AP2S1 regulates APP degradation through late endosome-lysosome fusion in cells and APP/PS1 mice.

AP2S1 is the sigma 2 subunit of adaptor protein 2 (AP2) that is essential for endocytosis. In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic ß-amyloid peptide (Aß). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and Aß in cells stably expressing human full-length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation. Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9-positive late endosomes (LE) to LAMP1-positive lysosomes, which was paralleled by the enhanced LE-lysosome fusion. In support, silencing of vacuolar protein sorting-associated protein 41 (VPS41) that is implicated in LE-lyso fusion prevented AP2S1-mediated regulation of APP degradation and translocalization. In APP/PS1 mice, an animal model of AD, AAV-mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and Aß, with the concomitant APP translocalization, LE-lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE-lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD.

Images of the month 1: Recurrent ischaemic stroke secondary to Eagle syndrome.

We present a case of a man who experienced recurrent ischaemic stroke secondary to an elongated styloid process compressing the cervical carotid artery.

Clinical Presentation and Outcomes of Acute Disseminated Encephalomyelitis in Adults Worldwide: Systematic Review and Meta-Analysis.

Background: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disorder that is often misdiagnosed. To improve early diagnosis, we performed a systematic review and meta-analysis of clinical features, outcomes for ADEM in adults. Methods: The PubMed, Embase, Web of Science and Cochrane Library databases were searched for studies reporting the clinical features of adults with ADEM between January 1990 and May 2021. A random-effects meta-analysis model was used to pool data on clinical features and functional outcomes. Results: Twelve studies examining 437 adults with ADEM met the inclusion criteria. Overall, the clinical features and diagnostic findings observed in more than two-thirds of the patients were white matter lesions [87.1%, 95% confidence interval (CI)=75-95.6], polyfocal onset (80.5%, 95% CI=50.5-98.9) and pyramidal signs (68.7%, 95% CI =40.0-91.9). The mortality rate was 7.8% (95% CI = 3.3-13.5), and the risk of residual deficits was 47.5% (95% CI = 31.8-63.4). Conclusions: Adults with ADEM had worse outcomes than children. Clinicians should maintain high clinical suspicion for patients presenting with certain clinical features and diagnostic findings.

Intrathecal therapy for tuberculous meningitis: propensity-matched cohort study.

OBJECTIVE: The study aimed to determine the safety and efficacy of intrathecally administered isoniazid (INH) and prednisolone in addition to systemic anti-TB therapy and compare it with systemic anti-TB therapy alone in adult patients with tuberculous meningitis (TBM). METHODS: In this retrospective study, patients were categorized into two groups: Group A patients received systematic anti-TB therapy alone, Group B patients received IT INH (50 mg) and prednisolone (25 mg) twice a week together with the same standard systemic anti-TB therapy as Group A, in addition to the standard systemic anti-TB therapy. Functional outcomes were compared between the two groups in a prosperity-matched cohort using propensity score matching (PSM) method. RESULTS: A total of 198 patients with TBM were enrolled. After PSM, 30 patients from each group were analyzed, so that there was no significant difference in the characteristics of the two groups. Mortality at follow-up was significantly lower among patients receiving additional IT therapy (4/30, 13.3%) compared with matched patients receiving systemic anti-TB therapy alone (11/30, 36.7%, P value = 0.037). CONCLUSIONS: In this propensity score-matched cohort, the addition of IT INH and prednisolone to systemic anti-TB therapy could be effective for the better outcome among adult TBM patients. Further large-scale, prospective, and randomized controlled trials are warranted to the best timing and indication of IT therapy.

Point spread function for the wide-field-of-view plenoptic cameras.

Recently, single or multi-layer spherical lens (monocentric lens) coupled with a microlens array (MLA) and an imaging sensor are under investigation to expand the field of view (FOV) for handheld plenoptic cameras. However, there lacks modeling the point spread functions (PSFs) for them to improve the imaging quality and to reconstruct the light field in the object space. In this paper, a generic image formation model is proposed for wide-FOV plenoptic cameras that use a monocentric lens and an MLA. By analyzing the optical characteristics of the monocentric lens, we propose to approximate it by a superposition of a series of concentric lenses with variable apertures. Based on geometry simplification and wave propagation, the equivalent imaging process of each portion of a wide-FOV plenoptic camera is modeled, based on which the PSF is derived. By comparing PSFs captured by real wide-FOV plenoptic camera and those generated by the proposed model, the validity of this model is verified. Further, reconstruction process is applied by deconvolving captured images with the PSFs generated by the proposed model. Experimental results show that the quality of reconstructed images is better than that of subaperture images, which demonstrates that our proposed PSF model is beneficial for imaging quality improvement and light field reconstruction.

Sulfuretin exerts diversified functions in the processing of amyloid precursor protein.

Sulfuretin is a flavonoid that protects cell from damage induced by reactive oxygen species and inflammation. In this study, we investigated the role of sulfuretin in the processing of amyloid precursor protein (APP), in association with the two catalytic enzymes the α-secretase a disintegrin and metalloproteinase (ADAM10), and the beta-site APP cleaving enzyme 1 (BACE1) that play important roles in the generation of ß amyloid protein (Aß) in Alzheimer's disease (AD). We found that sulfuretin increased the levels of the immature but not the mature form of ADAM10 protein. The enhanced ADAM10 transcription by sulfuretin was mediated by the nucleotides -444 to -300 in the promoter region, and was attenuated by silencing or mutation of transcription factor retinoid X receptor (RXR) and by GW6471, a specific inhibitor of peroxisome proliferator-activated receptor α (PPAR-α). We further found that sulfuretin preferentially increased protein levels of the immature form of APP (im-APP) but significantly reduced those of BACE1, sAPPß and ß-CTF, whereas Aß1-42 levels were slightly increased. Finally, the effect of sulfuretin on BACE1 and im-APP was selectively attenuated by the translation inhibitor cycloheximide and by lysosomal inhibitor chloroquine, respectively. Taken together, (1) RXR/PPAR-α signaling was involved in sulfuretin-mediated ADAM10 transcription. (2) Alteration of Aß protein level by sulfuretin was not consistent with that of ADAM10 and BACE1 protein levels, but was consistent with the elevated level of im-APP protein, suggesting that im-APP, an isoform mainly localized to trans-Golgi network, plays an important role in Aß generation.

Stable Eu3+/Cu2+-Functionalized Supramolecular Zinc(II) Complexes as Fluorescent Probes for Turn-On and Ratiometric Detection of Hydrogen Sulfide.

Fabrication of dual-emitting materials for H2S sensing under environmental and biological conditions is currently of great interest. In this work, a new chemically stable metal supramolecular complex [Zn2(pda)2(H2O)3]·(H2O)0.5 (Znpda, pda = 1,10-phenanthroline-2,9-dicarboxylic acid), with accessible uncoordinated carboxylic oxygen sites, is solvothermally synthesized. It can serve as a host in luminescent hybrid composites. By incorporating Eu3+ and Cu2+ in the supramolecular coordination network, we obtained the dual-emitting hybrid material Eu3+/Cu2+@Znpda, which simultaneously shows intense ligand and weak Eu3+ emissions in HEPES buffer solution. Since H2S can easily chelate with Cu2+ and recover the blocked "antenna effect" between the ligand and Eu3+, Eu3+/Cu2+@Znpda possesses both the turn-on and ratiomectric fluorescence response to H2S. Accordingly, we designed an IMPLICATION logic gate for H2S recognition by employing the fluorescence intensity ratio between the ligand and Eu3+ as the output signal. In addition, Eu3+/Cu2+@Znpda shows a fast response (<1 min) and high sensitivity (1.45 µM) to H2S over other interfering species in the HEPES buffer solution, highlighting its potential use for H2S sensing under environmental and biological conditions.

Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression.

Thioredoxin-2 (TXN2) is a mitochondrial protein and represents one of the intrinsic antioxidant enzymes. It has long been recognized that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of Alzheimer's disease (AD). We hypothesized that mitochondrial TXN2 might play a role in AD-like pathology. In this study, we found that in SH-SY5Y and HEK cells stably express full-length human amyloid-ß precursor protein (HEK-APP), TXN2 silencing or over-expression selectively increased or decreased the transcription of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), respectively, without altering the protein levels of others enzymes involved in the catalytic processing of APP. As a result, ß-amyloid protein (Aß) levels were significantly decreased by TXN2. In addition, in cells treated with 3-nitropropionic acid (3-NP) that is known to increase reactive oxygen species (ROS) and promote mitochondrial dysfunction, TXN2 silencing resulted in further enhancement of BACE1 protein levels, suggesting a role of TXN2 in ROS removal. The downstream signaling might involve NFκB, as TXN2 reduced the phosphorylation of p65 and IκBα; and p65 knockdown significantly attenuated TXN2-mediated regulation of BACE1. Concomitantly, the levels of cellular ROS, apoptosis-related proteins and cell viability were altered by TXN2 silencing or over-expression. In APPswe/PS1E9 mice, an animal model of AD, the cortical and hippocampal TXN2 protein levels were decreased at 12 months but not at 6 months, suggesting an age-dependent decline. Collectively, TXN2 regulated BACE1 expression and amyloidogenesis via cellular ROS and NFκB signaling. TXN2 might serve as a potential target especially for early intervention of AD.

Ubiquitination status does not affect Vps34 degradation.

Vps34 (vacuolar protein-sorting 34) plays important role in autophagy and endosomal trafficking. These processes are closely associated protein ubiquitination and degradation. We have hypothesized that Vps34 ubiquitination status would also control its degradation. Here, we report that our results did not support this assumption. In cells transiently transfected with ubiquitin (UB) constructs contained different lysine residues (Ks), Vps34 ubiquitination could occur regardless of the presence of any Ks in UB. However, Vps34 protein levels were not significantly altered in cells transiently transfected with these UB mutants. We further found that Vps34 protein was altered by pharmacological manipulation of E2/E3 activity; yet this effect was not significantly affected by UB overexpression. In vivo experiments revealed that in APP/PS1 mice, an animal model of Alzheimer's disease (AD), although ubiquitination of Vps34 was significantly reduced, Vps34 protein levels remained unchanged. Vps34 indeed was subjected to proteasomal or lysosomal degradation, as prolonged treatment of proteasomal inhibitor MG132 or lysosomal inhibitor chloroquine elevated Vps34 protein levels. We conclude that unlike most of other proteins, Vps34 ubiquitination is not closely associated with its degradation.

Enhanced anaerobic fermentation of waste activated sludge by NaCl assistant hydrolysis strategy: Improved bio-production of short-chain fatty acids and feasibility of NaCl reuse.

This study developed an economical approach for enhancing short-chain fatty acids (SCFAs) production from waste activated sludge (WAS) by NaCl assistant anaerobic fermentation. With NaCl addition at 20 g/L, sludge disintegration with extracellular polymeric substance (EPS) disruption and cell lysis were induced owing to the attack of osmotic pressure, which facilitated WAS solubilization with release of biodegradable organic matters. The SCOD sharply increased to 4092 mg/L (SCOD/TCOD = 23.9%) after 2-day hydrolysis, against 1462 mg/L in the control. After 4-day anaerobic fermentation, considerable SCFAs production of 288.2 mg COD/g VSS was achievable. More than 60% of the SCFAs was composed of acetic and propionic acids. The feasibility of bio-electrogenesis in microbial fuel cell (MFC) utilizing fermentative liquid was assessed. As such, the produced SCFAs could be consumed with energy recovery, thereby the used NaCl was reusable, which created environmental and economic benefits, e.g. reduced NaCl consumption and cost, negligible residual NaCl.

APOE ε4 Allele Is Associated with Elevated Levels of CSF VILIP-1 in Preclinical Alzheimer's Disease.

OBJECTIVES: Cerebrospinal fluid (CSF) visinin-like protein 1 (VILIP-1) has been suggested as a biomarker for neuron injury, which has been shown to have a important diagnostic value in symptomatic Alzheimer's disease (AD). The study purpose is investigating potential effects of apolipoprotein E (APOE) ε4 on CSF VILIP-1 levels among the preclinical AD. METHODS: A total of 110 subjects (including 43 APOE ε4 carriers and 67 ε4 non-carriers) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in the present study. RESULTS: The results showed that VILIP-1 concentrations in the CSF were statistically significantly increased in APOE ε4 carriers in comparison with non-carriers. Increased CSF VILIP-1 level was positively associated with the concentrations of both CSF-tau and P-tau levels. CONCLUSIONS: Our findings suggested that APOE ε4 might affect CSF VILIP-1 level in preclinical AD, indicating an important role of APOE ε4 in neuron injury leading to AD.

New-onset seizures in adults with tuberculous meningitis during long-term follow-up: Characteristics, functional outcomes and risk factors.

OBJECTIVE: This study aimed to determine the characteristics and risk factors of adult new-onset seizure patients with tuberculous meningitis (TBM) during long-term follow-up. METHODS: Patients with TBM who were seen between June 2012 and January 2018 were retrospectively reviewed and categorized into two groups based on the presence or absence of new-onset seizures. Seizure characteristics, functional outcomes and risk factors were assessed. RESULTS: A total of 223 patients with TBM were enrolled, including 20.6% (46/223) with seizures. In all, 39.1% (18/46) of the patients with new-onset seizures and 14.1% (25/177) of the patients without seizures died (p < 0.001). Seizures were classified as single (n = 14/46, 30.4%), repetitive (n = 25/46, 54.3%), or status epilepticus (n = 7/46, 15.2%). We found that non-single seizures (repetitive seizures and status epilepticus) were associated with mortality (P = 0.002, P = 0.022), while single seizures were not (P = 0.834). The independent risk factors associated with non-single seizures were cortical involvement (p = 0.007) and epileptiform discharges (p = 0.001). CONCLUSIONS: Non-single seizures were associated with poor functional outcomes and should be noted by the clinic. Cortical involvement and epileptiform discharges are independent risk factors for non-single seizures.

Cerebrospinal fluid levels of YKL-40 in prodromal Alzheimer's disease.

Recently, cerebrospinal fluid (CSF) YKL-40 levels were reported to be a promising candidate biomarker of glial inflammation in Alzheimer's disease (AD). To detect how APOE ε4 affects CSF YKL-40 levels in cognitively normal (CN) states, mild cognitive impairment (MCI) and AD dementia, data from 35 CN subjects, 63 patients with MCI, and 11 patients with AD from a cross-sectional study in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were investigated. The results showed that CSF YKL-40 concentrations were increased in the AD dementia group than in the CN group. CSF YKL-40 levels were higher in APOE ε4 carriers than in noncarriers with MCI. No statistically significant difference was found in CSF YKL-40 levels between APOE ε4 carrier and noncarriers in AD and CN subjects. CSF YKL-40 concentrations were tightly related to CSF tau and p-tau concentrations in the MCI group. Analysis implied that APOE ε4 might affect CSF YKL-40 levels in MCI subjects, suggesting a crucial role of APOE ε4 in neuroinflammation in detecting individuals who might convert to AD from MCI and, thus, as an effective predictive factor.

Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: systematic review and meta-analysis.

BACKGROUND: Tuberculous meningitis (TBM) is one of the most life-threatening infectious diseases. We performed a systematic review and meta-analysis of the clinical features, outcomes, and prognostic factors for TBM in adults. METHODS: PubMed, EMBASE, Cochrane CENTRAL, and Web of Science were searched for studies that reported the clinical outcomes and/or risk factors for death in adults with TBM between January 1990 and July 2018. A random-effects meta-analysis model was used to pool data on clinical features, outcomes, and risk factors for death. RESULTS: Thirty-two studies that examined 5023 adults who had TBM met the inclusion criteria. Overall, the mortality was 22.8% [95% confidence interval (CI) 18.9-26.8] and the risk of neurological sequelae was 28.7% (95% CI 22.8-35.1). The major risk factors for death (OR > 2 and P < 0.05) were advanced stage of disease (OR = 6.06, 95% CI 4.31-8.53), hydrocephalus (OR = 5.27, 95% CI 2.25-12.37), altered consciousness (OR 3.33, 95% CI 1.51-7.36), altered sensorium (OR 3.31, 95% CI 2.20-4.98), advanced age (> 60 years; OR = 2.64, 95% CI 1.27-5.51), and cerebral infarction (OR = 2.35, 95% CI 1.63-3.38). The clinical features and diagnostic findings present in more than four-fifths of the patients were fever (86.3%, 95% CI 82.4-89.8) and low CSF/serum glucose ratio (80.6%, 95% CI 64.8-92.6). CONCLUSIONS: Adults with TBM have high rates of mortality. Clinicians should maintain a high clinical suspicion for patients who present with certain clinical features, and should pay more attention to prognostic factors.

Mitochondrial methionine sulfoxide reductase B2 links oxidative stress to Alzheimer's disease-like pathology.

Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial protein that protects cell from oxidative stress. The antioxidant activity suggests that MSRB2 may play a role in the pathophysiology of Alzheimer's disease (AD). Here, we report that in APP/PS1 mice, an animal model of AD, MSRB2 protein levels were decreased in the hippocampus at both young (6 mon) and old (18 mon) age, and in the cortex only at an old age, respectively. In HEK293 cells that stably express human full-length ß-amyloid precursor protein (APP, HEK/APP), MSRB2 reduced the protein and mRNA levels of APP and ß-amyloid converting enzyme 1 (BACE1), and the consequent amyloid beta peptide (Aß) 1-40 and Aß1-42 levels. MSRB2 overexpression or knockdown also oppositely affected Tau phosphorylation at selective sites, with the concomitant alteration of the phosphorylated extracellular signal regulated kinase (p-ERK) and AMP-activated protein kinase (p-AMPK) levels. Moreover, in cells treated with long-term (24 h) hydrogen peroxide, the alterations of APP processing and Tau phosphorylation were reversed by MSRB2 overexpression. We further found that MSRB2-mediated regulation of APP transcription involved JNK and ERK signaling, as MSRB2 also reduced the levels of phosphorylated JNK (p-JNK), and JNK or ERK inhibitor attenuated the effect of MSRB2 on APP proteins and transcripts. Finally, MSRB2 reduced apoptosis-related proteins Bax and caspase3 and enhanced the anti-apoptotic protein Bcl2. These results indicated that the role for MSRB2 in AD-like pathology was closely associated with its antioxidant activity. By attenuating both amyloidogenesis and Tau phosphorylation, MSRB2 may serve as a potential therapeutic target for AD.

Wearable Carbon Nanotube-Based Biosensors on Gloves for Lactate.

Developing a simple and direct approach for interfacing a sensor and a target analyte is of great interest for fields such as medical diagnosis, threat detection, food quality control, and environmental monitoring. Gloves provide a unique interface for sensing applications. Here, we show for the first time the development of wearable carbon nanotube (CNT)-based amperometric biosensors painted onto gloves as a new sensing platform, used here for the determination of lactate. Three sensor types were studied, configured as: two CNT electrodes; one CNT electrode, and an Ag/AgCl electrode, and two CNT electrodes and an Ag/AgCl electrode. The sensors are constructed by painting the electrodes using CNT or Ag/AgCl inks. By immobilizing lactate oxidase onto the CNT-based working electrodes, the sensors show sensitive detections of lactate. Comparison of sensor performance shows that a combination of CNT and Ag/AgCl is necessary for highly sensitive detection. We anticipate that these findings could open exciting avenues for fundamental studies of wearable bioelectronics, as well as practical applications in fields such as healthcare and defense.

Clinical features, long-term clinical outcomes, and prognostic factors of tuberculous meningitis in West China: a multivariate analysis of 154 adults.

BACKGROUND: Tuberculosis is prevalent in China, which is the second greatest contributor to the global tuberculosis burden. Tuberculosis meningitis (TBM) is the most severe disease form but few reports describe long-term clinical outcomes and prognostic factors. Thus, we studied these features in Chinese TBM patients. METHODS: A retrospective follow-up study was used to collect clinical features and outcomes of adult TB meningitis at the First Affiliated Hospital of Chongqing Medical University from June 2012 to August 2015. Univariate analysis and multivariate analysis were used to identify predictive factors associated with outcomes at discharge and follow-up. RESULTS: TBM patients (N = 154) were a median age of 41 years (range: 16-82 years). Median time to follow-up was 26.4 months (range: 9.3-46.5 months) and 31% had poor outcomes at follow-up and limb weakness (p = 0.016), lower GCS scores (p < 0.001), cranial-nerve palsy (p = 0.024), and hydrocephalus (p = 0.009) were closely associated with these poor outcomes. Furthermore, a high neutrophil to lymphocytes ratio, high D-dimer, a low albumin to globulin ratio and slow background of EEG associated with poor outcomes as well. CONCLUSIONS: Mortality and disability associated with TBM are high in China. Limb weakness, GCS scores, cranial-nerve palsy and hydrocephalus were independent predictors of poor outcomes, and AGR, NLR, D-dimer, and EEG abnormalities may be prognostic factors of TBM.

Neurofibromin Regulates Seizure Attacks in the Rat Pilocarpine-Induced Model of Epilepsy.

Studies have shown that neurofibromin (NF1) restricts GABA release at inhibitory synapses and regulates dendritic spine formation, which may play an important role in temporal lobe epilepsy (TLE). NF1 expression was detected by double-label immunofluorescence, immunohistochemistry, and western blot analysis in the brains of pilocarpine-induced epilepsy model rats at 6 h, 24 h, 72 h, 7 days, 14 days, 30 days, and 60 days after kindling. NF1 was localized primarily in the nucleus and cytoplasm of neurons. NF1 protein levels significantly increased in the chronic phase (from 7 days until 60 days) in this epileptic rat model. After NF1 expression was knocked down by specific siRNA, the effects of kindling with pilocarpine were evaluated on the 7th day after kindling. The onset latencies of pilocarpine-induced seizures were elevated, and the seizure frequency and duration were reduced in these rats. Our study demonstrates that NF1 promoted seizure attacks in rats with pilocarpine-induced epilepsy.