bluuebunny/crossref_metadata_2025 huggingface dataset:
SomaticTARDBPvariants as a cause of semantic dementia
Authors: van Rooij Jeroen , Mol Merel O , Melhem Shamiram , van der Wal Pelle , Arp Pascal , Paron Francesca , Donker Kaat Laura , Seelaar Harro ,   Netherlands Brain Bank, Miedema Suzanne S M , Oshima Takuya , Eggen Bart J L , Uitterlinden André , van Meurs Joyce , van Kesteren Ronald E , Smit August B , Buratti Emanuele , van Swieten John C
Published: September 2020

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in neurodegenerative disease. Semantic dementia is characterized by a non-familial occurrence, early onset (<65 years), focal temporal atrophy and TDP-43 pathology. To test whether somatic variants in neural progenitor cells during brain development might lead to semantic dementia, we compared deep exome sequencing data of DNA derived from brain and blood of 16 semantic dementia cases. Somatic variants observed in brain tissue and absent in blood were validated using amplicon sequencing and digital PCR. We identified two variants in exon one of the TARDBP gene (L41F and R42H) at low level (1–3%) in cortical regions and in dentate gyrus in two semantic dementia brains, respectively. The pathogenicity of both variants is supported by demonstrating impaired splicing regulation of TDP-43 and by altered subcellular localization of the mutant TDP-43 protein. These findings indicate that somatic variants may cause semantic dementia as a non-hereditary neurodegenerative disease, which might be exemplary for other late-onset neurodegenerative disorders.
Serotonergic Innervations of the Orbitofrontal and Medial-prefrontal Cortices are Differentially Involved in Visual Discrimination and Reversal Learning in Rats
Authors: Alsiö Johan , Lehmann Olivia , McKenzie Colin , Theobald David E , Searle Lydia , Xia Jing , Dalley Jeffrey W , Robbins Trevor W
Published: September 2020

Cross-species studies have identified an evolutionarily conserved role for serotonin in flexible behavior including reversal learning. The aim of the current study was to investigate the contribution of serotonin within the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) to visual discrimination and reversal learning. Male Lister Hooded rats were trained to discriminate between a rewarded (A+) and a nonrewarded (B−) visual stimulus to receive sucrose rewards in touchscreen operant chambers. Serotonin was depleted using surgical infusions of 5,7-dihydroxytryptamine (5,7-DHT), either globally by intracebroventricular (i.c.v.) infusions or locally by microinfusions into the OFC or mPFC. Rats that received i.c.v. infusions of 5,7-DHT before initial training were significantly impaired during both visual discrimination and subsequent reversal learning during which the stimulus–reward contingencies were changed (A− vs. B+). Local serotonin depletion from the OFC impaired reversal learning without affecting initial discrimination. After mPFC depletion, rats were unimpaired during reversal learning but slower to respond at the stimuli during all the stages; the mPFC group was also slower to learn during discrimination than the OFC group. These findings extend our understanding of serotonin in cognitive flexibility by revealing differential effects within two subregions of the prefrontal cortex in visual discrimination and reversal learning.
Sustained Responses of Neutralizing Antibodies Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Recovered Patients and Their Therapeutic Applicability
Authors: Kim Yeon-Sook , Aigerim Abdimadiyeva , Park Uni , Kim Yuri , Park Hyoree , Rhee Ji-Young , Choi Jae-Phil , Park Wan Beom , Park Sang Won , Kim Yeonjae , Lim Dong-Gyun , Choi Ji-Yeob , Jeon Yoon Kyung , Yang Jeong-Sun , Lee Joo-Yeon , Shin Hyoung-Shik , Cho Nam-Hyuk
Published: September 2020

Background

Zoonotic coronaviruses have emerged as a global threat by causing fatal respiratory infections. Given the lack of specific antiviral therapies, application of human convalescent plasma retaining neutralizing activity could be a viable therapeutic option that can bridges this gap.

Methods

We traced antibody responses and memory B cells in peripheral blood collected from 70 recovered Middle East respiratory syndrome coronavirus (MERS-CoV) patients for 3 years after the 2015 outbreak in South Korea. We also used a mouse infection model to examine whether the neutralizing activity of collected sera could provide therapeutic benefit in vivo upon lethal MERS-CoV challenge.

Results

Anti-spike-specific IgG responses, including neutralizing activity and antibody-secreting memory B cells, persisted for up to 3 years, especially in MERS patients who suffered from severe pneumonia. Mean antibody titers gradually decreased annually by less than 2-fold. Levels of antibody responses were significantly correlated with fever duration, viral shedding periods, and maximum viral loads observed during infection periods. In a transgenic mice model challenged with lethal doses of MERS-CoV, a significant reduction in viral loads and enhanced survival was observed when therapeutically treated with human plasma retaining a high neutralizing titer (> 1/5000). However, this failed to reduce pulmonary pathogenesis, as revealed by pathological changes in lungs and initial weight loss.

Conclusions

High titers of neutralizing activity are required for suppressive effect on the viral replication but may not be sufficient to reduce inflammatory lesions upon fatal infection. Therefore, immune sera with high neutralizing activity must be carefully selected for plasma therapy of zoonotic coronavirus infection.
External validation of prognostic models: what, why, how, when and where?
Authors: Ramspek Chava L , Jager Kitty J , Dekker Friedo W , Zoccali Carmine , van Diepen Merel
Published: September 2020

Prognostic models that aim to improve the prediction of clinical events, individualized treatment and decision-making are increasingly being developed and published. However, relatively few models are externally validated and validation by independent researchers is rare. External validation is necessary to determine a prediction model’s reproducibility and generalizability to new and different patients. Various methodological considerations are important when assessing or designing an external validation study. In this article, an overview is provided of these considerations, starting with what external validation is, what types of external validation can be distinguished and why such studies are a crucial step towards the clinical implementation of accurate prediction models. Statistical analyses and interpretation of external validation results are reviewed in an intuitive manner and considerations for selecting an appropriate existing prediction model and external validation population are discussed. This study enables clinicians and researchers to gain a deeper understanding of how to interpret model validation results and how to translate these results to their own patient population.
Adoptive transfer of CX3CR1 transduced-T regulatory cells improves homing to the atherosclerotic plaques and dampens atherosclerosis progression
Authors: Bonacina Fabrizia , Martini Elisa , Svecla Monika , Nour Jasmine , Cremonesi Marco , Beretta Giangiacomo , Moregola Annalisa , Pellegatta Fabio , Zampoleri Veronica , Catapano Alberico Luigi , Kallikourdis Marinos , Norata Giuseppe Danilo
Published: September 2020

Aim

Loss of immunosuppressive response supports inflammation during atherosclerosis. We tested whether adoptive cell therapy (ACT) with Tregulatory cells (Tregs), engineered to selectively migrate in the atherosclerotic plaque, would dampen the immune-inflammatory response in the arterial wall in animal models of familial hypercholesterolaemia (FH).

Methods and results

FH patients presented a decreased Treg suppressive function associated to an increased inflammatory burden. A similar phenotype was observed in Ldlr −/− mice accompanied by a selective increased expression of the chemokine CX3CL1 in the aorta but not in other districts (lymph nodes, spleen, and liver). Treg overexpressing CX3CR1 were thus generated (CX3CR1+-Tregs) to drive Tregs selectively to the plaque. CX3CR1+-Tregs were injected (i.v.) in Ldlr −/− fed high-cholesterol diet (western type diet, WTD) for 8 weeks. CX3CR1+-Tregs were detected in the aorta, but not in other tissues, of Ldlr −/− mice 24 h after ACT, corroborating the efficacy of this approach. After 4 additional weeks of WTD, ACT with CX3CR1+-Tregs resulted in reduced plaque progression and lipid deposition, ameliorated plaque stability by increasing collagen and smooth muscle cells content, while decreasing the number of pro-inflammatory macrophages. Shotgun proteomics of the aorta showed a metabolic rewiring in CX3CR1+-Tregs treated Ldlr −/− mice compared to controls that was associated with the improvement of inflammation-resolving pathways and disease progression.

Conclusion

ACT with vasculotropic Tregs appears as a promising strategy to selectively target immune activation in the atherosclerotic plaque.
Clinical, Endoscopic and Histological Outcomes in Induction of Moderate-to-Severe Ulcerative Colitis: A Systematic Review with Meta-Analysis
Authors: Magro Fernando , Estevinho Maria Manuela , Dias Cláudia Camila , Correia Luís , Lago Paula , Ministro Paula , Portela Francisco , Feakins Roger , Danese Silvio , Peyrin-Biroulet Laurent
Published: September 2020

Background and Aims

Interest in histology for ulcerative colitis [UC] has increased recently. This systematic review and meta-analysis aims to assess, for the first time, whether histological outcomes are more informative than endoscopic and clinical outcomes in distinguishing the impact of intervention over placebo in induction trials.

Methods

MEDLINE, ScienceDirect and Cochrane Central Register of Controlled Trials were searched to identify randomized placebo-controlled trials [RCTs] enrolling moderate-to-severe UC patients. Studies were assessed using the Quality Assessment Tool for Studies with Diverse Designs. We analysed the pooled proportion of patients achieving clinical, endoscopic and histological remission and response after a pharmacological intervention and compared the results with those of placebo-treated patients by using a random-effects model.

Results

From 889 identified records, 13 RCTs were included. The odds ratio [OR] for remission was higher in patients receiving intervention than in those under placebo for clinical (OR 2.13, 95% confidence interval [CI] 1.33–3.43), endoscopic [OR 1.46, 95% CI 0.19–11.18] and histological remission [OR 1.85, 95% CI 1.20–2.84]. Significant differences were observed for all response outcomes [clinical: OR 2.27, 95% CI 1.84–2.85; endoscopic: OR 2.16, 95% CI 1.51–3.10; histological: OR 3.63, 95% CI, 1.41–9.36]. No significant heterogeneity existed; no subgroup effects were found for duration of the induction or histological scale [p > 0.05]. Clinical and histological remission and endoscopic response were concordant in discriminating interventions from placebo.

Conclusion

Histological outcomes are informative in trials of moderate-to-severe UC. Further studies analysing histology at the end of induction are needed to confirm its relevance in distinguishing the efficacy of an intervention over placebo in comparison to clinical and endoscopic outcomes and to explore its prognostic value.
The validity, reliability, sensitivity and responsiveness of a modified Patient Enablement Instrument (PEI-2) as a tool for serial measurements of health enablement
Authors: Bedford Laura Elizabeth , Yeung Maegan Hon Yan , Au Chi Ho , Tse Emily Tsui Yee , Yim Wing Yee , Yu Esther Yee Tak , Wong Carlos King Ho , Lam Cindy Lo Kuen
Published: September 2020

Background

Patient enablement is a core tenet of patient-centred and holistic primary care. The Patient Enablement Instrument (PEI) is a transitional measure limited in its ability to measure changes over time. A modified version, PEI-2, has been developed to measure enablement at a given time-point without comparison to a recalled baseline.

Objective

To assess the validity, reliability, sensitivity and responsiveness of PEI-2.

Methods

PEI-2 was modified from the Chinese PEI to assess enablement over 4 weeks in a prospective cohort study nested within a community support programme [Trekkers Family Enhancement Scheme (TFES)] in Hong Kong. Construct validity was assessed by factor analysis and convergent validity by Spearman’s correlations with health-related quality of life and depressive symptoms. Internal reliability was assessed using Cronbach’s alpha. Test–retest reliability was assessed by intraclass correlation (ICC), responsiveness by 12–24-month change in PEI-2 score and sensitivity by differences in change of PEI-2 score between TFES participants and a control group.

Results

PEI-2 demonstrated construct validity with all items loading on one factor (factor loadings >0.7). Convergent validity was confirmed by significant correlations with 12-item Short Form Questionnaire, version 2 (r = 0.1089–0.1919) and Patient Health Questionnaire-9 (r = −0.2030). Internal reliability was high (Cronbach’s alpha = 0.9095) and test–retest reliability moderate (ICC = 0.520, P = 0.506). Significant improvements in PEI-2 scores among the TFES group suggested good responsiveness (P < 0.001). The difference in change of PEI-2 scores between TFES and control was significant (P = 0.008), indicating good sensitivity.

Conclusions

This study supports the validity, reliability, sensitivity and responsiveness of PEI-2 in measuring changes in enablement, making it a promising tool for evaluating enablement in cohort and intervention studies.
General practitioner perceptions of assessment and reporting of absolute cardiovascular disease risk via pathology services: a qualitative study
Authors: Chapman Niamh , McWhirter Rebekah E , Schultz Martin G , Ezzy Douglas , Nelson Mark R , Sharman James E
Published: September 2020

Background

Guidelines for cardiovascular disease (CVD) prevention recommend assessment of absolute CVD risk to guide clinical management. Despite this, use among general practitioners (GPs) remains limited.

Objective

Pathology services may provide an appropriate setting to assess and report absolute CVD risk in patients attending for cholesterol measurement. This study aimed to explore GPs perceptions of such a service.

Methods

A focus group and semi-structured interviews were conducted with GPs (n = 18) in Tasmania, Australia, to identify perceptions of assessment and reporting of absolute CVD risk via pathology services. An example pathology report including absolute CVD risk was provided and discussed. Audio-recordings were transcribed and thematically coded by two researchers.

Results

Almost all GPs identified that absolute CVD risk assessed and reported via pathology services could address deficits in practice. First, by reducing the number of appointments required to collect risk factors. Second, by providing a systematic (rather than opportunistic) approach for assessment of absolute CVD risk. Third, by reducing misclassification of patient CVD risk caused by overreliance on clinical intuition. All GPs reported they would order absolute CVD risk when issuing a cholesterol referral if such a service was offered. GPs recommended improving the service by providing information on methods used to measure risk factors on the pathology report.

Conclusions

Absolute CVD risk assessed and reported via pathology services may address challenges of screening CVD risk experienced by GPs in practice and encourage dedicated follow-up care for CVD prevention.
Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome
Authors: Motahari Zahra , Maynard Thomas M , Popratiloff Anastas , Moody Sally A , LaMantia Anthony-S
Published: September 2020

We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel+/− mouse embryos, a genomically accurate 22q11.2DS model, and 3D imaging to identify and quantify phenotypes that could not be resolved using existing methods. We assessed these phenotypes in three 22q11.2-related genotypes to determine whether individual CN V motor and sensory axons wander, branch and sprout aberrantly in register with altered anterior–posterior hindbrain patterning and gross morphological disruption of CN V seen in LgDel+/−. In the additional 22q11.2-related genotypes: Tbx1+/−, Ranbp1−/−, Ranbp1+/− and LgDel+/−:Raldh2+/−; axon phenotypes are seen when hindbrain patterning and CN V gross morphology is altered, but not when it is normal or restored toward WT. This disordered growth of CN V sensory and motor axons, whose appropriate targeting is critical for optimal S/F/S, may be an early, critical determinant of imprecise innervation leading to inefficient oropharyngeal function associated with 22q11.2 deletion from birth onward.
No detrimental effects of desalination waste on temperate fish assemblages
Authors: Whitmarsh Sasha K , Barbara Greg M , Brook James , Colella Dimitri , Fairweather Peter G , Kildea Tim , Huveneers Charlie
Published: September 2020

Water resources are becoming increasingly scarce due to population growth and global changes in weather patterns. Desalination plants that extract freshwater from brackish or seawater are already being used worldwide, with many new plants being developed and built. The waste product from the extraction processes has an elevated salt concentration and can potentially cause substantial impacts to local marine flora and fauna. The present study assesses the impact of saline waste from a 100 GL/year desalination plant on southern Australian temperate fish assemblages, using baited remote underwater video. The study compared four reference sites to the impact site (desalination outfall) and found no evidence that the saline waste was having a detrimental effect on fish assemblages in proximity to the outfall, with species diversity and abundance comparable to those observed at reference sites. However, species diversity and abundance varied across geographical location, protection from fishing pressure, and reef type. Our study is one of the few assessing the ecological impacts of saline waste discharged from a large desalination plant and shows no decrease in fish diversity or abundance, which is the response typically associated with the negative impacts of anthropogenic activities on fish assemblages.
Nonpharmaceutical Interventions Used to Control COVID-19 Reduced Seasonal Influenza Transmission in China
Authors: Lei Hao , Xu Modi , Wang Xiao , Xie Yu , Du Xiangjun , Chen Tao , Yang Lei , Wang Dayan , Shu Yuelong
Published: September 2020

To suppress the ongoing COVID-19 pandemic, the Chinese government has implemented nonpharmaceutical interventions (NPIs). Because COVID-19 and influenza have similar means of transmission, NPIs targeting COVID-19 may also affect influenza transmission. In this study, the extent to which NPIs targeting COVID-19 have affected seasonal influenza transmission was explored. Indicators of seasonal influenza activity in the epidemiological year 2019–2020 were compared with those in 2017–2018 and 2018–2019. The incidence rate of seasonal influenza reduced by 64% in 2019–2020 (P < .001). These findings suggest that NPIs aimed at controlling COVID-19 significantly reduced seasonal influenza transmission in China.
Bim establishes the B-cell repertoire from early to late in the immune response
Authors: Sugimoto-Ishige Akiko , Harada Michishige , Tanaka Miho , Terooatea Tommy , Adachi Yu , Takahashi Yoshimasa , Tanaka Takashi , Burrows Peter D , Hikida Masaki , Takemori Toshitada
Published: September 2020

In T cell-dependent antibody responses, some of the activated B cells differentiate along extrafollicular pathways into low-affinity memory and plasma cells, whereas others are involved in subsequent germinal center (GC) formation in follicular pathways, in which somatic hypermutation and affinity maturation occur. The present study demonstrated that Bim, a proapoptotic BH3-only member of the Bcl-2 family, contributes to the establishment of the B-cell repertoire from early to late stages of immune responses to T cell-dependent antigens. Extrafollicular plasma cells grew in the spleen during the early immune response, but their numbers rapidly declined with the appearance of GC-derived progeny in wild-type mice. By contrast, conditional Bim deficiency in B cells resulted in expansion of extrafollicular IgG1+ antibody-forming cells (AFCs) and this expansion was sustained during the late response, which hampered the formation of GC-derived high-affinity plasma cells in the spleen. Approximately 10% of AFCs in mutant mice contained mutated VH genes; thus, Bim deficiency appears not to impede the selection of high-affinity AFC precursor cells. These results suggest that Bim contributes to the replacement of low-affinity antibody by high-affinity antibody as the immune response progresses.
Framing middle power foreign policy: trade, security, and human rights frames in Canadian and Australian foreign policy attitudes
Authors: Gravelle Timothy B
Published: September 2020

Middle power states in the Indo-Pacific region face a challenging foreign policy environment in light of geopolitical and economic rivalry between the United States and China. In this context, what factors shape the foreign policy attitudes of middle power publics? This article presents results from a set of survey-based experiments conducted in Canada and Australia, two archetypal middle power states located on the Pacific Rim. Demographically representative samples of both publics were presented with randomized vignettes highlighting facets of bilateral relations with the United States, regional partners (Mexico in the Canadian case, and Indonesia in the Australian case), and China. Results indicate that making different aspects of a particular relationship salient as part of the vignette shapes perceptions of and preferences toward relations with the state in question. Foreign policy attitudes are thus amenable to framing effects. Still, results point to different frames having greater relevance to different bilateral relationships.
Molecular mechanisms driving thein vivodevelopment of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDRPseudomonas aeruginosainfections
Authors: Arca-Suárez Jorge , Lasarte-Monterrubio Cristina , Rodiño-Janeiro Bruno-Kotska , Cabot Gabriel , Vázquez-Ucha Juan Carlos , Rodríguez-Iglesias Manuel , Galán-Sánchez Fátima , Beceiro Alejandro , González-Bello Concepción , Oliver Antonio , Bou Germán
Published: September 2020

Background

The development of resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of Pseudomonas aeruginosa infections is concerning.

Objectives

Characterization of the mechanisms leading to the development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR P. aeruginosa infections.

Methods

Four paired ceftolozane/tazobactam- and ceftazidime/avibactam-susceptible/resistant isolates were evaluated. MICs were determined by broth microdilution. STs, resistance mechanisms and genetic context of β-lactamases were determined by genotypic methods, including WGS. The OXA-10 variants were cloned in PAO1 to assess their impact on resistance. Models for the OXA-10 derivatives were constructed to evaluate the structural impact of the amino acid changes.

Results

The same XDR ST253 P. aeruginosa clone was detected in all four cases evaluated. All initial isolates showed OprD deficiency, produced an OXA-10 enzyme and were susceptible to ceftazidime, ceftolozane/tazobactam, ceftazidime/avibactam and colistin. During treatment, the isolates developed resistance to all cephalosporins. Comparative genomic analysis revealed that the evolved resistant isolates had acquired mutations in the OXA-10 enzyme: OXA-14 (Gly157Asp), OXA-794 (Trp154Cys), OXA-795 (ΔPhe153-Trp154) and OXA-824 (Asn143Lys). PAO1 transformants producing the evolved OXA-10 derivatives showed enhanced ceftolozane/tazobactam and ceftazidime/avibactam resistance but decreased meropenem MICs in a PAO1 background. Imipenem/relebactam retained activity against all strains. Homology models revealed important changes in regions adjacent to the active site of the OXA-10 enzyme. The blaOXA-10 gene was plasmid borne and acquired due to transposition of Tn6746 in the pHUPM plasmid scaffold.

Conclusions

Modification of OXA-10 is a mechanism involved in the in vivo acquisition of resistance to cephalosporin/β-lactamase inhibitor combinations in P. aeruginosa.
Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis
Authors: Kashour Zakariya , Riaz Muhammad , Garbati Musa A , AlDosary Oweida , Tlayjeh Haytham , Gerberi Dana , Murad M Hassan , Sohail M Rizwan , Kashour Tarek , Tleyjeh Imad M
Published: September 2020

Objectives

Clinical studies of chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 disease reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin on outcomes of COVID-19 patients.

Methods

We searched multiple databases, preprints and grey literature up to 17 July 2020. We pooled only adjusted-effect estimates of mortality using a random-effect model. We summarized the effect of CQ or HCQ on viral clearance, ICU admission/mechanical ventilation and hospitalization.

Results

Seven randomized clinical trials (RCTs) and 14 cohort studies were included (20 979 patients). Thirteen studies (1 RCT and 12 cohort studies) with 15 938 hospitalized patients examined the effect of HCQ on short-term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96–1.15, I2 = 0%). Six cohort studies examined the effect of the HCQ+azithromycin combination with a pooled adjusted OR of 1.32 (95% CI 1.00–1.75, I2 = 68.1%). Two cohort studies and four RCTs found no effect of HCQ on viral clearance. One small RCT demonstrated improved viral clearance with CQ and HCQ. Three cohort studies found that HCQ had no significant effect on mechanical ventilation/ICU admission. Two RCTs found no effect for HCQ on hospitalization risk in outpatients with COVID-19.

Conclusions

Moderate certainty evidence suggests that HCQ, with or without azithromycin, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19 or risk of hospitalization in outpatients with COVID-19.
Verification of Low-Density Lipoprotein Cholesterol Levels Measured by Anion-Exchange High-Performance Liquid Chromatography in Comparison with Beta Quantification Reference Measurement Procedure
Authors: Manita Daisuke , Yoshida Hiroshi , Koyama Isao , Nakamura Masakazu , Hirowatari Yuji
Published: September 2020

Background

A new lipoprotein testing method based on anion-exchange HPLC (AEX-HPLC) was recently established. We verified the accuracy of LDL-C levels, a primary therapeutic target for the prevention of cardiovascular disease (CVD), measured by AEX-HPLC comparing with LDL-C levels measured by beta quantification-reference measurement procedure (BQ-RMP), homogenous assays, and calculation methods.

Methods

We compared LDL-C levels measured by AEX-HPLC (adLDL-Ch: LDL-Ch and IDL-Ch) and BQ-RMP using blood samples from 52 volunteers. AdLDL-Ch levels were also compared with those measurements by homogeneous assays and calculation methods (Friedewald equation, Martin equation, and Sampson equation) using blood samples from 411 participants with dyslipidemia and/or type 2 diabetes.

Results

The precision and accuracy of adLDL-Ch were verified by BQ-RMP. The mean percentage bias [bias (%)] for LDL-C was 1.2%, and the correlation was y = 0.990x + 3.361 (r = 0.990). These results met the acceptable range of accuracy prescribed by the National Cholesterol Education Program. Additionally, adLDL-Ch levels were correlated with LDL-C levels measured by the 2 homogeneous assays (r > 0.967) and the calculation methods (r > 0.939), in serum samples from patients with hypertriglyceridemia.

Conclusions

AEX-HPLC is a reliable method for measuring LDL-C levels for CVD risk in daily clinical laboratory analyses.
Evaluation of Systemic Imidacloprid and Herbicide Treatments on Flatheaded Borer (Coleoptera: Buprestidae) Management in Field Nursery Production
Authors: Addesso Karla M , Oliver Jason B , Youssef Nadeer N , Fare Donna C
Published: September 2020

The flatheaded appletree borer, Chrysobothris femorata (Olivier) (Coleoptera: Buprestidae), and related species are deciduous tree pests. Female beetles prefer to oviposit at tree bases, and larvae tunnel beneath the bark, which weakens or kills young or newly transplanted trees. In the first objective of this study, Discus N/G (2.94% imidacloprid + 0.7% cyfluthrin) applied at six lower-than-labeled rates (0.0, 0.98, 1.97, 3.94, 5.91, and 7.87 ml/cm of average trunk dia.) was evaluated for protection of field-grown maples. A second objective evaluated imidacloprid with and without herbicides to assess the impact of weed competition at the tree base on insecticide effectiveness. A third objective determined relative imidacloprid concentrations in leaf tissue samples with ELISA and related to insecticide rates, herbicide treatments, and the level of flatheaded borer protection. In two trials, higher rates of insecticide were more effective at protecting trees, with rates ≥3.94 ml product/cm trunk diameter performing equivalently. Weed-free trees had more borer attacks and grew faster than trees in weedy plots. Imidacloprid content in leaf tissues had a trend for higher concentrations in smaller, weedy trees in the first season, but that pattern disappeared in subsequent years. Based on fewer attacks in weedy versus weed-free trees (60−90% reduction), it was concluded that weed presence can reduce borer attack success in nurseries independent of insecticide treatment, but tree growth was reduced by weed presence. In addition, Discus applied at rates >3.94 ml/cm did not confer added borer damage protection in weedy plots.
Novel −75°C SEM cooling stage: application for martensitic transformation in steel
Authors: Tsuzazki Kaneaki , Koyama Motomichi , Sasaki Ryosuke , Nakafuji Keiichiro , Oie Kazushi , Shibata Akinobu , Gondo Takashi , Miyazaki Hiroya , Akamine Hiroshi , Nishida Minoru
Published: September 2020

Microstructural changes during the martensitic transformation from face-centred cubic (FCC) to body-centred cubic (BCC) in an Fe-31Ni alloy were observed by scanning electron microscopy (SEM) with a newly developed Peltier stage available at temperatures to  −75°C. Electron channelling contrast imaging (ECCI) was utilized for the in situ observation during cooling. Electron backscatter diffraction analysis at ambient temperature (20°C) after the transformation was performed for the crystallographic characterization. A uniform dislocation slip in the FCC matrix associated with the transformation was detected at −57°C. Gradual growth of a BCC martensite was recognized upon cooling from −57°C to −63°C.
Ovarian malignant mixed Müllerian tumor: a rare case report from Tanzania
Authors: Pallangyo Angela , Pyuza Jeremia J , Andongolile Alice A , Mbwambo Daniel , Claver Jackson P , Koosa Ummil-Khairat , Lema Kennedy , Amsi Patrick , Nkya Gilbert , Mremi Alex
Published: September 2020

Malignant mixed Müllerian tumor of the ovary is rare aggressive tumor that is histologically defined by the presence of malignant epithelial and stromal components. We report a 37-year-old woman who consulted our facility complaining of abdominal distention and a painful palpable mass over her lower abdomen. Physical examination including computerized tomography revealed a complex cystic mass lesion on the left ovary with extensive omental involvement. Ovarian cancer was suspected and the patient underwent debulking surgery. The histopathology of the specimen revealed a high-grade tumor composed of both malignant epithelial and sarcomatous elements. Both epithelial and stromal components stained positive for p53 immunostaining. Before the initiation of chemotherapy, on 5th day postoperation, the patient was found unresponsive. The stage of the disease seems to be the most important prognostic factor, thus emphasis should be made to identify it in earlier stages.
An Unexpectedly Complex Mitoribosome in Andalucia godoyi, a Protist with the Most Bacteria-like Mitochondrial Genome
Authors: Valach Matus , Gonzalez Alcazar José Angel , Sarrasin Matt , Lang B Franz , Gray Michael W , Burger Gertraud
Published: September 2020

The mitoribosome, as known from studies in model organisms, deviates considerably from its ancestor, the bacterial ribosome. Deviations include substantial reduction of the mitochondrial ribosomal RNA (mt-rRNA) structure and acquisition of numerous mitochondrion-specific (M) mitoribosomal proteins (mtRPs). A broadly accepted view assumes that M-mtRPs compensate for structural destabilization of mt-rRNA resulting from its evolutionary remodeling. Since most experimental information on mitoribosome makeup comes from eukaryotes having derived mitochondrial genomes and mt-rRNAs, we tested this assumption by investigating the mitochondrial translation machinery of jakobids, a lineage of unicellular protists with the most bacteria-like mitochondrial genomes. We report here proteomics analyses of the Andalucia godoyi small mitoribosomal subunit and in silico transcriptomic and comparative genome analyses of four additional jakobids. Jakobids have mt-rRNA structures that minimally differ from their bacterial counterparts. Yet, with at least 31 small subunit and 44 large subunit mtRPs, the mitoriboproteome of Andalucia is essentially as complex as that in animals or fungi. Furthermore, the relatively high conservation of jakobid sequences has helped to clarify the identity of several mtRPs, previously considered to be lineage-specific, as divergent homologs of conserved M-mtRPs, notably mS22 and mL61. The coexistence of bacteria-like mt-rRNAs and a complex mitoriboproteome refutes the view that M-mtRPs were ancestrally recruited to stabilize deviations of mt-rRNA structural elements. We postulate instead that the numerous M-mtRPs acquired in the last eukaryotic common ancestor allowed mt-rRNAs to pursue a broad range of evolutionary trajectories across lineages: from dramatic reduction to acquisition of novel elements to structural conservatism.
Evolutionary Genomics of Niche-Specific Adaptation to the Cystic Fibrosis Lung in Pseudomonas aeruginosa
Authors: Dettman Jeremy R , Kassen Rees
Published: September 2020

The comparative genomics of the transition of the opportunistic pathogen Pseudomonas aeruginosa from a free-living environmental strain to one that causes chronic infection in the airways of cystic fibrosis (CF) patients remain poorly studied. Chronic infections are thought to originate from colonization by a single strain sampled from a diverse, globally distributed population, followed by adaptive evolution to the novel, stressful conditions of the CF lung. However, we do not know whether certain clades are more likely to form chronic infections than others and we lack a comprehensive view of the suite of genes under positive selection in the CF lung. We analyzed whole-genome sequence data from 1,000 P. aeruginosa strains with diverse ecological provenances including the CF lung. CF isolates were distributed across the phylogeny, indicating little genetic predisposition for any one clade to cause chronic infection. Isolates from the CF niche experienced stronger positive selection on core genes than those derived from environmental or acute infection sources, consistent with recent adaptation to the lung environment. Genes with the greatest differential positive selection in the CF niche include those involved in core cellular processes such as metabolism, energy production, and stress response as well as those linked to patho-adaptive processes such as antibiotic resistance, cell wall and membrane modification, quorum sensing, biofilms, mucoidy, motility, and iron homeostasis. Many genes under CF-specific differential positive selection had regulatory functions, consistent with the idea that regulatory mutations play an important role in rapid adaptation to novel environments.
Genome maintenance functions of a putative Trypanosoma brucei translesion DNA polymerase include telomere association and a role in antigenic variation
Authors: Leal Andrea Zurita , Schwebs Marie , Briggs Emma , Weisert Nadine , Reis Helena , Lemgruber Leandro , Luko Katarina , Wilkes Jonathan , Butter Falk , McCulloch Richard , Janzen Christian J
Published: September 2020

Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of one putative translesion Pol in African trypanosomes, which we now name TbPolIE. Previously, we demonstrated that TbPolIE is associated with telomeric sequences and here we show that RNAi-mediated depletion of TbPolIE transcripts results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. We also show that TbPolIE displays pronounced localization at the nuclear periphery, and that its depletion leads to chromosome segregation defects and increased levels of endogenous DNA damage. Finally, we demonstrate that TbPolIE depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this putative translesion DNA polymerase to host immune evasion by antigenic variation.
CK2 kinase-mediated PHF8 phosphorylation controls TopBP1 stability to regulate DNA replication
Authors: Feng Haihua , Lu Jingchen , Song Xiaotian , Thongkum Angkana , Zhang Fan , Lou Lihong , Reizes Ofer , Almasan Alexandru , Gong Zihua
Published: September 2020

ATR functions as a master regulator of the DNA-damage response. ATR activation requires the ATR activator, topoisomerase IIβ-binding protein 1 (TopBP1). However, the underlying mechanism of TopBP1 regulation and how its regulation affects DNA replication remain unknown. Here, we report a specific interaction between TopBP1 and the histone demethylase PHF8. The TopBP1/PHF8 interaction is mediated by the BRCT 7+8 domain of TopBP1 and phosphorylation of PHF8 at Ser854. This interaction is cell-cycle regulated and phosphorylation-dependent. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. Importantly, PHF8 regulates TopBP1 protein level by preventing its ubiquitination and degradation mediated by the E3 ligase UBR5. Interestingly, PHF8pS854 is likely to contribute to regulation of TopBP1 stability and DNA replication checkpoint. Further, both TopBP1 and PHF8 are required for efficient replication fork restart. Together, these data identify PHF8 as a TopBP1-binding protein and provide mechanistic insight into how PHF8 regulates TopBP1 stability to maintain DNA replication.
Post-translational modifications of hnRNP A1 differentially modulate retroviral IRES-mediated translation initiation
Authors: Barrera Aldo , Ramos Hade , Vera-Otarola Jorge , Fernández-García Leandro , Angulo Jenniffer , Olguín Valeria , Pino Karla , Mouland Andrew J , López-Lastra Marcelo
Published: September 2020

The full-length mRNAs of the human immunodeficiency virus type-1 (HIV-1), the human T-cell lymphotropic virus type-1 (HTLV-1), and the mouse mammary tumor virus (MMTV) harbor IRESs. The activity of the retroviral-IRESs requires IRES-transacting factors (ITAFs), being hnRNP A1, a known ITAF for the HIV-1 IRES. In this study, we show that hnRNP A1 is also an ITAF for the HTLV-1 and MMTV IRESs. The MMTV IRES proved to be more responsive to hnRNP A1 than either the HTLV-1 or the HIV-1 IRESs. The impact of post-translational modifications of hnRNP A1 on HIV-1, HTLV-1 and MMTV IRES activity was also assessed. Results show that the HIV-1 and HTLV-1 IRESs were equally responsive to hnRNP A1 and its phosphorylation mutants S4A/S6A, S4D/S6D and S199A/D. However, the S4D/S6D mutant stimulated the activity from the MMTV-IRES to levels significantly higher than the wild type hnRNP A1. PRMT5-induced symmetrical di-methylation of arginine residues of hnRNP A1 enabled the ITAF to stimulate the HIV-1 and HTLV-1 IRESs while reducing the stimulatory ability of the ITAF over the MMTV IRES. We conclude that retroviral IRES activity is not only dependent on the recruited ITAFs but also relies on how these proteins are modified at the post-translational level.
Epigenetic silencing of clustered tRNA genes in Arabidopsis
Authors: Hummel Guillaume , Berr Alexandre , Graindorge Stéfanie , Cognat Valérie , Ubrig Elodie , Pflieger David , Molinier Jean , Drouard Laurence
Published: September 2020

Beyond their key role in translation, cytosolic transfer RNAs (tRNAs) are involved in a wide range of other biological processes. Nuclear tRNA genes (tDNAs) are transcribed by the RNA polymerase III (RNAP III) and cis-elements, trans-factors as well as genomic features are known to influence their expression. In Arabidopsis, besides a predominant population of dispersed tDNAs spread along the 5 chromosomes, some clustered tDNAs have been identified. Here, we demonstrate that these tDNA clusters are transcriptionally silent and that pathways involved in the maintenance of DNA methylation play a predominant role in their repression. Moreover, we show that clustered tDNAs exhibit repressive chromatin features whilst their dispersed counterparts contain permissive euchromatic marks. This work demonstrates that both genomic and epigenomic contexts are key players in the regulation of tDNAs transcription. The conservation of most of these regulatory processes suggests that this pioneering work in Arabidopsis can provide new insights into the regulation of RNA Pol III transcription in other organisms, including vertebrates.
NG-Circos: next-generation Circos for data visualization and interpretation
Authors: Cui Ya , Cui Zhe , Xu Jianfeng , Hao Dapeng , Shi Jiejun , Wang Dan , Xiao Hui , Duan Xiaohong , Chen Runsheng , Li Wei
Published: September 2020

Circos plots are widely used to display multi-dimensional next-generation genomic data, but existing implementations of Circos are not interactive with limited support of data types. Here, we developed next-generation Circos (NG-Circos), a flexible JavaScript-based circular genome visualization tool for designing highly interactive Circos plots using 21 functional modules with various data types. To our knowledge, NG-Circos is the most powerful software to construct interactive Circos plots. By supporting diverse data types in a dynamic browser interface, NG-Circos will accelerate the next-generation data visualization and interpretation, thus promoting the reproducible research in biomedical sciences and beyond. NG-Circos is available at https://wlcb.oit.uci.edu/NG-Circos and https://github.com/YaCui/NG-Circos.
Treatment Switch to Dolutegravir With 2 Nucleoside Reverse-Transcriptase Inhibitors (NRTI) in Comparison to Continuation With Protease Inhibitor/Ritonavir Among Patients With Human Immunodeficiency Virus at Risk for Prior NRTI Resistance: A Cohort Analysis of Real-World Data
Authors: Sangaré Mohamed N’dongo , Baril Jean-Guy , de Pokomandy Alexandra , Ferreira Guerra Steve , Carabali Mabel , Laprise Claudie , Thomas Réjean , Klein Marina , Tremblay Cécile , Roger Michel , Pexos Costa , Greenwald Zoë R , Machouf Nima , Durand Madeleine , Hardy Isabelle , Dakouo Mamadou , Trevisan Andrea , Laporte Louise , Schnitzer Mireille E , Trottier Helen
Published: September 2020

Background

Switching antiretroviral regimens when human immunodeficiency virus (HIV) viremia is controlled for a new regimen is challenging when there is the potential for prior nucleoside reverse-transcriptase inhibitor (NRTI) resistance. The objective was to study virologic outcomes after switching to dolutegravir compared with remaining on a boosted protease inhibitor (protease inhibitor/ritonavir [PI/r]) regimen in people with HIV (PWH) with prior documented virologic failure and/or exposure to mono/dual NRTIs.

Methods

We used the Quebec HIV Cohort including 10 219 PWH whose data were collected at 4 sites in Montreal, Canada. We included all PWH with documented virologic failure or exposure to mono/dual NRTI therapy who were virologically suppressed on a PI/r-based regimen for at least 6 months on or after January 1, 2014 (n = 532). A marginal structural Cox model analysis was used to estimate the effect of the switch to dolutegravir on virologic outcome compared with remaining on PI/r. The outcome was defined as 2 consecutive viral loads (VLs) >50 copies/mL or 1 VL >50 copies/mL if it occurred at the last VL available.

Results

Among 532 eligible participants, 216 (40.6%) had their regimen switched to dolutegravir with 2 NRTIs, whereas 316 (59.4%) remained on the PI/r with 2 NRTIs. The weighted hazard ratio for the effect of dolutegravir switch on virologic failure compared with patients whose regimen remained on PI/r was 0.57 (95% confidence interval, 0.21–1.52).

Conclusions

We did not find evidence of an increased risk for virologic failure after switching to dolutegravir from PI/r among patients with previous virologic failure or prior exposure to mono/dual NRTI.
Radiative wind from a luminous star cluster
Authors: Fukue Jun
Published: September 2020

We reexamine the steady spherical wind from distributed sources, such as star clusters and a galactic center, taking into account the radiative force from distributed sources and mass reduction via orbital motions. We consider a cold dusty wind, an isothermal gaseous flow, and a nonisothermal general one without/with a central mass and a stagnation radius for various powers of source distributions. We perform singular point analysis for each case, and obtain a transonic solution, if one exists. We find that thermally driven outflows can emerge in limited situations, such that the source distribution is rather steep in the isothermal flow. On the other hand, under the appropriate conditions radiatively driven winds can easily be produced. Radiative cluster winds without a central mass could emerge from newly born star clusters or neutron star clusters, whereas those with a central mass could appear from active galactic nuclei. Radiative cluster winds would also operate in first star clusters.