bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo
Authors: Saito Taro , Chiku Tomoki , Oka Mikiko , Wada-Kakuda Satoko , Nobuhara Mika , Oba Toshiya , Shinno Kanako , Abe Saori , Asada Akiko , Sumioka Akio , Takashima Akihiko , Miyasaka Tomohiro , Ando Kanae 
Published: June 2021

Abstract
Accumulation of microtubule-associated tau protein is thought to cause neuron loss in a group of neurodegenerative diseases called tauopathies. In diseased brains, tau molecules adopt pathological structures that propagate into insoluble forms with disease-specific patterns. Several types of posttranslational modifications in tau are known to modulate its aggregation propensity in vitro, but their influence on tau accumulation and toxicity at the whole-organism level has not been fully elucidated. Herein, we utilized a series of transgenic Drosophila models to compare systematically the toxicity induced by five tau constructs with mutations or deletions associated with aggregation, including substitutions at seven disease-associated phosphorylation sites (S7A and S7E), deletions of PHF6 and PHF6* sequences (ΔPHF6 and ΔPHF6*), and substitutions of cysteine residues in the microtubule binding repeats (C291/322A). We found that substitutions and deletions resulted in different patterns of neurodegeneration and accumulation, with C291/322A having a dramatic effect on both tau accumulation and neurodegeneration. These cysteines formed disulfide bonds in mouse primary cultured neurons and in the fly retina, and stabilized tau proteins. Additionally, they contributed to tau accumulation under oxidative stress. We also found that each of these cysteine residues contributes to the microtubule polymerization rate and microtubule levels at equilibrium, but none of them affected tau binding to polymerized microtubules. Since tau proteins expressed in the Drosophila retina are mostly present in the early stages of tau filaments self-assembly, our results suggest that disulfide bond formation by these cysteine residues could be attractive therapeutic targets.
Defining the Role of Cellular Immune Signatures in Diagnostic Evaluation of Suspected Tuberculosis
Authors: Halliday Alice , Masonou Tereza , Tolosa-Wright Mica R , Guo Yanping , Hoang Long , Parker Robert , Boakye Aime , Takwoingi Yemisi , Badhan Amarjit , Jain Pooja , Marwah Ishita , Berrocal-Almanza Luis C , Deeks Jonathan , Beverley Peter , Kon Onn Min , Lalvani Ajit 
Published: June 2021

Abstract

Background
Diagnosis of paucibacillary tuberculosis (TB) including extrapulmonary TB is a significant challenge, particularly in high-income, low-incidence settings. Measurement of Mycobacterium tuberculosis (Mtb)-specific cellular immune signatures by flow cytometry discriminates active TB from latent TB infection (LTBI) in case-control studies; however, their diagnostic accuracy and clinical utility in routine clinical practice is unknown.

Methods
Using a nested case-control study design within a prospective multicenter cohort of patients presenting with suspected TB in England, we assessed diagnostic accuracy of signatures in 134 patients who tested interferon-gamma release assay (IGRA)-positive and had final diagnoses of TB or non-TB diseases with coincident LTBI. Cellular signatures were measured using flow cytometry.

Results
All signatures performed less well than previously reported. Only signatures incorporating measurement of phenotypic markers on functional Mtb-specific CD4 T cells discriminated active TB from non-TB diseases with LTBI. The signatures measuring HLA-DR+IFNγ + CD4 T cells and CD45RA−CCR7−CD127− IFNγ −IL-2−TNFα + CD4 T cells performed best with 95% positive predictive value (95% confidence interval, 90–97) in the clinically challenging subpopulation of IGRA-positive but acid-fast bacillus (AFB) smear-negative TB suspects.

Conclusions
Two cellular immune signatures could improve and accelerate diagnosis in the challenging group of patients who are IGRA-positive, AFB smear-negative, and have paucibacillary TB.
Commitment to dendritic cells and monocytes
Authors: Ohteki Toshiaki , Kawamura Shunsuke , Onai Nobuyuki 
Published: June 2021

AbstractDendritic cells (DCs) and monocytes are widely conserved immune cells in vertebrates that arise from hematopoietic stem cells via intermediate progenitors. The progenitors that strictly give rise to DCs or monocytes have been recently identified both in humans and in mice, thereby revealing their differentiation pathways. Advances in analysis technologies have further deepened our understanding of the development of DCs and monocytes from progenitor population-based to individual progenitor cell-based commitment. Since DC-committed progenitors, common DC progenitors (CDPs) and precursor conventional DCs (pre-cDCs) do not differentiate into monocytes, DCs are a distinct lineage from monocytes, although monocytes can acquire DC functions upon activation at tissues where they arrive.
Macrolide resistance in Mycoplasma genitalium in Catalonia, Spain: a 1 year prospective study
Authors: Lucena Nemirosky J , Espelt R , López Grado E , Sobrino J , Acera A , Pérez J , Jensen J S , Sánchez-Reus F , Prim N 
Published: June 2021

Abstract

Background
Mycoplasma genitalium is an emergent cause of sexually transmitted disease (STD). The first-line treatment is azithromycin, but macrolide resistance is increasing due to mutations in the 23S rRNA gene.

Objectives
To determine the rates of M. genitalium infection and macrolide resistance in an area adjacent to Barcelona.

Methods
This 1 year prospective study was performed in a heterogenous population that included both low- and high-risk patients. M. genitalium was detected in all specimens sent to our institution for STD detection. Epidemiological and relevant clinical data were collected in the positive cases. Characterization of macrolide-associated resistance was performed by 23S rDNA sequencing.

Results
Of the 3540 patients included, 132 (3.7%) were positive for M. genitalium. Another sexually transmitted bacteria was detected in 20.4% of the M. genitalium cases, and Chlamydia trachomatis (11%) was the most frequently co-detected microorganism. Only 61.4% of patients received an adequate initial treatment against M. genitalium. The test of cure (TOC) was performed in 42% of patients, and therapeutic failure was detected in 10 cases. The rate of macrolide resistance was 12.6% and the most prevalent mutation was A2058G. There was an association between macrolide resistance and a previous history of M. genitalium detection (P &lt; 0.001).

Conclusions
Our results support the contribution of the previous use of macrolides in resistant strains. Given the difficulties in performing TOC in all patients, the inclusion of macrolide resistance in the detection test should be mandatory.
An adamantamine derivative as a drug candidate for the treatment of visceral leishmaniasis
Authors: Pomel Sébastien , Cojean Sandrine , Pons Valérie , Cintrat Jean-Christophe , Nguyen Laetitia , Vacus Joël , Pruvost Alain , Barbier Julien , Gillet Daniel , Loiseau Philippe M 
Published: June 2021

Abstract

Background
This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania.

Objectives
To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages.

Methods
In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development.

Results
VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline.

Conclusions
VP343 has the properties of a good drug candidate and merits further investigations.
Characterizing the hyper-viscoelastic behavior of adhesive films
Authors: Hsu Hao-Hsun , Tsai Jia-Lin 
Published: June 2021

Abstract
In this study, the hyper-viscoelastic behavior of adhesive films was characterized. A constitutive model was developed by combining the Mooney–Rivlin hyperelastic model and a viscoelastic model expressed in terms of the Prony series to describe the constitutive behavior of the adhesive films. The material parameters of the developed constitutive model were determined through single-step stress relaxation tests conducted for 30 min at four strain levels: 100%, 200%, 300% and 400%. Based on the reduced gradient method, the optimized material parameters were then evaluated by curve fitting the experimental data. To validate the proposed constitutive model, we performed the tensile tests at different strain rates from 5 × 10−4 to 5 × 10−1 s−1 and the multistep stress relaxation tests on the adhesive films. The model predictions and experimental data were in good agreement. Thus, the proposed hyper-viscoelastic constitutive model with parameters determined through single-step stress relaxation tests is effective in characterizing the mechanical behavior of adhesive films.
Azilsartan ameliorates ventricular hypertrophy in rats suffering from pressure overload-induced cardiac hypertrophy by activating the Keap1–Nrf2 signalling pathway
Authors: Hou Ning , Li Li-Rong , Shi Yong-Ying , Yuan Wen-Chang , Zhao Gan-Jian , Liu Xia-Wen , Cai Shao-Ai , Huang Yin , Zhan Hao-Xin , Pan Wei-Biao , Luo Cheng-Feng 
Published: June 2021

Abstract

Objectives
Investigate if azilsartan protects against myocardial hypertrophy by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated pathways.

Methods
Abdominal aortic constriction (AAC)-induced cardiac hypertrophy in rats was applied. Azilsartan or vehicle was administered daily for 6 weeks in sham or AAC rats. Cardiac morphology and ventricular function were determined. Azilsartan effects upon neonatal rat cardiomyocyte (NRCM) hypertrophy and molecular mechanisms were studied in angiotensin (Ang) II-stimulated NRCMs in vitro. Nrf2-small interfering RNA (siRNA) was used to knockdown Nrf2 expression. Messenger RNA (mRNA)/protein expression of Kelch-like erythroid cell-derived protein (Keap)1 and Nrf2 and its downstream antioxidant enzymes was determined by real-time reverse transcription–quantitative polymerase chain reaction and western blotting, respectively.

Key findings
Azilsartan treatment ameliorated cardiac hypertrophy/fibrosis significantly in AAC rats. Azilsartan increased expression of Nrf2 protein but decreased expression of Keap1 protein. Upregulation of protein expression of Nrf2’s downstream antioxidant enzymes by azilsartan treatment was observed. Azilsartan inhibited Ang II-induced NRCM hypertrophy significantly and similar effects on the Keap1–Nrf2 pathway were observed in vivo. Nrf2 knockdown markedly counteracted the beneficial effects of azilsartan on NRCM hypertrophy and the Keap1–Nrf2 pathway.

Conclusions
Azilsartan restrained pressure overload-induced cardiac remodelling by activating the Keap1–Nrf2 pathway and increasing expression of downstream antioxidant enzymes to alleviate oxidative stress.
Definitions of biodiversity from urban gardeners
Authors: Norton Briony A , Shang Bowen , Ramsey Andrew D , Sheffield David 
Published: June 2021

Abstract
Living in urban environments can leave people disconnected from nature and less likely to engage with biodiversity conservation. Within urban areas, residential gardens can occupy large proportions of greenspace and provide important habitat for biodiversity. Understanding the views and knowledge of garden owners who have collective responsibility for managing these areas is therefore important. We aimed to understand how urban garden owners understand biodiversity. We surveyed garden owners in Derby, UK, across 20 census output areas spanning a socioeconomic spectrum. Residents were asked to explain their understanding of ‘biodiversity’ in a short definition format. Responses were classified using thematic and word frequency analyses. Of 255 respondents, approximately one-third were unable to provide a definition. Themes that emerged in frequency order were as follows: variety of species or environments, coexistence of organisms, conservation of nature, a synonym for habitat and uncommon answers not clearly related to biodiversity. Members of wildlife or gardening charities and people with higher levels of formal education were more likely to provide definitions in line with formal definitions. We detected no difference between keen and less keen gardeners and little association between definitions and gardening for wildlife behaviours. These short-form responses captured many themes longer and/or qualitative assessments have identified, illustrating a diversity and depth of understanding of the concepts of biodiversity, without necessarily adhering to the formal definition. Given the variety of understanding, at this critical period, technical terms, even common ones, should be used with an open mind about how people interpret and act on them.
The Evolutionary History of Wild, Domesticated, and FeralBrassica oleracea(Brassicaceae)
Authors: Mabry Makenzie E , Turner-Hissong Sarah D , Gallagher Evan Y , McAlvay Alex C , An Hong , Edger Patrick P , Moore Jonathan D , Pink David A C , Teakle Graham R , Stevens Chris J , Barker Guy , Labate Joanne , Fuller Dorian Q , Allaby Robin G , Beissinger Timothy , Decker Jared E , Gore Michael A , Pires J Chris 
Published: June 2021

AbstractUnderstanding the evolutionary history of crops, including identifying wild relatives, helps to provide insight for conservation and crop breeding efforts. Cultivated Brassica oleracea has intrigued researchers for centuries due to its wide diversity in forms, which include cabbage, broccoli, cauliflower, kale, kohlrabi, and Brussels sprouts. Yet, the evolutionary history of this species remains understudied. With such different vegetables produced from a single species, B. oleracea is a model organism for understanding the power of artificial selection. Persistent challenges in the study of B. oleracea include conflicting hypotheses regarding domestication and the identity of the closest living wild relative. Using newly generated RNA-seq data for a diversity panel of 224 accessions, which represents 14 different B. oleracea crop types and nine potential wild progenitor species, we integrate phylogenetic and population genetic techniques with ecological niche modeling, archaeological, and literary evidence to examine relationships among cultivars and wild relatives to clarify the origin of this horticulturally important species. Our analyses point to the Aegean endemic B. cretica as the closest living relative of cultivated B. oleracea, supporting an origin of cultivation in the Eastern Mediterranean region. Additionally, we identify several feral lineages, suggesting that cultivated plants of this species can revert to a wild-like state with relative ease. By expanding our understanding of the evolutionary history in B. oleracea, these results contribute to a growing body of knowledge on crop domestication that will facilitate continued breeding efforts including adaptation to changing environmental conditions.
Implementation of an Infectious Diseases Telehealth Consultation and Antibiotic Stewardship Program for 16 Small Community Hospitals
Authors: Vento Todd J , Veillette John J , Gelman Stephanie S , Adams Angie , Jones Peter , Repko Katherine , Stenehjem Edward A 
Published: June 2021

Abstract

Background
Telehealth improves access to infectious diseases (ID) and antibiotic stewardship (AS) services in small community hospitals (SCHs), but the optimal model has not been defined. We describe implementation and impact of an integrated ID telehealth (IDt) service for 16 SCHs in the Intermountain Healthcare system.

Methods
The Intermountain IDt service included a 24-hour advice line, eConsults, telemedicine consultations (TCs), daily AS surveillance, long-term AS program (ASP) support by an IDt pharmacist, and a monthly telementoring webinar. We evaluated program measures from November 2016 through April 2018.

Results
A total of 2487 IDt physician interactions with SCHs were recorded: 859 phone calls (35% of interactions), 761 eConsults (30%), and 867 TCs (35%). Of 1628 eConsults and TCs, 1400 (86%) were SCH provider requests, while 228 (14%) were IDt pharmacist generated. Six SCHs accounted for &gt;95% of interactions. Median consultation times for each initial telehealth interaction type were 5 (interquartile range [IQR], 5–10) minutes for phone calls, 20 (IQR, 15–25) minutes for eConsults, and 50 (IQR, 35–60) minutes for TCs. Thirty-two percent of consults led to in-person ID clinic follow-up. Bacteremia was the most common reason for consultation (764/2487 [31%]) and Staphylococcus aureus the most common organism identified. ASPs were established at 16 facilities. Daily AS surveillance led to 2229 SCH pharmacist and 1305 IDt pharmacist recommendations. Eight projects were completed with IDt pharmacist support, leading to significant reductions in meropenem, vancomycin, and fluoroquinolone use.

Conclusions
An integrated IDt model led to collaborative ID/ASP interventions and improvements in antibiotic use at 16 SCHs. These findings provide insight into clinical and logistical considerations for IDt program implementation.
Procedural Justice: New Approaches to Parliament’s Engagement with the Public?
Authors: Bochel Catherine 
Published: June 2021

Abstract
This article utilises the idea of procedural justice (‘fair processes’) as a tool for analysing the ways in which Parliament engages with the public. It concludes that the engagement work of individual services in Parliament often reflects such ideas, and suggests that procedural justice could have value in bringing new insights to the work of Parliament in this area.
Populist but Pluralist? Populist Attitudes and Preferences for Political Pluralism in Parliament and Government
Authors: Ellenbroek Victor , Meijers Maurits J , Krouwel André 
Published: June 2021

AbstractIn the ideational approach to populism, populism and pluralism do not go together. While evidence indeed suggests that populist politicians consider a politically pluralist parliament as an obstacle to the expression of the true people’s will in politics, it is however an open question whether ‘the people’, and especially those with high populist attitudes, are just as opposed towards pluralism in parliament and coalition government. Thus far, evidence of a negative relationship between populist attitudes and preferences for pluralism in politics has been inconclusive. We asked ca. 2000 Dutch respondents—raked to be representative of the population—to draw up their ideal assembly and to select the parties that they wish to be part of coalition government. Results show that populist attitudes positively associate with the total number of parties included in the assembly, and non-negatively with the number of parties in the coalition. Parties with government experience, however, are much less preferred. These results shed new light on the presumed incompatibility between populism and pluralism.
Not Just a Simple Sugar: Arabinose Metabolism and Function in Plants
Authors: Mariette Alban , Kang Hee Sung , Heazlewood Joshua L , Persson Staffan , Ebert Berit , Lampugnani Edwin R 
Published: June 2021

ABSTRACT
Growth, development, structure as well as dynamic adaptations and remodeling processes in plants are largely controlled by properties of their cell walls. These intricate wall structures are mostly made up of different sugars connected through specific glycosidic linkages but also contain many glycosylated proteins. A key plant sugar that is present throughout the plantae, even before the divergence of the land plant lineage, but is not found in animals, is l-arabinose (l-Ara). Here, we summarize and discuss the processes and proteins involved in l-Ara de novo synthesis, l-Ara interconversion, and the assembly and recycling of l-Ara-containing cell wall polymers and proteins. We also discuss the biological function of l-Ara in a context-focused manner, mainly addressing cell wall–related functions that are conferred by the basic physical properties of arabinose-containing polymers/compounds. In this article we explore these processes with the goal of directing future research efforts to the many exciting yet unanswered questions in this research area.
Altered Subprocesses of Working Memory in Patients with Fibromyalgia: An Event-Related Potential Study Using N-Back Task
Authors: Mercado Francisco , Ferrera David , Fernandes-Magalhaes Roberto , Peláez Irene , Barjola Paloma 
Published: June 2021

Abstract

Objective
Cognitive dysfunction in fibromyalgia has become a key symptom considered by patients as more disabling than pain itself. Experimental evidence from neuropsychological and neuroimaging studies indicates that such cognitive impairments are especially robust when patients need to set in motion working memory processes, suggesting the existence of an altered functioning underlying the cerebral cortices of the frontoparietal memory network. However, the temporal dynamics of working memory subprocesses have not yet been explored in fibromyalgia.

Subjects
Thirty-six right-handed women participated in the experiment, comprising 18 patients with fibromyalgia and 18 healthy controls.

Methods
Event-related potentials (ERPs) and behavioral responses were recorded while participants were engaged in a two-back working memory task. Principal component analyses were used to define and quantify the ERP components associated with working memory processes.

Results
Patients with fibromyalgia exhibited worse performance than the control group, as revealed by their number of errors in the working memory task. Moreover, both scalp parieto-occipital P2 and parieto-occipital P3 amplitudes were lower for patients than for healthy control participants. Regression analyses revealed that lower P3 amplitudes were observed in those patients with fibromyalgia reporting higher pain ratings.

Conclusions
The present results suggest that both encoding of information (as reflected by P2) and subsequently context updating and replacement (as seen in lower P3 amplitudes), as a part of working memory subprocesses, are impaired in fibromyalgia. Studying the temporal dynamics of working memory through the use of ERP methodology is a helpful approach to detect specific impaired cognitive mechanisms in this chronic pain syndrome. These new data could be used to develop more specific treatments adapted for each patient.