UHRF1P contributes to IL-17A-mediated systemic lupus erythematosus via UHRF1-MAP4K3 axis.

Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases.

Prevalence of small vessel disease and incidental DWI-positive lesions in patients with aneurysmal subarachnoid hemorrhage versus intracerebral hemorrhage.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) and intracerebral hemorrhage (ICH) are main forms of hemorrhagic stroke. Data regarding cerebral small vessel disease (SVD) burden and incidental small lesions on diffusion-weighted imaging (DWI) following aSAH are sparse. PATIENTS AND METHODS: We retrospectively analyzed a prospective cohort of aSAH and ICH patients with brain MRI within 30 days after onset from March 2015 to January 2023. White matter hyperintensity (WMH), lacune, perivascular space, cerebral microbleed (CMB), total SVD score, and incidental DWI lesions were assessed and compared between aSAH and ICH. Clinical and radiological characteristics associated with small DWI lesions in aSAH were investigated. RESULTS: We included 180 patients with aSAH (median age [IQR] 53 [47-61] years) and 299 with ICH (63 [53-73] years). DWI lesions were more common in aSAH than ICH (47.8% vs 14.4%, p < 0.001). Higher total SVD score was associated with ICH versus aSAH irrespective of hematoma location, whereas DWI lesions and strictly lobar CMBs were correlated with aSAH. Multivariable analysis showed that shorter time from onset to MRI, anterior circulation aneurysm rupture, CMB ⩾ 5, and total SVD score were associated with DWI lesions in aSAH. DISCUSSION AND CONCLUSION: Incidental DWI lesions and strictly lobar CMBs were more frequent in aSAH versus ICH whereas ICH had higher SVD burden. Incidental DWI lesions in aSAH were associated with multiple clinical and imaging factors. Longitudinal studies to investigate the dynamic change and prognostic value of the covert hemorrhagic and ischemic lesions in aSAH seem justified.

Clinical, Imaging Characteristics and Outcome of Intracerebral Hemorrhage Caused by Structural Vascular Lesions.

BACKGROUND: The objective of this study was to investigate the clinical, imaging, and outcome characteristics of intracerebral hemorrhage (ICH) caused by structural vascular lesions. METHODS: We retrospectively analyzed data from a prospective observational cohort study of patients with spontaneous ICH admitted to the First Affiliated Hospital of Chongqing Medical University between May 2016 and April 2021. Good outcome was defined as modified Rankin Scale score of 0-3 at 3 months. The clinical and imaging characteristics were compared between primary ICH and ICH caused by structural vascular lesions. Multivariable logistic regression analysis was performed to test the associations of etiology with clinical outcome. RESULTS: All patients enrolled in this study were Asian. Compared with patients with primary ICH, those with structural vascular lesions were younger (48 vs. 62 years, P < 0.001), had a lower incidence of hypertension (26.4% vs. 81.7%, P < 0.001) and diabetes (7.4% vs. 16.2%, P = 0.003), and had mostly lobar hemorrhages (49.1% vs. 22.8%). ICH from structural vascular lesions had smaller baseline hematoma volume (8.4 ml vs. 13.8 ml, P = 0.010), had lower mortality rate at 30 days and 3 months (5.8% vs. 12.0%, P = 0.020; 6.7% vs. 14.8%, P = 0.007), and are associated with better functional outcome at 3 months (88% vs.70.3%, P < 0.001). CONCLUSIONS: Compared with primary ICH, ICH due to vascular lesions has smaller hematoma volume and less severe neurological deficit at presentation and better functional outcomes.

SERPINA3: A novel inflammatory biomarker associated with cerebral small vessel disease burden in ischemic stroke.

BACKGROUND AND OBJECTIVE: Inflammation has emerged as a prominent risk factor for cerebral small vessel disease (CSVD). However, the specific association between various inflammatory biomarkers and the development of CSVD remains unclear. Serine proteinase inhibitor A3 (SERPINA3), Matrix metalloproteinase-9 (MMP-9), Tissue inhibitor metalloproteinase-1 (TIMP-1), Monocyte Chemoattractant Protein-1 (MCP-1) are several inflammatory biomarkers that are potentially involved in the development of CSVD. In this present study, we aimed to investigate the relationship between candidate molecules and CSVD features. METHOD: The concentration of each biomarker was measured in 79 acute ischemic stroke patients admitted within 72 h after symptom onset. The associations between blood levels of inflammatory markers and CSVD score were investigated, as well as each CSVD feature, including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (EPVS). RESULTS: The mean age was 69.0 ± 11.8 years, and 65.8% of participants were male. Higher SERPINA3 level (>78.90 ng/mL) was significantly associated with larger WMH volume and higher scores on Fazekas's scale in all three models. Multiple regression analyses revealed the linear association between absolute WMH burden and SERPINA3 level, especially in model 3 (ß = 0.14; 95% confidence interval [CI], 0.04-0.24 ; p = 0.008 ). Restricted cubic spline regression demonstrated a dose-response relationship between SERPINA3 level and larger WMH volume (p nonlineariy = 0.0366 and 0.0378 in model 2 and mode 3, respectively). Using a receiving operating characteristic (ROC) curve, plasma SERPINA3 level of 64.15 ng/mL distinguished WMH >7.8 mL with the highest sensitivity and specificity (75.92% and 60%, respectively, area under curve [AUC] = 0.668, p = 0.0102). No statistically significant relationship has been found between other candidate biomarkers and CSVD features. CONCLUSION: In summary, among four inflammatory biomarkers that we investigated, SERPINA3 level at baseline was associated with WMH severity, which revealed a novel biomarker for CSVD and validated its relationship with inflammation and endothelial dysfunction.

DUSP8 induces TGF-ß-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α.

Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T cell-specific Dusp8 conditional KO (T-Dusp8 cKO) mice, mass spectrometry analysis, ChIP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-ß signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels were induced in Pur-α-deficient T cells. In addition, T-Dusp8-cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of Il-9 mRNA levels in T cells and allergic responses of T-Dusp8-cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-α interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF-ß-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.

The correlation of urinary strontium with the risk of chronic kidney disease among the general United States population.

Background: This study sought to illustrate whether urinary strontium levels were related to developing chronic kidney disease (CKD) in the United States population. Methods: A total of 5,005 subjects were identified from the National Health and Nutrition Examination Survey 2011-2016. Survey-weighted logistic regression analysis, multivariate linear regression analysis, restricted cubic spline (RCS) plots curve and stratified analyses were undertaken to explicate the correlation between urinary strontium and CKD. Results: With the increase of urinary strontium, the incidence rate of CKD and urinary albumin to creatinine ratio (UACR) levels gradually decreased, and estimated glomerular filtration rate (eGFR) levels gradually increased. After controlling all confounders, only urinary strontium in the fourth quartile was correlated to a lower CKD prevalence (OR: 0.59; 95% CI, 0.44-0.79) compared to the lowest quartile. Multivariate linear regression analysis showed that urinary strontium was positively correlated with eGFR but negatively with UACR. RCS curve suggested a nonlinear relationship between urinary strontium and CKD (P for non-linearity <0.001). Stratified analyses indicated no significant difference in the correlation between urinary strontium and CKD among different subgroups. Conclusion: Urinary strontium was strongly correlated with a low risk of CKD, and this association was non-linear among the US population.

Ultraearly Intraventricular Hemorrhage Growth Predicts Early Neurologic Deterioration and Poor Functional Outcome After Acute Intracerebral Hemorrhage.

Background The presence of intraventricular hemorrhage (IVH) was extensively investigated and was associated with poor outcome in patients with intracerebral hemorrhage (ICH). However, the effect of the speed of ventricular bleeding on outcomes is unknown. Methods and Results We prospectively included patients with ICH who had baseline computed tomography scans within 6 hours after ictus between January 2016 and October 2021. The clinical characteristics were compared between patients with and without early neurologic deterioration (END). Ultraearly IVH growth (uIVHG) was defined as baseline IVH volume by onset-to-imaging time. The association between uIVHG and outcomes was assessed by using multivariable logistic regression analysis. We established the ultraearly IVH growth (uIVH) score and compared the areas under the receiver operating characteristic curves of the existing scores for predicting END. A total of 299 patients were finally enrolled. Of those, 38 patients (12.7%) experienced END at 24 hours and 89 patients (29.8%) had poor outcomes at 90 days. After adjustment for confounding factors, uIVHG (odds ratio, 1.061 [95% CI, 1.011-1.113]; P=0.016) was independently associated with END in multivariable analysis. A prediction score was developed on the basis of the logistic model. The uIVH score was developed as a sum of individual points (0-6) based on age, hematoma volume, National Institutes of Health Stroke Scale, hematoma expansion, and uIVHG ≥2.5 mL/h. In comparison with the ICH score and modified Emergency Department ICH Scale, the uIVH score exhibited best performance in the prediction of END. Conclusions uIVHG is associated with early neurologic deterioration and poor functional outcome in patients with ICH.

Incidence, characteristics and outcome of post-stroke recrudescence in the Chinese population: a single-centre observational study.

OBJECTIVES: The aim of our observational study was to investigate the incidence, clinical characteristics and outcome of post-stroke recrudescence (PSR) in the Chinese population. DESIGN AND SETTING: Single-centre prospective observational study in China. PARTICIPANTS: A total of 1114 patients who had a suspected stroke were prospectively screened from October 2020 to February 2022. OUTCOME MEASURES: The primary outcome was the proportion of patients with functional independence defined as a score of 0-2 on the modified Rankin Scale (mRS) at 3 months. Secondary outcomes were: early neurological improvement (ENI), defined as a National Institutes of Health Stroke Scale (NIHSS) score of 0 or an improvement of ≥2 points from admission at 24 hours; mortality within 3 months; stroke recurrence within 3 months and length of stay in hospital. RESULTS: A total of 959 patients with cerebral infarction and 30 patients without an available magnetic resonance imaging (MRI) scan were excluded. Among the 125 included patients, 27 cases of PSR (2.4%), 50 cases of transient ischaemic attack (TIA) (4.5%) and 48 cases of stroke mimics (SMs) (4.3%) were identified. A higher frequency of infection at admission (22.2% vs 2%, p=0.007) was observed in patients with PSR compared with patients with TIA, and a lower proportion of functional independence at 3 months (80% vs 98%, p=0.015) was seen. Patients with TIA had a higher frequency of ENI compared with patients with PSR and SMs (98% vs 59.3%, p<0.001; 98% vs 52.1%, p<0.001). Patients with PSR exhibited a higher frequency of grade 2 Fazekas deep white matter hyperintensity compared with those with SMs (33.3% vs 8.3%, p=0.010). CONCLUSIONS: PSR is not uncommon in patients presenting with stroke symptoms and can be distinguished from TIA and SMs based on a combination of clinical features and trigger in the Chinese population. The neurological deficits of patients with PSR often resolve within several days following the resolution of the trigger.

Protective efficacy of Toxoplasma gondii GRA12 or GRA7 recombinant proteins encapsulated in PLGA nanoparticles against acute Toxoplasma gondii infection in mice.

Background: Toxoplasma gondii is an apicomplexan parasite that affects the health of humans and livestock, and an effective vaccine is urgently required. Nanoparticles can modulate and improve cellular and humoral immune responses. Methods: In the current study, poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles were used as a delivery system for the T. gondii dense granule antigens GRA12 and GRA7. BALB/c mice were injected with the vaccines and protective efficacy was evaluated. Results: Mice immunized with PLGA+GRA12 exhibited significantly higher IgG, and a noticeable predominance of IgG2a over IgG1 was also observed. There was a 1.5-fold higher level of lymphocyte proliferation in PLGA+GRA12-injected mice compared to Alum+GRA12-immunized mice. Higher levels of IFN-g and IL-10 and a lower level of IL-4 were detected, indicating that Th1 and Th2 immune responses were induced but the predominant response was Th1. There were no significant differences between Alum+GRA7-immunized and PLGA+GRA7-immunized groups. Immunization with these four vaccines resulted in significantly reduced parasite loads, but they were lowest in PLGA+GRA12-immunized mice. The survival times of mice immunized with PLGA+GRA12 were also significantly longer than those of mice in the other vaccinated groups. Conclusion: The current study indicated that T. gondii GRA12 recombinant protein encapsulated in PLGA nanoparticles is a promising vaccine against acute toxoplasmosis, but PLGA is almost useless for enhancing the immune response induced by T. gondii GRA7 recombinant protein.

Neutrophil percentage to albumin ratio is associated with stroke-associated pneumonia and poor outcome in patients with spontaneous intracerebral hemorrhage.

Background: The purpose of this study was to investigate the diagnostic performance of the neutrophil percentage-to-albumin ratio (NPAR) for predicting stroke-associated pneumonia (SAP) and functional outcome in patients with intracerebral hemorrhage (ICH). Methods: We analyzed our prospective database of consecutive ICH patients who were admitted to the First Affiliated Hospital of Chongqing Medical University from January 2016 to September 2021. We included subjects with a baseline computed tomography available and a complete NPAR count performed within 6h of onset. The patients' demographic and radiological characteristics were analyzed. Good outcome was defined as a modifed Rankin Scale score of 0-3 at 90 days. Poor outcome was defined as a modifed Rankin Scale score of 4-6 at 90 days. Multivariable logistic regression models were used to investigate the association between NPAR, SAP, and functional outcome. Receiver operating characteristic (ROC) curve analysis was conducted to identify the optimal cutoff of NPAR to discriminate between good and poor outcomes in ICH patients. Results: A total of 918 patients with ICH confirmed by non-contrast computed tomography were included. Of those, 316 (34.4%) had SAP, and 258 (28.1%) had poor outcomes. Multivariate regression analysis showed that higher NPAR on admission was an independent predictor of SAP (adjusted odds ratio: 2.45; 95% confidence interval, 1.56-3.84; P<0.001) and was associated with increased risk of poor outcome (adjusted odd ratio:1.72; 95% confidence interval, 1.03-2.90; P=0.040) in patients with ICH. In ROC analysis, an NPAR of 2 was identified as the optimal cutoff value to discriminate between good and poor functional outcomes. Conclusion: Higher NPAR is independently associated with SAP and poor functional outcome in patients with ICH. Our findings suggest that early prediction of SAP is feasible by using a simple biomarker NPAR.

The prognostic effects of the geriatric nutritional risk index on elderly acute kidney injury patients in intensive care units.

Introduction: The geriatric nutritional risk index (GNRI), a nutritional screening tool specifically for the aging population, has been proven to be associated with worse outcomes in chronic kidney disease patients, especially in the hemodialysis population. However, the predictive validity of GNRI in critically ill elderly patients with acute kidney injury (AKI) is yet to be determined. This analysis sought to examine the prognostic effects of GNRI on elderly AKI patients in intensive care units (ICUs). Methods: We collected elderly AKI patient-relevant data from the Medical Information Mart for Intensive Care III database. AKI was diagnosed and staged according to the "Kidney Disease Improving Global Outcomes" criteria. In the study, 1-year mortality was considered the primary outcome, whereas in-hospital, ICU, 28-day and 90-day mortality, and prolonged length of stay in ICU and hospital were selected as the secondary outcomes. Results: In all, 3,501 elderly patients with AKI were selected for this study, with a 1-year mortality rate of 36.4%. We classified the study population into low (≤98) and high (>98) GNRI groups based on the best cutoff value. The incidence of endpoints was remarkably lower in patients with elevated GNRI (p < 0.001). When stratified by the AKI stage, patients with high GNRI at AKI stages 1, 2, and 3 had markedly lower 1-year mortality than those with low GNRI (all p < 0.05). The multivariable regression analysis identified the independent prognostic ability of GNRI on the research outcomes (all p < 0.05). Restricted cubic spline exhibited a linear correlation between GNRI and 1-year death (p for non-linearity = 0.434). The prognostic implication of GNRI on 1-year mortality was still significant in patients with the most subgroups. Conclusion: In critically ill elderly patients with AKI, elevated GNRI upon admission was strongly correlated with a lower risk of unfavorable outcomes.

SARS-CoV-2 spike protein enhances MAP4K3/GLK-induced ACE2 stability in COVID-19.

ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells was correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein-stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to the dissociation of ACE2 from its E3 ligase UBR4. Reduction in UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, and ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.

Higher Cerebral Small Vessel Disease Burden in Patients With Small Intracerebral Hemorrhage.

Objective: To investigate the association between cerebral small vessel disease (SVD) and hematoma volume in primary intracerebral hemorrhage (ICH). Methods: Patients from a prospective ICH cohort were enrolled. Admission and follow-up CT scan within 72 h after onset were reviewed to calculate the final hematoma volume. We evaluated cortical superficial siderosis and the global SVD score, including white matter hyperintensities, lacunes, enlarged perivascular space, and cerebral microbleeds on MRI. We conducted the multivariate logistic regression analyses to explore the association between SVD markers and small ICH, as well as hematoma volume. Hematoma location was stratified into lobar and non-lobar for subgroup analysis. Results: A total of 187 patients with primary ICH (mean age 62.4 ± 13.4 years, 67.9% male) were enrolled. 94 (50.2%) patients had small ICH. The multivariate logistic regression analysis showed an association between global SVD score and small ICH [adjusted odds ratio (aOR) 1.27, 95% CI 1.03-1.57, p = 0.027] and a trend of higher global SVD score towards non-lobar small ICH (aOR 1.23, 95% CI 0.95-1.58, p = 0.122). In the multivariate linear regression analysis, global SVD score was inversely related to hematoma volume of all ICH (ß = -0.084, 95% CI -0.142 to -0.025, p = 0.005) and non-lobar ICH (ß = -0.112, 95% CI -0.186 to -0.037, p = 0.004). Lacune (ß = -0.245, 95% CI -0.487 to -0.004, p = 0.046) was associated with lower non-lobar ICH volume. Conclusion: Global SVD score is associated with small ICH and inversely correlated with hematoma volume. This finding predominantly exists in non-lobar ICH.

Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus.

OBJECTIVES: MAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is unclear how GLK is upregulated in patients with SLE. METHODS: We enrolled 181 patients with SLE and 250 individuals without SLE (93 healthy controls and 157 family members of patients with SLE) in two independent cohorts from different hospitals/cities. Genomic DNAs of peripheral blood mononuclear cells were subjected to next-generation sequencing to identify GLK gene variants. The functional consequences of the identified GLK germline or somatic variants were investigated using site-directed mutagenesis and cell transfection, followed by reporter assays, mass spectrometry, immunoblotting, coimmunoprecipitation, and in situ proximity ligation assays. RESULTS: We identified 58 patients with SLE from Cohort #1 and #2 with higher frequencies of a somatic variant (chr2:39 477 124 A>G) in GLK 3'-untranslated region (UTR); these patients with SLE showed increased serum anti-double-stranded DNA levels and decreased serum C3/C4 levels. This somatic variant in 3'-UTR enhanced GLK mRNA levels in T cells. In addition, we identified five patients with SLE with GLK (A410T) germline variant in Cohort #1 and #2, as well as two other patients with SLE with GLK (K650R) germline variant in Cohort #1. Another GLK germline variant, A579T, was also detected in one patient with SLE from Cohort #2. Both GLK (A410T) and GLK (K650R) mutants inhibited GLK ubiquitination induced by the novel E3 ligase makorin ring-finger protein 4 (MKRN4), leading to GLK protein stabilisation. CONCLUSIONS: Multiple GLK germline and somatic variants cause GLK induction by increasing mRNA or protein stability in patients with SLE.

Efficacy of cathodal transcranial direct current stimulation on electroencephalographic functional networks in patients with focal epilepsy: Preliminary findings.

BACKGROUND: Neuromodulation is a promising therapeutic alternative for epilepsy. We aimed to explore the efficacy and safety of cathodal transcranial current direct stimulation (ctDCS) on electroencephalographic functional networks in focal epilepsy. METHODS: A sham-controlled, double-blinded, randomized study was conducted on 25 participants with focal epilepsy who underwent a 5-day, -1.0 mA, 20 min ctDCS, which targeted at the most active interictal epileptiform discharge (IED) region. We examined the electroencephalograms (EEGs) at baseline, immediately and at 4 weeks following ctDCS. The graph theory-based brain networks were established through time-variant partial directed coherence (TVPDC), and were calculated between each pair of EEG signals. The functional networks were characterized using average clustering coefficient, characteristic path length, and small-worldness index. The seizure frequencies, IEDs, graph-theory metrics and cognitive tests were compared. RESULTS: Preliminary findings indicated an IED reduction of 30.2% at the end of 5-day active ctDCS compared to baseline (p < 0.10) and a significant IED reduction of 33.4% 4 weeks later (p < 0.05). In terms of the EEG functional network, the small-worldness index significantly reduced by 3.5% (p < 0.05) and the characteristic path length increased by 1.8% (p < 0.10) at the end of the session compared to the baseline. No obvious change was found in the seizure frequency during follow-up (p > 0.05). The Mini-Mental State Examination (MMSE) showed no difference between the active and sham groups (p > 0.05). No severe adverse reactions were observed. CONCLUSIONS: In focal epilepsy, the 5-day consecutive ctDCS may potentially decrease the IEDs and ameliorate the EEG functional network, proposing a novel personalized therapeutic scenario for epilepsy.

Tailoring Heterogeneous Catalysts at the Atomic Level: In Memoriam, Prof. Chia-Kuang (Frank) Tsung.

Professor Chia-Kuang (Frank) Tsung made his scientific impact primarily through the atomic-level design of nanoscale materials for application in heterogeneous catalysis. He approached this challenge from two directions: above and below the material surface. Below the surface, Prof. Tsung synthesized finely controlled nanoparticles, primarily of noble metals and metal oxides, tailoring their composition and surface structure for efficient catalysis. Above the surface, he was among the first to leverage the tunability and stability of metal-organic frameworks (MOFs) to improve heterogeneous, molecular, and biocatalysts. This article, written by his former students, seeks first to commemorate Prof. Tsung's scientific accomplishments in three parts: (1) rationally designing nanocrystal surfaces to promote catalytic activity; (2) encapsulating nanocrystals in MOFs to improve catalyst selectivity; and (3) tuning the host-guest interaction between MOFs and guest molecules to inhibit catalyst degradation. The subsequent discussion focuses on building on the foundation laid by Prof. Tsung and on his considerable influence on his former group members and collaborators, both inside and outside of the lab.

MAP4K3/GLK Promotes Lung Cancer Metastasis by Phosphorylating and Activating IQGAP1.

Overexpression of the serine/threonine kinase GLK/MAP4K3 in human lung cancer is associated with poor prognosis and recurrence, however, the role of GLK in cancer recurrence remains unclear. Here, we report that transgenic GLK promotes tumor metastasis and cell migration through the scaffold protein IQ motif-containing GTPase-activating protein 1(IQGAP1). GLK transgenic mice displayed enhanced distant metastasis. IQGAP1 was identified as a GLK-interacting protein; two proline-rich regions of GLK and the WW domain of IQGAP1 mediated this interaction. GLK and IQGAP1 colocalized at the leading edge including filopodia and lamellipodia of migrating cells. GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. GLK-induced cell migration and lung cancer metastasis were abolished by IQGAP1 depletion. Consistently, human NSCLC patient tissues displayed increased phospho-IQGAP1, which correlated with poor survival. Collectively, GLK promotes lung cancer metastasis by binding to, phosphorylating, and activating IQGAP1. SIGNIFICANCE: These findings show the critical role of the GLK-IQGAP cascade in cell migration and tumor metastasis, suggesting it as a potential biomarker and therapeutic target for lung cancer recurrence.

Two new chromene derivatives from Artemisia songarica.

Two new chromene derivatives, songaricachromenes A (1) and B (2), were isolated from Artemisia songarica, along with 10 known compounds (3-12). The structures and stereochemistry of the new compounds were elucidated by analyses of the NMR, MS, and electronic circular dichroism (ECD) data. All the isolates (1-12) were evaluated for their NO inhibitory effects on LPS-stimulated BV-2 microglial cells.

Axons of Passage and Inputs to Superior Cervical Ganglion in Rat.

Wheat germ agglutinin-horseradish peroxidase was injected into the entire (0.8 µL) or partial (rostral or caudal, 0.1-0.3 µL) superior cervical ganglion (SCG) of the rat (male Sprague-Dawley, N = 35) to examine the distribution of neurons in the middle (MCG) and inferior (ICG) cervical ganglion that send axons bypass the SCG. Whole-mounts of the SCG, cervical sympathetic trunk (CST), MCG, ICG, and sections of the brainstem and spinal cord were prepared. With entire SCG tracer injection, neurons were labeled evenly in the MCG (left: 258, right: 121), ICG (left: 848, right: 681), and CST (up to 770). Some neurons grouped in a single bulge just rostral to the MCG, which we termed as the "premiddle cervical ganglion" (pMCG). The left pMCG (120) is larger and has more neurons than the right pMCG (82). Centrally, neurons were labeled in lamina IX of cervical segments (C1: 18%, C2: 46%, C3: 33%, C4: 3%), intermediate zone of thoracic segments (T1: 31%, T2: 35%, T3: 27%, T4: 7%), and intermediate reticular nuclei (96%) and perifacial zone (4%) of brainstem. The rostral and caudal SCG injection selectively labeled neurons mainly in brainstem, C1-C2 and in T1-T2, respectively. Before projecting to their peripheral targets, many neurons in pMCG, MCG and ICG run rostrally within the CST rather than segmentally through the closest rami, from the level of SCG or above. Neurons in pMCG and MCG may have similar or complementary function and those in brainstem may be involved in the vestibulo-autonomic interaction. Anat Rec, 301:1906-1916, 2018. © 2018 Wiley Periodicals, Inc.

GABAA Receptor Activity Suppresses the Transition from Inter-ictal to Ictal Epileptiform Discharges in Juvenile Mouse Hippocampus.

Exploring the transition from inter-ictal to ictal epileptiform discharges (IDs) and how GABAA receptor-mediated action affects the onset of IDs will enrich our understanding of epileptogenesis and epilepsy treatment. We used Mg2+-free artificial cerebrospinal fluid (ACSF) to induce epileptiform discharges in juvenile mouse hippocampal slices and used a micro-electrode array to record the discharges. After the slices were exposed to Mg2+-free ACSF for 10 min-20 min, synchronous recurrent seizure-like events were recorded across the slices, and each event evolved from inter-ictal epileptiform discharges (IIDs) to pre-ictal epileptiform discharges (PIDs), and then to IDs. During the transition from IIDs to PIDs, the duration of discharges increased and the inter-discharge interval decreased. After adding 3 µmol/L of the GABAA receptor agonist muscimol, PIDs and IDs disappeared, and IIDs remained. Further, the application of 10 µmol/L muscimol abolished all the epileptiform discharges. When the GABAA receptor antagonist bicuculline was applied at 10 µmol/L, IIDs and PIDs disappeared, and IDs remained at decreased intervals. These results indicated that there are dynamic changes in the hippocampal network preceding the onset of IDs, and GABAA receptor activity suppresses the transition from IIDs to IDs in juvenile mouse hippocampus.