bluuebunny/crossref_metadata_2025 huggingface dataset:
Attitudes matter—welfare work and migration in Sweden
Authors: Schütze Carolin
Published: January 2019

This paper investigates the factors that influence Swedish welfare workers’ attitudes towards migrants and how these attitudes are associated with their encounters with migrant users. Due to increased migration over the last decade, Sweden is now considered an immigrant nation. Migrants with the right to reside in Sweden are included within the larger welfare system. This paper argues that preconceived notions about migrants can affect the welfare services that they receive. Results from an online survey with a sample of 1,319 welfare practitioners reveal that welfare workers’ attitudes play a significant role when it comes to how they perceive their encounters with migrant users. The findings demonstrate that more favourable attitudes towards migrants were predicted mainly by personal contact with migrants and that different organisational contexts result in different experiences of encounters with migrant users. Less favourable attitudes towards migrants were primarily predicted by a strong ethnic national identity. Most importantly, the findings show that welfare workers’ who have more favourable attitudes towards migrants are less likely to perceive their encounters with migrant users as difficult. This paper contributes to welfare and migration research in two ways. First, this study provides additional support for previous claims from qualitative research by supporting the assumptions that preconceived negative ideas about migrants have meaning for practical welfare work. Second, this paper integrates two streams of research—attitude formation theory and street-level bureaucracy theory—thus expanding existing assumptions about what determines welfare practices with migrants.
Skull Base Manifestations of Erdheim-Chester Disease: A Case Series and Systematic Review
Authors: Marinelli John P , Peters Pierce A , Vaglio Augusto , Van Gompel Jamie J , Lane John I , Carlson Matthew L
Published: January 2019

BACKGROUND

Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis. Up to 50% of patients develop central nervous system involvement, and a subset of these patients can present with isolated tumor-like masses.

OBJECTIVE

To describe the skull base manifestations of ECD with an emphasis on aspects most pertinent to surgeons who may be referred such patients for primary evaluation.

METHODS

Scopus, Web of Science, and PubMed were searched from database inception to May 1, 2018 for articles reporting skull base ECD. An institutional retrospective analysis of all patients treated at the authors’ institution since January 1, 1996 was also performed to supplement these data.

RESULTS

Of 465 retrieved articles, 18 studies totaling 20 patients met inclusion criteria. Institutional review identified an additional 7 patients. Collectively, the median age at diagnosis was 49 yr (interquartile range, 42-58) with a 4:1 male-to-female ratio. Patients frequently presented with diplopia (48%), headache (30%), dysarthria (22%), and vertigo or imbalance (22%), though trigeminal hypesthesia (11%), facial nerve paresis (7%), hearing loss (7%), and trigeminal neuralgia (7%) were also observed. ECD commonly mimicked meningioma (33%), trigeminal schwannoma (8%), neurosarcoidosis (8%), and skull base lymphoma (8%).

CONCLUSION

Discrete skull base lesions frequently mimic more common pathology such as meningioma or cranial nerve schwannomas. Medical therapy comprises the initial treatment for symptomatic skull base disease. Surgical resection is not curative and the utility of surgical intervention is largely limited to biopsy to establish diagnosis and/or surgical debulking to relieve mass effect.
Safety and immunogenicity of tetanus/diphtheria vaccination in patients with rheumatic diseases—a prospective multi-centre cohort study
Authors: Bühler Silja , Jaeger Veronika Katharina , Adler Sabine , Bannert Bettina , Brümmerhoff Carolin , Ciurea Adrian , Distler Oliver , Franz Juliane , Gabay Cem , Hagenbuch Niels , Herzog Christian , Hasler Paul , Kling Kerstin , Kyburz Diego , Müller Rüdiger , Nissen Michael John , Siegrist Claire-Anne , Villiger Peter Matthias , Walker Ulrich A. , Hatz Christoph
Published: January 2019

Objectives

We aimed to assess the safety and immunogenicity of a diphtheria/tetanus vaccine booster dose in three different patient groups with rheumatic diseases on a variety of immunosuppressive/immunomodulatory medications compared with healthy controls (HCs).

Methods

We conducted a multi-centre prospective cohort study in Switzerland. We enrolled patients with RA, axial SpA/PsA, vasculitis (Behçet’s disease, ANCA-associated vasculitis) and HCs. Diphtheria/tetanus vaccination was administered according to the Swiss vaccination recommendations. Blood samples were drawn before vaccination, and 1 month and 3 months afterwards. Antibody concentrations against vaccine antigens were measured by ELISA. Immunogenicity was compared between patient and medication groups. A mixed model was applied for multivariate analysis. Missing data were dealt with using multiple imputation.

Results

Between January 2014 and December 2015, we enrolled 284 patients with rheumatic diseases (131 RA, 114 SpA/PsA, 39 vasculitis) and 253 HCs. Of the patients, 89% were on immunosuppressive/immunomodulatory medication. Three months post-vaccination 100% of HCs vs 98% of patients were protected against tetanus and 84% vs 73% against diphtheria. HCs and SpA/PsA patients had significantly higher responses than RA and vasculitis patients. Assessing underlying diseases and medications in a multivariate model, rituximab was the only factor negatively influencing tetanus immunogenicity, whereas only MTX treatment had a negative influence on diphtheria antibody responses. No vaccine-related serious adverse events were recorded.

Conclusion

Diphtheria/tetanus booster vaccination was safe. Tetanus vaccination was immunogenic; the diphtheria component was less immunogenic. Vaccine responses were blunted by rituximab and MTX.

Trial registration

ClinicalTrials.gov, http://clinicaltrials.gov, Identifier: NCT01947465.
Expanding Knowledge of the Host Range of Tomato chlorosis virus and Host Plant Preference of Bemisia tabaci MEAM1
Authors: Fariña Arnaldo E. , Rezende Jorge A. M. , Wintermantel William M.
Published: January 2019

The crinivirus Tomato chlorosis virus (ToCV) is often found infecting tomato crops in Brazil, with variable incidence, but associated with prevalence of its primary vector, Bemisia tabaci MEAM1. ToCV control is difficult because there are no resistant commercial tomato varieties or hybrids available and chemical spray for control of the whitefly vector has not been effective. The present study evaluated the partial host range of a Brazilian isolate of ToCV and the preference of B. tabaci MEAM1 for oviposition on those species identified as susceptible to the virus. Subsequently, transmission tests were performed using plants of each ToCV host species as sources of inoculum to elucidate the epidemiological importance of nontomato sources of inoculum for infection of tomato. Among 80 species experimentally inoculated, 25 were susceptible, including 6 previously not known to be hosts (Jaltomata procumbens, Physalis pruinosa, Solanum aculeatissimum, S. viarum, Beta vulgaris var. cicla, and Chenopodium quinoa). Preference of whitefly for oviposition and infection by ToCV under free-choice transmission tests varied among the susceptible species. When ToCV-infected tomato, eggplant, and C. quinoa were used separately as sources of inoculum for virus transmission to tomato plants, mean percentages of infected plants were 76.6, 3, and 0%, respectively. Average oviposition of Bemisia tabaci on these three hosts were 2.7, 10.6, and 0.0 eggs/cm2, respectively. Additional studies will be necessary to evaluate the importance of ToCV host plants under field conditions and their efficiency as sources of inoculum for virus acquisition and transmission to tomato crops.
Cryobiotechnology: A Double-Edged Sword for Obligate Plant Pathogens
Authors: Zhao Lei , Wang Minrui , Li Jingwei , Cui Zhenhua , Volk Gayle M. , Wang Qiaochun
Published: January 2019

Pathogen-free stock plants are required as propagation materials in nurseries and healthy materials are needed in germplasm exchange between countries or regions through quarantine programs. In addition, plant gene banks also prefer to maintain pathogen-free germplasm collections. Shoot tip cryotherapy is a novel biotechnology method whereby cryopreservation methods are used to eradicate obligate pathogens from vegetatively propagated plants. Long-term preservation of pathogens is necessary in all types of virus-related basic research and applications such as antigen preparation for virus detection by immunology-based methods, production of plant-based vaccines, genetic transformation to produce virus-derived resistant transgenic plants, and bionanotechnology to produce nano drugs. Obligate plant pathogens such as viruses and viroids are intracellular parasites that colonize only living cells of the hosts. Therefore, their long-term preservation is difficult. Cryotreatments cannot completely eradicate the obligate pathogens that do not infect meristematic cells and certain proportions of plants recovered from cryotreatments are still pathogen-infected. Furthermore, cryotreatments often fail to eradicate the obligate pathogens that infect meristematic cells. Cryopreservation can be used for the long-term cryopreservation of the obligate plant pathogens. Thus, cryobiotechnology functions as a double-edged sword for plant pathogen eradication and cryopreservation. This review provides updated a synthesis of advances in cryopreservation techniques for eradication and cryopreservation of obligate plant pathogens.
Characterization of Tomato Necrotic Spot Virus, a Subgroup 1 Ilarvirus Causing Necrotic Foliar, Stem, and Fruit Symptoms in Tomatoes in the United States
Authors: Bratsch Sara A. , Grinstead Samuel , Creswell Tom C. , Ruhl Gail E. , Mollov Dimitre
Published: January 2019

The genomic, biological, and serological characterization of tomato necrotic spot virus (ToNSV), a virus first described infecting tomato in California, was completed. The complete genomic sequence identified ToNSV as a new subgroup 1 ilarvirus distinct from the previously described tomato-infecting ilarviruses. We identified ToNSV in Indiana in 2017 and 2018 and in Ohio in 2018. The coat protein coding region of the isolates from California, Indiana, and Ohio have 94 to 98% identity, while the same isolates had 99% amino acid identity. ToNSV is serologically related to TSV, a subgroup 1 ilarvirus, and shows no serological relationship to ilarviruses in the other subgroups. In tomato, ToNSV caused symptoms of necrotic spots and flecks on leaves, necrotic streaking on stems, and necrotic spots and circular patterns on fruit resulting in a yield loss of 1 to 13%. These results indicate that ToNSV is a proposed new subgroup 1 ilarvirus causing a necrotic spotting disease of tomato observed in California, Indiana, and Ohio.
Genetic Diversity of ‘Candidatus Liberibacter asiaticus’ Revealed by Short Tandem Repeats and Prophage Typing Indicates Population Homogeneity in Brazil
Authors: da Silva Priscila Alves , Fassini Camila Giacomo , Sampaio Laís Simões , Dequigiovanni Gabriel , Zucchi Maria Imaculada , Wulff Nelson Arno
Published: January 2019

‘Candidatus Liberibacter asiaticus’ is the most common huanglongbing-associated bacteria, being present in Asia, South, Central, and North America. Genomic approaches enabled sequencing of ‘Ca. L. asiaticus’ genomes, allowing for a broader assessment of its genetic variability with the application of polymerase chain reaction (PCR)-based tools such as microsatellite or short tandem repeat (STR) analysis. Although these tools contributed to a detailed analysis of strains from Japan, China, and the United States, Brazilian strains were analyzed in either too few samples with several STRs or in several strains with only a single microsatellite and a single PCR marker. We used 573 ‘Ca. L. asiaticus’ strains, mainly collected from São Paulo State (SPS), in our genetic analyses, employing three STRs and several prophage PCR markers. STR revealed a homogeneous population regardless of sampling year or geographic regions of SPS. Thirty-eight haplotypes were recognized with a predominance of VNTR_005 higher than 10 repeats, with VNTR_002 and VNTR_077 containing 11 and 8 repeats, respectively. This haplotype is indicated as class HE, which comprised 80.28% of strains. Classes HA and HB, predominant in Florida, were not found. A new genomic organization in the junction of prophages SC2 and SC1 is prevalent in Brazilian strains, indicating gene rearrangement and a widespread occurrence of a type 1 prophage as well as the presence of a type 2-like prophage. Our results indicate that ‘Ca. L. asiaticus’ populations are homogeneous and harbor a new genomic organization in prophages type 1 and 2.
A rare presentation of hypovolemic shock secondary to Whipple’s disease
Authors: Tandon Parul , Huang Vivian , Jaffer Nasir , Kirsch Richard , Croitoru Kenneth
Published: January 2019

Whipple’s disease is a rare, multisystem infection caused by the Gram-positive Tropheryma whippelii organism. In addition to neurological and rheumatological manifestations, this disease can result in significant gastrointestinal symptoms such as malabsorption, diarrhea, and weight loss. Given the diagnostic challenge and rare occurrence, a high index of suspicion is critical to prevent morbidity and mortality from this otherwise highly infectious disease transmitted via the fecal-oral route. We present a very rare but near-fatal case of hypovolemic shock secondary to protein-losing enteropathy and gastrointestinal bleeding from small bowel T. whippelii infection. Furthermore, the epidemiology, clinical presentation, diagnosis, and management of Whipple’s disease is reviewed.
Coping in African Americans With Inflammatory Bowel Disease
Authors: Scott Patricia D. , Lockhart Joan S. , Jakub Karen E. , Zoucha Rick , Nguyen Geoffrey C.
Published: January 2019

Given the chronic nature of inflammatory bowel disease, understanding the coping behaviors of individuals affected with the disease is important to influence health outcomes. Although minorities comprise a significant portion of individuals with the disease, little is known about the potential influence of one's culture, specifically among African Americans, on coping with inflammatory bowel disease. This integrative literature review examined the past decade of research related to the coping behaviors of African Americans living with inflammatory bowel disease to identify opportunities for further research. Five studies were identified via database searches of PubMed, PsychInfo, CINAHL, and the Cochrane Library and limited to studies published in English, full-text, peer-reviewed, and adult samples that included African Americans. Findings lacked information specific to coping in African Americans. Results were categorized by coping and disease activity, acquisition of knowledge, and personal coping. An association between poor coping behaviors and active disease was reported. The disease frequently hindered academic pursuits of college students, with increased knowledge about the disease associated with the use of better coping strategies. Personal coping behaviors were reported in stressful social situations, food choices, and religion. Results emphasized the need for future research to explore the influence of culture on the coping behaviors of African Americans with inflammatory bowel disease.
Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma
Authors: Jain Neeraj , Havranek Ondrej , Singh Ram Kumar , Khashab Tamer , Shirazi Fazal , Sehgal Lalit , Samaniego Felipe
Published: January 2019

Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse following a complete response or are refractory to therapy. The activated subtype of diffuse large B-cell lymphoma relies upon B-cell receptor signaling for survival; this signaling can be modulated by the activity of Bruton’s tyrosine kinase. Targeting that kinase with its inhibitor ibrutinib provides a potential therapeutic approach for the activated B-cell subtype of diffuse large B-cell lymphoma. However, non-Hodgkin lymphoma is often resistant to ibrutinib or soon develops resistance after exposure to it. In this study, we explored the development of acquired ibrutinib resistance. After generating three isogenic ibrutinib-resistant diffuse large B-cell lymphoma cell lines, we investigated the deregulated pathways that are associated with colony formation, growth rates, and tumorigenic properties. We found that reduced levels of Bruton’s tyrosine kinase and enhanced phosphatidylinositol 3-kinase/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of phosphatidylinositol-3-kinase-beta expression in those cells drove resistance and was reversed by the blocking activity of phosphatidylinositol-3-kinase-beta/delta. Treatment with the selective phosphatidylinositol-3-kinase-beta/delta dual inhibitor KA2237 reduced both tumorigenic properties and survival-based phosphatidylinositol-3-kinase/AKT/mTOR signaling of these ibrutinib-resistant cells. Additionally, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited the metabolic growth of these ibrutinib-resistant cells. This study elucidates the compensatory upregulated phosphatidylinositol-3-kinase/AKT axis that emerges in ibrutinib-resistant cells.
Necrotizing Soft Tissue Infections Staphylococcus aureus - but not Streptococcus pyogenes-isolates display high rate of internalization and cytotoxicity toward human myoblasts
Authors: Baude Jessica , Bastien Sylvère , Gillet Yves , Leblanc Pascal , Itzek Andreas , Tristan Anne , Bes Michèle , Duguez Stephanie , Moreau Karen , Diep Binh An , Norrby-Teglund Anna , Henry Thomas , Vandenesch François ,   and INFECT Study Group
Published: January 2019

Necrotizing Soft Tissue Infections (NSTIs), often reaching the deep fascia and muscle, are mainly caused by group A Streptococcus (GAS) and to a lesser extent by Staphylococcus aureus (SA). Conversely SA is a leading etiologic agent of pyomyositis suggesting that SA could have a specific tropism for the muscle. To assess the pathogenicity of these two bacterial species for muscles cells in comparison to keratinocytes, adhesion and invasion of NSTI-GAS and NSTI-SA were assessed on these cells. Bloodstream infections (BSI) SA isolates and non-invasive coagulase negative Staphylococci (CNS) isolates were used as controls.

SA isolates from NSTI and from BSI exhibited stronger internalization into human keratinocytes and myoblasts than CNS or NSTI-GAS. While the median level of SA internalization culminated at 2% in human keratinocytes, it reached over 30% in human myoblasts due to a higher percentage of infected myoblasts (>11%) as compared to keratinocytes (<3%) assessed by transmission electron microscopy. Higher cytotoxicity for myoblasts of NSTI-SA as compared to BSI-SA, was attributed to higher levels of psmα and RNAIII transcripts in NSTI group as compared to hematogenous group. However, the two groups were not discriminated at the genomic level. The cellular basis of high internalization rate in myoblasts was attributed to higher expression of α5β1 integrin in myoblasts as compared to keratinocytes. Major contribution of FnbpAB-integrin α5β1 pathway to internalization was confirmed by isogenic mutants.

Our findings suggest the contribution of NSTI-SA severity by its unique propensity to invade and kill myoblasts, a property not shared by NSTI-GAS.

Importance

Necrotizing Soft Tissue Infection (NSTI) is a severe infection caused mainly by group A Streptococcus (GAS) and occasionally by S. aureus (SA); the latter being more often associated with pyomyositis. NSTIs frequently involve the deep fascia and may provoke muscle necrosis. The goal of this study was to determine the tropism and pathogenicity of these two bacterial species for muscle cells. The results revealed a high tropism of SA for myoblasts and myotubes followed by cytotoxicity as opposed to GAS that did not invade these cells. This study uncover a novel mechanism of SA contribution to NSTI with a direct muscle involvement, while in GAS NSTI this is likely indirect, for instance, secondary to vascular occlusion.
The mutational constraint spectrum quantified from variation in 141,456 humans
Authors: Karczewski Konrad J. , Francioli Laurent C. , Tiao Grace , Cummings Beryl B. , Alföldi Jessica , Wang Qingbo , Collins Ryan L. , Laricchia Kristen M. , Ganna Andrea , Birnbaum Daniel P. , Gauthier Laura D. , Brand Harrison , Solomonson Matthew , Watts Nicholas A. , Rhodes Daniel , Singer-Berk Moriel , England Eleina M. , Seaby Eleanor G. , Kosmicki Jack A. , Walters Raymond K. , Tashman Katherine , Farjoun Yossi , Banks Eric , Poterba Timothy , Wang Arcturus , Seed Cotton , Whiffin Nicola , Chong Jessica X. , Samocha Kaitlin E. , Pierce-Hoffman Emma , Zappala Zachary , O’Donnell-Luria Anne H. , Minikel Eric Vallabh , Weisburd Ben , Lek Monkol , Ware James S. , Vittal Christopher , Armean Irina M. , Bergelson Louis , Cibulskis Kristian , Connolly Kristen M. , Covarrubias Miguel , Donnelly Stacey , Ferriera Steven , Gabriel Stacey , Gentry Jeff , Gupta Namrata , Jeandet Thibault , Kaplan Diane , Llanwarne Christopher , Munshi Ruchi , Novod Sam , Petrillo Nikelle , Roazen David , Ruano-Rubio Valentin , Saltzman Andrea , Schleicher Molly , Soto Jose , Tibbetts Kathleen , Tolonen Charlotte , Wade Gordon , Talkowski Michael E. ,   Genome Aggregation Database (gnomAD) Consortium, Neale Benjamin M. , Daly Mark J. , MacArthur Daniel G.
Published: January 2019

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved human mutation rate model, we classify human protein-coding genes along a spectrum representing tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.
Multicenter Analysis of Dosing Protocols for Sotalol Initiation
Authors: Biswas Minakshi , Levy Andrew , Weber Rachel , Tarakji Khaldoun , Chung Mina , Noseworthy Peter A. , Newton-Cheh Christopher , Rosenberg Michael A.
Published: January 2019

Sotalol is a Vaughan-Williams Class III antiarrhythmic medication that is commonly used in the management of both atrial and ventricular arrhythmias. Like others in this class, sotalol carries a risk of the potentially lethal arrhythmia torsade de pointes due to its effect of prolonging the QT interval on ECG. For this reason, many centers admit patients for telemetry monitoring during the initial 2-3 days of dosing. However, despite its widespread use, little information is available about the dosing protocols used during this initiation process. In this multicenter investigation, we examine the characteristics of various dose protocols in 213 patients who initiated sotalol over a 4-year period. Of these patients, over 90% were able to successfully complete the dosing regimen (i.e., were discharged on the medication). Significant bradycardia, excessive QT prolongation, and ineffectiveness were the main reasons for failed completion. We found that any dose adjustment was one of the strongest univariate predictors of successful initiation (OR 6.6, 95%CI 1.3 – 32.7, p = 0.021), while initial dose, indication, and resting heart rate or QT interval on baseline ECG did not predict successful initiation. Several predictors of any dose adjustment were identified, and included diabetes, hypertension, presence of pacemaker, heart failure diagnosis, and depressed LV ejection fraction. Using marginal structural models (i.e., inverse probability weighting based on probability of a dose adjustment), we verified that these factors also predicted successful initiation via preventing any dose adjustment, and suggests that consideration of these factors may result in higher likelihood of successful initiation in future investigations. In conclusion, we found that the majority of patients admitted for sotalol initiation are successfully discharged on the medication, often without a single adjustment in the dose. Our findings suggest that several factors predicting lack of dose adjustment could be used clinically to identify patients who could potentially undergo outpatient initiation, although prospective studies are needed to verify this approach.
How lucky was the genetic investigation in the Golden State Killer case?
Authors: Edge Michael (Doc) , Coop Graham
Published: January 2019

Long-range forensic familial searching is a new method in forensic genetics. In long-range search, a sample of interest is genotyped at single-nucleotide polymorphism (SNP) markers, and the genotype is compared with a large database in order to find relatives. Here, we perform some simple calculations that explore the basic phenomena that govern long-range searching. Two opposing phenomena—one genealogical and one genetic—govern the success of the search in a database of a given size. As one considers more distant genealogical relationships, any target sample is likely to have more relatives—on average, one has more second cousins than first cousins, and so on. But more distant relatives are also harder to detect genetically. Starting with third cousins, there is an appreciable chance that a given genealogical relationship will not be detectable genetically. Given the balance of these genealogical and genetic phenomena and the size of databases currently queryable by law enforcement, it is likely that most people with substantial recent ancestry in the United States are accessible via long-range search.

Note

This material was originally posted on the Coop lab site on May 7th, 2018, soon after the reporting of the arrest of Joseph DeAngelo in the Golden State Killer case, one of the first high-profile uses of long-range familial search. Subsequently, Erlich et al. (2018) published a detailed analysis in a large empirical dataset along with a theoretical analysis of a model similar to the one we use here, obtaining results broadly consistent with the ones presented here. Because Erlich and colleagues kindly cited this work when describing their model, we thought it would be appropriate to post this material in a venue where it is more easily cited.
Neuroinflammation and functional connectivity in Alzheimer’s disease: interactive influences on cognitive performance
Authors: Passamonti L. , Tsvetanov K.A. , Jones P.S. , Bevan-Jones W.R. , Arnold R. , Borchert R.J. , Mak E. , Su L. , O’Brien J.T. , Rowe J.B.
Published: January 2019

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer’s disease. We test the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment.

We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 humans (13 females/15 males) with clinical diagnosis of probable Alzheimer’s disease or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy humans (8 females/6 males). Source-based ‘inflammetry’ was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were pre-processed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal co-variance between neuroinflammation and brain connectivity profiles, in relation to group and cognitive status.

Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, medial, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.

Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer’s disease. Neuroinflammation, and its association with functionally-relevant reorganisation of brain networks, is proposed as a target for emerging immuno-therapeutic strategies aimed at preventing or slowing the emergence of dementia.

Significance Statement

Neuroinflammation is an important aspect of Alzheimer’s disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit.

Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between inflammation and functional network connectivity is relevant to cognitive impairment.

We suggest that future studies should address how neuroinflammation relates to network function as AD progresses; and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.
Streptomycesendophytes promote the growth ofArabidopsis thaliana
Authors: Worsley Sarah F. , Newitt Jake , Rassbach Johannes , Batey Sibyl F. D. , Holmes Neil A. , Murrell J. Colin , Wilkinson Barrie , Hutchings Matthew I.
Published: January 2019

Streptomycesbacteria are ubiquitous in soils and are well-known for producing secondary metabolites, including antimicrobials. Increasingly, they are being isolated from plant roots and several studies have shown they are specifically recruited to the rhizosphere and the endosphere of the model plantArabidopsis thaliana. Here we test the hypothesis thatStreptomycesbacteria have a beneficial effect onA. thalianagrowth and could potentially be used as plant probiotics. To do this, we selectively isolated streptomycetes from surface washedA. thalianaroots and generated high quality genome sequences for five strains which we named L2, M2, M3, N1 and N2. Re-infection ofA. thalianaplants with L2, M2 and M3 significantly increased plant biomass individually and in combination whereas N1 and N2 had a negative effect on plant growth, likely due to their production of polyene natural products which can bind to phytosterols and reduce plant growth. N2 exhibits broad spectrum antimicrobial activity and makes filipin-like polyenes, including 14-hydroxyisochainin which inhibits the Take-all fungus,Gaeumannomyces graminisvar.tritici. N2 antifungal activity as a whole was upregulated ~2-fold in response to indole-3-acetic acid (IAA) suggesting a possible role during competition in the rhizosphere. Furthermore, coating wheat seeds with N2 spores protected wheat seedlings against Take-all disease. We conclude that at least some soil dwelling streptomycetes confer growth promoting benefits onA. thalianawhile others might be exploited to protect crops against disease.

Importance

It is vital that we reduce our reliance on agrochemicals and there is increasing interest in using bacterial strains to promote plant growth and protect against disease. Our study follows up reports thatArabidopsis thalianaspecifically recruitsStreptomycesbacteria to its roots. In particular, we test the hypothesis that these bacteria can offer benefits to theirA. thalianahosts and that strains isolated from these plants might be used as probiotics. We isolatedStreptomycesstrains from surface washedA. thalianaroots and genome sequenced five phylogenetically distinct strains. Genome mining and bioassays indicated that all five strains have plant growth promoting properties, including production of IAA, siderophores and ACC deaminase activity. Three strains significantly increasedA. thalianagrowthin vitroand when applied in combination in soil. Another produces potent filipin-like antifungal metabolites and we used it as a seed coating to protect germinating wheat seeds against the fungal pathogenGaeumannomyces graminisvar.tritici(wheat Take-all fungus). We conclude that introducing an optimal combination ofStreptomycesstrains into the root microbiome can provide significant benefits to plants.
Yorkie controls tube length and apical barrier integrity in the developingDrosophilaairways
Authors: Papadopoulos Dimitrios K. , Tomancak Pavel , Tsarouhas Vasilios , Samakovlis Christos , Knust Elisabeth , Skouloudaki Kassiani
Published: January 2019

Epithelial organ size and shape depend on cell shape changes, cell-matrix communication and apical membrane growth. TheDrosophilaembryonic tracheal network is an excellent model to study these processes. Here, we show that the transcriptional co-activator of the Hippo pathway, Yorkie (YAP in vertebrates), plays distinct roles in the developingDrosophilaairways. Yorkie exerts a cytoplasmic function by bindingDrosophilaTwinstar, the orthologue of the vertebrate actin-severing protein Cofilin, to regulate F-actin levels and apical cell membrane size, which are required for proper tracheal tube elongation. Second, Yorkie controls water-tightness of tracheal tubes by transcriptional regulation of the enzymeδ-aminolevulinate synthase(Alas). We conclude that Yorkie has a dual role in tracheal development to ensure proper tracheal growth and functionality.

Short Summary

This work identified an alternative role of the transcriptional co-activator Yorkie (Yki) in controlling water impermeability and tube size of the developingDrosophilaairways. Tracheal impermeability is triggered by Yki-mediated transcriptional regulation ofδ-aminolevulinate synthase,Alas, whereas tube elongation is controlled by binding of Yki to the actin severing factor Twinstar.
Disease-associated scaffold protein CNK2 modulates PSD size and influences trafficking of new synaptic binding partner TNIK
Authors: Zieger Hanna L. , Kunde Stella-Amrei , Rademacher Nils , Schmerl Bettina , Shoichet Sarah A.
Published: January 2019

Scaffold proteins are responsible for structural organisation within cells; they form complexes with other proteins to facilitate signalling pathways and catalytic reactions. The scaffold protein connector enhancer of kinase suppressor of Ras 2 (CNK2) is predominantly expressed in neural tissues and was recently implicated in X-linked intellectual disability (ID). We have investigated the role of CNK2 in neurons in order to contribute to our understanding of how CNK2 alterations might cause developmental defects, and we have elucidated a functional role for CNK2 in the molecular processes that govern morphology of the postsynaptic density (PSD). We have also identified novel CNK2 interaction partners and explored their functional interdependency with CNK2. We focussed on the novel interaction partner TRAF2- and NCK-interacting kinase TNIK, which is also associated with ID. Both CNK2 and TNIK are expressed in neuronal dendrites and concentrated in dendritic spines, and staining with synaptic markers indicates a clear postsynaptic localisation. Importantly, our data highlight that CNK2 plays a role in directing TNIK subcellular localisation, and in neurons, CNK2 participates in ensuring that this multifunctional kinase is present at desirable levels at synaptic sites. In summary, our data indicate that CNK2 expression is critical for modulating PSD morphology; moreover, our study highlights a role for CNK2 in directing the localisation of regulatory proteins within the cell. Importantly, we describe a novel link between CNK2 and the regulatory kinase TNIK, and provide evidence supporting the idea that these proteins play complementary roles in the regulation of dendritic spine growth and maintenance.
Sequence-dependent trafficking of GDE2, a GPI-specific phospholipase promoting neuronal differentiation
Authors: Salgado-Polo Fernando , van Veen Michiel , van den Broek Bram , Leyton-Puig Daniela , Baas Roy , Perrakis Anastassis , Moolenaar Wouter H. , Matas-Rico Elisa
Published: January 2019

GDE2 is a six-transmembrane glycerophosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby influences biological signaling cascades. GDE2 promotes neuronal differentiation cell-autonomously through glypican cleavage and is a prognostic marker in neuroblastoma, while GDE2 deficiency causes progressive neurodegeneration in mice and developmental defects in zebrafish. However, the regulation of GDE2 remains unclear. Here we show that in undifferentiated neuronal cells, GDE2 undergoes constitutive internalization and traffics back along both fast and slow recycling routes, while a small percentage is sorted to late endosomes. GDE2 trafficking is dictated by distinctive C-terminal tail sequences that determine secretion, endocytosis and recycling preference, respectively, and thereby regulate GDE2 function both positively and negatively. Our study reveals the sequence determinants of GDE2 trafficking and surface localization, and provides insight into the control of GPI-anchored protein activities with potential implications for nervous system disorders associated with impaired trafficking and beyond.
RE-EVALUATION OF MEFV GENE VARIANTS: UTILITY OF A GENE SPECIFIC THRESHOLD IN REDUCING THE NUMBER OF VARIANTS OF UNKNOWN SIGNIFICANCE
Authors: Accetturo Matteo , D’Uggento Angela Maria , Portincasa Piero , Stella Alessandro
Published: January 2019

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory syndrome caused by mutations in the MEFV gene. MEFV variants are still in large part classified as variant of uncertain significance (VOUS), or with classification unresolved, posing significant challenges in the clinical diagnosis of Familial Mediterranean Fever (FMF). REVEL is a recently developed variant metapredictor tool. To reduce the number of MEFV variants with ambiguous classification we extracted the REVEL score for all missense variants reported at the locus specific database INFEVERS, and analyzed its correlation with expert-based classification and localization in the MEFV-encoded pyrin protein functional domains.

The data set of 216 missense variants was divided in four classification categories (BENIGN, VOUS, PATHOGENIC and UNRESOLVED). MEFV variants were plotted onto the pyrin protein, the distribution of REVEL scores in each category was computed and means, confidence intervals, and area under the receiver operating curve were calculated.

We observed a non-random distribution of pathogenic variants along the functional domains of the pyrin protein. The REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases (INSAID). Sensitivity, specificity, and accuracy were calculated for different cutoff values of REVEL scores and a gene-specific threshold was computed with confidence boundary limits. A REVEL score of 0.298 was the best performing cut-off to reclassify 96 MEFV gene variants previously of uncertain significance or unsolved thus reducing their proportion from 61.6% to 17.6%.

In conclusion, the combination of available expert information with highly sensitive predictor tools yields to more accurate interpretation of clinical consequences of MEFV gene variants. This approach should bring to a better genetic counseling and patient management.

Author summary

We aimed to refine MEFV gene variants classification using the metapredictor REVEL. We demonstrate that a gene-specific threshold is effective for accurate variants’ classification. Using this threshold, we reduced significantly the proportion of MEFV variants with an ambiguous classification. The proposed classification could represent a useful resource for variant interpretation in the context of FMF diagnosis.
The SUMO ligase Su(var)2-10 controls eu- and heterochromatic gene expression via establishment of H3K9 trimethylation and negative feedback regulation
Authors: Ninova Maria , Godneeva Baira , Ariel Chen Yung-Chia , Luo Yicheng , Prakash Sharan J. , Jankovics Ferenc , Erdélyi Miklós , Tóth Katalin Fejes , Aravin Alexei A.
Published: January 2019

Chromatin is critical for genome compaction and gene expression. On a coarse scale, the genome is divided into euchromatin, which harbors the majority of genes and is enriched in active chromatin marks, and heterochromatin, which is gene-poor but repeat-rich. The conserved molecular hallmark of heterochromatin is the H3K9me3 modification, which is associated with gene silencing. We found that inDrosophiladeposition of most of the H3K9me3 mark depends on SUMO and the SUMO-ligase Su(var)2-10, which recruits the histone methyltransferase complex SetDB1/Wde. In addition to repressing repeats, H3K9me3 also influences expression of both hetero- and euchromatic host genes. High H3K9me3 levels in heterochromatin are required to suppress spurious non-canonical transcription and ensure proper gene expression. In euchromatin, a set of conserved genes is repressed by Su(var)2-10/SetDB1-induced H3K9 trimethylation ensuring tissue-specific gene expression. Several components of heterochromatin are themselves repressed by this pathway providing a negative feedback mechanism to ensure chromatin homeostasis.

Highlights

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Proper expression of host genes residing in heterochromatin requires Su(var)2-10-dependent installation of the H3K9me3 mark to suppress spurious non-canonical transcription.

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A set of euchromatic host genes is repressed by transposon-independent installation of H3K9me3 in a process that depends on Su(var)2-10 and SUMO.

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Installation of H3K9me3 via Su(var)2-10 ensures tissue-specific gene expression.

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H3K9me3-dependent silencing of genes encoding proteins involved in heterochromatin formation provides negative feedback regulation to maintain heterochromatin homeostasis.
Neanderthal introgression reintroduced functional alleles lost in the human out of Africa bottleneck
Authors: Rinker David C. , Simonti Corinne N. , McArthur Evonne , Shaw Douglas , Hodges Emily , Capra John A.
Published: January 2019

Neanderthal ancestry remains across modern Eurasian genomes, and introgressed sequences influence diverse phenotypes, including immune, skin, and neuropsychiatric diseases. Interpretation of introgressed sequences has focused on alleles derived in the Neanderthal lineage. Here, we demonstrate that Neanderthal introgression also reintroduced thousands of ancestral hominin alleles lost in the Eurasian out of Africa bottleneck. Combining evolutionary simulations, expression quantitative trait loci (eQTL), massively parallel reporter assay (MPRA) data, and in vitro validation, we show that reintroduced alleles (RAs) have different fitness effects than Neanderthal-derived alleles (NDAs) and that some RAs regulate gene expression independent of NDAs. Illustrating the broad potential influence of RAs, we find that over 70% of known phenotype associations with NDAs are equally associated with RAs. Finally, we discover enrichment for RA eQTL activity in several tissues, with strongest enrichment in the brain. In summary, our study reveals that Neanderthal introgression supplied Eurasians with many lost functional variants and demonstrates that RAs must be considered when evaluating the effects of introgression.

ONE SENTENCE SUMMARY

Neanderthal interbreeding with modern humans restored to Eurasians, hundreds of thousands of ancient alleles that were lost in the out of Africa bottleneck.
High-speed device synchronization in optical microscopy with an open-source hardware control platform
Authors: Colville Marshall J. , Park Sangwoo , Zipfel Warren R. , Paszek Matthew J.
Published: January 2019

Recent advances in fluorescence microscopy have enabled the visualization of subcellular structures at unprecedented resolution. However, the complexity of state-of-the-art microscopes has increased considerably, often requiring the precise control and synchronization of multiple peripheral devices at high speeds. Drawing inspiration from open-source prototyping systems, like the Arduino, we describe the development of a new control platform that adopts the best features of these systems – affordability, facile programmability, and flexible connectivity – but with the scientific-grade inputs and outputs (I/O) and built-in routines that are necessary to control peripherals in advanced microscopy applications. Notably, our platform includes waveform generators and I/O for point-and azimuthal-scanning of excitation in laser-based applications. As a proof of concept, we show how the integration of waveform generation, multiplexed analog outputs, and native hardware triggers into a single central hub provides a versatile platform for performing fast circle-scanning acquisitions, including ring scanning-angle interference microscopy (SAIM), total internal reflection fluorescence (TIRF and ring TIRF) microscopy, and multiangle TIRF (MA-TIRF). We also demonstrate how the low communication latency of our hardware platform can reduce image intensity and reconstruction artifacts arising from synchronization errors produced by software control. Our complete platform, including hardware design files, firmware, API, software, and all associated source code, will be hosted for community-based development and collaboration.
Interacting cells driving the evolution of multicellular life cycles
Authors: Gao Yuanxiao , Traulsen Arne , Pichugin Yuriy
Published: January 2019

Evolution of complex multicellular life begun from the emergence of life cycle involving formation of cell clusters. Opportunity for cells to interact within clusters provided them an advantage over unicellular life forms. However, what kind of interactions may lead to the evolution of multicellular life cycles? Here, we combine evolutionary game theory with a model for the emergence of multicellular groups to investigate how cell interactions can influence reproduction modes during the early stages of the evolution of multicellularity. We identify evolutionary optimal life cycles as those which maximize the population growth rate. Among all interactions captured by two-player games, only eight life cycles were found to be evolutionarily optimal. Moreover, the vast majority of games promotes either of two classes of life cycles: (i) splitting into unicellular propagules or (ii) fragmentation into two offspring clusters of equal (or almost equal) size. Our findings indicate that the three most important characteristics, determining whether multicellular life cycles will evolve, are average performance of homogeneous groups, heterogeneous groups, and solitary cells.