.21. Additionally, the pooled results showed that ARR (PAC/PRA) had a sensitivity of 0.91 (95% CI: 0.86-0.95), a specificity of 0.91 (95% CI: 0.90-0.93), a positive LR of 7.30 (95% CI: 2.99-17.99), a negative LR of 0.10 (95% CI: 0.04-0.26), and SAUC of 0.976, respectively. The DOR of ARR (PAC/PRA) was 155.52. Additionally, we conducted a subgroup analysis for the different thresholds (<35 or ≥35) of PAC/PRC. The results showed that the DOR of the cut-off ≥35 groups was higher than the cut-off <35 groups (DOR = 340.15, 95% CI: 38.32-3019.66; DOR = 116.40, 95% CI = 23.28-581.92). CONCLUSIONS: The research results suggest that the determination of ARR (PAC/PRC) and ARR (PAC/PRA) was all effective screening tools for PA. The diagnostic accuracy and diagnostic value of ARR (PAC/PRC) are higher than ARR (PAC/PRA). In addition, within a certain range, the higher the threshold, the better the diagnostic value.

Deficiency in Beclin1 attenuates alcohol-induced cardiac dysfunction via inhibition of ferroptosis.

BACKGROUND: Binge drinking leads to compromised mitochondrial integrity and contractile function in the heart although little effective remedy is readily available. Given the possible derangement of autophagy in ethanol-induced cardiac anomalies, this study was designed to examine involvement of Beclin1 in acute ethanol-induced cardiac contractile dysfunction, in any, and the impact of Beclin1 haploinsufficiency on ethanol cardiotoxicity with a focus on autophagy-related ferroptosis. METHODS: WT and Beclin1 haploinsufficiency (BECN+/-) mice were challenged with ethanol for one week (2 g/kg, i.p. on day 1, 3 and 7) prior to assessment of cardiac injury markers (LDH, CK-MB), cardiac geometry, contractile and mitochondrial integrity, oxidative stress, lipid peroxidation, apoptosis and ferroptosis. RESULTS: Ethanol exposure compromised cardiac geometry and contractile function accompanied with upregulated Beclin1 and autophagy, mitochondrial injury, oxidative stress, lipid peroxidation and apoptosis, and ferroptosis (GPx4, SLC7A11, NCOA4). Although Beclin1 deficiency did not affect cardiac function in the absence of ethanol challenge, it alleviated ethanol-induced changes in cardiac injury biomarkers, cardiomyocyte area, interstitial fibrosis, echocardiographic and cardiomyocyte mechanical properties along with mitochondrial integrity, oxidative stress, lipid peroxidation, apoptosis and ferroptosis. Ethanol challenge evoked pronounced ferroptosis (downregulated GPx4, SLC7A11 and elevated NCOA4, lipid peroxidation), the effect was alleviated by Beclin1 haploinsufficiency. Inhibition of ferroptosis using LIP-1 rescued ethanol-induced cardiac mechanical anomalies. In vitro study noted that ferroptosis induction using erastin abrogated Beclin1 haploinsufficiency-induced response against ethanol. CONCLUSIONS: In sum, our data suggest that Beclin1 haploinsufficiency benefits acute ethanol challenge-induced myocardial remodeling and contractile dysfunction through ferroptosis-mediated manner.

Elavl2 Regulates Retinal Function Via Modulating the Differentiation of Amacrine Cells Subtype.

Purpose: The neuronal ELAV-like proteins (nElavls; Elavl2, Elavl3, Elavl4) have been known to regulate neuronal differentiation, maintenance, and axonogenesis in the brain. However, the specific role of nElavls in retina remains unclear. Here, we attempted to identify the expression pattern of Elavl2 during retinogenesis and aimed to decipher the function of Elavl2 in the retina. Methods: We have used the Cre-loxP system to conditionally inactivate Elavl2 in order to examine its role in developing retina. Eyes were collected for histology, immunohistochemistry, and TUNEL analysis to identify the structure of retina, and examined by RNA sequencing to analyze the function and pathway enrichment of differentially expressed genes in transgenic mice. Moreover, the mechanism by which Elavl2 regulates the differentiation of amacrine cells (ACs) was explored by RNA immunoprecipitation assays. Finally, eyes were functionally assessed by whole-cell patch-clamp, electroretinography (ERG) and optomotor response. Results: Elavl2 was expressed in retinal progenitor cells and retinal ganglion cells (RGCs), ACs, and horizontal cells. Retina-specific ablation of Elavl2 led to the loss of ACs and the transcription factors involved in ACs differentiation were also downregulated. In addition, the spontaneous activities of RGCs were obviously increased in Elavl2-deficient mice. Meanwhile, the loss of ACs that induced by Elavl2 deficiency lead to a decrease in ERG responses and visual acuity. Conclusions: Elavl2 is an intrinsic factor that involved in the differentiation of ACs subtype during retinogenesis, and essential for maintaining the normal retinal function.

Mapping Regional Homogeneity and Functional Connectivity of the Visual Cortex in Resting-State fMRI.

A combined regional homogeneity (ReHo) and functional connectivity (FC) method, a type of noninvasive functional magnetic resonance imaging (fMRI) method, has been used to evaluate synchronous neuronal activity changes in retinitis pigmentosa (RP). The purpose of this study is to describe our method for analysis of intra- and interregional synchronizations of changes in neuronal activity in RP patients. The advantages of the combined ReHo and FC method are that it is both noninvasive and sufficiently sensitive to investigate changes in cerebral synchronous neuronal activity changes in vivo. Here, 16 RP patients and 14 healthy controls closely matched in age, sex, and education underwent resting-state fMRI scans. Two sample t-tests were conducted to compare ReHo and FC across groups. Our results showed that visual network disconnection and reorganization of the retino-thalamocortical pathway and dorsal visual stream occurred in the RP patients. Here, we describe the details of this method, its use, and the impact of its key parameters in a step-by-step manner.