(PLOS) The ancient cemetery of Mözs-Icsei d?l? in present-day Hungary holds clues to a unique community formation during the beginnings of Europe's Migration Period, according to a study published April 29, 2020 in the open-access journal PLOS ONE by Corina Knipper from the Curt-Engelhorn-Center for Archaeometry, Germany, István Koncz, Tivadar Vida from the Eötvös Loránd University, Budapest, Hungary and colleagues.

(American Geriatrics Society) The COVID-19 pandemic has placed unprecedented pressure on societies worldwide, given the pandemic's rapid, often deadly spread. In health care, the pandemic has raised the pressing question of how society should allocate scarce resources during a crisis. This is the question experts addressed today in a new position statement published by the American Geriatrics Society (AGS) in the Journal of the American Geriatrics Society (DOI: 10.1111/jgs.16537).

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

Liye Chen
May 1, 2020; 19:871-883
Research

Background: Accurate definition of the extent and severity of left-ventricular assist device (LVAD) infection may facilitate therapeutic decision making and targeted surgical intervention. Here, we explore the value of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for guidance of patient management. Methods: Fifty-seven LVAD-carrying patients received 85 whole-body ¹⁸F-FDG PET/CT scans for the work-up of device infection. Clinical follow-up was obtained over a period of up to two years. Results: PET/CT showed various patterns of infectious involvement of the 4 LVAD components: driveline entry point (77% of cases), subcutaneous driveline path (87%), pump pocket (49%) and outflow tract (58%). Driveline smears revealed staphylococcus or pseudomonas strains as the underlying pathogen in a majority of cases (48 and 34%, respectively). At receiver-operating characteristics analysis, an ¹⁸F-FDG standardized uptake value (SUV) >2.5 was most accurate to identify smear-positive driveline infection. Infection of 3 or all 4 LVAD components showed a trend towards lower survival vs infection of 2 or less components (P = 0.089), while involvement of thoracic lymph nodes was significantly associated with adverse outcome (P = 0.001 for nodal SUV above vs below median). Finally, patients that underwent early surgical revision within 3 months after PET/CT (n = 21) required significantly less inpatient hospital care during follow-up when compared to those receiving delayed surgical revision (n = 11; p<0.05). Conclusion: Whole-body ¹⁸F-FDG PET/CT identifies the extent of LVAD infection and predicts adverse outcome. Initial experience suggests that early image-guided surgical intervention may facilitate a less complicated subsequent course.

Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behcet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ~40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

8 October 2019

Mustafa Yalcinkaya
Apr 1, 2020; 61:492-504
Research Articles

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.

Loss of pancreatic β-cell mass and function as a result of sustained ER stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog (Hh) signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca²⁺-ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the Hh signaling receptor Smoothened (SMO) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced β-cell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and, in cells lacking ABCG1 or the 24-OHC synthesizing enzyme CYP46A1, restored the protective activity of HDL. Inhibition of SMO countered the beneficial effects of HDL and also LDL, and SMO agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the SMO-activated transcription factor glioma-associated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and β-cell death involves the transport, generation, and mobilization of oxysterols for activation of the Hh signaling receptor SMO

Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway, endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines if lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS1 cells, primary rodent and human β-cells in vitro against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of pro-apoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Akita mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Akita littermates. These are the first studies in any cell type demonstrating lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues, and it exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. Here, we demonstrate that MANF is abundantly expressed in normal corneal epithelial cells; however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in streptozotocin-induced type 1 diabetic C57BL/6 mice. Recombinant human MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycemia-induced endoplasmic reticulum (ER) stress and ER stress–mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific small interfering RNA (siRNA). Finally, we reveal that the subconjunctival injection of MANF-specific siRNA prevents corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK.

21 July 2014

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

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.

Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in nonischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. Although ¹⁸F-FDG accumulates in inflammatory leukocytes and thus may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure-overload heart failure. We aimed to evaluate whether inflammation with ¹⁸F-FDG can be serially imaged in the early stages of pressure-overload–induced heart failure and to compare the time course with functional impairment assessed by cardiac MRI. Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC) (n = 22), sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at 2 and 8 d after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. ¹⁸F-FDG PET scans were acquired at 3 and 7 d after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evoked rapid left ventricular dilation compared with sham (end-systolic volume, day 2: 40.6 ± 10.2 μL vs. 23.8 ± 1.7 μL, P < 0.001). Contractile function was similarly impaired (ejection fraction, day 2: 40.9% ± 9.7% vs. 59.2% ± 4.4%, P < 0.001). The severity of contractile impairment was proportional to histology-defined myocardial macrophage density on day 8 (r = –0.669, P = 0.010). PET imaging identified significantly higher left ventricular ¹⁸F-FDG accumulation in TAC mice than in sham mice on day 3 (10.5 ± 4.1 percentage injected dose [%ID]/g vs. 3.8 ± 0.9 %ID/g, P < 0.001) and on day 7 (7.8 ± 3.7 %ID/g vs. 3.0 ± 0.8 %ID/g, P = 0.006), though the efficiency of cardiomyocyte suppression was variable among TAC mice. The ¹⁸F-FDG signal correlated with ejection fraction (r = –0.75, P = 0.01) and ventricular volume (r = 0.75, P < 0.01). Western immunoblotting demonstrated a 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at 8 d after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricular geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using ¹⁸F-FDG PET imaging. More selective inflammatory tracers are requisite to identify the diffuse local inflammation in pressure overload.

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

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

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.

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.

The Connecticut Foundation for Dental Outreach has postponed the Connecticut Mission of Mercy Free Dental Clinic scheduled for March 20-21 in Danbury, Connecticut, "out of abundant caution" amid the coronavirus disease outbreak.

Communities across the U.S. still need to expand hospital capacity to manage new COVID-19 cases, even as some states loosen social distancing restrictions, a study published Wednesday by JAMA Network Open says.

OBJECTIVE

To determine the effects of dapagliflozin in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) on left ventricular (LV) remodeling using cardiac MRI.

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.

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.

BRUSSELS — While the European Union has called on Member States to expand channels for foreign workers as a way to meet labour market needs and potentially tackle spontaneous migration, they have struggled to deliver on this pledge. To date, policies have focused more on attracting high-skilled workers, but less attention has been paid to admission of low- or middle-skilled nationals. Policymakers would do well not to overestimate the potential of legal channels to reduce irregular migration.

By Emily Reynolds. But self-assessed intelligence was not actually related to objective measures of intelligence

The new curriculum would teach all students about tribes and Indian culture in North Dakota.

Nebraska's education department released an interactive instructional materials map last week, showing what curricula districts have adopted for English-language arts, math, and K-8 science.

A statewide survey of educators in Tennessee provides critical insights into connections that exist between standards, curriculum, professional development, and ultimately student success.

Seek Academy in Newark, N.J., has added a social justice class for students in kindergarten through 4th grades to help them make sense of some of the most controversial issues of the day, including the "take the knee" debate.

Gov. Dannel Malloy will seek to dramatically adjust the way Connecticut distributes more than $4 billion of state aid, he told legislators in his annual address, as the legislature gets back to business for the 2017 session.

A federal judge dismissed most claims in a lawsuit challenging Connecticut's restrictions on magnet schools, charter schools, and school choice programs, saying there is no fundamental right to equal education opportunity under the U.S. Constitution.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

The state's highest court allowed some claims brought on behalf of relatives of victims of the 2012 mass shooting at Sandy Hook Elementary School to proceed against the firearms industry.

These tools encourage school administrators to gather as much information as possible about the students who will be entering kindergarten and the early-learning offerings in their communities.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

The state, which earned a B, is one of the nation’s wealthiest and turned in strong performances in the school finance arena and in areas such as preschool and kindergarten enrollment.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

The Difficulties Of South American Football