bluuebunny/crossref_metadata_2025 huggingface dataset:
Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation
Authors: Erfinanda Lasti , Ravindran Krishnan , Kohse Franziska , Gallo Kathleen , Preissner Robert , Walther Thomas , Kuebler Wolfgang M.
Published: August 2020

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1–7)viathe Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1–7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1–7)/Mas signalling may protect females over males in ALI/ARDS.

Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas−/−) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER)in vitro.

In 734 090 Charité inpatients (2005–2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and femaleMas−/−mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombinin vitro. This effect was alleviated by Mas-receptor blockade.

Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediatedviaenhanced Ang(1–7)/Mas signalling as a result of oestrogen-dependent Mas expression.
NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
Authors: Louzada Ruy Andrade , Corre Raphaël , Ameziane El Hassani Rabii , Meziani Lydia , Jaillet Madeleine , Cazes Aurélie , Crestani Bruno , Deutsch Eric , Dupuy Corinne
Published: August 2020

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF)-β1/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular hydrogen peroxide (H2O2­­)-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis.

Ourin vivodata (idiopathic pulmonary fibrosis patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1+/−and DUOX1−/−) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-β1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H2O2promoted the duration of TGF-β1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation.

These findings highlight a role for DUOX1-derived H2O2in a positive feedback that amplifies the signalling output of the TGF-β1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis.
Long-term trends of asthma, allergic rhinitis and atopic eczema in young Finnish men: a retrospective analysis, 1926–2017
Authors: Reijula Jere , Latvala Jari , Mäkelä Mika , Siitonen Simo , Saario Mari , Haahtela Tari
Published: August 2020

The aim of this study was to assess the long-term time trends of the prevalence of asthma, allergic rhinitis and atopic eczema in young Finnish men.

A retrospective analysis was carried out on cross-sectional data from the Finnish Defence Forces taken from call-up examinations of candidates for military conscription and examinations of conscripts discharged from service because of poor health. Roughly 1.7 million men aged 18‒19 years (98% of men of conscription age) were examined from 1966 to 2017. A proportional but unknown number of young men were examined from 1926 to 1961.

The main outcome measures were asthma recorded at call-up examination as the main diagnosis in 1926‒2017 and any diagnosis in 1997‒2017, exemption or discharge from military service due to asthma, and allergic rhinitis and atopic eczema recorded as the main diagnosis in 1966‒2017 and any diagnosis in 1997‒2017.

During 1926–1961 the prevalence of asthma remained low at between 0.02% and 0.08%. A linear rise began between 1961 and 1966, with a 12-fold increase in the prevalence from 0.29% in 1966 to 3.44% in 2001. Thereafter, the prevalence of asthma as the main diagnosis stabilised but continued to increase to 5.19% in 2017 if secondary diagnoses of asthma were included. Exemption rates from military service due to asthma have similarly increased but fluctuated more. The prevalence of allergic rhinitis increased from 0.06% to 10.70% and atopic eczema from 0.15% to 2.90% during the period 1966‒2017.

In Finland, an increase in asthma and allergic conditions among young men became evident in the mid-1960s. The increase slowed in the 2000s and may be levelling off in the 2020s.
Giant planktic larvae of anomalan crustaceans and their unusual compound eyes
Authors: Gundi Paula , Cecchin Chiara , Fetzer Lara-Leonie , Haug Carolin , Melzer Roland R. , Haug Joachim T.
Published: August 2020

Crustacean larvae are usually recognised as small organisms, below one millimeter body size. However, in different crustacean groups such as Stomatopoda, Polychelida, or Achelata, also very large larvae occur with sizes of 20 mm and beyond. Also from few meiuran species (“short-tailed” crustaceans, including crabs, hermit crabs, or squat lobsters), rather large larvae are known, though still considerably smaller than 20 mm. We present here two specimens of anomalan meiuran larvae, each with a total length of 24 mm, which by far exceed the previously known/reported maximum sizes of meiuran larvae. Yet, both specimens exhibit characters that indicate their identity as zoea larvae (first larval phase with several stages), most likely shortly before the metamorphosis to the megalopa (second larval phase with one stage). Due to this early developmental state, it is difficult to provide a narrower systematic identification of the larvae. In addition to the description of the developmental status of all appendages, we also investigated the gizzard and especially the compound eyes. The latter possess a mixture of hexagonal, intermediate, and square-shaped facets in an unusual arrangement. We documented the exact arrangement of the facets in both specimens and discuss the possible re-structuring during metamorphosis. The arrangement of the different types of facets indicates that transformation to an adult eye structure takes place over several moults and that the facets are being rearranged in this process. The findings demonstrate that also meiuran larvae contribute to the fraction of the macro-plankton.
Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain
Authors: García-Magro Nuria , Negredo Pilar , Martin Yasmina B. , Nuñez Ángel , Avendaño Carlos
Published: August 2020

Background

Stimulation of the occipital or trigeminal nerves has been successfully used to treat chronic refractory neurovascular headaches such as migraine or cluster headache, and painful neuropathies. Convergence of trigeminal and occipital sensory afferents in the ‘trigeminocervical complex’ (TCC) from cutaneous, muscular, dural, and visceral sources is a key mechanism for the input-induced central sensitization that may underlie the altered nociception. Both excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) mechanisms are involved in modulating nociception in the spinal and medullary dorsal horn neurons, but the mechanisms by which nerve stimulation effects occur are unclear. This study was aimed at investigating the acute effects of electrical stimulation of the greater occipital nerve (GON) on the responses of neurons in the TCC to the mechanical stimulation of the vibrissal pad.

Methods

Adult male Wistar rats were used. Neuronal recordings were obtained in laminae II-IV in the TCC in control, sham and infraorbital chronic constriction injury (CCI-IoN) animals. The GON was isolated and electrically stimulated. Responses to the stimulation of vibrissae by brief air pulses were analyzed before and after GON stimulation. In order to understand the role of the neurotransmitters involved, specific receptor blockers of NMDA (AP-5), GABAA (bicuculline, Bic) and Glycine (strychnine, Str) were applied locally.

Results

GON stimulation produced a facilitation of the response to light facial mechanical stimuli in controls, and an inhibition in CCI-IoN cases. AP-5 reduced responses to GON and vibrissal stimulation and blocked the facilitation of GON on vibrissal responses found in controls. The application of Bic or Str significantly reduced the facilitatory effect of GON stimulation on the response to vibrissal stimulation in controls. However, the opposite effect was found when GABAergic or Glycinergic transmission was prevented in CCI-IoN cases.

Conclusions

GON stimulation modulates the responses of TCC neurons to light mechanical input from the face in opposite directions in controls and under CCI-IoN. This modulation is mediated by GABAergic and Glycinergic mechanisms. These results will help to elucidate the neural mechanisms underlying the effectiveness of nerve stimulation in controlling painful craniofacial disorders, and may be instrumental in identifying new therapeutic targets for their prevention and treatment.
Alternative Strategy to Reduce Surface Recombination for InGaN/GaN Micro-light-Emitting Diodes—Thinning the Quantum Barriers to Manage the Current Spreading
Authors: Chang Le , Yeh Yen-Wei , Hang Sheng , Tian Kangkai , Kou Jianquan , Bi Wengang , Zhang Yonghui , Zhang Zi-Hui , Liu Zhaojun , Kuo Hao-Chung
Published: August 2020

Owing to high surface-to-volume ratio, InGaN-based micro-light-emitting diodes (μLEDs) strongly suffer from surface recombination that is induced by sidewall defects. Moreover, as the chip size decreases, the current spreading will be correspondingly enhanced, which therefore further limits the carrier injection and the external quantum efficiency (EQE). In this work, we suggest reducing the nonradiative recombination rate at sidewall defects by managing the current spreading effect. For that purpose, we properly reduce the vertical resistivity by decreasing the quantum barrier thickness so that the current is less horizontally spreaded to sidewall defects. As a result, much fewer carriers are consumed in the way of surface nonradiative recombination. Our calculated results demonstrate that the suppressed surface nonradiative recombination can better favor the hole injection efficiency. We also fabricate the μLEDs that are grown on Si substrates, and the measured results are consistent with the numerical calculations, such that the EQE for the proposed μLEDs with properly thin quantum barriers can be enhanced, thanks to the less current spreading effect and the decreased surface nonradiative recombination.
Genome-Wide Association Study for Yield and Yield Related Traits under Reproductive Stage Drought in a Diverse indica-aus Rice Panel
Authors: Bhandari Aditi , Sandhu Nitika , Bartholome Jérôme , Cao-Hamadoun Tuong-Vi , Ahmadi Nourollah , Kumari Nilima , Kumar Arvind
Published: August 2020

Background

Reproductive-stage drought stress is a major impediment to rice production in rainfed areas. Conventional and marker-assisted breeding strategies for developing drought-tolerant rice varieties are being optimized by mining and exploiting adaptive traits, genetic diversity; identifying the alleles, and understanding their interactions with genetic backgrounds for their increased contribution to drought tolerance. Field experiments were conducted in this study to identify marker-trait associations (MTAs) involved in response to yield under reproductive-stage (RS) drought. A diverse set of 280 indica-aus accessions was phenotyped for ten agronomic traits including yield and yield-related traits under normal irrigated condition and under two managed reproductive-stage drought environments. The accessions were genotyped with 215,250 single nucleotide polymorphism markers.

Results

The study identified a total of 219 significant MTAs for 10 traits and candidate gene analysis within a 200 kb window centred from GWAS identified SNP peaks detected these MTAs within/ in close proximity to 38 genes, 4 earlier reported major grain yield QTLs and 6 novel QTLs for 7 traits out of the 10. The significant MTAs were mainly located on chromosomes 1, 2, 5, 6, 9, 11 and 12 and the percent phenotypic variance captured for these traits ranged from 5 to 88%. The significant positive correlation of grain yield with yield-related and other agronomic traits except for flowering time, observed under different environments point towards their contribution in improving rice yield under drought. Seven promising accessions were identified for use in future genomics-assisted breeding programs targeting grain yield improvement under drought.

Conclusion

These results provide a promising insight into the complex genetic architecture of grain yield under reproductive-stage drought in different environments. Validation of major genomic regions reported in the study will enable their effectiveness to develop drought-tolerant varieties following marker-assisted selection as well as to identify genes and understanding the associated physiological mechanisms.
Using full chloroplast genomes of ‘red’ and ‘yellow’ Bixa orellana (achiote) for kmer based identification and phylogenetic inference
Authors: Villacrés-Vallejo Jorge , Aranda-Ventura José , Wallis Anna , Cagle Robin , Handy Sara M. , Davis Jeffery , Reed Elizabeth , Zhang Shu , Strain Errol , Pava-Ripoll Monica , Erickson David , Ramachandran Padmini , Ottesen Andrea
Published: August 2020

Background

Full chloroplast genomes provide high resolution taxonomic discrimination between closely related plant species and are quickly replacing single and multi-locus barcoding regions as reference materials of choice for DNA based taxonomic annotation of plants. Bixa orellana, commonly known as “achiote” and “annatto” is a plant used for both human and animal foods and was thus identified for full chloroplast sequencing for the Center for Veterinary Medicine (CVM) Complete Chloroplast Animal Feed database. This work was conducted in collaboration with the Instituto de Medicina Tradicional (IMET) in Iquitos, Peru. There is a wide range of color variation in pods of Bixa orellana for which genetic loci that distinguish phenotypes have not yet been identified. Here we apply whole chloroplast genome sequencing of “red” and “yellow” individuals of Bixa orellana to provide high quality reference genomes to support kmer database development for use identifying this plant from complex mixtures using shotgun data. Additionally, we describe chloroplast gene content, synteny and phylogeny, and identify an indel and snp that may be associated with seed pod color.

Results

Fully assembled chloroplast genomes were produced for both red and yellow Bixa orellana accessions (158,918 and 158,823 bp respectively). Synteny and gene content was identical to the only other previously reported full chloroplast genome of Bixa orellana (NC_041550). We observed a 17 base pair deletion at position 58,399–58,415 in both accessions, relative to NC_041550 and a 6 bp deletion at position 75,531–75,526 and a snp at position 86,493 in red Bixa orellana.

Conclusions

Our data provide high quality reference genomes of individuals of red and yellow Bixa orellana to support kmer based identity markers for use with shotgun sequencing approaches for rapid, precise identification of Bixa orellana from complex mixtures. Kmer based phylogeny of full chloroplast genomes supports monophylly of Bixaceae consistent with alignment based approaches. A potentially discriminatory indel and snp were identified that may be correlated with the red phenotype.
Performances of Adaptive MultiBLUP, Bayesian regressions, and weighted-GBLUP approaches for genomic predictions in Belgian Blue beef cattle
Authors: Gualdrón Duarte José Luis , Gori Ann-Stephan , Hubin Xavier , Lourenco Daniela , Charlier Carole , Misztal Ignacy , Druet Tom
Published: August 2020

Background

Genomic selection has been successfully implemented in many livestock and crop species. The genomic best linear unbiased predictor (GBLUP) approach, assigning equal variance to all SNP effects, is one of the reference methods. When large-effect variants contribute to complex traits, it has been shown that genomic prediction methods that assign a higher variance to subsets of SNP effects can achieve higher prediction accuracy. We herein compared the efficiency of several such approaches, including the Adaptive MultiBLUP (AM-BLUP) that uses local genomic relationship matrices (GRM) to automatically identify and weight genomic regions with large effects, to predict genetic merit in Belgian Blue beef cattle.

Results

We used a population of approximately 10,000 genotyped cows and their phenotypes for 14 traits, mostly related to muscular development and body dimensions. According to the trait, we found that 4 to 25% of the genetic variance could be associated with 2 to 12 genomic regions harbouring large-effect variants. Noteworthy, three previously identified recessive deleterious variants presented heterozygote advantage and were among the most significant SNPs for several traits. The AM-BLUP resulted in increased reliability of genomic predictions compared to GBLUP (+ 2%), but Bayesian methods proved more efficient (+ 3%). Overall, the reliability gains remained thus limited although higher gains were observed for skin thickness, a trait affected by two genomic regions having particularly large effects. Higher accuracies than those from the original AM-BLUP were achieved when applying the Bayesian Sparse Linear Mixed Model to pre-select groups of SNPs with large effects and subsequently use their estimated variance to build a weighted GRM. Finally, the single-step GBLUP performed best and could be further improved (+ 3% prediction accuracy) by using these weighted GRM.

Conclusions

The AM-BLUP is an attractive method to automatically identify and weight genomic regions with large effects on complex traits. However, the method was less accurate than Bayesian methods. Overall, weighted methods achieved modest accuracy gains compared to GBLUP. Nevertheless, the computational efficiency of the AM-BLUP might be valuable at higher marker density, including with whole-genome sequencing data. Furthermore, weighted GRM are particularly useful to account for large variance loci in the single-step GBLUP.
Peptidorhamnomannan from Lomentospora prolificans modulates the inflammatory response in macrophages infected with Candida albicans
Authors: Xisto Mariana Ingrid Dutra da Silva , Santos Suelen S. , Rossato Luana , Yoshikawa Fábio Seiti Yamada , Haido Rosa Maria Tavares , de Almeida Sandro Rogério , Barreto-Bergter Eliana
Published: August 2020

Background

Peptidorhamnomannan is a glycoconjugate that consists of a peptide chain substituted by O- and N-linked glycans, present on the cell surface of Lomentospora prolificans, a saprophytic fungus which is widely distributed in regions with temperate climates. O-linked oligosaccharides from peptidorhamnomannan isolated from Lomentospora prolificans conidia are recognized by macrophages mediating macrophage - conidia interaction. In this work, peptidorhamnomannan was isolated from L. prolificans mycelium cell wall and its role in macrophage - Candida albicans interaction was evaluated.

Results

Purified peptidorhamnomannan inhibits the reactivity of rabbit immune sera to mycelial and conidia forms of L. prolificans, indicating that this glycoconjugate is exposed on the fungal surface and can mediate interaction with host immune cells. We demonstrated that peptidorhamnomannan leads to TNF-α production in J774 macrophages for 1, 2 and 3 h of incubation, suggesting that this glycoconjugate may have a beneficial role in the response to fungal infections. In order to confirm this possibility, the effect of peptidorhamnomannan on the macrophage - C. albicans interaction was evaluated. Macrophages treated with peptidorhamnomannan led to a lower fungal survival, suggesting that peptidorhamnomannan induces an increased fungicidal activity in macrophages. Furthermore, TNF-α levels were measured in supernatants after macrophage - C. albicans interaction for 1, 2 and 3 h. Peptidorhamnomannan treatment led to a higher TNF-α production at the beginning of the interaction. However, the release of TNF-α was not maintained after 1 h of incubation. Besides, peptidorhamnomannan did not show any inhibitory or fungicidal effect in C. albicans when used at 100 μg/ml but it was able to kill C. albicans at a concentration of 400 μg/ml.

Conclusion

We suggest that peptidorhamnomannan acts as a molecular pattern on the invading pathogen, promotes TNF-α production and, thus, increases macrophage fungicidal activity against Candida albicans.
Stand When You Can: development and pilot testing of an intervention to reduce sedentary time in assisted living
Authors: Voss M. L. , Pope J. P. , Larouche R. , Copeland J. L.
Published: August 2020

Background

Prolonged daily sedentary time is associated with increased risk of cardiometabolic diseases, impaired physical function, and mortality. Older adults are more sedentary than any other age group and those in assisted living residences accumulate more sedentary time as they often have little need to engage in light-intensity or standing activities such as cleaning or meal preparation. This “low movement” environment can hasten functional decline. Thus, the purpose of this study was to develop a multi-level intervention to reduce and interrupt sedentary time within assisted living residences and conduct a pilot study to determine if the intervention is feasible and if further testing is warranted.

Methods

“Stand When You Can” (SWYC) was developed using a Social Ecological framework based on a review of literature and consultation with residents and staff at assisted living residences. After development, a six-week pilot study was conducted in two different residences with 10 older adults (82.2 ± 8.7 years). Before and after the 6 weeks, ActivPAL™ inclinometers were used to measure daily movement behaviours and self-report questionnaires assessed time spent in different sedentary behaviours and quality of life. Physical function was assessed using the Short Physical Performance Battery. Paired sample t-tests examined pre-post differences for pooled data and individual sites. At the end of the pilot study, feedback on the intervention was gathered from both residents and staff to examine feasibility.

Results

There was a trend towards a decrease in self-reported sitting time (142 min/day; p = 0.09), although device-measured sedentary time did not change significantly. Participants with lower physical function at baseline showed clinically meaningful improvements in physical function after the 6 weeks (p = 0.04, Cohen’s d = 0.89). There was no change in quality of life. Residents and staff reported that the intervention strategies were acceptable and practical.

Conclusion

This study suggests that a multi-level intervention for reducing prolonged sedentary time is feasible for implementation at assisted living residences. The intervention could potentially help delay functional decline among older adults when they transition to a supportive living environment. Longer and larger trials to test the efficacy of SWYC are necessary.

Trial registration

Name of Clinical Trial Registry: clinicaltrials.gov

Trial Registration number: NCT04458896.

Date of registration: July 8, 2020. (Retrospectively registered).
The impact of frailty on admission to home care services and nursing homes: eight-year follow-up of a community-dwelling, older adult, Spanish cohort
Authors: Cegri Francisco , Orfila Francesc , Abellana Rosa M. , Pastor-Valero María
Published: August 2020

Background

Frailty in older adults is a common multidimensional clinical entity, a state of vulnerability to stressors that increases the risk of adverse outcomes such as functional decline, institutionalization or death. The aim of this study is to identify the factors that anticipate the future inclusion of community-dwelling individuals aged ≥70 years in home care programmes (HC) and nursing homes (NH), and to develop the corresponding prediction models.

Methods

A prospective cohort study was conducted in 23 primary healthcare centers located in Catalonia, Spain, with an eight-year follow-up (2005–2013). The cohort was made up of 616 individuals. Data collection included a baseline multidimensional assessment carried out by primary health care professionals. Outcome variables were collected during follow-up by consulting electronic healthcare records, and the Central Registry of Catalonia for mortality. A prognostic index for a HC and NH at 8 years was estimated for each patient. Death prior to these events was considered a competing risk event, and Fine–Gray regression models were used.

Results

At baseline, mean age was 76.4 years and 55.5% were women. During follow-up, 19.2% entered a HC program, 8.2% a NH, and 15.4% died without presenting an event. Of those who entered a NH, 31.5% had previously been in a HC program.

Multivariate models for a HC and NH showed that the risk of a HC entry was associated with older age, dependence on the Instrumental Activities of Daily Living, and slow gait measured by Timed-up-and-go test. An increased risk of being admitted to a NH was associated with older age, dependence on the Instrumental Activities of Daily Living, number of prescriptions, and the presence of social risk.

Conclusions

Prognostic models based on comprehensive geriatric assessments can predict the need for the commencement of HC and NH admission in community-dwelling older adults. Our findings underline the necessity to measure functional capacity, mobility, number of prescriptions, and social aspects of older adults in primary healthcare centers. In such a setting they can be offered longitudinal holistic assessments so as to benefit from preventive actions in order to remain independent in the community for as long as possible.
Point-of-care thrombocyte function testing using multiple-electrode aggregometry in dengue patients: an explorative study
Authors: de Jong Wesley , Asmarawati Tri Pudy , Verbeek Inge , Rusli Musofa , Hadi Usman , van Gorp Eric , Goeijenbier Marco
Published: August 2020

Background

Dengue virus (DENV) causes the hospitalisation of an estimated 500,000 people every year. Outbreaks can severely stress healthcare systems, especially in rural settings. It is difficult to discriminate patients who need to be hospitalized from those that do not. Earlier work identified thrombocyte count and subsequent function as a promising prognostic marker of DENV severity. Herein, we investigated the potential of quantitative thrombocyte function tests in those admitted in the very early phase of acute DENV infections, using Multiplate™ multiple-electrode aggregometry to explore its potential in triage.

Methods

In this prospective cohort study all patients aged ≥13 admitted to Universitas Airlangga Hospital in Surabaya, Indonesia with a fever (≥38 °C) between 25 January and 1 August 2018 and with a clinical suspicion of DENV, were eligible for inclusion. Exclusion criteria were a thrombocyte count below 100 × 109/L and the use of any medication with a known anticoagulant effect, nonsteroidal anti-inflammatory drugs and acetyl salicylic acid. Clinical data was collected and blood was taken on admission, day 1 and day 7. Samples were tested for acute DENV, using Panbio NS1 ELISA. Platelet aggregation using ADP-, TRAP- and COL-test were presented as Area Under the aggregation Curve (AUC). Significance was tested between DENV+, probably DENV, fever of another origin, and healthy controls (HC).

Results

A total of 59 patients (DENV+ n = 10, DENV probable n = 25, fever other origin n = 24) and 20 HC were included. We found a significantly lower thrombocyte aggregation in the DENV+ group, compared with both HCs and the fever of another origin group (p < .001). Low ADP AUC values on baseline correlated to a longer hospital stay in DENV+ and probable DENV cases.

Conclusion

Thrombocyte aggregation induced by Adenosine diphosphate, Collagen and Thrombin receptor activating peptide-6 is impaired in human DENV cases, compared with healthy controls and other causes of fever. This explorative study provides insights to thrombocyte function in DENV patients and could potentially serve as a future marker in DENV disease.
A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial to assess the efficacy of adjunctive N-Acetylcysteine for treatment-resistant PTSD: a study protocol
Authors: Maier Alice , Dharan Anita , Oliver Gina , Berk Michael , Redston Suzy , Back Sudie E. , Kalivas Peter , Ng Chee , Kanaan Richard A.
Published: August 2020

Background

Most patients with Posttraumatic Stress Disorder (PTSD) suffer residual symptoms following first-line treatment. Oxidative stress has been implicated in the pathophysiology of PTSD. N-acetylcysteine (NAC) is a precursor of the brain’s primary antioxidant, glutathione, and may diminish oxidative cellular damage. An 8-week pilot study of NAC in veterans with PTSD found that symptoms were significantly reduced in the NAC group compared to placebo. This study aims to confirm these findings with a larger sample in a double-blind, placebo-controlled trial to further explore the efficacy of NAC as an adjunctive therapy in treatment-resistant PTSD.

Methods

A multicentre, randomised, double-blind, placebo-controlled trial for adult patients who still meet criteria for PTSD following first-line treatment. The intervention comprises either NAC as a fixed dose regime of 2.7 g/day (900 mg three times daily) administered orally for 12 weeks, or placebo. Standard care for PTSD will continue in addition, including other pharmacotherapies. Detailed clinical data will be collected at randomisation and weeks 4, 8, 12, 16, and 64 post-randomisation, with self-report measures completed weekly from baseline to 16 weeks and at 64 weeks post-randomisation. Blood-based biomarkers will be collected at baseline and 12 weeks to assess the mechanism of effect. The primary outcome measure will be change in Clinician-Administered PTSD Scale for DSM-5 at 12 weeks compared with baseline. Secondary outcomes will be change in quality of life, depression, anxiety, substance use and craving, and somatic symptoms. With 126 completed participants (63 per arm), the study is powered at 80% to detect a true difference in the primary outcome measure using a two-tailed analysis with alpha = 0.05, beta = 0.2.

Discussion

This is the first multicentre, double blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. NAC has an established safety profile, is readily available and easy to administer, and has a favourable tolerability profile, therefore making it an attractive adjunctive therapy. Inclusion of blood analyses to assess potential target engagement biomarkers of oxidative stress and neuroinflammation may help gauge the biological mechanisms of effect of NAC.

Trial registration

ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.
Predictors for the use of traditional Chinese medicine among inpatients with first-time stroke: a population-based study
Authors: Chen Wei-Sen , Hsu Hung-Chih , Chuang Yi-Wen , Lee Meng , Lu Kuan-Yu , Chen Yi-Fei , Chen Chien-Min
Published: August 2020

Background

Stroke is one of the major causes of death and disability. The treatments that are provided to patients during hospitalization after an acute stroke are very important in stabilizing their medical condition and enabling the recovery of their motor functions. However, limited information is available regarding the use of traditional Chinese medicine (TCM) during hospitalization for first-time stroke patients. The researchers aimed to investigate the factors affecting TCM use and to provide clinicians with comprehensive information on TCM use among first-time stroke inpatients in Taiwan.

Methods

The researchers collected and analyzed data, including patient characteristics, TCM use, and TCM prescription patterns, from the National Health Insurance Research Database in Taiwan for first-time stroke inpatients between 2006 and 2012.

Results

Among the 89,162 first-time stroke patients, 7455 were TCM users, and 81,707 were TCM nonusers. The predictors for TCM use were as follows: age, 45–64 or < 45 years; men; living in a level 2, 4, or 7 urbanized area; insured amount ≥ 576 USD per month; ischemic stroke; hospitalized for first-time stroke for 8–14 days, 15–28 days, or ≥ 29 days; stroke severity index score 0–9 or 10–19; Charlson–Deyo comorbidity index score 0 or 1–2; hospitalization in a regional or community hospital; receiving rehabilitation; and previous experience with outpatient TCM use. An increase in the number of TCM users was observed from 2006 to 2012. Furthermore, 68.8–79.7% of TCM users used acupuncture only, while 17.8–26.1% used both acupuncture and Chinese herbal medicine.

Conclusions

An increasing number of first-time stroke patients have been choosing TCM as a complementary treatment during hospitalization. Moreover, TCM use is associated with demographic, clinical, and socioeconomic characteristics. These findings may help clinicians comprehensively understand the trend and the important factors affecting TCM utilization among patients who are hospitalized due to first-time stroke.
Evaluation of an in-house indirect enzyme-linked immunosorbent assay of feline panleukopenia VP2 subunit antigen in comparison to hemagglutination inhibition assay to monitor tiger antibody levels by Bayesian approach
Authors: Areewong Chanakan , Rittipornlertrak Amarin , Nambooppha Boondarika , Fhaikrue Itsarapan , Singhla Tawatchai , Sodarat Chollada , Prachasilchai Worapat , Vongchan Preeyanat , Sthitmatee Nattawooti
Published: August 2020

Background

Feline panleukopenia virus (FPV) is an etiologic pathogen of feline panleukopenia that infects all members of Felidae including tigers (Panthera tigris). Vaccinations against FPV among wild felid species have long been practiced in zoos worldwide. However, few studies have assessed the tiger immune response post-vaccination due to the absence of a serological diagnostic tool. To address these limitations, this study aimed to develop an in-house indirect enzyme-linked immunosorbent assay (ELISA) for the monitoring of tiger antibody levels against the feline panleukopenia vaccine by employing the synthesized subunit capsid protein VP2. An in-house horseradish peroxidase (HRP) conjugated rabbit anti-tiger immunoglobulin G (IgG) polyclonal antibody (HRP-anti-tiger IgG) was produced in this study and employed in the assay. It was then compared to a commercial HRP-conjugated goat anti-cat IgG (HRP-anti-cat IgG). Sensitivity and specificity were evaluated using the Bayesian model with preferential conditional dependence between HRP-conjugated antibody-based ELISAs and hemagglutination-inhibition (HI) tests.

Results

The posterior estimates for sensitivity and specificity of two indirect ELISA HRP-conjugated antibodies were higher than those of the HI test. The sensitivity and specificity of the indirect ELISA for HRP-anti-tiger IgG and HRP-anti-cat IgG were 86.5, 57.2 and 86.7%, 64.6%, respectively, while the results of the HI test were 79.1 and 54.1%. In applications, 89.6% (198/221) and 89.1% (197/221) of the tiger serum samples were determined to be seropositive by indirect ELISA testing against HRP-anti-tiger and HRP-anti-cat, respectively.

Conclusion

To the best of our knowledge, the specific serology assays for the detection of the tiger IgG antibody have not yet been established. The HRP-anti-tiger IgG has been produced for the purpose of developing the specific immunoassays for tigers. Remarkably, an in-house indirect ELISA based on VP2 subunit antigen has been successfully developed in this study, providing a potentially valuable serological tool for the effective detection of tiger antibodies.
CircPOSTN/miR-361-5p/TPX2 axis regulates cell growth, apoptosis and aerobic glycolysis in glioma cells
Authors: Long Niya , Chu Liangzhao , Jia Jun , Peng Shuo , Gao Yuan , Yang Hua , Yang Yaoming , Zhao Yan , Liu Jian
Published: August 2020

Background

Glioma is the most primary central nervous system tumor in adults. The 5 year survival rate for glioma patients remains poor, although treatment strategies had improved in the past few decades. The cumulative studies have shown that circular RNA (circRNA) is associated with glioma process, so the purpose of this study is to clarify the function of circPOSTN in glioma.

Methods

The expression levels of circPOSTN, miR-361-5p, and targeting protein for Xenopus kinesin-like protein 2 (TPX2) were assessed with real-time quantitative polymerase chain reaction (RT-qPCR). The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) and flow cytometry assays were executed to examine proliferation and apoptosis of glioma cells, respectively. Western blot was applied to assess protein expression. The glucose metabolism of glioma cells was analyzed by testing the glucose consumption, lactate production, ATP level, reactive oxygen species (ROS) accumulation and performing Seahorse XF assay. The interaction relationship between miR-361-5p and circPOSTN or TPX2 was analyzed by bioinformatics database and dual-luciferase reporter assay. The influences of circPOSTN silencing in vivo were observed by a xenograft experiment.

Results

CircPOSTN was overexpressed in glioma tissues and cells. Absence of circPOSTN in glioma cells promoted apoptosis while impeded proliferation and aerobic glycolysis, which were mitigated by silencing miR-361-5p. What’s more, loss-of-functional experiment suggested that knockdown of TPX2 repressed proliferation and aerobic glycolysis, while induced apoptosis in glioma cells. In addition, circPOSTN targetedly regulated TPX2 expression in glioma cells via sponging miR-361-5p. In vivo study revealed that deficiency of circPOSTN restrained tumor growth.

Conclusion

Mechanistically, circPOSTN regulated cell growth, apoptosis, and aerobic glycolysis in glioma through miR-361-5p/TPX2 axis.
Evaluation of the upregulation and surface expression of hypoxanthine guanine phosphoribosyltransferase in acute lymphoblastic leukemia and Burkitt’s B cell lymphoma
Authors: Townsend Michelle H. , Ence Zac E. , Cox Taylor P. , Lattin John E. , Burrup Weston , Boyer Michael K. , Piccolo Stephen R. , Robison Richard A. , O’Neill Kim L.
Published: August 2020

Background

The aim of this study is to determine whether Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) could be used as a biomarker for the diagnosis and treatment of B cell malignancies. With 4.3% of all new cancers diagnosed as Non-Hodgkin lymphoma, finding new biomarkers for the treatment of B cell cancers is an ongoing pursuit. HPRT is a nucleotide salvage pathway enzyme responsible for the synthesis of guanine and inosine throughout the cell cycle.

Methods

Raji cells were used for this analysis due to their high HPRT internal expression. Internal expression was evaluated utilizing western blotting and RNA sequencing. Surface localization was analyzed using flow cytometry, confocal microscopy, and membrane biotinylation. To determine the source of HPRT surface expression, a CRISPR knockdown of HPRT was generated and confirmed using western blotting. To determine clinical significance, patient blood samples were collected and analyzed for HPRT surface localization.

Results

We found surface localization of HPRT on both Raji cancer cells and in 77% of the malignant ALL samples analyzed and observed no significant expression in healthy cells. Surface expression was confirmed in Raji cells with confocal microscopy, where a direct overlap between HPRT specific antibodies and a membrane-specific dye was observed. HPRT was also detected in biotinylated membranes of Raji cells. Upon HPRT knockdown in Raji cells, we found a significant reduction in surface expression, which shows that the HPRT found on the surface originates from the cells themselves. Finally, we found that cells that had elevated levels of HPRT had a direct correlation to XRCC2, BRCA1, PIK3CA, MSH2, MSH6, WDYHV1, AK7, and BLMH expression and an inverse correlation to PRKD2, PTGS2, TCF7L2, CDH1, IL6R, MC1R, AMPD1, TLR6, and BAK1 expression. Of the 17 genes with significant correlation, 9 are involved in cellular proliferation and DNA synthesis, regulation, and repair.

Conclusions

As a surface biomarker that is found on malignant cells and not on healthy cells, HPRT could be used as a surface antigen for targeted immunotherapy. In addition, the gene correlations show that HPRT may have an additional role in regulation of cancer proliferation that has not been previously discovered.
Bismuth chelate as a contrast agent for X-ray computed tomography
Authors: Fu Ji-jun , Guo Jun-jie , Qin Ai-ping , Yu Xi-yong , Zhang Qiang , Lei Xue-ping , Huang Yu-gang , Chen Ming-yue , Li Jie-xia , Zhang Yu , Liu Jing-ping , Dang Yuan-ye , Wu Dan , Zhao Xiao-ya , Lin Zhong-xiao , Lin Yin-lei , Li Song-pei , Zhang Ling-yan
Published: August 2020

Backgrounds

Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time—consuming.

Methods

In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent.

Results

The preparation method is easy and cost—effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first—order elimination kinetics and, it has a short half—life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility.

Conclusions

This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.
Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation
Authors: Varghese Anu Mary , Ghosh Mausam , Bhagat Savita Kumari , Vijayalakshmi K. , Preethish-Kumar Veeramani , Vengalil Seena , Chevula Pradeep-Chandra-Reddy , Nashi Saraswati , Polavarapu Kiran , Sharma Meenakshi , Dhaliwal Rupinder Singh , Philip Mariamma , Nalini Atchayaram , Alladi Phalguni Anand , Sathyaprabha Talakad N. , Raju Trichur R.
Published: August 2020

Background

Cerebrospinal fluid from amyotrophic lateral sclerosis patients (ALS-CSF) induces neurodegenerative changes in motor neurons and gliosis in sporadic ALS models. Search for identification of toxic factor(s) in CSF revealed an enhancement in the level and enzyme activity of chitotriosidase (CHIT-1). Here, we have investigated its upregulation in a large cohort of samples and more importantly its role in ALS pathogenesis in a rat model.

Methods

CHIT-1 level in CSF samples from ALS (n = 158), non-ALS (n = 12) and normal (n = 48) subjects were measured using ELISA. Enzyme activity was also assessed (ALS, n = 56; non-ALS, n = 10 and normal-CSF, n = 45). Recombinant CHIT-1 was intrathecally injected into Wistar rat neonates. Lumbar spinal cord sections were stained for Iba1, glial fibrillary acidic protein and choline acetyl transferase to identify microglia, astrocytes and motor neurons respectively after 48 h of injection. Levels of tumour necrosis factor-α and interleukin-6 were measured by ELISA.

Findings

CHIT-1 level in ALS-CSF samples was increased by 20-fold and it can distinguish ALS patients with a sensitivity of 87% and specificity of 83.3% at a cut off level of 1405.43 pg/ml. Enzyme activity of CHIT-1 was also 15-fold higher in ALS-CSF and has a sensitivity of 80.4% and specificity of 80% at cut off value of 0.1077989 μmol/μl/min. Combining CHIT-1 level and activity together gave a positive predictive value of 97.78% and negative predictive value of 100%. Administration of CHIT-1 increased microglial numbers and astrogliosis in the ventral horn with a concomitant increase in the levels of pro-inflammatory cytokines. Amoeboid-shaped microglial and astroglial cells were also present around the central canal. CHIT-1 administration also resulted in the reduction of motor neurons.

Conclusions

CHIT-1, an early diagnostic biomarker of sporadic ALS, activates glia priming them to attain a toxic phenotype resulting in neuroinflammation leading to motor neuronal death.