bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation and characterization of a laforin nanobody inhibitor
Authors: Simmons Zoe R. , Sharma Savita , Wayne Jeremiah , Li Sheng , Kooi Craig W. Vander , Gentry Matthew S. 
Published: January 2021

AbstractMutations in the gene encoding the glycogen phosphatase laforin result in the fatal childhood epilepsy Lafora disease (LD). A cellular hallmark of LD is cytoplasmic, hyper-phosphorylated, glycogen-like aggregates called Lafora bodies (LBs) that form in nearly all tissues and drive disease progression. Additional tools are needed to define the cellular function of laforin, understand the pathological role of laforin in LD, and determine the role of glycogen phosphate in glycogen metabolism. We present the generation and characterization of laforin nanobodies. We identify multiple classes of specific laforin-binding nanobodies and determine their binding epitopes using hydrogen deuterium exchange (HDX) mass spectrometry. Further, one family of nanobodies is identified that serves as an inhibitor of laforin catalytic activity. The laforin nanobodies are an important set of tools that open new avenues to define unresolved questions.
Long‐term safety of combination treatment with methotrexate and tumor necrosis factor (TNF)‐α antagonists versus TNF‐α antagonists alone in psoriatic patients
Authors: Hoffmann Jochen H. O. , Knoop Christian , Schäkel Kunt , Enk Alexander H. , Hadaschik Eva N. 
Published: January 2021

AbstractMethotrexate, a folic acid analog, is the conventional systemic anti‐psoriatic agent most commonly chosen for combination with biologics in the treatment of psoriasis. Real‐world long‐term safety data of this combination versus biologic treatment alone in dermatological practice are sparse. Here, we present results of a comparative retrospective study of laboratory dynamics and adverse events in psoriatic patients receiving a tumor necrosis factor (TNF)‐α antagonist (adalimumab or etanercept) with and without concomitant methotrexate (176 treatment courses, mean duration of 629 days). Co‐treatment with methotrexate significantly (P < 0.05) correlated with a decrease of leukocyte, neutrophil and erythrocyte counts and an increase of glutamate pyruvate transaminase (GPT) (Pearson correlation, n > 148). The relative risk for a Common Terminology Criteria for Adverse Events (CTCAE) grade 1–2 laboratory adverse event was significantly elevated to 1.11 for anemia and 1.16 for a GPT increase if the patients received concomitant methotrexate at the time the laboratory test was performed. Combination treatment was given for equal or more than 30% of the time (MTX≥30%) during 12% of the treatment courses. During these treatment courses, dynamics of leukocyte (−8.1%), neutrophil (−8.1%), erythrocyte (−3.2%) counts and GPT (+16.9%) from baseline to average under treatment were significantly more pronounced. CTCAE grade 3–4 laboratory adverse events occurred in 9.5% and 5.2% of treatment courses with and without MTX≥30%, respectively (p = 0.70), and affected transaminases in 90% of the cases. Methotrexate was discontinued due to CTCAE grade 3–4 laboratory adverse events in 4.25% of the treatment courses with MTX of 30% or more. Elevated baseline γ‐glutamyl transferase levels significantly predicted the occurrence of CTCAE grade 3–4 laboratory adverse events and should trigger investigations for pre‐existing liver disease or alcohol abuse. In conclusion, our comparative data supplement previous short‐term studies and support a tolerable long‐term safety profile of the combination treatment. However, given the additional toxicities and low evidence for benefits, alternative options such as biologic monotherapy or switching to a different biologic should be considered in a dermatological setting.
Downregulation of hepatitis C virus replication by miR‐196a using lentiviral vectors
Authors: Shafaati Maryam , Jamalidoust Marzieh , Kargar Mohammad , Arefian Ehsan , Kafilzadeh Farshid 
Published: January 2021

AbstractHepatitis C virus (HCV) is a positive‐sense, single‐stranded RNA virus that causes chronic hepatitis and hepatocellular carcinoma. Cellular microRNAs (miRNAs) directly modulate the viral infectivity and indirectly through targeting virus‐related host factors. They play an essential role in the progression of different stages of HCV infection. The roles of miR‐196 family in HCV infection and hepatocellular carcinoma progression remain poorly understood. Using ViTa databases, miR‐196a as a high‐score miRNA targeting the NS5A region of HCV genome was selected. Using dual luciferase assay and an established cell‐cultured HCV (HCVcc) system, the effect of miR‐196a on HCV genome was assessed. In silico analysis demonstrated the significant role of miR‐196a in the downregulation of HCV replication. Using dual luciferase assay, the liver‐specific miR‐196a and NS5A gene binding was confirmed. To assess the experimental role of miR‐196a, an HCVcc system was established in the Huh 7.5 cell lines. The HCV‐RNA 1b derived from an infected patient was transfected into Huh 7.5 cells containing miR‐196a lentiviral vectors (Huh 7.5/miR‐196a), mocks (Huh 7.5/mock vector), and naïve Huh 7.5 cells. The rate of reduction of the HCV genome replication was assessed using relative real‐time PCR assay. These results represent miR‐196a overexpression and its roles in regulating HCV genome replication. However, miR‐196a may inhibit HCV replication and accelerate the early stages of apoptosis. Overexpression of miR‐196a in Huh 7.5 replicon cell is a potential new strategy to prevent hepatitis C infection. The results of this study suggest that miR‐196a directly downregulates HCV replication and may serve as a new antiviral therapy.
Stewardship Codes and the Role of Institutional Investors in Corporate Governance: An International Comparison and Typology
Authors: Klettner Alice 
Published: January 2021

AbstractOver recent decades, share ownership of listed companies has concentrated into the hands of large institutional investors, challenging the traditional agency theory view of corporate governance as a mechanism to resolve the separation of ownership and control. Alternative theories have emerged to explain the role of institutional investors in corporate governance, each with a slightly different view on the motivations of these powerful shareholders and the nature of their relationship with corporate management. These theories share a common thread – the concept of investor stewardship – yet each theory applies it differently. This paper explores whether institutional investors should act primarily as stewards of their investee companies (agency theory), stewards of beneficiaries’ funds (agency capitalism), stewards of a market/economy (universal ownership) or stewards of society (stakeholder theory), and whether this varies internationally. Through an analysis of national stewardship codes, the paper determines which of these theoretical approaches are most strongly reflected in emerging stewardship policy across the world. It presents a typology of stewardship codes as a framework for understanding cross‐country variation in investor stewardship policy. Stewardship codes influence the shareholder–manager relationship and can encourage integration of wider economic and societal concerns into corporate finance.
A patient‐centered knowledge translation tool for treat‐to‐target strategy in rheumatoid arthritis: Patient and rheumatologist perspectives
Authors: Benham Helen , Chiu Hedva , Tesiram Joanne , Mehdi Ahmed , Landsberg Peter , Grosman Sergei , Harrison Andrew , Nash Peter , Thomas Ranjeny , Langbecker Danette , Van Driel Mieke 
Published: January 2021

AbstractAimImplementation of treat‐to‐target (T2T) for rheumatoid arthritis (RA) presents many challenges and an evidence‐practice gap has emerged. This study assessed clinician and patient barriers to the implementation of an RA‐T2T strategy and developed a knowledge translation (KT) tool for use in “real‐life” clinical settings.MethodsSurveys of patients and rheumatologists measured agreement with RA‐T2T recommendations and use in daily practice. Patient knowledge and perceptions were assessed as was clinician willingness to alter practice and barriers to RA‐T2T using visual analog scales. An electronic KT‐tool was developed and a two‐phase usability trial undertaken to assess use in clinical interactions.ResultsNinety‐one percent of patients had no prior knowledge of RA‐T2T but agreed with the recommendations showing mean level agreement scores (8.39‐9.54, SD 2.37‐1.54). Ninety percent were willing to try RA‐T2T, 49% felt their treatment could be improved and 28% wanted more involvement in treatment decisions. Rheumatologists agreed with RA‐T2T recommendations (7.30‐9.27, SD 2.59‐0.91). Barriers to implementation identified by rheumatologists included time, appointment availability and perceived patient reluctance to escalate medications. Usability experiences with the KT‐tool were tracked and clinicians reported it was easy to use (100%), resulted in a discussion of RA‐T2T (73%) and a target being set for 63% of consults. Patients reported they read (92%) and understood (87%) the information in the KT‐tool, and that a target was set in 62% of interactions.ConclusionsRA‐T2T uptake in clinical practice may be improved through understanding local clinician and patient barriers and an implementation strategy utilizing a patient‐driven KT‐tool.
Crizotinib for recurring non‐small‐cell lung cancer with EML4‐ALK fusion genes previously treated with alectinib: A phase II trial
Authors: Harada Daijiro , Isozaki Hideko , Kozuki Toshiyuki , Yokoyama Toshihide , Yoshioka Hiroshige , Bessho Akihiro , Hosokawa Shinobu , Takata Ichiro , Takigawa Nagio , Hotta Katsuyuki , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: January 2021

AbstractBackgroundThe efficacy of crizotinib treatment for recurring EML4‐ALK‐positive non‐small cell lung cancer (NSCLC) previously treated with alectinib is unclear. Based on our preclinical findings regarding hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway activation as a potential mechanism of acquired resistance to alectinib, we conducted a phase II trial of the anaplastic lymphoma kinase/MET inhibitor, crizotinib, in patients with alectinib‐refractory, EML4‐ALK‐positive NSCLC.MethodsPatients with ALK‐rearranged tumors treated with alectinib immediately before enrolling in the trial received crizotinib monotherapy. The objective response rate was the primary outcome of interest.ResultsNine (100%) patients achieved a partial response with alectinib therapy with a median treatment duration of 6.7 months. Crizotinib was administered with a median treatment interval of 50 (range, 20–433) days. The overall response rate was 33.3% (90% confidence interval [CI]: 9.8–65.5 and 95% CI: 7.5–70.1), which did not reach the predefined criteria of 50%. Two (22%) patients who achieved a partial response had brain metastases at baseline. Progression‐free survival (median, 2.2 months) was not affected by the duration of treatment with alectinib. The median survival time was 24.1 months. The most common adverse events were an increased aspartate transaminase/alanine transaminase (AST/ALT) ratio (44%) and appetite loss (33%); one patient developed transient grade 4 AST/ALT elevation, resulting in treatment discontinuation. Other adverse events were consistent with those previously reported; no treatment‐related deaths occurred.ConclusionsAlthough the desired response rate was not achieved, crizotinib monotherapy following treatment with alectinib showed efficacy alongside previously described adverse events.
Impact of Caffeine on Ethanol‐Induced Stimulation and Sensitization: Changes in ERK and DARPP‐32 Phosphorylation in Nucleus Accumbens
Authors: Porru Simona , López‐Cruz Laura , Carratalá‐Ros Carla , Salamone John D. , Acquas Elio , Correa Mercè 
Published: January 2021

BackgroundCaffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)‐related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD‐1 mice.MethodsAcute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol‐induced (1.5 to 3.5 g/kg) changes in open‐field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor‐dependent phosphorylation markers were assessed: extracellular signal‐regulated kinase (pERK), and dopamine‐and cAMP‐regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP‐32‐Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol‐sensitized (1.5 g/kg) mice.ResultsAcute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol ‐induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol‐induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol‐sensitized mice in an ethanol‐free state resulted in blunted stimulant effects compared with those seen in ethanol‐naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP‐32(Thr75) immunoreactivity.ConclusionsThe present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol‐sensitized animals.
CYP2D6*10 polymorphism and the enantioselective O‐desmethylation of S‐(+)‐ and R‐(‐)‐venlafaxine in Japanese psychiatric patients
Authors: Sasaki Taro , Yasui‐Furukori Norio , Komahashi‐Sasaki Hazuki , Shinozaki Masataka , Hayashi Yuki , Kato Kazuko , Inoue Yoshimasa , Tsuchimine Shoko , Watanabe Takashi , Sugawara Norio , Shimoda Kazutaka 
Published: January 2021

AbstractAccording to previous studies, R‐(‐)‐venlafaxine (VEN) has higher enantioselectivity than S‐(+)‐VEN, and the plasma concentration of R‐(‐)‐VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady‐state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O‐desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S‐(+)‐VEN were approximately 1.9‐fold higher than those of R‐(‐)‐VEN. The plasma concentrations of S‐(+)‐VEN and R‐(‐)‐VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S‐(+)‐VEN and R‐(‐)‐VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R‐(‐)‐ODV/R‐(‐)‐VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R‐(‐)‐VEN and S‐(+)‐VEN. Further studies are needed to examine how these findings affect clinical practice.
Influence of external forces on actin‐dependent T cell protrusions during immune synapse formation
Authors: Zucchetti Andrés Ernesto , Paillon Noémie , Markova Olga , Dogniaux Stéphanie , Hivroz Claire , Husson Julien 
Published: January 2021

Background InformationWe have previously observed that in response to antigenic activation, T cells produce actin‐rich protrusions that generate forces involved in T cell activation. These forces are influenced by the mechanical properties of antigen‐presenting cells (APCs). However, how external forces, which can be produced by APCs, influence the dynamic of the actin protrusion remains unknown. In this study, we quantitatively characterised the effects of external forces in the dynamic of the protrusion grown by activated T cells.ResultsUsing a micropipette force probe, we applied controlled compressive or pulling forces on primary T lymphocytes activated by an antibody‐covered microbead, and measured the effects of these forces on the protrusion generated by T lymphocytes. We found that the application of compressive forces slightly decreased the length, the time at which the protrusion stops growing and retracts and the velocity of the protrusion formation, whereas pulling forces strongly increased these parameters. In both cases, the applied forces did not alter the time required for the T cells to start growing the protrusion (delay). Exploring the molecular events controlling the dynamic of the protrusion, we showed that inhibition of the Arp2/3 complex impaired the dynamic of the protrusion by reducing both its maximum length and its growth speed and increasing the delay to start growing. Finally, T cells developed similar protrusions in more physiological conditions, that is, when activated by an APC instead of an activating microbead.ConclusionsOur results suggest that the formation of the force‐generating protrusion by T cells is set by an intracellular constant time and that its dynamic is sensitive to external forces. They also show that actin assembly mediated by actin‐related protein Arp2/3 complex is involved in the formation and dynamic of the protrusion.SignificanceActin‐rich protrusions developed by T cells are sensory organelles that serve as actuators of immune surveillance. Our study shows that forces experienced by this organelle modify their dynamic suggesting that they might modify immune responses. Moreover, the quantitative aspects of our analysis should help to get insight into the molecular mechanisms involved in the formation of the protrusion.
Drought and soil nutrients effects on symbiotic nitrogen fixation in seedlings from eight Neotropical legume species
Authors: McCulloch Lindsay A. , Piotto Daniel , Porder Stephen 
Published: January 2021

AbstractSymbiotic nitrogen fixation is a dominant source of nitrogen to many terrestrial ecosystems and thus may influence their responses to global change. High legume species diversity and abundance are thought to lead to high rates of symbiotic nitrogen fixation in Neotropical forests. However, how changes in water and nutrient availability will affect symbiotic nitrogen fixation has only recently been explored, even as droughts begin to increase in severity and frequency in the Neotropics. To explore these effects, we grew eight species of Neotropical woody legume seedlings in a shadehouse for four months while manipulating soil water, phosphorus, and molybdenum availability. Overall, drought reduced nodule biomass, nitrogenase activity (acetylene reduction g‐1 nodule), and acetylene reduction per seedling by 33%, 27%, and 41%, respectively, but reduced seedling biomass by only 18%. Species varied in the manifestation of drought effects. For example, drought reduced the probability that nodules formed in some species, but in others reduced the nitrogenase activity or acetylene reduction per seedling. In contrast, the effects of phosphorus and molybdenum availability were more species‐specific. However, fertilization did affect (both positively and negatively) one or more symbiotic nitrogen fixation response variables in two of the eight species. Our results indicate drought reduces symbiotic nitrogen fixation in Neotropical legume seedlings, but the mechanism of response may be species‐specific. Therefore, predicting the response of symbiotic nitrogen fixation in the Neotropics to a changing climate, with expected increases in drought frequency and severity, may require grappling with the diversity of responses among nitrogen‐fixing legumes.Abstract in Portuguese is available with online material
Assessment of mirror movements in children and adolescents with unilateral cerebral palsy: reliability of the Woods and Teuber scale
Authors: Magne Victoria A , Adde Lars , Hoare Brian , Klingels Katrijn , Simon‐Martinez Cristina , Mailleux Lisa , Lydersen Stian , Elvrum Ann‐Kristin G 
Published: January 2021

AimTo investigate the inter‐ and intrarater reliability of the Woods and Teuber scale to detect mirror movements in children and adolescents with unilateral cerebral palsy (CP).MethodA convenience sample of children and adolescents with unilateral CP (n=68; 31 males, 37 females; mean age 12y 2mo, SD 3y 6mo) in Manual Ability Classification levels I to III was recruited from Norway, Australia, and Belgium. Three therapists scored mirror movements according to the Woods and Teuber scale from three video‐recorded tasks at two separate time points. A two‐way, mixed model regression was used to calculate intraclass correlation coefficients (ICCs) reflecting overall inter‐ and intrarater reliability. In addition, ICCs for each hand and task were calculated separately.ResultsThe overall interrater reliability ICC was 0.90 and the corresponding intrarater reliability ICC was 0.92. The ICCs for each hand ranged from 0.86 to 0.92 and for each task from 0.63 to 0.89.InterpretationThe Woods and Teuber scale shows excellent reliability for scoring mirror movements in children and adolescents with unilateral CP. The assessment is easy to administer with no need for specific equipment and scoring can be determined from short video recordings, making it a feasible instrument in research and clinical practice.
The Gulf Cooperation Council states: Crystallization of the regional cooperation and alliances amid dwindling resources
Authors: Tok Evren 
Published: January 2021

AbstractThe Gulf Cooperation Council (GCC) states can be divided into two main camps in terms of hydrocarbon endowment per capita which can partially account for differences in policy directions. Kuwait, Qatar, and the UAE (the rich triplet) have small populations while having large hydrocarbon (oil and natural gas) endowments compared to Bahrain, Oman, and Saudi Arabia. Kuwait, Qatar, and the UAE have been effectively using their excess wealth in the form of investment for domestic economic diversification and overseas investments through their sovereign wealth funds (SWFs). Therefore, the rich triplet perceives the upcoming threat of decarbonization of the world's energy system lighter than the remaining members of the GCC in view of their prosperity. The expected decrease in oil demand and revenue within the next decade will put further strain on the relationship between these states.