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INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA‐sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co‐expression network analysis (WGCNA) and deconvolution analysis identified AD‐associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD‐associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell‐type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. Highlights: We comprehensively analyze the blood transcriptomes of a well‐characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease.Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers.Immune‐associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Existing blood‐based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood‐based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood‐based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD‐related endophenotypes in three independent cohorts from Chinese or European‐descent populations. RESULTS: The 21‐protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic‐specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood‐based, multi‐pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. Highlights: The authors developed a blood‐based biomarker assay for Alzheimer's disease.The 21‐protein assay classifies AD/MCI and indicates brain amyloid pathology.The 21‐protein assay can simultaneously assess activities of five biological processes.Ethnic‐specific dysregulations of biological processes in AD were revealed. [ABSTRACT FROM AUTHOR]

The in-situ photosynthetic activity in tropical intertidal benthic diatom in response to environmental variation was assessed in this study by measuring chlorophyll fluorescence. The investigation was carried out during the lowest tide in January (non-rainy day) and February 2013 (post-rainy day) at two sampling sites (A and B) from each selected location (Pantai Jerejak, Teluk Bahang and Tanjung Bungah, Pulau Pinang, Malaysia). Samples of surface sediment (top 0.5 cm) were collected, and chlorophyll a extracted as biomass estimation. Assessments of the photosynthetic activity of benthic diatoms were made using a pulse-amplitude modulated (PAM) fluorometer. Fifty-three species were identified, representing 27 genera from the three studied locations. Both locations showed similarities in species diversity and abundance. Two-way ANOVA showed no significant differences (p = 0.430) in species richness (Margalef Index) among sampling locations, with an average value of 6.33±0.247. Both intertidal flats were dominated by Cocconeis, Navicula, Actinoptychus, and Diploneis. The community has low maximum quantum yields, Fv/Fm (ranging from 0.170 to 0.340) and is often light-limited (Photoacclimation Index, Ek, ranging from 67.96 to 236.71 µmol photons m-2 s-1). The relative electron transport rate (rETRmax) was low, with values ranging from 3.45 to 35.51 across three sampling locations. Fluctuation in salinity has caused a decrease in photosynthetic activity. This study suggests that the low values indicated a poorly adapted benthic microalgal community that is constantly light-limited. However, time-series data is needed to determine the ability of these communities to adapt to the changing environment. [ABSTRACT FROM AUTHOR]

Abstract Background Genomic aberrations can be used to determine cancer diagnosis and prognosis. Clinically relevant novel aberrations can be discovered using high-throughput assays such as Single Nucleotide Polymorphism (SNP) arrays and next-generation sequencing, which typically provide aggregate signals of many cells at once. However, heterogeneity of tumor subclones dramatically complicates the task of detecting aberrations. Results The aggregate signal of a population of subclones can be described as a linear system of equations. We employed a measure of allelic imbalance and total amount of DNA to characterize each locus by the copy number status (gain, loss or neither) of the strongest subclonal component. We designed simulated data to compare our measure to existing approaches and we analyzed SNP-arrays from 30 melanoma samples and transcriptome sequencing (RNA-Seq) from one melanoma sample. We showed that any system describing aggregate subclonal signals is underdetermined, leading to non-unique solutions for the exact copy number profile of subclones. For this reason, our illustrative measure was more robust than existing Hidden Markov Model (HMM) based tools in inferring the aberration status, as indicated by tests on simulated data. This higher robustness contributed in identifying numerous aberrations in several loci of melanoma samples. We validated the heterogeneity and aberration status within single biopsies by fluorescent in situ hybridization of four affected and transcriptionally up-regulated genes E2F8, ETV4, EZH2 and FAM84B in 11 melanoma cell lines. Heterogeneity was further demonstrated in the analysis of allelic imbalance changes along single exons from melanoma RNA-Seq. Conclusions These studies demonstrate how subclonal heterogeneity, prevalent in tumor samples, is reflected in aggregate signals measured by high-throughput techniques. Our proposed approach yields high robustness in detecting copy number alterations using high-throughput technologies and has the potential to identify specific subclonal markers from next-generation sequencing data.

Abstract Activating mutations in BRAF kinase are common in melanomas. Clinical trials with PLX4032, the mutant-BRAF inhibitor, show promising preliminary results in patients selected for the presence of V600E mutation. However, activating V600K mutation is the other most common mutation, yet patients with this variant are currently excluded from the PLX4032 trials. Here we present evidence that a patient bearing the BRAF V600K mutation responded remarkably to PLX4032, suggesting that clinical trials should include all patients with activating BRAF V600E/K mutations.

Wine is a product of grape juice fermentation by yeast. Terroir is a term that encompasses all environmental factors and interactions at a specific geographical site, resulting in the development of regional-specific microbial strains and grape metabolites. In this study we determine the distribution of vineyard-associated wine yeast strains and characterize the flavonoid profile of Pinot Noir grapes among 3 sub-regions in the Okanagan Valley (OV), a major wine region in British Columbia, Canada. Pinot Noir grape samples were collected from 13 vineyards among 3 sub-regions of the OV, namely Kelowna (KE), Naramata-Penticton (NP) and Oliver-Osoyoos (OO), within a week prior to the winery harvesting date in 2016 and 2017. A total of 156 spontaneous Pinot Noir fermentations were conducted and vineyard-associated Saccharomyces strains were isolated from fermentations that reached two-thirds sugar depletion. Using microsatellite genotyping, we identified 103 Saccharomyces cerevisiae strains and 9 Saccharomyces uvarum strains. We also identified Saccharomyces paradoxus in one vineyard using ITS sequencing. We developed a microsatellite database of 160 commercial S. cerevisiae strains to determine the identity of the isolated strains and we include the database herein. Commercial strains were widely distributed across the three sub-regions. Forty-two of our 103 S. cerevisiae strains were equivalent or highly similar to commercial strains whereas the remaining 61 were considered as 'unknown' strains. Two S. uvarum strains were previously isolated in other OV studies and none matched the S. uvarum commercial strain BMV58. S. cerevisiae population structure was driven by sub-region, although S. cerevisiae populations did not differ significantly across vintages. S. uvarum and S. paradoxus were only identified in the 2017 vintage, demonstrating dynamic wine yeast populations between vintages. We found that the flavonoid profile of Pinot Noir grapes from the same 13 vineyards was also affected by sub-regional terroir. The anthocyanin content was lower and the proportion of methoxylated anthocyanins and flavonols was higher in Pinot Noir grapes from OO, the warmer sub-region as compared to KE, the cooler sub-region. Our study demonstrates that both yeast populations and metabolites associated with the Pinot Noir variety have sub-regional variation within a viticultural area. [ABSTRACT FROM AUTHOR]

Abstract: Post‐transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single‐center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy‐proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow‐up time of 6.4 (1.6‐14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re‐ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999. [ABSTRACT FROM AUTHOR]

Abstract: The significance of post‐transplant HLA DSA and chronic AMR in LT is an emerging field of study. Although OPV has previously been described as a histopathologic finding in DSA‐positive adult LT recipients, it was not included in the recent Banff criteria for chronic AMR. Our aim was to describe the association between OPV and chronic AMR in pediatric LT recipients. A retrospective review of 67 liver biopsies performed between November 2014 and April 2016 in 45 pediatric LT recipients identified four patients with OPV. Clinical status, liver biochemistry, the presence of DSA, and available non‐HLA antibody testing, as well as histopathologic features of chronic AMR, were assessed. All four patients with OPV had class II DSA and histopathologic features of chronic AMR based on the Banff criteria. Two patients were noted to have non‐HLA antibodies. Three patients are undergoing treatment with IVIG but have persistent DSA. Two patients have graft failure and are awaiting retransplantation. In conclusion, OPV is a histopathologic finding associated with chronic AMR in pediatric LT recipients. Further studies are needed to elucidate whether OPV is reversible and/or amenable to medical therapy. [ABSTRACT FROM AUTHOR]

More than ten years after the initial description of the humoral theory of transplantation by Dr. Paul I. Terasaki, the significance of humoral alloimmunity in liver transplantation has yet to be clearly defined. The liver allograft has an inherent tolerogenic capacity which confers its resistance to cell-mediated as well as antibody-mediated rejection. Nevertheless, the protection against alloimmunity is not complete, and antibody-mediated tissue injury can occur in the liver graft under specific circumstances. In this article the evidence on the clinicopathologic effects of donor-specific alloantibodies in liver transplantation will be examined and interpreted in parallel with lessons learned from renal transplantation. The unique anatomic and immunologic features of the liver will be reviewed to gain new insights into the complex interactions between humoral immune system and the liver allograft. [ABSTRACT FROM AUTHOR]

Background: Historically, traditional Chinese medicine has been widely used to treat stroke. Based on the theory of Chinese medicine and the modern pharmacological knowledge of herbal medicines, we have designed a neuroprotective formula called Post-Stroke Rehabilitation (PSR), comprising seven herbs -- Astragalus membranaceus (Fisch.) Bunge, Salvia miltiorrhiza Bunge, Paeonia lactiflora Pall., Cassia obtusifolia L., Ligusticum chuanxiong Hort., Angelica sinensis (Oliv.) Diels, and Glycyrrhiza uralensis Fisch. We aim to examine the neuroprotective activity of PSR in vitro and in vivo, and to explore the underlying molecular mechanisms, to better understand its therapeutic effect and to further optimize its efficacy. Methods: PSR extract or vehicle was applied to primary rat neurons to examine their survival effects against N- methyl-D-aspartate (NMDA)-elicited excitotoxicity. Whole-cell patch-clamp recording was conducted to examine the NMDA-induced current in the presence of PSR. ERK- and CREB-activation were revealed by western blot analysis. Furthermore, PSR was tested for CRE promoter activation in neurons transfected with a luciferase reporter. The protective effect of PSR was then studied in the rat middle cerebral artery occlusion (MCAO) model. MCAO rats were either treated with PSR extract or vehicle, and their neurobehavioral deficit and cerebral infarct were evaluated. Statistical differences were analyzed by ANOVA or t-test. Results: PSR prominently reduced the death of cultured neurons caused by NMDA excitotoxicity in a dose-dependent manner, indicating its neuroprotective property. Furthermore, PSR significantly reduced NMDA-evoked current reversibly and activated phosphorylation of ERK and CREB with distinct time courses, with the latter's kinetics slower. PSR also triggered CRE-promoter activity as revealed by the increased expression of luciferase reporter in transfected neurons. PSR effectively reduced cerebral infarct and deficit in neurological behavior in MCAO rats when PSR decoction was administered starting either 6 days before or 6 h after onset of ischemia. Conclusions: PSR is neuroprotective both in vitro and in vivo -- it protects cultured neurons against NMDA excitotoxicity, and effectively reduces ischemic injury and neurobehavioral deficit in MCAO rats in both the pre- and post-treatment regimens. The underlying neuroprotective mechanisms may involve inhibition of NMDA receptor current and activation of ERK and CREB. This study provides important preclinical data necessary for the further development of PSR for stroke treatment. [ABSTRACT FROM AUTHOR]

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis. [ABSTRACT FROM AUTHOR]

Compounds that have the ability to both strengthen synaptic function and facilitate neuroprotection are valuable cognitive enhancers that may improve health and quality of life, as well as retard age-related cognitive deterioration. Medicinal plants are an abundant source of potential cognitive enhancers. Here we report that anemoside A3 (AA3) isolated from Pulsatilla chinensis modulates synaptic connectivity in circuits central to memory enhancement. AA3 specifically modulates the function of AMPA-type glutamate receptors (AMPARs) by increasing serine phosphorylation within the GluA1 subunit, which is a modification required for the trafficking of GluA1-containing AMPARs to synapses. Furthermore, AA3 administration activates several synaptic signaling molecules and increases protein expressions of the neurotrophin brain-derived neurotrophic factor and monoamine neurotransmitters in the mouse hippocampus. In addition to acting through AMPARs, AA3 also acts as a non-competitive NMDA receptor (NMDAR) modulator with a neuroprotective capacity against ischemic brain injury and overexcitation in rats. These findings collectively suggest that AA3 possesses a unique ability to modulate the functions of both AMPARs and NMDARs. Concordantly, behavioral studies indicate that AA3 not only facilitates hippocampal long-term potentiation but also enhances spatial reference memory formation in mice. These multifaceted roles suggest that AA3 is an attractive candidate for further development as a cognitive enhancer capable of alleviating memory dysfunctions associated with aging and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The inaugural Youth Olympic Games 2010 was one of the major sporting events held in Singapore. It brought together 3,600 young athletes from 295 countries to compete in 26 sport events. Conducted during the Games, this study sought to evaluate the impact of the Games on local residents by using a total of 34 impact statement items. An exploratory factor analysis was conducted to categorize the impact statements under a smaller number of meaningful factors. Specifically, the impact statement items related to the positive impact were categorized under the following three factors: Long-Term Social Benefits to Singapore, Tourism Benefits, and Economic Benefits. The impact statements pertaining to the negative impact were placed under the following three factors: Quality of Life, Social Behavior, and Preparation for the Games. A cluster analysis was also performed: there were three clusters of residents--Enthusiasts, Enthusiasts With Reservations, and Skeptics. In general, residents were supportive of the Games and perceived the Games to have a positive impact on the country. But there are negative perceptions of the Games too, such as its negative impact on the environment, the inconveniences created, and the disruptiveness to their lives. [ABSTRACT FROM AUTHOR]

Learning and memory require orchestrated regulation of both structural and functional synaptic plasticity in the hippocampus. While a neuropeptide alpha-melanocyte-stimulating hormone, a-MSH, has been implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored. In this study, we report that activation of MC4R enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA receptors. We show that activation of postsynaptic MC4R increases the number of mature dendritic spines and enhances surface expression of AMPA receptor subunit GluAl, resulting in synaptic accumulation of GluAl-containing AMPA receptors. Moreover, MC4R stimulates surface GluAl trafficking through phosphorylation of GluAl at Ser845 in a Gas-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolishes the MC4R-mediated enhancement of neurotransmission and hippocampal long-term potentiation. Importantly, in vivo application of MC4R agonists increases LTP in the mouse hippocampal CAI region. These findings reveal that MC4R in the hippocampus plays a critical role in the regulation of structural and functional plasticity. [ABSTRACT FROM AUTHOR]

The Formula 1 Grand Prix was held in Singapore for the first time in September 2008. While Singapore had previous experience hosting international events, nothing in the past could be compared to this inaugural event because it brought with it a unique set of impacts, as evidenced by past research into car races held elsewhere. For this reason, this study explores how this major motor sport event impacted its host residents through their perceptions of social-cultural aspects. This is important because it can affect the well-being and quality of the life of local residents, two necessary antecedents for their continued support of the car race in the future. A survey of 96 residents was conducted to elicit responses to host residents" perceptions of social-cultural impacts of the F1. Chi-square analysis was used to explore relationships between different types of respondents and their perceived social-cultural impacts. Residents were largely homogenous with regard to attitudes toward the positive and negative impacts, although there were more discrepancies associated with the negative issues. Results were compared to previous studies of car race events and social exchange and social representation theories were used to help contextualize the data. While residents largely supported the F1 event suggestions were provided so as to better manage the social-cultural impacts. [ABSTRACT FROM AUTHOR]

BRAFV600E/K is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells that are BRAFV600E/K and BRAFWT showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAFV600E/K, it activated the pathway in the resistant BRAFWT cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAFWT melanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control. Furthermore, PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility of cells from advanced lesions. The results suggest that the drug can confer an advantage to BRAFWT primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses. [ABSTRACT FROM AUTHOR]

Decitabine, an epigenetic modifier that reactivates genes otherwise suppressed by DNA promoter methylation, is effective for some, but not all cancer patients, especially those with solid tumors. It is commonly recognized that to overcome resistance and improve outcome, treatment should be guided by tumor biology, which includes genotype, epigenotype, and gene expression profile. We therefore took an integrative approach to better understand melanoma cell response to clinically relevant dose of decitabine and identify complementary targets for combined therapy. We employed eight different melanoma cell strains, determined their growth, apoptotic and DNA damage responses to increasing doses of decitabine, and chose a low, clinically relevant drug dose to perform whole-genome differential gene expression, bioinformatic analysis, and protein validation studies. The data ruled out the DNA damage response, demonstrated the involvement of p21Cip1 in a p53-independent manner, identified the TGFb pathway genes CLU and TGFBI as markers of sensitivity to decitabine and revealed an effect on histone modification as part of decitabine-induced gene expression. Mutation analysis and knockdown by siRNA implicated activated b-catenin/MITF, but not BRAF, NRAS or PTEN mutations as a source for resistance. The importance of protein stability predicted from the results was validated by the synergistic effect of Bortezomib, a proteasome inhibitor, in enhancing the growth arrest of decitabine in otherwise resistant melanoma cells. Our integrative analysis show that improved therapy can be achieved by comprehensive analysis of cancer cells, identified biomarkers for patient's selection and monitoring response, as well as targets for improved combination therapy. [ABSTRACT FROM AUTHOR]

The current study retrospectively reviewed the cases of 68 patients who had undergone total laryngectomy and tracheoesophageal puncture (TEP) over a 16-year period. Fifty-one patients underwent primary TEP and 17 underwent secondary TEP. Nearly 80% of patients who received TEP at the time of laryngectomy achieved excellent voice quality perceptually. In contrast, only 50% of secondary TEP patients achieved excellent voice ratings. This difference was statistically robust (p = 0.03). Although both surgical and prosthesis-related complications occurred more frequently following primary TEP, statistically significant differences were not achieved. Neither pre- nor postoperative radiotherapy had any effect on voice restoration or complication rates. Based on these data, primary TEP may be preferable for several reasons, including a greater likelihood of successful voice restoration, a shorter duration of postoperative aphonia, and the elimination of the need for a second operation and interim tube feedings. [ABSTRACT FROM AUTHOR]

Background In 2003 the National Institute of Clinical Excellence published guidelines recommending the use of brain natriuretic peptipe (BNP) and the electrocardiogram (ECG) as part of the diagnostic work up of individuals with heart failure. However, the guideline did not address whether one test was superior to the other or whether performing both tests was superior to performing single tests. Aim To investigate the relative test accuracy of the ECG, BNP, N terminal-pro brain natriuretic peptide (NT-proBNP) and combinations of two or more tests in the diagnosis of left ventricular systolic dysfunction (LVSD) in the primary care setting. Design of study Cohort studies making within-subject comparisons of intervention diagnostic test(s) with reference standard results. Method Standard systematic review methodology was followed. Results Thirty-two primary studies met the review inclusion criteria. Studies were of variable quality and highly clinically heterogeneous, therefore restricting the use of meta-analysis. Within these limitations BNP, NT-proBNP and the ECG all had similar test sensitivity (>80% in the majority of studies). Specificity of the three tests was not as good. Three studies directly comparing BNP and the ECG found no difference in sensitivity and limited support for improved specificity of BNP. Two studies found no difference in sensitivity and limited evidence for an improvement in specificity for the combination of the ECG and BNP compared to single tests. Conclusion On the basis of existing evidence, the ECG, BNP and NT-proBNP are useful in excluding a diagnosis of LVSD (good sensitivity). However, use of abnormal test results to select individuals for echocardiography may overwhelm services. There is currently no evidence to justify the use of one test over another or the use of tests in combination. The additional cost of BNP is not self-evidently justified by improved test accuracy. Further research is needed to directly compare the diagnostic performance of these tests in homogeneous, representative primary care populations. [ABSTRACT FROM AUTHOR]