bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro profiling of orphan G protein coupled receptor (GPCR) constitutive activity
Authors: Watkins Lyndsay R. , Orlandi Cesare 
Published: March 2021

Background and PurposeMembers of the GPCR family are targeted by a significant fraction of the available FDA‐approved drugs. However, the physiological role and pharmacological properties of many GPCRs remain unknown, representing untapped potential in drug design. Of particular interest are ~100 less‐studied GPCRs known as orphans because their endogenous ligands are unknown. Intriguingly, disease‐causing mutations identified in patients, together with animal studies, have demonstrated that many orphan receptors play crucial physiological roles and, thus, represent attractive drug targets.Experimental ApproachThe majority of deorphanized GPCRs demonstrate coupling to Gi/o. However, a limited number of techniques allow the detection of intrinsically small constitutive activity associated with Gi/o protein activation, which represents a significant barrier in our ability to study orphan GPCR signalling. Using luciferase reporter assays, we effectively detected constitutive Gs, Gq and G12/13 protein signalling by unliganded receptors and introducing various G protein chimeras, we provide a novel, highly sensitive tool capable of identifying Gi/o coupling in unliganded orphan GPCRs.Key ResultsUsing this approach, we measured the constitutive activity of the entire class C GPCR family that includes eight orphan receptors and a subset of 20 prototypical class A GPCR members, including 11 orphans. Excitingly, this approach illuminated the G protein coupling profile of eight orphan GPCRs (GPR22, GPR137b, GPR88, GPR156, GPR158, GPR179, GPRC5D and GPRC6A) previously linked to pathophysiological processes.Conclusion and ImplicationsWe provide a new platform that could be utilized in ongoing studies in orphan receptor signalling and de‐orphanization efforts.
The enigma of persistent symptoms in hypothyroid patients treated with levothyroxine: A narrative review
Authors: Perros Petros , Van Der Feltz‐Cornelis Christina , Papini Enrico , Nagy Endre V. , Weetman Anthony P. , Hegedüs Laszlo 
Published: March 2021

AbstractA significant minority of patients with hypothyroidism report persistent symptoms despite achieving normal thyroid biochemistry after levothyroxine (L‐T4) replacement. Four principal lines of thinking, which are not mutually exclusive, may explain this enigma. The ‘low tissue liothyronine hypothesis’ emphasizes the potential imperfections of L‐T4 replacement therapy that may lead to hypothyroidism in some tissues such as the brain, while others (eg hypothalamus) are euthyroid. The ‘Somatic Symptom and Related Disorders hypothesis’ draws attention to an incidental coexistence of a diagnosis of Somatic Symptom and Related Disorders in patients with treated hypothyroidism. The ‘autoimmune neuroinflammation hypothesis’ highlights the potential consequences of inflammatory mediators due to thyroid autoimmunity (the commonest cause of hypothyroidism) on the brain. The ‘comorbidities and psychosocial hypothesis’ implicates a variety of physical and psychosocial factors that have been noted to be associated with a diagnosis of hypothyroidism, which may be primarily the cause of persistent complaints. Over the past twenty years, a great deal of time and effort has been expended pursuing the ‘low tissue liothyronine hypothesis’, which has failed to yield results that translate to patient benefits. This has skewed the balance in clinical practice, in favour of pursuing answers relating to L‐T4 and liothyronine combination treatment, while the alternative explanations have been downplayed and potentially useful interventions have been given insufficient attention.
Visualization of Tensor Fields in Mechanics
Authors: Hergl Chiara , Blecha Christian , Kretzschmar Vanessa , Raith Felix , Günther Fabian , Stommel Markus , Jankowai Jochen , Hotz Ingrid , Nagel Thomas , Scheuermann Gerik 
Published: March 2021

AbstractTensors are used to describe complex physical processes in many applications. Examples include the distribution of stresses in technical materials, acting forces during seismic events, or remodeling of biological tissues. While tensors encode such complex information mathematically precisely, the semantic interpretation of a tensor is challenging. Visualization can be beneficial here and is frequently used by domain experts. Typical strategies include the use of glyphs, color plots, lines, and isosurfaces. However, data complexity is nowadays accompanied by the sheer amount of data produced by large‐scale simulations and adds another level of obstruction between user and data. Given the limitations of traditional methods, and the extra cognitive effort of simple methods, more advanced tensor field visualization approaches have been the focus of this work. This survey aims to provide an overview of recent research results with a strong application‐oriented focus, targeting applications based on continuum mechanics, namely the fields of structural, bio‐, and geomechanics. As such, the survey is complementing and extending previously published surveys. Its utility is twofold: (i) It serves as basis for the visualization community to get an overview of recent visualization techniques. (ii) It emphasizes and explains the necessity for further research for visualizations in this context.
Risks posed by SARS‐CoV‐2 to North American bats during winter fieldwork
Authors: Cook Jonathan D. , Grant Evan H. C. , Coleman Jeremy T. H. , Sleeman Jonathan M. , Runge Michael C. 
Published: March 2021

AbstractThe virus that causes COVID‐19 likely evolved in a mammalian host, possibly Old‐World bats, before adapting to humans, raising the question of whether reverse zoonotic transmission to bats is possible. Wildlife management agencies in North America are concerned that the activities they authorize could lead to transmission of SARS‐CoV‐2 to bats from humans. A rapid risk assessment conducted in April 2020 suggested that there was a small but significant possibility that SARS‐CoV‐2 could be transmitted from humans to bats during summer fieldwork, absent precautions. Subsequent challenge studies in a laboratory setting have shed new information on these risks, as has more detailed information on human epidemiology and transmission. This inquiry focuses on the risk to bats from winter fieldwork, specifically surveys of winter roosts and handling of bats to test for white‐nose syndrome or other research needs. We use an aerosol transmission model, with parameter estimates both from the literature and from formal expert judgment, to estimate the risk to three species of North American bats, as a function of several factors. We find that risks of transmission are lower than in the previous assessment and are notably affected by chamber volume and local prevalence of COVID‐19. Use of facemasks with high filtration efficiency or a negative COVID‐19 test before field surveys can reduce zoonotic risk by 65 to 88%.
Research trends in U.S. national parks, the world's “living laboratories”
Authors: Vukomanovic Jelena , Randall Joshua 
Published: March 2021

AbstractU.S. national parks are essential public assets for preserving natural and cultural resources and for decades have provided natural laboratories for scholarly research. However, park research, and how it may be biased, has not been inventoried at a national scale. Such a synthesis is crucial for assessing research needs and planning for the future. Here, we present the first comprehensive summary of national park research using nearly 7,000 peer‐reviewed research articles published since 1970. We report when and where these studies occurred, what academic disciplines were most represented, and who funded the research. Our findings show that publication rates increased rapidly during the 1990s and 2000s, but since about 2013 have declined. Over half of the studies occurred in five parks, with Yellowstone representing over a third of all studies, followed by Everglades, Great Smoky Mountains, Glacier, and Yosemite. Nearly half of the studies occurred in the Northwestern Forested Mountains ecoregion. The life sciences, particularly ecological studies, contributed the majority of park research, although the earth sciences dominated several arid ecoregions of the West. Federal agencies funded the largest proportion of research, followed by U.S. universities, non‐profit organizations, federal programs (mainly the National Science Foundation), state agencies, and private industry. Over a quarter of the research was supported by international sources. Recent declines in scholarly output suggest that national park research directions and funding opportunities should be examined.
Feasibility and pilot efficacy of cognitive remediation for people in residential substance use treatment
Authors: Allan Julaine , Thompson Anna , Carlyle Molly , Thomas Matthew , Medalia Alice 
Published: March 2021

AbstractIntroductionThere are high rates of cognitive impairment among people seeking treatment for problematic substance use, which is rarely addressed in treatment programs. The aim of this pilot study was to evaluate the feasibility and outcomes of the neuropsychological and educational approach to cognitive remediation (NEAR) in a residential substance treatment setting.MethodsA non‐randomised trial conducted between November 2018 and November 2019, compared outcomes for 34 residents who received cognitive remediation (CR) plus treatment as usual (TAU) to 31 residents who received TAU only. Number of groups and attendance, and a measure of client satisfaction assessed feasibility. Cognitive function was assessed at baseline (service admission), and at 2 and 6 months post‐admission.ResultsA total of 95 CR groups were delivered over a 36‐week time period with a high degree of treatment fidelity and acceptability to participants. Cognitive outcomes improved across both the CR+TAU and TAU groups by 2 months, which was maintained at 6 months for outcomes related to executive functioning. There were no significant differences between the CR+TAU and TAU groups at 2 or 6 months, although a large effect size and confidence intervals indicated a potentially larger change in cognitive flexibility after receiving CR.Discussion and ConclusionsThis study contributes to our understanding of the implementation of CR in the alcohol and other drug rehabilitation setting. It is feasible to incorporate the NEAR program in treatment. The small sample size and lower than expected treatment dose likely contributed to the lack of significant findings.
Localization of interictal discharge origin: A simultaneous intracranial electroencephalographic–functional magnetic resonance imaging study
Authors: Tehrani Negar , Wilson William , Pittman Daniel J. , Mosher Victoria , Peedicail Joseph S. , Aghakhani Yahya , Beers Craig A. , Gaxiola‐Valdez Ismael , Singh Shaily , Goodyear Bradley G. , Federico Paolo ,   Calgary Comprehensive Epilepsy Program collaborators
Published: March 2021

AbstractObjectiveScalp electroencephalographic (EEG)–functional magnetic resonance imaging (fMRI) studies suggest that the maximum blood oxygen level‐dependent (BOLD) response to an interictal epileptiform discharge (IED) identifies the area of IED generation. However, the maximum BOLD response has also been reported in distant, seemingly irrelevant areas. Given the poor postoperative outcomes associated with extra‐temporal lobe epilepsy, we hypothesized this finding is more common when analyzing extratemporal IEDs as compared to temporal IEDs. We further hypothesized that a subjective, holistic assessment of other significant BOLD clusters to identify the most clinically relevant cluster could be used to overcome this limitation and therefore better identify the likely origin of an IED. Specifically, we also considered the second maximum cluster and the cluster closest to the electrode contacts where the IED was observed.MethodsMaps of significant IED‐related BOLD activation were generated for 48 different IEDs recorded from 33 patients who underwent intracranial EEG‐fMRI. The locations of the maximum, second maximum, and closest clusters were identified for each IED. An epileptologist, blinded to these cluster assignments, selected the most clinically relevant BOLD cluster, taking into account all available clinical information. The distances between these BOLD clusters and their corresponding IEDs were then measured.ResultsThe most clinically relevant cluster was the maximum cluster for 56% (27/48) of IEDs, the second maximum cluster for 13% (6/48) of IEDs, and the closest cluster for 31% (15/48) of IEDs. The maximum clusters were closer to IED contacts for temporal than for extratemporal IEDs (p = .022), whereas the most clinically relevant clusters were not significantly different (p = .056).SignificanceThe maximum BOLD response to IEDs may not always be the most indicative of IED origin. We propose that available clinical information should be used in conjunction with EEG‐fMRI data to identify a BOLD cluster representative of the IED origin.
Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits
Authors: Bansal Seema , Agrawal Madhunika , Mahendiratta Saniya , Kumar Subodh , Arora Shiyana , Joshi Rupa , Prajapat Manisha , Sarma Phulen , Prakash Ajay , Chopra Kanwaljit , Medhi Bikash 
Published: March 2021

AbstractBackgroundIt is well accepted that PI3k/Akt signaling pathway is a potential therapeutic window which regulates metabolism and energy homeostasis within the brain, and is an important mediator of normal neuronal physiological functions. Dysregulation of this pathway results in impaired insulin signaling, learning and memory and neuronal survival.ObjectivesElucidating the role of everolimus in intracerebroventricular (ICV) streptozotocin induced Insulin/IGF‐1 dependent PI3K/Akt/mTOR pathway dysregulation and associated neurobehavioral deficits.MethodsRats were administered with streptozotocin (3 mg/kg) intracerebroventricular, followed by administration of everolimus (1 mg/kg) orally for 21 days. After that, Morris water maze and passive avoidance tests were performed for assessment of memory. Animals were sacrificed to evaluate brain insulin pathway dysfunction, neurotrophic, apoptotic, inflammatory, and biochemical markers in rat brain. To elucidate the mechanism of action of everolimus, PI3K inhibitor, wortmannin was administered in the presence of everolimus in one group.ResultsStreptozotocin administration resulted in a significant decrease of brain insulin, insulin growth factor‐1 levels, and alterations in behavioral, neurotrophic (BDNF), inflammatory (TNF‐α), apoptotic (NF‐κB, Bcl2 and Bax) and biochemical (AChE and ChAT assay) parameters in comparison to sham group rats. Everolimus significantly mitigated the deleterious behavioral, biochemical, and molecular changes in rats having central insulin dysfunction. However, the protective effect of everolimus was completely abolished when it was administered in the presence of wortmannin.ConclusionFindings from the study reveal that mTOR inhibitors can be an important treatment strategy for neurobehavioral deficits occurring due to central insulin pathway dysfunction. Protective effect of drugs is via modulation of PI3K/Akt pathway.
Crystal structure of an inulosucrase from Halalkalicoccusjeotgali B3T, a halophilic archaeal strain
Authors: Ghauri Komal , Pijning Tjaard , Munawar Nayla , Ali Hazrat , Ghauri Muhammad A. , Anwar Munir A. , Wallis Russell 
Published: March 2021

Several archaea harbor genes that code for fructosyltransferase (FTF) enzymes. These enzymes have not been characterized yet at structure–function level, but are of extreme interest in view of their potential role in the synthesis of novel compounds for food, nutrition, and pharmaceutical applications. In this study, 3D structure of an inulin‐type fructan producing enzyme, inulosucrase (InuHj), from the archaeon Halalkalicoccus jeotgali was resolved in its apo form and with bound substrate (sucrose) molecule and first transglycosylation product (1‐kestose). This is the first crystal structure of an FTF from halophilic archaea. Its overall five‐bladed β‐propeller fold is conserved with previously reported FTFs, but also shows some unique features. The InuHj structure is closer to those of Gram‐negative bacteria, with exceptions such as residue E266, which is conserved in FTFs of Gram‐positive bacteria and has possible role in fructan polymer synthesis in these bacteria as compared to fructooligosaccharide (FOS) production by FTFs of Gram‐negative bacteria. Highly negative electrostatic surface potential of InuHj, due to a large amount of acidic residues, likely contributes to its halophilicity. The complex of InuHj with 1‐kestose indicates that the residues D287 in the 4B‐4C loop, Y330 in 4D‐5A, and D361 in the unique α2 helix may interact with longer FOSs and facilitate the binding of longer FOS chains during synthesis. The outcome of this work will provide targets for future structure–function studies of FTF enzymes, particularly those from archaea.
Improving reliability of high‐strength steel designed against fatigue limit using surface crack nondamaging technology by shot peening
Authors: Nam Ki‐Woo , Ando Kotoji , Kim Min‐Heon , Takahashi Koji 
Published: March 2021

AbstractRecently, surface crack nondamaging technology has been developed to render harmless surface cracks that can reduce the fatigue limit of metals by 20–60%. This is due to the effects of compressive residual stress induced by shot peening. To improve the reliability of high‐strength steel equipment designed against fatigue limit using surface crack nondamaging technology, the following characteristics were determined: (1) the effects of surface crack aspect ratio on maximum harmless crack depth (ahlm) at high‐strength steel for three residual stress distributions; (2) the relationship between the maximum allowable crack depth (acrN) andahlmassuming the value of safety factor; (3) the relationship between minimum detectable crack depth via nondestructive inspection(aNDI)andahlm, assuming that nondestructive inspection could detect the crack with sufficient probability; and (4) the relationships betweenahlm,aNDI, andacrN.
Education market with the Chinese characteristics: The rise of minban and transnational higher education in China
Authors: Mok Ka Ho 
Published: March 2021

AbstractIn the last few decades, the Chinese higher education system has changed considerably from an elitist model to a massified one with public and minban/transnational provisions. Accordingly, this study sets out against the context of higher education expansion initiated in late 1998 to critically examine the major trends of non‐state (including minban and transnational) higher education developments. More specifically, it discusses how minban higher education has transformed and why transnational higher education has evolved and become far more popular in China. Against the marketisation and privatisation of education context, this article focuses on reviewing policy change and university governance to diversify higher education provision through the market forces/non‐state provision. A critical examination of the changing state‐market‐education relationship would enable us to appreciate the complex social, economic and political issues that the Chinese government has to tackle, especially when the country confronts the dilemma of adopting a more liberal approach in reform with the fear of excessive external influences to the political regime or a more conservative approach which would limit the country's further development. The present article contributes to a better understanding of the ‘education market’ formation in China.
Metacognitive attitude for decision making at a university hospital
Authors: Lins Marcos Estellita , Pamplona Leonardo , Lins Angela Estellita , Lyra Karina 
Published: March 2021

AbstractIn the present study, we argue for the urgency of including a metacognitive attitude in decision‐making processes in complex social problems, with insights for the debate on decision sciences. We explore overlooked possibilities from the understanding of metacognitive schemes, subjectivity, and the intersubjective elements that participate and interfere in the decision‐making process. We discuss the relationship between metacognition as a state of consciousness, decision making, and the paradoxical nature of complex systems. We also propose a method to help eliciting personal and group metacognitive content named Complex Holographic Assessment of Paradoxical Problems—CHAP2. It intends to support decision making through the graphic visualization of mental schemas, thus enhancing metacognition. This, in turn, emerged as a promising way to promote a more systemic view of a given social problem. We believe that this work contributes with pathways to develop this metacognitive approach and achieve consensus solutions, obtained through the interaction between different agents, with the problematic situation being modeled according to the particular views of the actors involved.
Proteolytic Shedding of Human Colony‐Stimulating Factor 1 Receptor and its implication
Authors: Wei Yue , Ma Menghui , Lin Sheng , Li Xin , Shu Yue , Wang Ziwei , Zhou Yuhang , Hu Banglian , Cheng Baoying , Duan Shengshun , Huang Xiaohua , Xu Huaxi , Zhang Yun‐Wu , Zheng Honghua 
Published: March 2021

AbstractBoth Colony‐stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells‐2 (TREM2) are trans‐membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia‐expressed genes associated with neurodegenerative disease have recently been grouped under the term “microgliopathy”. Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N‐terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C‐terminal fragment (CTF) of CSF1R intra‐membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ‐secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ‐secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.