A. Seesanea and I. E. Verbitsky
St. Petersburg Math. J. 31 (2020), 557-572.
Abstract, references and article information

Actinobacillus pleuropneumoniae (App) is the etiological agent of acute porcine pneumonia and responsible for severe economic losses worldwide. The capsule polymer of App serotype 1 (App1) consists of [4)-GlcNAc-β(1,6)-Gal-α-1-(PO4-] repeating units that are O-acetylated at O-6 of the GlcNAc. It is a major virulence factor and was used in previous studies in the successful generation of an experimental glycoconjugate vaccine. However, the application of glycoconjugate vaccines in the animal health sector is limited, presumably because of the high costs associated with harvesting the polymer from pathogen culture. Consequently, here we exploited the capsule polymerase Cps1B of App1 as an in vitro synthesis tool and an alternative for capsule polymer provision. Cps1B consists of two catalytic domains, as well as a domain rich in tetratricopeptide repeats (TPRs). We compared the elongation mechanism of Cps1B with that of a ΔTPR truncation (Cps1B-ΔTPR). Interestingly, the product profiles displayed by Cps1B suggested processive elongation of the nascent polymer, whereas Cps1B-ΔTPR appeared to work in a more distributive manner. The dispersity of the synthesized products could be reduced by generating single-action transferases and immobilizing them on individual columns, separating the two catalytic activities. Furthermore, we identified the O-acetyltransferase Cps1D of App1 and used it to modify the polymers produced by Cps1B. Two-dimensional NMR analyses of the products revealed O-acetylation levels identical to those of polymer harvested from App1 culture supernatants. In conclusion, we have established a protocol for the pathogen-free in vitro synthesis of tailored, nature-identical App1 capsule polymers.

Elena Lorente
Apr 7, 2020; 0:RA120.002014v1-mcp.RA120.002014
Research

Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by ¹⁸F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes: HK1 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR-inhibitors, high expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of FDG uptake-associated genes correlated positively with higher glucose uptake in AR and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient pre-clinical method for monitoring non-radioactive glucose uptake.

Human antibody response studies are largely restricted to periods of high immune activity (e.g. vaccination). To comprehensively understand the healthy B cell immune repertoire and how this changes over time and through natural infection, we conducted immune repertoire RNA sequencing on flow cytometry-sorted B cell subsets to profile a single individual's antibodies over 11 months through two periods of natural viral infection. We found that 1) a baseline of healthy variable (V) gene usage in antibodies exists and is stable over time, but antibodies in memory cells consistently have a different usage profile relative to earlier B cell stages; 2) a single complementarity-determining region 3 (CDR3) is potentially generated from more than one VJ gene combination; and 3) IgG and IgA antibody transcripts are found at low levels in early human B cell development, suggesting that class switching may occur earlier than previously realized. These findings provide insight into immune repertoire stability, response to natural infections, and human B cell development.

In episode 32, Techworld's Scott Carey looks at Amazon's Echo and finds a dystopian future world in which our household appliances listen to us and talk back. Digital Arts editor Neil Bennett (15:06) explains why Tesla now has to design products for stupid people, and Macworld's David Price explains why mums don't like Apple's iOS 10 (28:00). We also discuss the beauty and lyricism of the German language.  

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Colorectal cancer (CRC) arises as the consequence of progressive changes from normal epithelial cells through polyp to tumor, and thus is an useful model for studying metabolic shift. In the present study, we studied the metabolomic profiles using high analyte specific gas chromatography/mass spectrometry (GC/MS) and liquid chromatography tandem mass spectrometry (LC/MS/MS) to attain a systems-level view of the shift in metabolism in cells progressing along the path to CRC. Colonic tissues including tumor, polyps and adjacent matched normal mucosa from 26 patients with sporadic CRC from freshly isolated resections were used for this study. The metabolic profiles were obtained using GC/MS and LC/MS/MS. Our data suggest there was a distinct profile change of a wide range of metabolites from mucosa to tumor tissues. Various amino acids and lipids in the polyps and tumors were elevated, suggesting higher energy needs for increased cellular proliferation. In contrast, significant depletion of glucose and inositol in polyps revealed that glycolysis may be critical in early tumorigenesis. In addition, the accumulation of hypoxanthine and xanthine, and the decrease of uric acid concentration, suggest that the purine biosynthesis pathway could have been substituted by the salvage pathway in CRC. Further, there was a step-wise reduction of deoxycholic acid concentration from mucosa to tumors. It appears that to gain a growth advantage, cancer cells may adopt alternate metabolic pathways in tumorigenesis and this flexibility allows them to adapt and thrive in harsh environment.

The human leucocyte antigen (HLA)-B*27:05 allele and the endoplasmic reticulum-resident aminopeptidases are strongly associated with ankylosing spondylitis (AS), a chronic inflammatory spondyloarthropathy. This study examined the effect of endoplasmic reticulum aminopeptidase 2 (ERAP2) in the generation of the natural HLA-B*27:05 ligandome in live cells. Complexes of HLA-B*27:05-bound peptide pools were isolated from human ERAP2-edited cell clones and the peptides were identified using high throughput mass spectrometry analyses. The relative abundance of thousand ligands was established by quantitative tandem mass spectrometry and bioinformatics analysis. The residue frequencies at different peptide position, identified in presence or absence of ERAP2, determined structural features of ligands and their interactions with specific pockets of antigen binding site of HLA-B*27:05 molecule. Sequence alignment of ligands identified with species of bacteria associated with HLA-B*27-dependent reactive arthritis was performed. In the absence of ERAP2, peptides with N-terminal basic residues, and minority canonical P2 residues are enriched in the natural ligandome. Further, alterations of residue frequencies and hydrophobicity profile at P3, P7, and P positions were detected. In addition, several ERAP2-dependent cellular peptides were highly similar to protein sequences of arthritogenic bacteria, including one human HLA-B*27:05 ligand fully conserved in a protein from Campylobacter jejuni. These findings highlight the pathogenic role of this aminopeptidase in the triggering of AS autoimmune disease.

Invitation Only Research Event

Event participants

Oscar Jonsson, Director, Stockholm Free World Forum (Frivärld)
Mathieu Boulègue, Research Fellow, Russia and Eurasia Programme, Chatham House
Chair: ​Alice Billon-Galland, Research Associate, Europe Programme, Chatham House

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 x 10^–6) with replication at Bonferroni-corrected P < 8.6 x 10^–4. Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 10^–4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood–derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat–associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

The increasing prevalence of type 2 diabetes poses a major challenge to societies worldwide. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach, measuring serum levels of 4,137 proteins in 5,438 elderly Icelanders and identified 536 proteins associated with prevalent and/or incident type 2 diabetes. We validated a subset of the observed associations in an independent case-control study of type 2 diabetes. These protein associations provide novel biological insights into the molecular mechanisms that are dysregulated prior to and following the onset of type 2 diabetes and can be detected in serum. A bi-directional two-sample Mendelian randomization analysis indicated that serum changes of at least 23 proteins are downstream of the disease or its genetic liability, while 15 proteins were supported as having a causal role in type 2 diabetes.

D. Grahame Hardie
Jul 1, 2013; 62:2164-2172
Perspectives in Diabetes

Jay S. Skyler
Feb 1, 2017; 66:241-255
Perspectives in Diabetes

Invitation Only Research Event

Event participants

Oscar Jonsson, Director, Stockholm Free World Forum (Frivärld)
Mathieu Boulègue, Research Fellow, Russia and Eurasia Programme, Chatham House
Chair: ​Alice Billon-Galland, Research Associate, Europe Programme, Chatham House

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give you...

Invitation Only Research Event

Members Event

Event participants

Professor Dieter Helm CBE, Professor of Energy Policy, University of Oxford

Chair: David Shukman, Science Editor, BBC News

El Salvador is the smallest country in Central America yet the most densely populated. A stagnant economy, high levels of crime and violence, and natural disasters have pushed growing numbers of people to migrate without authorization or seek asylum abroad, mostly in the United States. This article explores historical and contemporary emigration from El Salvador.

From earthquakes to drought, natural disasters and climate change played a key role in migration flows in 2015. Climate-induced migration surfaced as a concern at the United Nations Climate Change Conference (known as COP21) as international organizations and policymakers have begun to recognize the growing challenges, and potential protection obligations, of such movement.

Renza Scibilia
Jul 1, 2019; 37:302-303
Book Reviews

OBJECTIVE

On the basis of urinary steroidal gas chromatography-mass spectrometry (GC-MS), we previously defined a novel concept of a disease-specific "steroid metabolomic signature" and reclassified childhood obesity into five groups with distinctive signatures. The objective of the current study was to delineate the steroidal signature of insulin resistance (IR) in obese children.

Nearly 22 million immigrants—about half of the overall immigrant population—were naturalized U.S. citizens in fiscal year 2017. In the same year, more than 707,000 immigrants became U.S. citizens. Naturalized citizens tend to have higher incomes and educational attainment compared to other immigrants, as this data-rich article explores.

Psychologists once conducted a simple experiment with far-reaching implications: They asked people to describe an instance in their lives when they had hurt someone and another instance when they had been hurt by someone else. The incidents that people described were similar whether they saw...

Macfarlane's journey begins on the Icknield Way, which runs over the chalk downs of Sussex. He starts out on a bicycle along an old Roman road that runs past an Iron Age hill-fort. As he cycles past the hill-fort he falls, damages his bicyle, and breaks a rib.However, Macfarlane gets up and continues his journey. He views the accident as

A warning, I thought superstitiously, had been issued to me: that the going would not be easy and that romanticism would be quickly punished. It was only a few miles later that I remembered the letter a friend had sent me when I told him about my plan to walk the Icknield Way. Take care as you pass the ring-fort, he had written back. When I mentioned the fall later, he was unamazed."This was an entry fee to the old ways, charged at one of the usual tollbooths, " he said. "Now you can proceed. You're in. Bone for chalk: you've paid your due." It was the first of several incidents along the old ways that I still find hard to explain away rationally." (p.43).

Throughout the book, Macfarlane risks meeting the supernatural. He spends the nights camping near Iron Age barrows. He sleeps in circular Pictish shielings. Finally he decides to sleep in Chanctonbury RIng in Sussex because author Laurie Lee had slept there while walking over England in the 1930's.

I first learned about Chanctonbury Ring when I read about called Sussex Cottage written by Esther Meynell in 1936. The ring contains a temple built by the Romans on a previously inhabited Bronze and Iron Age fort site. According to legend, Julius Caesar and his legions ride around the ring. It is also possible to summon the devil by running around it a certain number of times. There are a number of internet sites with chilling stories of uncanny experiences in Chanctonbury Ring:

http://www.sussexarch.org.uk/saaf/chanctonbury.html#folk

http://www.delcoghosts.com/chanctonbury.html

http://www.telegraph.co.uk/earth/outdoors/6454719/Devils-Dyke-is-not-for-the-faint-hearted-walker.html

http://ufofreeparanormal.com/node/62


Oblivious to the possibility that he may be rousing some kind of supernatural being, Macfarlane spends a night in Chanctonbury Ring, but gets little rest. First he walks around the ring, then beds down for the night. He is awoken by  human-sounding voices moving around the ring until two voices meet directly over his head. Eventually the voices go away and he is able to go back to sleep although he does not feel rested in the morning. Later in the day Macfarlane meets up up with an archaeologist friend and they discuss why it was a bad idea to sleep in the ring. However, it is not until he gets home that Macfarlane researches the folklore of Chanctonbury Ring and realizes that it is one of the most malevolently haunted spots in England.

What's interesting is that while Macfarlane is aware of the many centuries of human history that his paths have run through, and of the theories that the paths exist throughout time, he does little research on the supernatural history of the places where he travels. These places seem to do their best to make him aware of their history and their special qualities. The supernatural seems to forcibly come to him although he does his best to remain ignorant of its existence.

When I reread the Green Knowe books, what struck me most about them was how much time the children in the books - Tolly, Ping, Ida, Oskar, Susan,and Jacob spent exploring the outdoors. Tolly climbs the beech tree to pretend that he is a sailor boy on the mast of a ship:

This syrup is delicious and well worth the time involved. While it tastes sweet it is natural and sugar-free. Add a tablespoonful to any chopped fresh fruit - berries, mango, pineapple, papaya, banana, grapes - and it will balance and enhance the flavours. It's also great served over waffles, crepes or ice cream.

OBJECTIVE

We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk.

Governors in several natural resource-dependent states said recently they will have to continue to cut public education funding because prices for oil and coal have not rebounded.

"This report is the final report for the Orange-bellied Parrot Habitat Management and Restoration Project carried out on King Island. The report relates to the activity period starting 30th of June 2007 and finishing on the 25th of May 2008."--Introduction.

This report provides an overview of the implementation of the Water plan (Mary Basin) 2006 and summarises the findings of the assessments undertaken for the last five years. The plan supports urban water supply and a variety of industries including significant agricultural production, a growing tourism industry and fisheries.

Prediabetic state -- Prevention.

Krefft, Gerard, 1830-1881.

Botany -- Northern Territory.

Paris : Béchet jeune, 1827-1829.

Paris : Béchet : Bailliere : Crevot, 1823.

Leipzig : C.F. Winter, 1861.

Leipzig : S. Hirzel, 1881.

Budapest : Franklin-Verein, 1895.

Bingen am Rhein : Selbstverlag des Verfassers, 1885.

London : Macmillan, 1891.