7 January 2020

Cancer Survival is related to tumor volume. FDG PET measurement of tumor volume holds promise but is not yet a clinical tool. Measurements come in two forms: the total lesion volume (TLV) based on the number of voxels in the tumor and secondly the total lesion glycolysis (TLG) which is the TLV multiplied by the average SUL per voxel of the tumor (SUL is the standardize uptake value normalized for lean mass). In this study we measured tumor volume in patients with malignant pleural mesothelioma (MPM). METHODS: A threshold-based program in IDL was developed to measure tumor volume in FDG PET images. 19 patients with malignant pleural mesothelioma (MPM) were studied before and after two cycles (6 weeks) of chemo-immunotherapy. Measurements included the total lesion volume (TLV), Total Lesion Glycolysis (TLG), the sum of the SULs in the tumor (SUL- total), a measure of total FDG uptake, and the average SUL per voxel. RESULTS: Baseline MPM volumes (TLV) ranged from 11 to 2610 cc. TLG values ranged from 32 to 8552 SUL-cc and were strongly correlated with TLV. While tumor volumes ranged over 3 orders of magnitude, the average SUL per voxel, SUL-average, stayed within a narrow range of 2.4 to 5.3 units. Thus, TLV was the major component of TLG while SUL-average was a minor component and was essentially constant. Further evaluation of SUL-average showed that in this cohort it’s two components SUL-total and tumor volume changed in parallel and were strongly correlated, r= 0.99, p<.01. Thus, whether the tumors were large or small, the FDG uptake as measured by SUL-total was proportional to the total tumor volume. Conclusion: TLG equals TLV multiplied by the average SUL per voxel, essentially TLV multiplied by a constant. Thus TLG, commonly considered a measure of "metabolic activity" in tumors, is also in this cohort a measure of tumor volume. The constancy of SUL per voxel is due to FDG uptake being proportional to tumor volume. Thus, in this study, the FDG uptake was also a measure of volume.

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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Join host David Price for a dive into all things tech: Round 43. Things go mobile as Senior Staff Writer at PC Advisor and Macworld UK Henry Burrell tells us why Sky getting into the market is a big deal. Quad-play ahoy. Then fellow Senior Staff Writer Lewis Painter (14 mins) tells us why No Man's Sky is still making the headlines, this time for making stuff up. How far have companies taken false advertising in recent years? Third up is Techworld editor Charlotte Jee (25 mins) to talk about how the government has perhaps avoided taking responsibility when it comes to sex-ed and instead suggested it ban sexting - is that even possible? Listen on to find out.  

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This manuscript has been withdrawn by the Author.

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.

4 February 2020

Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson’s, Huntington’s, and Alzheimer’s diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases.

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.

The C-type lectin receptors (CLRs) form a family of pattern recognition receptors that recognize numerous pathogens, such as bacteria and fungi, and trigger innate immune responses. The extracellular carbohydrate-recognition domain (CRD) of CLRs forms a globular structure that can coordinate a Ca2+ ion, allowing receptor interactions with sugar-containing ligands. Although well-conserved, the CRD fold can also display differences that directly affect the specificity of the receptors for their ligands. Here, we report crystal structures at 1.8–2.3 Å resolutions of the CRD of murine dendritic cell-immunoactivating receptor (DCAR, or Clec4b1), the CLR that binds phosphoglycolipids such as acylated phosphatidyl-myo-inositol mannosides (AcPIMs) of mycobacteria. Using mutagenesis analysis, we identified critical residues, Ala136 and Gln198, on the surface surrounding the ligand-binding site of DCAR, as well as an atypical Ca2+-binding motif (Glu-Pro-Ser/EPS168–170). By chemically synthesizing a water-soluble ligand analog, inositol-monophosphate dimannose (IPM2), we confirmed the direct interaction of DCAR with the polar moiety of AcPIMs by biolayer interferometry and co-crystallization approaches. We also observed a hydrophobic groove extending from the ligand-binding site that is in a suitable position to interact with the lipid portion of whole AcPIMs. These results suggest that the hydroxyl group-binding ability and hydrophobic groove of DCAR mediate its specific binding to pathogen-derived phosphoglycolipids such as mycobacterial AcPIMs.

Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation.

In cyanobacteria, metabolic pathways that use the nitrogen-rich amino acid arginine play a pivotal role in nitrogen storage and mobilization. The N-terminal domains of two recently identified bacterial enzymes: ArgZ from Synechocystis and AgrE from Anabaena, have been found to contain an arginine dihydrolase. This enzyme provides catabolic activity that converts arginine to ornithine, resulting in concomitant release of CO2 and ammonia. In Synechocystis, the ArgZ-mediated ornithine–ammonia cycle plays a central role in nitrogen storage and remobilization. The C-terminal domain of AgrE contains an ornithine cyclodeaminase responsible for the formation of proline from ornithine and ammonia production, indicating that AgrE is a bifunctional enzyme catalyzing two sequential reactions in arginine catabolism. Here, the crystal structures of AgrE in three different ligation states revealed that it has a tetrameric conformation, possesses a binding site for the arginine dihydrolase substrate l-arginine and product l-ornithine, and contains a binding site for the coenzyme NAD(H) required for ornithine cyclodeaminase activity. Structure–function analyses indicated that the structure and catalytic mechanism of arginine dihydrolase in AgrE are highly homologous with those of a known bacterial arginine hydrolase. We found that in addition to other active-site residues, Asn-71 is essential for AgrE's dihydrolase activity. Further analysis suggested the presence of a passage for substrate channeling between the two distinct AgrE active sites, which are situated ∼45 Å apart. These results provide structural and functional insights into the bifunctional arginine dihydrolase–ornithine cyclodeaminase enzyme AgrE required for arginine catabolism in Anabaena.

Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.

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

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

4 February 2020

In this article, I share my two final case studies, which examine changing our cultural attitudes to enhance productivity. Case study #5 – The role of punctuality An entrepreneur named Michael Fairbanks, who specialises in developing...

Pleural effusions are common, with an estimated 1-1.5 million new cases in the United States and 200 000-250 000 in the United Kingdom each year. Rahul Bhatnagar, academic clinical lecturer at the University of Bristol, describes how pleural effusions may be investigated and treated in the community and secondary care, with a particular focus on...

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...

THE EDITOR, Madam: The Jamaican Government and local private-sector power brokers are still way behind and woefully lacking in investing, financially and otherwise, in Jamaica’s number one most powerful, most famous, most influential, and most...

Clinical studies have suggested that changes in peripheral nerve microcirculation may contribute to nerve damage in diabetic polyneuropathy (DN). High-sensitivity troponin T (hsTNT) assays have been recently shown to provide predictive values for both cardiac and peripheral microangiopathy in type 2 diabetes (T2D). This study investigated the association of sciatic nerve structural damage in 3 Tesla (3T) magnetic resonance neurography (MRN) with hsTNT and N-terminal pro-brain natriuretic peptide serum levels in patients with T2D. MRN at 3T was performed in 51 patients with T2D (23 without DN, 28 with DN) and 10 control subjects without diabetes. The sciatic nerve’s fractional anisotropy (FA), a marker of structural nerve integrity, was correlated with clinical, electrophysiological, and serological data. In patients with T2D, hsTNT showed a negative correlation with the sciatic nerve’s FA (r = –0.52, P < 0.001), with a closer correlation in DN patients (r = –0.66, P < 0.001). hsTNT further correlated positively with the neuropathy disability score (r = 0.39, P = 0.005). Negative correlations were found with sural nerve conduction velocities (NCVs) (r = –0.65, P < 0.001) and tibial NCVs (r = –0.44, P = 0.002) and amplitudes (r = –0.53, P < 0.001). This study is the first to show that hsTNT is a potential indicator for structural nerve damage in T2D. Our results indirectly support the hypothesis that microangiopathy contributes to structural nerve damage in T2D.

21 July 2014

Invitation Only Research Event

Invitation Only Research Event

Event participants

Dr Ashwini Swain, Fellow, CUTS Institute for Regulation and Competition
Glada Lahn, Senior Research Fellow, Energy, Environment and Resources, Chatham House
Dr Gareth Price, Senior Research Fellow, Asia Programme, Chatham House

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

2 September 2015

This paper explores the potential of using public procurement policy to promote the uptake of sustainable food products in order to reduce imports of agricultural products associated with deforestation.

28 January 2016

Private-sector commitments and government policies, a loss of support for biofuels, and health concerns over the consumption of palm oil and beef, are factors that may help to restrict the further expansion of agricultural land into forest areas.

Invitation Only Research Event

Event participants

Ian Mitchell, Co-Director, Development Cooperation in Europe; Senior Policy Fellow and Associate Fellow, Energy, Environment and Resources Department, Chatham House
Chair: Ana Yang, Head of Land Use and Food Systems, Hoffmann Centre for Sustainable Resource Economy, Chatham House

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.

In Brazil, where the majority of colonial-era residents were African slaves and their children, millions of immigrants have joined a conversation about race and identity that continues today. Brazil is home to the largest Japanese population outside of Japan, as well as significant European, Latin American, and Middle Eastern populations. This country profile explores historical and contemporary migration patterns in Brazil.

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.

The recent rise in xenophobia in Hungary stands in marked contrast with the country's rich migration history. After 390,000 migrants and asylum seekers arrived in 2015, the government of Viktor Orbán issued policies to significantly limit migration and enacted a law criminalizing humanitarian assistance to migrants. This country profile examines Hungary’s migration past and present, tracing the country’s multicultural heritage to the current wave of anti-immigrant sentiment.

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.

An expert discussion on the findings of the National Agricultural Workers Survey (NAWS) related to immigrants, along with an overview of farm labor in 2015 and discussion on how current and possible future immigration policies might impact immigrant workers in the agricultural sector.

An expert discussion on the findings of the National Agricultural Workers Survey (NAWS) related to immigrants, along with an overview of farm labor in 2015 and discussion on how current and possible future immigration policies might impact immigrant workers in the agricultural sector.

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

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.

The COVID-19 pandemic has left a path of destruction in urban centers throughout the northeastern United States, but the next outbreak hotspots could have even deadlier effects in rural areas.

New Zealand drew global attention for its unity and support for the Muslim community targeted during the horrific Christchurch attacks. Yet the country's road to inclusion has been far from straightforward, and amid rising diversity it is grappling with the best way to achieve inclusion for its multiethnic population, including indigenous Māori peoples and migrants. This article outlines the opportunities and challenges to fostering multiculturalism against a backdrop of bicultural policies.

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...

During the 2015–16 migration crisis, European asylum systems were stretched to a breaking point. Yet many of the structural issues that contributed to failures to register newcomers, insufficient reception capacity, and growing backlogs of asylum cases existed before—and many remain unresolved. This report critically evaluates Common European Asylum System legal and operational shortcomings at a time when reform is on the table.

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.

Recently while listening to WNYC, I heard a segment about the lack of diversity in children's literature. While the US's population is becoming more diverse, it is apparently not reflected in children's books. Lucy Maria Boston was a head of the curve since four of the Green Knowe books could be regarded as multicultural since they contain not only Asian and African main characters but also a physically disabled character and deal with the issues of slavery and exile due to war.

Ping, a young refugee from Burma, is the main human character in A Stranger at Greene Knowe and a supporting character in The River at Green Knowe and An Enemy at Green Knowe. Ping has spent most of his life in a hostel for displaced children and goes to stay at Green Knowe during his summer holiday. He is eventually asked by Mrs. Oldknow to live with her and Tolly at Green Knowe. His experiences as a homeless child trapped in the grey world of the London home cause him to appreciate not only the natural world around the house but also to empathize with the escaped gorilla, Hanno. Boston wanted to dedicate Stranger to a gorilla keeper that she knew but was forbidden to do so by the zoo since it portrayed captivity for animals as cruel and harmful to the animal. When Green Knowe is under siege from evil in Enemy, Ping calls back Hanno with a traditional prayer to help save the house.

Jacob, in Treasure at Green Knowe, is bought as a child in a slave auction by Captain Oldknowe as a companion for the Captain's blind daughter, Susan. Susan's mother is uninterested in Susan since she views her as an unmarriageable burden. Susan's blindness puts her outside of the normal constraints for an upper-class girl so she can spend her time climbing trees with Jacob and learning how to write with him and their tutor Jonathan. Susan's brother Sefton views Jacob as less than human, buying him clothes patterned on those of an organ-grinder's monkey. Both Jacob and Susan rely on each other to navigate the rules of a society that views them as worthless because of their respective race and disability. They work together to educate themselves and lead successful adult lives despite their differences in race, sex, and station.

Despite the fifty or so years since they were written, the books still hold up due to the quality of the writing, the strong characterizations, and the universal themes. They are well-worth being placed on any reading list, multicultural or not. Good children's books should be read whether or not they are written by US authors.

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.

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.

A push to open a center devoted to research and professional development for rural K-12 holds promise for educators who work in small, isolated communities.