bluuebunny/crossref_metadata_2025_split huggingface dataset:
D1 receptors in the anterior cingulate cortex modulate basal mechanical sensitivity threshold and glutamatergic synaptic transmission
Authors: Darvish-Ghane Soroush , Quintana Clémentine , Beaulieu Jean-Martin , Martin Loren J. 
Published: September 2020

AbstractThe release of dopamine (DA) into target brain areas is considered an essential event for the modulation of many physiological effects. While the anterior cingulate cortex (ACC) has been implicated in pain related behavioral processes, DA modulation of synaptic transmission within the ACC and pain related phenotypes remains unclear. Here we characterized a Crispr/Cas9 mediated somatic knockout of the D1 receptor (D1R) in all neuronal subtypes of the ACC and find reduced mechanical thresholds, without affecting locomotion and anxiety. Further, the D1R high-efficacy agonist SKF 81297 and low efficacy agonist (±)-SKF-38393 inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) currents in the ACC. Paradoxically, the D1R antagonists SCH-23390 and SCH 33961 when co-applied with D1R agonists produced a robust short-term synergistic depression of AMPAR currents in the ACC, demonstrating an overall inhibitory role for D1R ligands. Overall, our data indicate that absence of D1Rs in the ACC enhanced peripheral sensitivity to mechanical stimuli and D1R activation decreased glutamatergic synaptic transmission in ACC neurons.
LncRNA PSMB8-AS1 contributes to pancreatic cancer progression via modulating miR-382-3p/STAT1/PD-L1 axis
Authors: Zhang Hao , Zhu Changhao , He Zhiwei , Chen Shiyu , Li Lin , Sun Chengyi 
Published: September 2020

Abstract
Background
Accumulating evidence demonstrates the essential role of long non-coding RNA (lncRNA) in various types of cancers, including pancreatic cancer. However, the functions and regulation mechanism of lncRNA PMSB8-AS1 in pancreatic cancer are largely unclear.

Methods
Quantitative reverse transcription PCR (qRT-PCR) is used to examine the expression of PMSB8-AS1 in PC tissues and PC cell lines. The effect of PMSB8-AS1 on the proliferation of PC cells was detected using CCK8 assay, colony assay, and flow cytometry. The effect of PMSB8-AS1 on the migration and invasion of pancreatic cancer cells was detected using a wound-healing assay and transwell migration assay. Bioinformatic analysis, double luciferase reporting assay, western blot, and rescue experiments were used to detect the regulatory relationship between PMSB8-AS1, miR-382–3p, STAT1, and PD-L1.

Results
PMSB8-AS1 expression was upregulated in PC tissues and cell lines and positively associated with the worst survival in patients with PC. The in vitro and in vivo assays demonstrated that overexpression of PMSB8-AS1 significantly promoted pancreatic cancer cell proliferation, migration, and invasion, whereas knockdown of PMSB8-AS1 suppressed cell proliferation, migration, invasion, and EMT, and decreased apoptosis of PC cells. Besides, PMSB8-AS1 directly bound to miR-382–3p downregulated its expression. Besides, PMSB8-AS1 reversed the effect of miR-382–3p on the growth and metastasis of PC cells, which might be targeted on STAT1. Furthermore, STAT1 is the transcriptional factor that activates the expression of PD-L1.

Conclusion
lncRNA PMSB8-AS1 promotes pancreatic cancer progression via STAT1 by sponging miR-382–3p involving regulation PD-L1.
(1,3)-β-d-Glucan-based empirical antifungal interruption in suspected invasive candidiasis: a randomized trial
Authors: De Pascale Gennaro , Posteraro Brunella , D’Arrigo Sonia , Spinazzola Giorgia , Gaspari Rita , Bello Giuseppe , Montini Luca Maria , Cutuli Salvatore Lucio , Grieco Domenico Luca , Di Gravio Valentina , De Angelis Giulia , Torelli Riccardo , De Carolis Elena , Tumbarello Mario , Sanguinetti Maurizio , Antonelli Massimo 
Published: September 2020

Abstract
Background
(1,3)-β-d-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis.

Methods
This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-d-glucan was negative ((1,3)-β-d-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-d-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment.

Results
We randomized 108 patients into the (1,3)-β-d-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1–3] in the (1,3)-β-d-glucan group vs. 10 days [6–13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94–8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-β-d-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-β-d-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23).

Conclusions
In critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-β-d-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population.

Trial registration
ClinicalTrials.gov, NCT03117439, retrospectively registered on 18 April 2017
How to deal with a temporary suspension and restarting your trial: our experiences and lessons learnt
Authors: Constable Lynda , Davidson Tracey , Breeman Suzanne , Cotton Seonaidh , McDonald Alison , Wileman Samantha , Norrie John 
Published: September 2020

AbstractWhilst the issues around early termination of randomised controlled trials (RCTs) are well documented in the literature, trials can also be temporarily suspended with the real prospect that they may subsequently restart. There is little guidance in the literature as to how to manage such a temporary suspension. In this paper, we describe the temporary suspension of a trial within our clinical trials unit because of concerns over the safety of transvaginal synthetic mesh implants. We also describe the challenges, considerations, and lessons learnt during the suspension that we are now applying in the current COVID-19 pandemic which has led to activities in many RCTs across the world undergoing a temporary suspension.There were three key phases within the temporary suspension: the decision to suspend, implementation of the suspension, and restarting. Each of these phases presented individual challenges which are discussed within this paper, along with the lessons learnt. There were obvious challenges around recruitment, delivery of the intervention, and follow-up. Additional challenges included communication between stakeholders, evolving risk assessment, updates to trial protocol and associated paperwork, maintaining site engagement, data-analysis, and workload within the trial team and Sponsor organisation.Based on our experience of managing a temporary suspension, we developed an action plan and guidance (see Additional File 1) for managing a significant trial event, such as a temporary suspension. We have used this document to help us manage the suspension of activities within our portfolio of trials during the current COVID-19 pandemic.
A strategy for synergistic ethanol yield and improved production predictability through blending feedstocks
Authors: Persson Michael , Galbe Mats , Wallberg Ola 
Published: September 2020

Abstract
Background
The integration of first- and second-generation bioethanol processes has the potential to accelerate the establishment of second-generation bioethanol on the market. Cofermenting pretreated wheat straw with a glucose-rich process stream, such as wheat grain hydrolysate, in a simultaneous saccharification and fermentation process could address the technical issues faced during the biological conversion of lignocellulose to ethanol. For example, doing so can increase the final ethanol concentration in the broth and mitigate the effects of inhibitors formed during the pretreatment. Previous research has indicated that blends of first- and second-generation substrates during simultaneous saccharification and fermentation have synergistic effects on the final ethanol yield, an important parameter in the process economy. In this study, enzymatic hydrolysis and simultaneous saccharification and fermentation were examined using blends of pretreated wheat straw and saccharified wheat grain at various ratios. The aim of this study was to determine the underlying mechanisms of the synergy of blending with regard to the yield and volumetric productivity of ethanol.

Results
Replacing 25% of the pretreated wheat straw with wheat grain hydrolysate during simultaneous saccharification and fermentation was sufficient to decrease the residence time needed to deplete soluble glucose from 96 to 24 h and shift the rate-limiting step from ethanol production to the rate of enzymatic hydrolysis. Further, a synergistic effect on ethanol yield was observed with blended substrates, coinciding with lower glycerol production. Also, blending substrates had no effect on the yield of enzymatic hydrolysis.

Conclusions
The effects of substrate blending on the volumetric productivity of ethanol were attributed to changes in the relative rates of cell growth and cell death due to alterations in the concentrations of substrate and pretreatment-derived inhibitors. The synergistic effect of substrate blending on ethanol yield was attributed in part to the decreased production of cell mass and glycerol. Thus, it is preferable to perform simultaneous saccharification and fermentation with substrate blends rather than pure substrates with regard to yield, productivity, and the robustness of the process.
Multiscale analysis of lignocellulose recalcitrance towards OrganoCat pretreatment and fractionation
Authors: Weidener Dennis , Dama Murali , Dietrich Sabine K. , Ohrem Benedict , Pauly Markus , Leitner Walter , Domínguez de María Pablo , Grande Philipp M. , Klose Holger 
Published: September 2020

Abstract
Background
Biomass recalcitrance towards pretreatment and further processing can be related to the compositional and structural features of the biomass. However, the exact role and relative importance to those structural attributes has still to be further evaluated. Herein, ten different types of biomass currently considered to be important raw materials for biorefineries were chosen to be processed by the recently developed, acid-catalyzed OrganoCat pretreatment to produce cellulose-enriched pulp, sugars, and lignin with different amounts and qualities. Using wet chemistry analysis and NMR spectroscopy, the generic factors of lignocellulose recalcitrance towards OrganoCat were determined.

Results
The different materials were processed applying different conditions (e.g., type of acid catalyst and temperature), and fractions with different qualities were obtained. Raw materials and products were characterized in terms of their compositional and structural features. For the first time, generic correlation coefficients were calculated between the measured chemical and structural features and the different OrganoCat product yields and qualities. Especially lignin-related factors displayed a detrimental role for enzymatic pulp hydrolysis, as well as sugar and lignin yield exhibiting inverse correlation coefficients. Hemicellulose appeared to have less impact, not being as detrimental as lignin factors, but xylan-O-acetylation was inversely correlated with product yield and qualities.

Conclusion
These results illustrate the role of generic features of lignocellulosic recalcitrance towards acidic pretreatments and fractionation, exemplified in the OrganoCat strategy. Discriminating between types of lignocellulosic biomass and highlighting important compositional variables, the improved understanding of how these parameters affect OrganoCat products will ameliorate bioeconomic concepts from agricultural production to chemical products. Herein, a methodological approach is proposed.
Bacillus sphaericus exposure reduced vector competence of Anopheles dirus to Plasmodium yoelii by upregulating the Imd signaling pathway
Authors: Yu Shasha , Wang Pan , Qin Jie , Zheng Hong , Wang Jing , Liu Tingting , Yang Xuesen , Wang Ying 
Published: September 2020

Abstract
Background
Vector control with Bacillus sphaericus (Bs) is an effective way to block the transmission of malaria. However, in practical application of Bs agents, a sublethal dose effect was often caused by insufficient dosing, and it is little known whether the Bs exposure would affect the surviving mosquitoes’ vector capacity to malaria.

Methods
A sublethal dose of the Bs 2362 strain was administrated to the early fourth-instar larvae of Anopheles dirus to simulate shortage use of Bs in field circumstance. To determine vector competence, mosquitoes were dissected and the oocysts in the midguts were examined on day 9–11 post-infection with Plasmodium yoelii. Meanwhile, a SYBR quantitative PCR assay was conducted to examine the transcriptional level of the key immune molecules of mosquitoes, and RNA interference was utilized to validate the role of key immune effector molecule TEP1.

Results
The sublethal dose of Bs treatment significantly reduced susceptibility of An. dirus to P. yoelii, with the decrease of P. yoelii infection intensity and rate. Although there existed a melanization response of adult An. dirus following challenge with P. yoelii, it was not involved in the decrease of vector competence as no significant difference of melanization rates and densities between the control and Bs groups was found. Further studies showed that Bs treatment significantly increased TEP1 expression in the fourth-instar larvae (L4), pupae (Pu), 48 h post-infection (hpi) and 72 hpi (P < 0.001). Further, gene-silencing of TEP1 resulted in disappearance of the Bs impact on vector competence of An. dirus to P. yoelii. Moreover, the transcriptional level of PGRP-LC and Rel2 were significantly elevated by Bs treatment with decreased expression of the negative regulator Caspar at 48 hpi, which implied that the Imd signaling pathway was upregulated by Bs exposure.

Conclusions
Bs exposure can reduce the vector competence of An. dirus to malaria parasites through upregulating Imd signaling pathway and enhancing the expression of TEP1. The data could not only help us to understand the impact and mechanism of Bs exposure on Anopheles’ vector competence to malaria but also provide us with novel clues for wiping out malaria using vector control.
Efficacy of combination products containing sarolaner, moxidectin and pyrantel (Simparica Trio™) or afoxolaner and milbemycin (NexGard Spectra®) against induced infestations of Ixodes holocyclus in dogs
Authors: Packianathan Raj , Hodge Andrew , Bruellke Natalie , Jackson Chrissie , Maeder Steven 
Published: September 2020

Abstract
Background
The Australian paralysis tick, Ixodes holocyclus, causes tick paralysis in dogs and cats in the eastern coastal regions of Australia. Prevention is the best option to protect dogs against this potentially fatal disease and sarolaner provides rapid and sustained efficacy against I. holocyclus. In this laboratory study, the efficacy of two combination endectocides containing sarolaner + moxidectin + pyrantel (Simparica Trio™) and afoxolaner + milbemycin (NexGard Spectra®) was evaluated against an artificial infestation of I. holocyclus.

Methods
Twenty-four (n =24) foxhounds were randomly allocated to three treatment groups and artificially infested with 30 adult female viable ticks on Days − 1, 7, 14, 21, 28 and 35. On Day 0, dogs in each treatment group were treated with either Drontal® (control group), Simparica Trio™ at the label dose to provide minimum doses of sarolaner (1.2 mg/kg), moxidectin (24 µg/kg) and pyrantel (5 mg/kg) or NexGard Spectra® to provide minimum doses of afoxolaner (2.5 mg/kg) and milbemycin (0.5 mg/kg). Live tick counts were performed at 48 and 72 hours after treatment and after each re-infestation on Days 7, 14, 21, 28 and 35. Efficacy was determined at each time point relative to counts for control dogs based on geometric means.

Results
Against an existing infestation, efficacy of both Simparica Trio™ and NexGard Spectra® was 99.6% and 100% at 48 and 72 h time points, respectively (P = 1.000). Against subsequent weekly infestations, treatment with Simparica Trio™ and NexGard Spectra® resulted in efficacy of ≥ 97.7% and ≥ 95.5% (P ≥ 0.0911), respectively at the 48 h time point and at the 72 h time point, Simparica Trio™ and NexGard Spectra® resulted in efficacy of ≥ 99.0% and ≥ 98.4% (P ≥ 0.0511), respectively. There were no treatment-related adverse events in the study.

Conclusions
Single doses of Simparica Trio™ and NexGard Spectra® were highly efficacious and provided comparable efficacy against the Australian paralysis tick, I. holocyclus for up to 35 days.
Meta-transcriptomic identification of Trypanosoma spp. in native wildlife species from Australia
Authors: Ortiz-Baez Ayda Susana , Cousins Kate , Eden John-Sebastian , Chang Wei-Shan , Harvey Erin , Pettersson John H.-O. , Carver Scott , Polkinghorne Adam , Šlapeta Jan , Rose Karrie , Holmes Edward C. 
Published: September 2020

AbstractBackgroundWildlife species carry a remarkable diversity of trypanosomes. The detection of trypanosome infection in native Australian fauna is central to understanding their diversity and host-parasite associations. The implementation of total RNA sequencing (meta-transcriptomics) in trypanosome surveillance and diagnosis provides a powerful methodological approach to better understand the host species distribution of this important group of parasites.MethodsWe implemented a meta-transcriptomic approach to detect trypanosomes in a variety of tissues (brain, liver, lung, skin, gonads) sampled from native Australian wildlife, comprising four marsupials (koala,Phascolarctos cinereus; southern brown bandicoot,Isoodon obesulus; swamp wallaby,Wallabia bicolor; bare-nosed wombat,Vombatus ursinus), one bird (regent honeyeater,Anthochaera phrygia) and one amphibian (eastern dwarf tree frog,Litoria fallax). Samples corresponded to both clinically healthy and diseased individuals. Sequencing reads werede novoassembled into contigs and annotated. The evolutionary relationships among the trypanosomatid sequences identified were determined through phylogenetic analysis of18SrRNA sequences.ResultsWe detected trypanosome sequences in all six species of vertebrates sampled, with positive samples in multiple organs and tissues confirmed by PCR. Phylogenetic analysis indicated that the trypanosomes infecting marsupials were related to those previously detected in placental and marsupial mammals, while the trypanosome in the regent honeyeater grouped with avian trypanosomes. In contrast, we provide the first evidence for a trypanosome in the eastern dwarf tree frog that was phylogenetically distinct from those described in other amphibians.ConclusionsTo our knowledge, this is the first meta-transcriptomic analysis of trypanosomes in native Australian wildlife, expanding the known genetic diversity of these important parasites. We demonstrated that RNA sequencing is sufficiently sensitive to detect low numbers ofTrypanosomatranscripts and from diverse hosts and tissues types, thereby representing an effective means to detect trypanosomes that are divergent in genome sequence.
ROS-mediated NLRP3 inflammasome activation participates in the response against Neospora caninum infection
Authors: Li Lu , Wang Xiao-Cen , Gong Peng-Tao , Zhang Nan , Zhang Xu , Li Shan , Li Xin , Liu Shao-Xiong , Zhang Xiao-Xu , Li Wei , Li Jian-Hua , Zhang Xi-Chen 
Published: September 2020

Abstract
Background
Neospora caninum is an obligate intracellular protozoan that causes neosporosis, N. caninum infection is a major cause of abortion in cattle worldwide. Currently, specific treatment for neosporosis is not available. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytoplasmic protein complex that plays an important role in host defense against N. caninum infection, but the underlying mechanisms are poorly understood.

Methods
The reactive oxygen species (ROS) inhibitor and the ROS inducer, wild-type (WT) and NLRP3-deficient peritoneal macrophages or mice were used to investigate the role of ROS in NLRP3 inflammasome activation and controlling parasite burdens. ROS production, cell death and cell viability, production of inflammasome-mediated IL-1β or IL-18, cleavage of caspase-1 and NLRP3 expression, as well as parasite burdens were detected.

Results
In vitro, N. caninum induced ROS generation in a dose-dependent manner in peritoneal macrophages. The pretreatment of ROS inhibitor N-acetyl-l-cysteine (NAC) significantly attenuated N. caninum-induced ROS production, LDH release, IL-1β secretion and NLRP3 expression, whereas N. caninum proliferation was notably increased. In contrary, the ROS inducer pyrogallol (PG) significantly enhanced ROS production and NLRP3 inflammasome activity and decreased the parasite burden in N. caninum-infected peritoneal macrophages. NADPH-dependent ROS-mediated NLRP3 inflammasome activation induced by N. caninum can also be confirmed by using the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI). However, the NAC or DPI pre-treatment or PG treatment did not significantly alter N. caninum-induced inflammasome activities and parasite proliferation in Nlrp3−/− peritoneal macrophages. In vivo, IL-18 releases in serum and parasite burdens in peritoneal exudate cells were significantly increased in PG-treated WT mice after infection with N. caninum; however, IL-18 productions and parasite burdens were not changed in PG-treated Nlrp3−/− mice. Furthermore, PG treatment in WT mice infected with N. caninum significantly decreased the mortality, weight loss and parasite burdens in tissues and histopathological lesions.

Conclusions
Neospora caninum-induced NADPH-dependent ROS generation plays an important role in NLRP3 inflammasome activation and controlling parasites. The ROS inducer PG can control N. caninum infection mainly by promoting NLRP3 inflammasome activation. ROS-mediated NLRP3 inflammasome axis can be a potential therapeutic target for neosporosis.