Increased cysteinyl-tRNA synthetase drives neuroinflammation in Alzheimer's disease.

BACKGROUND: Microglia-mediated neuroinflammation in Alzheimer's disease (AD) is not only a response to pathophysiological events, but also plays a causative role in neurodegeneration. Cytoplasmic cysteinyl-tRNA synthetase (CARS) is considered to be a stimulant for immune responses to diseases; however, it remains unknown whether CARS is involved in the pathogenesis of AD. METHODS: Postmortem human temporal cortical tissues at different Braak stages and AD patient-derived serum samples were used to investigate the changes of CARS levels in AD by immunocytochemical staining, real-time PCR, western blotting and ELISA. After that, C57BL/6J and APP/PS1 transgenic mice and BV-2 cell line were used to explore the role of CARS protein in memory and neuroinflammation, as well as the underlying mechanisms. Finally, the associations of morphological features among CARS protein, microglia and dense-core plaques were examined by immunocytochemical staining. RESULTS: A positive correlation was found between aging and the intensity of CARS immunoreactivity in the temporal cortex. Both protein and mRNA levels of CARS were increased in the temporal cortex of AD patients. Immunocytochemical staining revealed increased CARS immunoreactivity in neurons of the temporal cortex in AD patients. Moreover, overexpression of CARS in hippocampal neurons induced and aggravated cognitive dysfunction in C57BL/6J and APP/PS1 mice, respectively, accompanied by activation of microglia and the TLR2/MyD88 signaling pathway as well as upregulation of proinflammatory cytokines. In vitro experiments showed that CARS treatment facilitated the production of proinflammatory cytokines and the activation of the TLR2/MyD88 signaling pathway of BV-2 cells. The accumulation of CARS protein occurred within dense-core Aß plaques accompanied by recruitment of ameboid microglia. Significant upregulation of TLR2/MyD88 proteins was also observed in the temporal cortex of AD. CONCLUSIONS: The findings suggest that the neuronal CARS drives neuroinflammation and induces memory deficits, which might be involved in the pathogenesis of AD.

Potentially active compounds that improve PAD through angiogenesis: A review.

Peripheral arterial disease (PAD) has been historically neglected, which has resulted in a lack of effective drugs in clinical practice. However, with the increasing prevalence of diseases like atherosclerosis and diabetes, the incidence of PAD is rising and cannot be ignored. Researchers are exploring the potential of promoting angiogenesis through exogenous compounds to improve PAD. This paper focuses on the therapeutic effect of natural products (Salidroside, Astragaloside IV, etc.) and synthetic compounds (Cilostazol, Dapagliflozin, etc.). Specifically, it examines how they can promote autocrine secretion of vascular endothelial cells, enhance cell paracrine interactions, and regulate endothelial progenitor cell function. The activation of these effects may be closely related to PI3K, AMPK, and other pathways. Overall, these exogenous compounds have promising therapeutic potential for PAD. This study aims to summarize the potential active compounds, provide a variety of options for the search for drugs for the treatment of PAD, and bring light to the treatment of patients.

Pathogenicity of Avian Polyomaviruses and Prospect of Vaccine Development.

Polyomaviruses are nonenveloped icosahedral viruses with a double-stranded circular DNA containing approximately 5000 bp and 5-6 open reading frames. In contrast to mammalian polyomaviruses (MPVs), avian polyomaviruses (APVs) exhibit high lethality and multipathogenicity, causing severe infections in birds without oncogenicity. APVs are classified into 10 major species: Adélie penguin polyomavirus, budgerigar fledgling disease virus, butcherbird polyomavirus, canary polyomavirus, cormorant polyomavirus, crow polyomavirus, Erythrura gouldiae polyomavirus, finch polyomavirus, goose hemorrhagic polyomavirus, and Hungarian finch polyomavirus under the genus Gammapolyomavirus. This paper briefly reviews the genomic structure and pathogenicity of the 10 species of APV and some of their differences in terms of virulence from MPVs. Each gene's genomic size, number of amino acid residues encoding each gene, and key biologic functions are discussed. The rationale for APV classification from the Polyomavirdae family and phylogenetic analyses among the 10 APVs are also discussed. The clinical symptoms in birds caused by APV infection are summarized. Finally, the strategies for developing an effective vaccine containing essential epitopes for preventing virus infection in birds are discussed. We hope that more effective and safe vaccines with diverse protection will be developed in the future to solve or alleviate the problems of viral infection.

A detailed assessment of liver function in patients with hepatocellular carcinoma via the modified albumin-bilirubin (mALBI) grade.

Recently, the albumin-bilirubin (ALBI) score, a continuous index consisting of only albumin and bilirubin, has been developed for objectively assessing liver function in patients with hepatocellular carcinoma (HCC). However, the ALBI score was arbitrarily categorized into three ALBI grades based on two artificially predetermined cutoff points with no explanation and statistical grounds, causing a considerable loss of discriminatory ability. This study aims to propose a modified ALBI (mALBI) grade for offering a detailed evaluation of hepatic reserve and specify its role during clinical practice in the HCC setting. The study population comprised 3540 HCC patients treated with mainstream therapies including hepatectomy (n=2056), thermal ablation (n=550), and transcatheter arterial chemoembolization (n=934) from 2002 to 2017. The ALBI score was stratified into four mALBI grades through a recently proposed statistical method aiming to select the optimal cutoff points of a continuous predictive variable by maximizing the discriminative ability in a multivariable Cox regression model. The mALBI grade had an overall better discriminatory ability than the ALBI grade in predicting overall survival through Harrell's C-index (0.614 vs. 0.598, P<0.001). Both visual inspections of Kaplan-Meier curves and calculation of hazard ratios displayed a more subtle evaluation of liver function using the mALBI grade. Moreover, the newly identified cut-point (ALBI score = -2.29) between the mALBI grade 2a and 2b was much closer to a 30% retention rate of indocyanine green at 15 minutes, an indicator for the performance of a subsegmentectomy. The newly proposed mALBI grade provides a more subtle assessment of liver function to guide clinical decision-making and predicts the prognosis of HCC patients more accurately than the original ALBI grade.

More Liver Metastases Detected Intraoperatively Indicates Worse Prognosis for Colorectal Liver Metastases Patients after Resection Combined with Microwave Ablation.

Background: Whether more tumor numbers detected in surgery compared to preoperative image affecting survival of colorectal liver metastases (CRLM) patients after hepatectomy combined with microwave ablation (MWA) remains unclear. Methods: From 2013 to 2018, 85 CRLM patients who underwent hepatectomy combined with MWA were retrospectively assessed. Compared to the tumor numbers in preoperative image, patients with equal intraoperative tumor numbers were defined as the equal number group (n = 45); patients detected more tumor numbers in surgery were defined as the more number group (n = 40). Clinicopathological factors and prognosis were compared between two groups. Results: Compared to the equal number group, the more number group was characterized by more lymphatic metastasis, synchronous metastasis of liver lesion, and tumor numbers over 5 (all P < 0.05). Median survival time was 46.7 months and 26.8 months in the equal and more number group. Significantly worse overall survival (OS) was found in more number group to the equal number group (P = 0.027). In Cox analysis, more tumor number than image and high level of carbohydrate antigen 19-9 (CA19-9) were poor prognostic factors for OS. Conclusion: In patients receiving hepatectomy combined with MWA, detecting more liver metastases in surgery than preoperative image indicates poor long-term survival. These patients were characterized by more lymphatic metastasis, synchronous metastasis of liver lesion, and tumor numbers over 5. Intensive follow-up to detect early recurrence and potent postoperative therapy to improve survival may be justified in patients detected more tumor numbers in surgery with a high CA19-9 level.

Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans.

Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived daf-2/insulin receptor mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of daf-2 function, that EIF-2α pS49 potently inhibits protein synthesis and daf-2 longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.

Exposure-time-dependent subcellular staging of gold nanoparticles deposition and vesicle destruction in mice livers.

Several advances in nanomedicine have been accompanied by rising concerns about the bioaccumulation and toxicity of gold nanoparticles (AuNPs). Here, we assessed the in vivo fate of diversely sized AuNPs that were injected into mice as a computed tomography contrast agent and examined with multi-scale analyses across the organ, tissue, cell, and subcellular levels. After focusing on the strong detected accumulation in livers, our data revealed a set of three clear, exposure-time-dependent patterns based on i) AuNPs deposit morphology and ii) readily identifiable phenotypes for AuNP-impacted subcellular vesicles. Importantly, we detected no obvious differences in liver function, liver cell apoptosis, or autophagy upon exposure to AuNPs. Thus, our study illustrates an accessible experimental and high-resolution data interpretation framework for quickly obtaining and contextualizing informative trends about any AuNP-triggered patterns of subcellular damage in nanomedicine studies; these can help guide cytotoxity and safety testing of diagnostic nanomedical technologies.

Correlation between goose circovirus and goose parvovirus with gosling feather loss disease and goose broke feather disease in southern Taiwan.

BACKGROUND: Goslings in several Taiwanese farms experienced gosling feather loss disease (GFL) at 21-35 days and goose broke feather disease (GBF) at 42-60 days. The prevalence ranges from a few birds to 500 cases per field. It is estimated that about 12,000 geese have been infected, the morbidity is 70-80% and the mortality is 20-30%. OBJECTIVES: This study aims to investigate the pathogens that cause GFL and GBF. Focus on the study of the correlation between goose circovirus (GoCV) and goose parvovirus (GPV) with the goose feather loss in southern Taiwan. Furthermore, a phylogenetic tree was established to align the differences between southern and northern Taiwan and compare with virus strains from China and Europe. METHODS: Samples were collected from animal hospitals. Molecular and microscopy diagnostics were used to examine 92 geese. Specific quantitative polymerase chain reaction (Q-PCR) assays are performed to evaluate GPV and GoCV viral loads and simultaneously evaluated the feather loss conditions in geese with the scoring method. RESULTS: High prevalence of GoCV and GPV infection in geese showing signs of GFL and GBF. Inclusion body was detected in the feather follicles and Lieberkühn crypt epithelial cells. The Q-PCR showed the high correlation between feather loss and viruses during 3rd-5th week. However, the infection was not detected using the same test in 60 healthy geese. CONCLUSIONS: Thus, GFL and GBF appear to be significantly closely related to GoCV and GPV. The geese feathers showed increasing recovery after being quarantined and disinfected.

Risk of Recurrence and Metastasis for Patients with T1N0M0 Esophageal Carcinoma Who Achieve Completed Resection via Endoscopic Submucosal Resection: Evidence for the Appropriateness of the Watch and Wait Follow-Up Strategy.

PURPOSE: Endoscopic submucosal dissection (ESD) is a widely performed procedure for esophageal carcinoma when the depth of invasion reaches the epithelium and lamina propria. However, ESD for esophageal carcinoma with depth of invasion exceeding the muscularis mucosa is controversial. This study aimed to evaluate the long-term outcomes of ESD for T1N0M0 (tumor invading the mucosa and submucosa [T1], no regional lymph node metastasis [N0], no distant metastasis [M0]) esophageal cancer. PATIENTS AND METHODS: Esophageal cancer was evaluated via pathology and computed tomography (CT) in consecutive patients with negative margin and without additional therapy. A total of 84 patients were included. The mean follow-up time was 42 (range, 9-99) months. RESULTS: No recurrence and metastasis were detected in the M1 and M2 group. The 5-year locoregional recurrence rate and distant metastasis rate were 4.2% and 5.6% for the M3 group and were 0% and 1.4% for the SM group, respectively. The 3- and 5-year overall survival were 94.4% (M1+M2 group, 95.0%; M3 group, 95.0%; SM group, 92.9%) and 80.9% (M1+M2 group, 95.0%; M3 group, 95.0%; SM group, 92.9%). Meanwhile, the 3- and 5-year disease-specific survival rates were 100% (M1+M2 group, 100%; M3 group, 100%; SM group, 100%) and 90.8% (M1+M2 group, 100%; M3 group, 90.0%; SM group, 85.7%). The major complications were postoperative strictures, most of which were grade 1-2. In total, two (4.8%) and one (1.2%) patient developed grade 3 and 5 late esophageal strictures, respectively. CONCLUSION: ESD complete resection yields low recurrence and metastasis rates in early esophageal cancer (T1N0M0). Thus, additional treatment is not necessary, and a watch and wait strategy may be reasonable.

The efficacy and safety of long- versus short-interval transarterial chemoembolization in unresectable hepatocellular carcinoma.

Background: To compare the efficacy and safety of long- versus short-interval of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) patients. Methods: This retrospective analysis enrolled 574 patients with unresectable HCC who underwent at least two sessions of TACE between January 2007 and December 2014. The patients were divided into a short-interval group (SIG) and a long-interval group (LIG) based on the median TACE interval of the first two sessions. Propensity score matching (PSM) identified 476 patients for a comparison of overall survival (OS) and safety. Results: Before matching, the LIG had a longer OS than the SIG (Median: 12.1 vs. 8.7 months; P = 0.003). After matching, median OS in the SIG and LIG were 9.1 and 14.2 months (P < 0.001). The 1-, 2-, and 3-year survival rates were 37.5%, 17.1%, and 9.9% for SIG and 50.1%, 19.3%, and 11.6% for LIG, respectively. The TACE interval was an independent prognostic factor for OS. The LIG had a longer OS than the SIG in Barcelona Clinic liver cancer (BCLC) stage C patients (Median: 10.2 vs. 5.8 months; P < 0.001), but not in BCLC-A or B. The postoperative adverse rates were similar in matched SIG and LIG patients (29.4% vs. 33.6%, P = 0.324). Conclusions: A long interval between the first two sessions of TACE resulted in a better OS than a short interval in patients with unresectable BCLC C-stage HCC.

A peptide-based near-infrared fluorescence probe for dynamic monitoring senile plaques in Alzheimer's disease mouse model.

In vivo monitoring neuropathological changes in Alzheimer's disease (AD) animal model is critical for drug development. Here, by integrating blood-brain barrier penetrable peptide, we have developed a peptide probe which based on angiopep-2. Angiopep-based probe exhibited high binding affinity to Aß aggregates and labeled senile plaques in vivo. Remarkably, the in vivo near-infrared imaging data revealed that fluorescence signals of this probe were nearly 3-fold higher in the brains of 16-month-old APP/PS1 transgenic mice compared to C57 mice and exhibited linear correlation with the senile plaques load process in 4-, 8-, 16-month-old APP/PS1 transgenic mice. Moreover, senile plaques load was detected in vivo as early as 4 months of age that even at the very beginning of plaques developed in APP/PS1 transgenic mice. Taken together, this novel peptide-based probe achieved dynamic monitoring senile plaques in APP/PS1 transgenic mice and have been ready to use in drug development in AD mouse model.

6-Methoxy-indanone derivatives as potential probes for ß-amyloid plaques in Alzheimer's disease.

A series of 6-methoxy indanone derivatives was synthesized and evaluated as potential probes for ß-amyloid plaque imaging in Alzheimer's disease (AD). Two derivatives (5d and 5k) displayed significant binding abilities in fluorescent staining experiments using the brain sections of AD patients. Two derivatives showed high binding affinities to ß-amyloid aggregates (5j, Ki = 5.82 ± 0.19 nM) and brain homogenates of AD patients (5j, Ki = 18.96 ± 0.28 nM) in in vitro binding assay. With a log P value of 3.45, [125I]5k exhibited an excellent initial brain uptake (5.29%ID g-1, 2 min after i.v.) and a fast clearance from the brain in biodistribution experiments in normal mice. In autoradiography, [125I]5k exhibited an obvious binding ability to ß-amyloid plaques and a relatively low nonspecific binding in the brain sections of AD patients (in vitro) and APP/PS1 transgenic mice (in vitro and ex vivo). Results suggest that 5k is a potential probe for detecting ß-amyloid plaques in vivo.

Clinicopathological characteristics and outcomes in stage I-III mucinous gastric adenocarcinoma: a retrospective study at a single medical center.

BACKGROUND: The clinicopathological characteristics and outcomes of mucinous gastric adenocarcinoma (GC) remain unclear. We report the clinicopathological features and prognosis of patients with mucinous histology who underwent radical-intent gastrectomy. METHODS: We reviewed the medical records of 1470 patients with pathologically proven undifferentiated GC undergoing radical-intent gastrectomy between 1995 and 2007. The patients were stratified into three groups according to their histological type: mucinous carcinoma (MC), signet ring cell carcinoma (SRCC), and poorly differentiated carcinoma (PDC). Clinicopathological factors affecting prognosis were collected prospectively and analyzed. RESULTS: In stage III MC, the age and size were significantly greater and larger than in SRCC and PDC; a lower proportion of perineural invasion was identified in MC, and female predominance was noted in SRCC in comparison with MC and PDC. The cumulative overall survival rates of stage I-III GC patients with MC were significantly superior compared to those with PDC, but not SRCC. Stage III GC patients with MC had a better prognosis than those with SRCC or PDC; the difference in survival was not evident in stages I or II. CONCLUSIONS: Thus, MC presents with different clinicopathological features and prognosis from SRCC and PDC. The patients with stage III gastric MC had favorable outcomes.

Prostate calcification worsen lower urinary tract symptoms in middle-aged men.

OBJECTIVE: To investigate the correlation between prostatic calcification and lower urinary tract symptoms (LUTS) in a sample of middle-aged men receiving health checkups. METHODS: Subjects aged 40 years or older who voluntarily underwent transrectal prostate ultrasound (TRUS) and fulfilled International Prostate Symptoms Score (IPSS) as part of their medical checkup were enrolled in this study. The prostatic calcification grading and prostate volume (PV) were measured by TRUS. The medical history, demographics, and metabolic markers were also evaluated. Logistic regression was used to analyze the correlation between prostatic calcification and LUTS. RESULTS: A total of 604 men were enrolled as study subjects. The prostatic calcification grading was significantly associated with age and PV instead of metabolic markers. Compared to the nonprostatic calcification group, the moderate/marked prostatic calcification group had a significantly higher age-adjusted IPSS (8.69 vs 6.87, P <.01), quality of life (QOL) score (2.57 vs 2.17, P <.01), storage score (3.74 vs 3.06, P = .01), voiding score (4.95 vs 3.72, P <.01), and more maximum flow rate <15 mL/sec (40.4% vs 24.5%, P <.01). Prostatic calcification grading was positively correlated with age-adjusted IPSS, QOL, voiding, and storage scores (all P for trend <.05). Further multivariate analysis indicated that moderate/marked prostatic calcification was an independent risk factors for moderate to severe LUTS (odds ratio [OR] = 1.68, P = .02). CONCLUSION: Prostatic calcification worsened IPSS, QOL, storage, voiding symptoms, and maximum urine flow (Qmax) in middle-aged men receiving a health checkup. Moderate/marked prostatic calcification was an independent risk factor for moderate to severe LUTS.

The binding of resveratrol to monomer and fibril amyloid beta.

As currently understood, Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is driven by the aggregation of amyloid beta (Aß) protein. It has been shown that resveratrol (RES) may attenuate amyloid ß peptide-induced toxicity, promote Aß clearance and reduce senile plaques. However, it remains to be determined whether RES could interact directly with Aß. The aim of the present study was to examine the direct binding of RES to monomer and fibril Aß. Using surface plasmon resonance (SPR) and proton nuclear magnetic resonance ((1)H NMR), our results identified the direct binding of RES to Aß. The ability of RES to bind to both fibril and monomer Aß(1-40 and 1-42) was further analyzed by SPR. The binding response of RES to fAß(1-42) was higher than that to monomer Aß(1-42), whereas the binding response of RES to fAß(1-40) was lower than that to monomer Aß(1-40). The K(D) of RES for fibril Aß(1-40 or 1-42) was higher than that for the corresponding monomer Aß. Compared to the control compound Congo red (CR), the binding responses of RES to monomer Aß(1-42) and Aß(1-40) were stronger, but binding to fibril Aß(1-42) was weaker, and the K(D)s of RES with both monomer and fibril Aß(1-40) and Aß(1-42) were higher than that of CR. When Aß(1-40 or 1-42) was co-incubated with RES (50µM), the thioflavin T fluorescence of the mixture was weakened, and the number and length of amyloid fibrils were decreased. Furthermore, the results of staining in consecutive brain slices from AD patients showed that RES (10(-4)M) could stain senile plaques. These results indicated that RES could bind directly to Aß in different states, which may provide new insight into the protective properties of RES against AD.

Novel indanone derivatives as potential imaging probes for ß-amyloid plaques in the brain.

Molecular imaging probes to detect senile plaques (SPs) might help the early diagnosis of Alzheimer's disease (AD). In this study, a novel series of indanone derivatives were synthesized and characterized. In in vitro binding studies, compound 2e exhibited a K(i) value of 16 nM with a human AD brain homogenate. Although they displayed relatively low affinities for 2i and 2j--with K(i) values of 99 and 237 nM, respectively--the SPs in AD brain sections were positively stained by 2j. A method for in situ micro-autoradiography of AD brain was developed in this study and showed clear labeling of SPs by [(125)I]2i and [(125)I]2j. Both [(125)I]2i and [(125)I]2j had suitable lipophilicities and displayed high initial uptake and rapid clearance from the mouse brains. Furthermore, [(125)I]2i and [(125)I]2j were more stable in human brain homogenates than in mouse brain homogenates. These data suggest that such indanone derivatives might represent potential amyloid imaging agents for the detection of SPs in AD.