Incorporating Genomic Analysis In The Clinical Practice Of Hepatology

In the past two decades, whole-exome sequencing has been successfully demonstrated as an indispensable instrument in uncovering the genetic etiology underlying numerous types of unexplained liver disease. Characterization of these illnesses into distinct molecular disease entities has revolutionized understanding of pathophysiology and has translated into improved guidance on management, treatment and prognosis for patients. However, hepatologists have been slow to welcome the technology into their mainstream clinical practice, largely due to inadequate training in genomic medicine. There thus remains a pressing need to create various forums through which clinicians can gain better appreciation for the value of genetic analysis in the field of hepatology and amass the knowledge and confidence to incorporate genetic analysis into their own clinical practice. To address this need, we aimed to facilitate the dissemination of new information on liver disease with an underlying genetic etiology through a two-pronged approach: (1) the generation of an online database housing genotype-phenotype correlation information for diseases affecting the liver, and (2) the promotion of a multidisciplinary Hepatology Genome Rounds series. In this Thesis, we detail the creation of a comprehensive database focused on genetic liver diseases, reflecting the genotypic and phenotypic profiles of more than 7,500 individuals with genetic variants across 269 genes. This newly developed database will provide clinicians and researchers a centralized source for information on genotype-phenotype correlation to aid in diagnosis and education. In addition, we demonstrate that the Hepatology Genome Rounds series, which is an interdisciplinary forum highlighting hepatology cases of clinical interest and educational value, is an important venue for the distribution of genomic knowledge within the field of hepatology and for providing ongoing education to providers and trainees in genomic medicine. We describe our single-center experience, which has led to the reconsideration of diagnoses in two patients and an improved understanding of genotype-phenotype correlations across all cases. As the value of genetic analysis continues to emerge in understanding human disease and pathophysiology, we foresee similar approaches being adopted at other institutions and in additional specialties in coming years for further propagation of genomics in clinical medicine

Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic

BACKGROUND: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study\u27s objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines. METHODS: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation. FINDINGS: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p\u3c0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p\u3c0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile. INTERPRETATION: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Towards Understanding Consumer Processing of Negative Word-of-Mouth Communication: The Roles of Opinion Agreement and Organizational Response

Towards Understanding Consumer Processing of Negative Word-of-Mouth Communication: The Roles of Opinion Agreement and Organizational Response Chung Hun Lee School of Hospitality Management The Pennsylvania State University and David Cranage School of Hospitality Management The Pennsylvania State University ABSTRACT The proliferation of the Internet has given birth to a number of complaint Web Sites where dissatisfied and frustrated consumers can easily articulate their opinions and comments on products, services, or companies. Online consumer reviews can have strong effects on consumers’ evaluations in addition to product attribute information, especially when they are negative. Many organizations struggle with the question how to deal with online forums that discuss their products and services. Nevertheless, little attention has been directed to identifying the influence of online complaint on potential consumers’ behaviors as well as the influence of corporate response strategies to online complaints. In an attempt to bridge this gap, this study examines the process by which consumers integrate online complaint messages and attribute information into their service evaluations and how consensus in messages affects this process. Additionally, it will examine how a company’s response strategies to online complaints affect the perception of potential consumers on attribution as well as their evaluations about the company’s service. Keywords: online consumer reviews, opinion consensus, response strategies, attitude change. INTRODUCTION This study seeks to understand the process by which consumers integrate online critic opinions and assimilate information (i.e., electronic negative word-of-mouth communication) into their service evaluations and subsequent purchasing decisions. The study also will examine how critic consensus and organizational responses to critic opinions affect this process. This is an increasingly important research area because as the Internet and other information technologies have become a central platform for consumers’ daily activities, very large amounts of negative information about brands and companies have been generated and have become widely prevalent in the marketplace. The resulting negative impact on profitability has become devastating, especially in the hospitality industry. Nevertheless, there has been limited systematic academic and practical investigation into how consumers process negative information about the brands they like, and further translate it into attitude change. This research intends to start a theory-based stream of research addressing these issues. Based on this theoretical understanding of how consumers process negative information, we aim to develop organizational strategies for handling negative information. Prior research suggests that negative word of mouth (NWOM) has a significant detrimental effect on a company’s image, reputation, and sales (Herr et al., 1991). Never has this NWOM effect been as powerful as it is today. The expansion of the Internet has created a platform for broadcasting virtual opinions (or electronic WOM (eWOM) communication) to consumers, and for incrementally disseminating eWOM to a wider array of people (Hennig-Thurau et al., 2004). Given the increasing possibility of consumers being exposed to negative eWOM about a company and its offerings, and the potential devastation it can have on a company’s reputation, market share, and profitability, it is very important to understand the following questions: How do consumers process NWOM and react to it? To what extent does NWOM damage positive attitudes towards a company and its offerings and purchasing confidence? How should a company respond to NWOM in order to preserve its reputation? SIGNIFICANCE AND IMPLICATION OF STUDY Addressing these questions bridges research gaps that have not been adequately addressed regarding consumer behavior. First, although prior research has emphasized the impact of negative information about a company and its offerings on consumer purchasing decisions and company sales (Chevalier & Mayzlin, 2006), few have attempted to identify the process by which consumers integrate negative information into product evaluation. Literature in public relations and publicity has addressed this issue to some extent, and a “negativity effect” has been discovered (e.g., Ahluwalia, Burnkrant, & Unnava, 2000). That is, when presented with both positive and negative information during the evaluation process, consumers place more weight on the negative than the positive and shift their attitudes in the negative direction. Herr et al. (1991) argue that this effect may arise because consumers find the negative information to be more diagnostic, useful, and informative than the positive information for categorizing targets into evaluative categories, and because positive or less negative information is commonly provided for all products, including those of high-, average-, and low-quality (Skowronski & Carlston, 1987). However, the question that needs to be addressed is whether the negativity effect found in the context of negative publicity can be also observed in the context of WOM communication. Although some consumer WOM researchers have found a stronger influence of NWOM on consumer brand evaluation (Ahluwalia, 2002) and on the purchase intentions of prospective consumers (Park & Lee, 2009), it has been tested in conditions where consumers are given either positive or negative WOM, but not a mixture of both. This research will examine the negativity effect when a combination of positive and negative WOM is provided by manipulating the proportion of NWOM. Second, the Internet has created an online WOM platform where consumers share their opinions with other unknown customers. Compared to traditional face-to-face WOM communication, the online WOM platform has unique characteristics that may influence the way consumers process WOM and make purchasing decisions (Lee, Park, & Han, 2008). For example, the online consumer review forum enables consumers to view both positive and negative WOM simultaneously from various sources. In addition, given that online consumer reviews are written and accumulated in the collection, they are measurable. That is, consumers are easily able to count the number of positive and negative opinions and evaluate the quality of products/service. These features of online WOM have opened a new research venue: opinion consensus and conformity effect. Current study pursues this research area by examining the effect of the proportion of NWOM regarding a company’s service on the consumer evaluation process and purchasing decisions in an online WOM communication environment. Third, few studies have been interested in how organizations should handle negative information. In service failure and recovery literature, organizational responses to negative situations (i.e., service failures and customer complaints) have gained a lot of attention as potential recovery strategies have been developed to soothe dissatisfied customers and prevent further negative consequences such as NWOM and switching behavior. However, work investigating how an organization’s response to NWOM influences potential customers while evaluating a company and deciding to purchase its product or service has been very limited. Recognizing the influence of WOM is important to marketing decisions regarding customer service, especially in regard to justifying expenditures on complaint handling, customer retention, and service recovery, as well as preventing potential customers from choosing other alternatives. Thus, this study seeks evidence of whether the organizational response to NWOM has a significant effect on the attitudes and purchasing probability of potential consumers. Specifically, we would like to know whether responding to an online review is more effective than not responding to it. And, if organizations choose to respond online to negative reviews, what constitutes an appropriate and effective response? This research has both academic and practical contributions. First, it proposes a model that facilitates an understanding of causal attribution in the online context by examining complaint messages as well as responses from both consumers and companies. Second, it explores the primary response strategies of a company to protect its reputation from online complaints. Third, it provides a way of furthering an empirical test of the relationship between online complaints and corporate responses from an observer’s perspective. Reference: Ahluwalia, R. (2002). How prevalent is the negativity effect in consumer environments? Journal of Consumer Research, 29(September), 270-279. Chevalier, J. A., & Mayzlin, D. (2006). The effect of word of mouth on sales: Online book reveiws. Journal of Marketing Research, 43, 345-354. Hennig-Thurau, T., Gwinner, K. P., Walsh, G., & Gremle, D. D. (2004). Electronic word-of-mouth via consumer-opinion platforms: What motivates consumers to articulate themselves on the Internet? Journal of Interactive Marketing, 18(1), 38-52. Herr, P. M., Kardes, F. R., & Kim, J. (1991). Effects of word-of-mouth and product-attribute information on persuasion: An accessibility-diagnosticity perspective. Journal of Consumer Research, 17(3), 454-462. Lee, J., Park, D. H., & Han, I. (2008). The effect of negative online consumer reviews on product attitude: An information processing view. Electronic Commerce Resaerch and Application, 7, 341-352. Park, C., & Lee, T. M. (2009). Information direction, website reputation and eWOM: effect: A moderating role of product type. Journal of Business Research, 62(1), 61-67. Skowronski, J. J., & Carlston, D. E. (1987). Social judgment and social memory: The role of cue diagnosticity in negativity, positivity, and extremity biases. Journal of Personality and Social Psychology, 52, 689-699

Mass spectrometric analysis of the glycosphingolipid-derived glycans from miniature pig endothelial cells and islets: identification of NeuGc epitope in pig islets

Glycosphingolipid (GSL) is a major component of the plasma membrane in eukaryotic cells that is involved directly in a variety of immunological events via cell-to-cell or cell-to-protein interactions. In this study, qualitative and quantitative analyses of GSL-derived glycans on endothelial cells and islets from a miniature pig were performed and their glycosylation patterns were compared. A total of 60 and 47 sialylated and neutral GSL-derived glycans from the endothelial cells and islets, respectively, were characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and collision-induced fragmentation using positive-ion electrospray ionization (ESI) ion-trap tandem mass spectrometry (MS/MS). In accordance with previous immunohistochemistry studies, the alpha-Gal-terminated GSL was not detected but NeuGc-terminated GSLs were newly detected from miniature pig islets. In addition, the neutral GSL-derived glycans were relatively quantified by derivatization with carboxymethyl trimethylammonium hydrazide (so called Girard`s T reagent) and MALDI-TOF MS. The structural information of the GSL-derived glycans from pig endothelial cells and islets suggests that special attention should be paid to all types of glycoconjugates expressed on pig tissues or cells for successful clinical xenotransplantation. Copyright (C) 2009 John Wiley & Sons, Ltd.Kim YG, 2009, J MASS SPECTROM, V44, P1087, DOI 10.1002/jms.1587Gil GC, 2008, ANAL BIOCHEM, V379, P45, DOI 10.1016/j.ab.2008.04.039Kim YG, 2008, PROTEOMICS, V8, P2596, DOI 10.1002/pmic.200700972Jang KS, 2008, BIOTECHNOL BIOPROC E, V13, P445, DOI 10.1007/s12257-008-0141-1Li YS, 2008, GLYCOBIOLOGY, V18, P166, DOI 10.1093/glycob/cwm127Kang P, 2007, ANAL CHEM, V79, P6064, DOI 10.1021/ac062098rParry S, 2007, GLYCOBIOLOGY, V17, P646, DOI 10.1093/glycob/cwm024Kim JH, 2007, XENOTRANSPLANTATION, V14, P60, DOI 10.1111/j.1399-3089.2006.00364.xMilland J, 2006, J IMMUNOL, V176, P2448Kim YG, 2006, PROTEOMICS, V6, P1133Ezzelarab M, 2005, IMMUNOL CELL BIOL, V83, P396, DOI 10.1111/j.1440-1711.2005.01344.xKim D, 2005, CELL BIOL INT, V29, P638, DOI 10.1016/j.cellbi.2005.03.016Kuwaki K, 2005, NAT MED, V11, P29, DOI 10.1038/nm1171Kirchhof N, 2004, XENOTRANSPLANTATION, V11, P396, DOI 10.1111/j.1399-3089.2004.00157.xKolber-Simonds D, 2004, P NATL ACAD SCI USA, V101, P7335Komoda H, 2004, XENOTRANSPLANTATION, V11, P237, DOI 10.1111/j.1399-3089.2004.00121.xMiwa Y, 2004, XENOTRANSPLANTATION, V11, P247, DOI 10.1111/j.1399-3089.2004.00126.xMorelle W, 2004, RAPID COMMUN MASS SP, V18, P2637, DOI 10.1002/rcm.1668Phelps CJ, 2003, SCIENCE, V299, P411, DOI 10.1126/science.1078942TAYLOR ME, 2003, INTRO GLYCOBIOLOGYRudd PM, 2001, SCIENCE, V291, P2370VARKI A, 1999, ESSENTIALS GLYCOBIOLHeald KA, 1999, J MOL MED-JMM, V77, P169Bouhours D, 1998, GLYCOCONJUGATE J, V15, P1001Hallberg EC, 1998, GLYCOBIOLOGY, V8, P637van der Burg MPM, 1998, TRANSPLANT P, V30, P362Bouhours D, 1997, GLYCOCONJUGATE J, V14, P29DWEK RA, 1995, BIOCHEM SOC T, V23, P1COOPER DKC, 1994, IMMUNOL REV, V141, P31JALALIARAGHI K, 1994, GLYCOCONJUGATE J, V11, P266MCKENZIE IFC, 1994, TRANSPL IMMUNOL, V2, P81VARKI A, 1993, GLYCOBIOLOGY, V3, P97HENDRICKS SP, 1990, J BIOL CHEM, V265, P17621DOMON B, 1988, GLYCOCONJUGATE J, V5, P397CIUCANU I, 1984, CARBOHYD RES, V131, P209