bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the Potential Anti-Neuroinflammatory Effect of Minocycline in Chronic Low Back Pain: Protocol for a randomized, double-blind, placebo-controlled trial
Authors: Morrissey Erin J. , Alshelh Zeynab , Knight Paulina C. , Saha Atreyi , Kim Minhae , Torrado-Carvajal Angel , Zhang Yi , Edwards Robert R. , Pike Chelsea , Locascio Joseph J. , Napadow Vitaly , Loggia Marco L. 
Published: June 2022

ABSTRACTIntroductionChronic pain is an extremely prevalent public health issue. However, the underlying mechanisms are poorly understood, thus limiting effective treatment options. Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a potential treatment target. However, it is currently unknown whether modulating neuroinflammation effectively alleviates pain in humans. This trial tests the hypothesis that minocycline, an FDA-approved tetracycline antibiotic and effective glial cell inhibitor in animals, reduces neuroinflammation and may reduce pain symptoms in humans with chronic low back pain.Methods and analysisThis study is a randomized, double-blind, placebo-controlled clinical trial. Subjects, aged 18-65, with a confirmed diagnosis of chronic (≥ six months) low back pain (cLBP) and a self-reported pain rating of at least four out of ten (for at least half of the days during an average week) are enrolled via written, informed consent. Eligible subjects are randomized to receive a 14-day course of either active drug (minocycline) or placebo. Before and after treatment, subjects are scanned with integrated Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) using [11C]PBR28, a second-generation radiotracer for the 18 kDa translocator protein (TSPO), which is highly expressed in glial cells and thus a putative marker of neuroinflammation. Pain levels are evaluated via daily surveys, collected seven days prior to the start of medication, and throughout the 14 days of treatment. General linear models are used to assess pain levels and determine the treatment effect on brain (and spinal cord) TSPO signal.Ethics and disseminationThis study was approved by the Massachusetts General Hospital Institutional Review Board (Protocol Number: 2017P000179) and the U.S. Food and Drug Administration (IND Number: 142546). The results of the study will be disseminated via publications in peer-reviewed journals, presentations at conferences globally, and through various media.Trial registration numberClinicalTrials.gov (NCT03106740)Strengths and limitations of this studyThis is the first project to image the potential neuro-inflammatory effect of minocycline in a chronic pain condition.The use of simultaneous PET/MRI allows us to collect additional, ancillary MRI data that can be used to perform a comprehensive neurophysiological assessment of subjects.The sample size (n∼50 per group) is relatively small to detect a clinical response. An additional limitation is the relatively short treatment duration (i.e., 2-weeks).
Dam Site and Vegetation Selection by Reintroduced Beaver (Castor canadensis) on the San Pedro Riparian National Conservation Area, Arizona
Authors: Radke Marcia F. 
Published: June 2022

AbstractBeaver (Castor canadensis) were reintroduced on the San Pedro Riparian National Conservation Area (SPRNCA) after having been extirpated. The two most obvious effects from this keystone species, dam construction and herbivory, have not been studied on the SPRNCA. The purpose of this research was to determine any preference for dam sites, vegetation preferences, or if beaver may travel longer distances for preferred food or dam materials. Individual dams remained or were rebuilt in the same location on average every 2.4 years. Dam building was disproportionate to availability of sites, with beaver more commonly building dams at the confluence of the San Pedro River and tributaries. The size of areas with impacts to vegetation from beaver herbivory averaged 0.34 ha (2.5 ac), containing an average of 40.7 trees. Beaver exhibited a preference for smaller-sized cottonwood (Populus fremontii) trees over larger cottonwood trees and smaller or larger Goodding’s willow (Salix gooddingii), both in terms of whether trees were eaten and left standing or felled, and distance beaver travelled from water to the tree. Management implications include continued research on effects of beaver, management of invasive plant species, use of cottonwood genotypes with high tannin levels during restoration projects, further augmentation of beaver, use of beaver-dam analogues, and continued closure to hunting and trapping of beaver.
Direct Assessment of Nitrative Stress in Lipid Environments: Applications of a Designer Lipid-Based Biosensor for Peroxynitrite
Authors: Gutierrez Bryan , Aggarwal Tushar , Erguven Huseyin , Stone M. Rhia L. , Guo Changjiang , Bellomo Alyssa , Abramova Elena , Stevenson Emily R. , Gow Andrew J. , Izgu Enver Cagri 
Published: June 2022

ABSTRACTLipid environments can be chemically impacted by peroxynitrite (ONOO−), a reactive species generated under nitrative stress. Molecular tools used for investigating ONOO−reactivity in biological membranes remain underdeveloped, available probes lack the ability of subcellular localization, and the standard methods for detecting ONOO−in vivoare indirect. Here we investigated ONOO−in diverse lipid environments (biomimetic giant vesicles, live mammalian cells, and within the lung lining) using a biocompatible and membrane-localized phospholipid namedDPPC-TC-ONOO−. This designer lipid and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine self-assemble to giant vesicles that respond to ONOO−by generating fluorescence. These vesicles remain intact after sensing ONOO−and exhibit excellent selectivity against other redox species. We deliveredDPPC-TC-ONOO−into live HeLa and RAW cells via lipid nanoparticles (LNPs). Cytokine-induced nitrative stress led to enhanced fluorescence of the lipid clusters, primarily in the endoplasmic reticulum. These LNPs allowed the detection of ONOO−reactivity and nitrative stress around bronchioles within precision cut lung slices in response to acute lung injury (ALI). Furthermore, the use of the LNPs allowed for the detection of pulmonary macrophages from bronchoalveolar lavage following ALI in C57BL6/J but not inNos2−/–mice. These investigations revealed significant advantages ofDPPC-TC-ONOO−over its non-amphiphilic analog. Our work presents (i) an unprecedented function for biomimetic membranes, (ii) the potential of LNPs for delivering designer lipids into cells and tissues, (iii) real-time imaging of endogenous ONOO−at the organelle level in mammalian cells, and (iv) a direct method of studying nitrative stress due to ALIex vivoandin vivo.
AIM1-dependent high basal SA accumulation modulates stomatal aperture in rice
Authors: Xu Lei , Zhao Hongyu , Wang Junbin , Wang Xuming , Jia Xianqing , Xu Zhuang , Li Ruili , Jiang Kun , Chen Zhixiang , Luo Jie , Xie Xiaodong , Yi Keke 
Published: June 2022

AbstractThe basal levels of salicylic acid (SA), an important plant hormone, vary dramatically among plant species. In the shoot, for example, the monocot plant rice contains almost 100 times higher SA levels than the dicot model plant Arabidopsis. Despite its high basal levels, neither the biosynthetic pathway nor the biological functions of SA is well understood in rice. Here, we report that the synthesis of basal SA in rice shoot is not altered in the mutant for the ISOCHORISMATE SYNTHASE (ICS) gene, but drastically reduced in the mutant for OsAIM1, which encodes a beta-oxidation enzyme in the phenylalanine ammonia-lyase (PAL) pathway. Analogous to its role in thermogenesis, compromised SA accumulation in the Osaim1 mutant led to a lower shoot temperature than wild-type plants. However, this shoot temperature defect was resulted from increased transpiration due to elevated steady-state stomatal aperture in the mutant. Furthermore, the high basal shoot SA level is required for sustained expression of WRKY45 to modulate the steady-state stomatal aperture and shoot temperature in rice. Taken together, these results provide the direct genetic evidence for the critical role of the PAL pathway in the biosynthesis of high levels of basal SA, which play an important role in the regulation of steady-state stomatal aperture to promote fitness under both normal and stress conditions.
Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia
Authors: Kozlova Maria I. , Shalaeva Daria N. , Dibrova Daria V. , Mulkidjanian Armen Y 
Published: June 2022

AbstractAlthough P-loop foldnucleoside triphosphatases (also known as Walker NTPases) are ubiquitous, their catalytic mechanism remains obscure. Based on a comparative structural analysis of 3136 Mg-NTP-containing catalytic sites, we propose a common scheme of activated catalysis for P-loop NTPases where a hydrogen bond (H-bond) between the strictly conserved, Mg-coordinating Ser/Thr of the Walker A motif ([Ser/Thr]WA) and the conserved aspartate of the Walker B motif (AspWB) plays the key role. We found that this H-bond is very short in the structures with bound transition state (TS) analogs. We suggest that the proton affinities of these two residues reverse in the TS so that the proton relocates from [Ser/Thr]WAto AspWB. The anionic [Ser/Thr]WAwithdraws then a proton from the (catalytic) water molecule, and the nascent hydroxyl anion attacks gamma-phosphate. When the gamma-phosphate group breaks away, the trapped proton relays from AspWB, via [Ser/Thr]WA, to beta-phosphate and compensates for its developing negative charge.
I Am A Scientist: Overcoming implicit bias in STEM through explicit representations of diversity in lectures
Authors: Henri Dominic , Coates Kirra , Hubbard Katharine 
Published: June 2022

AbstractThe lack of diversity in Science, Technology, Engineering and Mathematics (STEM) is a significant issue for the sector. Many organisations and educators have identified lack of representation of historically marginalised groups within teaching materials as a potential barrier to students feeling that a STEM career is something that they can aspire to. A key barrier to addressing the issue is providing accessible and effective evidence-based approaches for educators to implement. In this study, we explore the potential for adapting presentation slides within lectures to ‘humanise’ the scientists involved, presenting their full names and photographs alongside a Harvard style reference. We adopt a questionnaire based methodology, and survey 161 undergraduates and postgraduates at a UK civic university. We first establish that students project implicit biases onto a hypothetical reference, with over 50% of students assuming the scientist was male and Western. We then explore what students think of the ‘humanised’ slide design, concluding that most students see it as good pedagogical practice, with some students positively changing their perceptions about diversity in science. We were unable to compare responses by ethnicity, but find evidence that female and non-binary students are more likely to see this as good pedagogical practice, perhaps reflecting white male fragility in being exposed to initiatives designed to highlight diversity. We conclude that humanised powerpoint slides are a potentially effective tool to highlight diversity of scientists within existing research-led teaching, but highlight that this is only a small intervention that needs to sit alongside more substantive work to address the lack of diversity in STEM.
Limited Role of Antithrombin Deficiency in Nephrotic Syndrome-Associated Hypercoagulopathy
Authors: Abdelghani Eman , Waller Amanda P. , Wolfgang Katelyn J. , Stanek Joseph R. , Parikh Samir V. , Rovin Brad H. , Smoyer William E. ,   the PNRC Investigators,   the NEPTUNE Investigators, Kerlin Bryce A. 
Published: June 2022

ABSTRACTBackgroundNephrotic syndrome is associated with an acquired hypercoagulopathy thought to drive its predisposition for venous thromboembolism. Previous studies have suggested that urinary antithrombin loss leading to acquired antithrombin deficiency is the primary mechanism underlying this hypercoagulopathy, but this hypothesis has not been directly tested. The objectives of this study were to test the influence of antithrombin levels on hypercoagulopathy in nephrotic syndrome patient samples and perform meta-analyses to evaluate the likelihood of antithrombin deficiency in nephrotic syndrome patients.DesignSamples from 3 independent nephrotic syndrome cohorts were analyzed. Antithrombin antigen and activity assays were performed using ELISA and amidolytic assays, respectively. Plasma thrombin generation, albumin, and urine protein-to-creatinine ratios were determined using established methods. Meta-analyses were performed by combining these new data with previously published data.ResultsAntithrombin levels were not consistently related to either plasma albumin or proteinuria. Antithrombin was quantitatively related to hypercoagulopathy in adult nephrotic syndrome. Whereas antithrombin activity was inconsistently associated with hypercoagulopathy in childhood nephrotic syndrome. Notably, hypercoagulopathy did not differ between patients with normal antithrombin levels and those with levels below the threshold used to define clinical antithrombin deficiency (<70%). Moreover, ex vivo antithrombin supplementation did not significantly alter hypercoagulopathy in antithrombin deficient plasma samples. Moreover, the meta-analyses demonstrated that antithrombin deficiency is not a uniform feature of nephrotic syndrome but may be more common in children than adults.ConclusionsThese data suggest that antithrombin deficiency plays only a limited role in the mechanisms underlying the acquired hypercoagulopathy of nephrotic syndrome. Moreover, antithrombin deficiency is not present in all nephrotic syndrome patients and is more likely in children than adults despite the higher risk for venous thromboembolism in adults than children. Future studies should focus on identifying antithrombin-independent mechanisms that better explain the pathophysiology of hypercoagulopathy in nephrotic syndrome.
Diagnostic accuracy and limit of detection of ten malaria parasite lactate dehydrogenase-based rapid tests for Plasmodium knowlesi and P. falciparum
Authors: Tan Angelica F. , binti Sakam Sitti Saimah , Rajahram Giri S. , William Timothy , Isnadi Mohammad Faruq Abd Rachman , Daim Sylvia , Barber Bridget E , Kho Steven , Sutherland Colin J. , Anstey Nicholas M. , Yerlikaya Seda , van Schalkwyk Donelly A , Grigg Matthew J. 
Published: June 2022

AbstractBackgroundPlasmodium knowlesi causes zoonotic malaria across Southeast Asia. First-line diagnostic microscopy cannot reliably differentiate P. knowlesi from other human malaria species. Rapid diagnostic tests (RDTs) designed for P. falciparum and P. vivax are used routinely in P. knowlesi co-endemic areas despite potential cross-reactivity for species-specific antibody targets.MethodsTen RDTs were evaluated: nine to detect clinical P. knowlesi infections from Malaysia, and nine assessing limit of detection (LoD) for P. knowlesi (PkA1-H.1) and P. falciparum (Pf3D7) cultures. Targets included Plasmodium-genus parasite lactate dehydrogenase (pan-pLDH) and P. vivax (Pv)-pLDH.ResultsSamples were collected prior to antimalarial treatment from 127 patients with microscopy-positive PCR-confirmed P. knowlesi mono-infections. Median parasitaemia was 788/µL (IQR 247-5,565/µL). Pan-pLDH sensitivities ranged from 50.6% (95% CI 39.6–61.5) (SD BIOLINE) to 87.0% (95% CI 75.1–94.6) (First Response® and CareStart™ PAN) compared to reference PCR. Pv-pLDH RDTs detected P. knowlesi with up to 92.0% (95% CI 84.3-96.7%) sensitivity (Biocredit™). For parasite counts ≥200/µL, pan-pLDH (Standard Q) and Pv-pLDH RDTs exceeded 95% sensitivity. Specificity of RDTs against 26 PCR-confirmed negative controls was 100%. Sensitivity of the 6 highest performing RDTs were not significantly different when comparing samples taken before and after (median 3 hours) antimalarial treatment. Parasite ring stages were present in 30% of pre-treatment samples, with ring stage proportions (mean 1.9%) demonstrating inverse correlation with test positivity of Biocredit™ and two CareStart™ RDTs.For cultured P. knowlesi, CareStart™ PAN demonstrated the lowest LoD at 25 parasites/µL; LoDs of other pan-pLDH ranged from 98 to >2000 parasites/µL. Pv-pLDH LoD for P. knowlesi was 49 parasites/µL. P. falciparum-pLDH or histidine-rich-protein-2 channels did not react with P. knowlesi.ConclusionSelected RDTs demonstrate sufficient performance for detection of all human malaria species including P. knowlesi in co-endemic areas where microscopy is not available, particularly for higher parasite counts, although cannot reliably differentiate among non-falciparum malaria.
Compliant citizens, defiant rebels or neither? Exploring changing COVID-19 vaccine attitudes and decisions in Bradford, UK: Findings from a follow-up qualitative study
Authors: Lockyer Bridget , Moss Rachael H , Endacott Charlotte , Islam Shahid , Sheard Laura 
Published: June 2022

AbstractBackgroundCOVID-19 vaccines have been the central pillar of the public health response to the pandemic, intended to enable us to ‘live with Covid’. It is important to understand COVID-19 vaccines attitudes and decisions in order to maximise uptake through an empathetic lens.ObjectiveTo explore the factors that influenced people’s COVID-19 vaccines decisions and how attitudes towards the vaccines had changed in an eventful year.Design and participantsThis is a follow up study that took place in Bradford, UK one year after the original study, between October 2021 and January 2022. In-depth phone interviews were conducted with 12 (of the 20 originally interviewed) people from different ethnic groups and areas of Bradford. Reflexive thematic analysis was conducted.Results11 of the 12 participants interviewed had received both doses of the COVID-19 vaccine and most intended to have a booster dose. Participants described a variety of reasons why they had decided to have the vaccines, including: feeling at increased risk at work; protecting family and others in their communities, unrestricted travel and being influenced by the vaccine decisions of family, friends and colleagues. All participants discussed ongoing interaction with COVID-19 misinformation and for some this meant they were uneasy about their decision to have the vaccine. They described feeling overloaded by and disengaged from COVID-19 information, which they often found contradictory and some felt mistrustful of the UK government’s motives and decisions during the pandemic.ConclusionsThe majority of participants had managed to navigate an overwhelming amount of circulating COVID-19 misinformation and chosen to have two or more COVID-19 vaccines, even if they had been previously said they were unsure. However, these decisions were complicated, and demonstrate the continuum of vaccine hesitancy and acceptance. This follow up study underlines that vaccine attitudes are changeable and contextual.Patient or Public ContributionThe original study was developed through a rapid community and stakeholder engagement process in 2020. Discussion with the Bradford Council Public Health team and the public through the Bradford COVID-19 Community Insights Group was undertaken in 2021 to identify important priorities for this follow up study.
Coating formulation change is the root cause for inferior bioefficacy of long-lasting insecticidal nets in Papua New Guinea
Authors: Bubun Nakei , Anetul Evodia , Koinari Melanie , Freeman Tim , Karl Stephan 
Published: June 2022

Abstract/SummaryIn a study published in Nature Communications in August 2020, we demonstrated an abrupt decrease in the bioefficacy of long-lasting insecticidal nets (LLINs) for malaria prevention delivered to Papua New Guinea (PNG) between 2012 and 2013. This coincided with a rise in malaria cases in the country. At the time of publication of the original article, we were unable to pinpoint the exact reasons for the observed shift towards inferior product performance and stated that ‘further studies are required to determine the underlying cause of the observed reduced bioefficacy of these LLINs’ 1. Due to the potentially significant public health implications (hundreds of millions of this specific LLIN product had been distributed globally), our study led to discussions and speculation among stakeholders. Here, we present data unequivocally showing that the observed reduction in the ability to kill mosquitoes of these LLINs is a direct result of a manufacturing change that occurred at the same time.
Dissecting the invasion of Galleria mellonella by Yersinia enterocolitica reveals metabolic adaptations and a role of a phage lysis cassette in insect killing
Authors: Sänger Philipp-Albert , Wagner Stefanie , Liebler-Tenorio Elisabeth , Fuchs Thilo M. 
Published: June 2022

AbstractThe human pathogen Yersinia enterocolitica strain W22703 is characterized by its toxicity towards invertebrates that requires the insecticidal toxin complex (Tc) proteins encoded by the pathogenicity island Tc-PAIYe. Molecular and pathophysiological details of insect larvae infection and killing by this pathogen, however, have not been dissected. Here, we applied oral infection of Galleria mellonella (Greater wax moth) larvae to study the colonisation, proliferation, tissue invasion, and killing activity of W22703. We demonstrated that this strain is strongly toxic towards the larvae, in which they proliferate by more than three orders of magnitude within six days post infection. Deletion mutants of genes tcaA and tccC were atoxic for the insect. W22703 ΔtccC, in contrast to W22703 ΔtcaA, initially proliferated before being eliminated from the host, thus confirming TcaA and TccC as membrane-binding Tc subunit and ADP-ribosylating enzyme, respectively. Time course experiments revealed a Tc-dependent infection process starting with midgut colonisation that is followed by invasion of the hemolymph where the pathogen elicits morphological changes of hemocytes and strongly proliferates. The in vivo transcriptome of strain W22703 shows that the pathogen undergoes a drastic reprogramming of central cell functions and gains access to numerous carbohydrate and amino acid resources within the insect. Strikingly, a mutant lacking a phage-related holin/endolysin (HE) cassette, which is located within Tc-PAIYe, resembled the phenotypes of W22703 ΔtcaA, suggesting that this dual lysis cassette is an example for a phage-related function that has been adapted for the release of a bacterial toxin.