Identification of leukocyte surface P2X7 as a biomarker associated with Alzheimer\u27s disease

Alzheimer\u27s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ -ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD

Measurements of differential cross sections of Z/gamma*+jets+X events in proton anti-proton collisions at sqrt{s}=1.96 TeV

We present cross section measurements for Z/gamma*+jets+X production, differential in the transverse momenta of the three leading jets. The data sample was collected with the D0 detector at the Fermilab Tevatron proton anti-proton collider at a center-of-mass energy of 1.96 TeV and corresponds to an integrated luminosity of 1 fb-1. Leading and next-to-leading order perturbative QCD predictions are compared with the measurements, and agreement is found within the theoretical and experimental uncertainties. We also make comparisons with the predictions of four event generators. Two parton-shower-based generators show significant shape and normalization differences with respect to the data. In contrast, two generators combining tree-level matrix elements with a parton shower give a reasonable description of the the shapes observed in data, but the predicted normalizations show significant differences with respect to the data, reflecting large scale uncertainties. For specific choices of scales, the normalizations for either generator can be made to agree with the measurements.Comment: Published in PLB. 11 pages, 3 figure

Factors associated with inadequate receipt of components and non-use of antenatal care services in India : a regional analysis

Background: Failure to use antenatal care (ANC) and inadequate receipt of components of ANC pose a significant risk for the pregnant woman and the baby. This study aimed to examine a regional analysis of factors associated with receiving no ANC and inadequate receipt of components of ANC services among Indian women. Method: Information from 173,970 women of reproductive age 15–49 years from the 2019–21 India National Family Health Survey (NFSH-5) was analysed. Logistic regression analyses that adjusted for cluster and survey weights were conducted to assess the socio-demographic and other factors associated with receiving non-use of ANC and inadequate receipt of components of ANC, respectively, in the six regions and 28 states, and 8 union territories in India. Results: Across regions in India, 7% of women reported no ANC, and the prevalence of inadequate and adequate receipt of components of ANC in all six regions ranged from 67 to 89% and 8% to 24%, respectively. Of all the 36 federated entities, the prevalence of inadequate receipt of ANC components was less than two-thirds in Tamil Nadu, Puducherry, Andaman and the Nicobar Islands, Odisha, and Gujarat. Our analyses revealed that associated factors vary by region, state, and union territories. Women from poor households reported increased odds of receiving no ANC in North, East and North-eastern regions. Women who reported no schooling in South, East and Central regions were associated with increased odds of receiving no ANC. Women from poor households in Himachal Pradesh, Bihar, Uttar Pradesh, Nagaland, Manipur, Uttar Pradesh, and Madhya Pradesh states reported significantly higher odds of inadequate components ANC than women from rich households. The receipt of inadequate components of ANC was significantly higher among women who never read magazines in Delhi, Ladakh, Karnataka, Telangana, Jharkhand, Maharashtra, Uttar Pradesh, Chhattisgarh, Arunachal Pradesh, Manipur, and Mizoram states in India. Conclusion: A better understanding of the factors associated with and incorporating them into the short- and long-term intervention strategies, including free financial support from the Indian government to encourage pregnant women from lower socioeconomic groups to use health services across all regions, states and union territories

Altered Negative Unconscious Processing in Major Depressive Disorder: An Exploratory Neuropsychological Study

Major depressive disorder (MDD) has been characterized by abnormalities in emotional processing. However, what remains unclear is whether MDD also shows deficits in the unconscious processing of either positive or negative emotions. We conducted a psychological study in healthy and MDD subjects to investigate unconscious emotion processing and its valence-specific alterations in MDD patients.We combined a well established paradigm for unconscious visual processing, the continuous flash suppression, with positive and negative emotional valences to detect the attentional preference evoked by the invisible emotional facial expressions.Healthy subjects showed an attentional bias for negative emotions in the unconscious condition while this valence bias remained absent in MDD patients. In contrast, this attentional bias diminished in the conscious condition for both healthy subjects and MDD.Our findings demonstrate for the first time valence-specific deficits specifically in the unconscious processing of emotions in MDD; this may have major implications for subsequent neurobiological investigations as well as for clinical diagnosis and therapy

Genomic insights into rapid speciation within the world's largest tree genus Syzygium

The relative importance of the mechanisms underlying species radiation remains unclear. Here, the authors combine reference genome assembly and population genetics analyses to show that neutral forces have contributed to the radiation of the most species-rich tree genus Syzygium. Species radiations, despite immense phenotypic variation, can be difficult to resolve phylogenetically when genetic change poorly matches the rapidity of diversification. Genomic potential furnished by palaeopolyploidy, and relative roles for adaptation, random drift and hybridisation in the apportionment of genetic variation, remain poorly understood factors. Here, we study these aspects in a model radiation, Syzygium, the most species-rich tree genus worldwide. Genomes of 182 distinct species and 58 unidentified taxa are compared against a chromosome-level reference genome of the sea apple, Syzygium grande. We show that while Syzygium shares an ancient genome doubling event with other Myrtales, little evidence exists for recent polyploidy events. Phylogenomics confirms that Syzygium originated in Australia-New Guinea and diversified in multiple migrations, eastward to the Pacific and westward to India and Africa, in bursts of speciation visible as poorly resolved branches on phylogenies. Furthermore, some sublineages demonstrate genomic clines that recapitulate cladogenetic events, suggesting that stepwise geographic speciation, a neutral process, has been important in Syzygium diversification.Peer reviewe

Genomic insights into rapid speciation within the world's largest tree genus Syzygium

Acknowledgements Y.W.L. was supported by a postgraduate scholarship research grant from the Ministry of National Development, Singapore awarded through the National Parks Board, Singapore (NParks; NParks’ Garden City Fund). Principal research funding from NParks and the School of Biological Sciences (SBS), Nanyang Technological University (NTU), Singapore, is acknowledged. We thank Peter Preiser, Associate Vice President for Biomedical and Life Sciences, for facilitating NTU support, and Kenneth Er, CEO of NParks, for facilitating research funding through that organisation. V.A.A. and C.L. were funded by SBS, NTU for a one-year research leave. V.A.A. and C.L. also acknowledge support from the United States National Science Foundation (grants 2030871 and 1854550, respectively). S.R. was supported by a postdoctoral research fellowship under the NTU Strategic Plant Programme. S.R. and N.R.W.C. acknowledge funding from NTU start-up and the Academy of Finland (decisions 318288, 319947) grants to J.S. Fieldwork conducted by Y.W.L. was supported by an Indonesian Government RISTEK research permit (Application ID: 1517217008) and an Access License from the Sabah State government [JKM/MBS.1000-2/2JLD.7(84)]. T.N.C.V. is grateful to the Assemblée de la Province Nord and Assemblée de la Province Sud (New Caledonia) for facilitating relevant collection permits. A.N. was partly supported by the Research Project Promotion Grant (Strategic Research Grant No. 17SP01302) from the University of the Ryukyus, and partly by the Environment Research and Technology Development Fund (JPMEERF20204003) from the Environmental Restoration and Conservation Agency of Japan. Fieldwork in Fiji conducted by R.B. was hosted and facilitated by Elina Nabubuniyaka-Young (The Pacific Community’s Centre for Pacific Crops and Trees, Fiji). We thank the NTU-Smithsonian Partnership for tree data obtained for the Bukit Timah Nature Reserve (BTNR) long-term forest dynamics plots. Administrative support provided by Mui Hwang Khoo-Woon and Peter Ang at the molecular laboratory of the Singapore Botanic Gardens (SBG) is acknowledged. Rosie Woods and Imalka Kahandawala (DNA and Tissue Bank, Royal Botanic Gardens, Kew) facilitated additional DNA samples. Daniel Thomas (SBG) and Yan Yu (Sichuan University) commented on biogeographical analyses. NovogeneAIT in Singapore is acknowledged for personalised sequencing service.Peer reviewedPublisher PD

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

ChIP-seq Defined Genome-Wide Map of TGFβ/SMAD4 Targets: Implications with Clinical Outcome of Ovarian Cancer

Deregulation of the transforming growth factor-β (TGFβ) signaling pathway in epithelial ovarian cancer has been reported, but the precise mechanism underlying disrupted TGFβ signaling in the disease remains unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate genome-wide screening of TGFβ-induced SMAD4 binding in epithelial ovarian cancer. Following TGFβ stimulation of the A2780 epithelial ovarian cancer cell line, we identified 2,362 SMAD4 binding loci and 318 differentially expressed SMAD4 target genes. Comprehensive examination of SMAD4-bound loci, revealed four distinct binding patterns: 1) Basal; 2) Shift; 3) Stimulated Only; 4) Unstimulated Only. TGFβ stimulated SMAD4-bound loci were primarily classified as either Stimulated only (74%) or Shift (25%), indicating that TGFβ-stimulation alters SMAD4 binding patterns in epithelial ovarian cancer cells. Furthermore, based on gene regulatory network analysis, we determined that the TGFβ-induced, SMAD4-dependent regulatory network was strikingly different in ovarian cancer compared to normal cells. Importantly, the TGFβ/SMAD4 target genes identified in the A2780 epithelial ovarian cancer cell line were predictive of patient survival, based on in silico mining of publically available patient data bases. In conclusion, our data highlight the utility of next generation sequencing technology to identify genome-wide SMAD4 target genes in epithelial ovarian cancer and link aberrant TGFβ/SMAD signaling to ovarian tumorigenesis. Furthermore, the identified SMAD4 binding loci, combined with gene expression profiling and in silico data mining of patient cohorts, may provide a powerful approach to determine potential gene signatures with biological and future translational research in ovarian and other cancers

Diverse Applications of Nanomedicine

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic. \ua9 2017 American Chemical Society

Development of a brief multidisciplinary education programme for patients with osteoarthritis

Background Osteoarthritis (OA) is a prevalent progressive musculoskeletal disorder, leading to pain and disability. Patient information and education are considered core elements in treatment guidelines for OA; however, there is to our knowledge no evidence-based recommendation on the best approach, content or length on educational programmes in OA. Objective: to develop a brief, patient oriented disease specific multidisciplinary education programme (MEP) to enhance self-management in patients with OA. Method Twelve persons (80% female mean age 59 years) diagnosed with hand, hip or knee OA participated in focus group interviews. In the first focus group, six participants were interviewed about their educational needs, attitudes and expectations for the MEP. The interviews were transcribed verbatim and thereafter condensed. Based on results from focus group interviews, current research evidence, clinical knowledge and patients' experience, a multidisciplinary OA team (dietist, nurse, occupational therapist, pharmacist, physical therapist and rheumatologist) and a patient representative developed a pilot-MEP after having attended a work-shop in health pedagogics. Finally, the pilot-MEP was evaluated by a second focus group consisting of four members from the first focus group and six other experienced patients, before final adjustments were made. Results The focus group interviews revealed four important themes: what is OA, treatment options, barriers and coping strategies in performing daily activities, and how to live with osteoarthritis. Identified gaps between patient expectations and experience with the pilot-programme were discussed and adapted into a final MEP. The final MEP was developed as a 3.5 hour educational programme provided in groups of 6-9 patients. All members from the multidisciplinary team are involved in the education programme, including a facilitator who during the provision of the programme ensures that the individual questions are addressed. As part of an ongoing process, a patient representative regularly attends the MEP and gives feedback concerning content and perceived value. Conclusion A MEP has been developed to enhance self-management in patients with OA attending a multidisciplinary OA outpatient clinic. The effectiveness of the MEP followed by individual consultations with members of the multidisciplinary team is currently evaluated in a randomised controlled trial with respect to patient satisfaction and functioning