bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opportunities and challenges for the development of M1 muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits
Authors: Nguyen Huong T. M. , van der Westhuizen Emma T. , Langmead Christopher J. , Tobin Andrew B. , Sexton Patrick M. , Christopoulos Arthur , Valant Celine 
Published: November 2022

Targeting allosteric sites of M1 muscarinic acetylcholine receptors (M1 receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M1 receptor. This has led to the identification of a structurally diverse range of highly selective M1 PAMs. In preclinical models, M1 PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M1 PAMs have reached early‐stage clinical trials, with many of them failing to progress further due to on‐target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M1 receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M1 PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M1 PAMs from bench‐side to bedside.LINKED ARTICLESThis article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc
Recurrent missense variants in clonal hematopoiesis‐related genes present in the general population
Authors: Ariste Olivier , de la Grange Pierre , Veitia Reiner A. 
Published: November 2022

AbstractClonal hematopoiesis (CH) consists in an abnormal expansion of a hematopoietic stem cell bearing an advantageous somatic variant. A survey of known recurrent somatic missense variants in DNMT3A, SF3B1, SRSF2, and TP53, some of the most prominent genes underlying CH of indeterminate potential (CHIP), in gnomAD noncancer database shows the presence of 73 variants. Many of them reach frequencies higher than 0.01% in various populations and, in many cases, are enriched in specific populations. Consistent with a potential involvement in CHIP, we found that the age distribution of the carriers is shifted towards old ages. Moreover, the variant allele frequencies are on average lower than 50%, expected for germline heterozygous variants. The pervasive presence of some of such variants in blood DNA from elder individuals is compatible with CHIP of somatic origin. On practical grounds, CHIP can lead to misclassification of somatic variants in cancer‐predisposition genes as inherited, which bear consequences for the affected individuals and their families.
Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data
Authors: Hartley Taila , Soubry Élisabeth , Acker Meryl , Osmond Matthew , Couse Madeline , Gillespie Meredith K. , Ito Yoko , Marshall Aren E. , Lemire Gabrielle , Huang Lijia , Chisholm Caitlin , Eaton Alison J. , Price E. Magda , Dowling James J. , Ramani Arun K. , Mendoza‐Londono Roberto , Costain Gregory , Axford Michelle M. , Szuto Anna , McNiven Vanda , Damseh Nadirah , Jobling Rebekah , de Kock Leanne , Mojarad Bahareh A. , Young Ted , Shao Zhuo , Hayeems Robin Z. , Graham Ian D. , Tarnopolsky Mark , Brady Lauren , Armour Christine M. , Geraghty Michael , Richer Julie , Sawyer Sarah , Lines Matthew , Mercimek‐Andrews Saadet , Carter Melissa T. , Graham Gail , Kannu Peter , Lazier Joanna , Li Chumei , Aul Ritu B. , Balci Tugce B. , Dlamini Nomazulu , Badalato Lauren , Guerin Andrea , Walia Jagdeep , Chitayat David , Cohn Ronald , Faghfoury Hanna , Forster‐Gibson Cynthia , Gonorazky Hernan , Grunebaum Eyal , Inbar‐Feigenberg Michal , Karp Natalya , Morel Chantal , Rusnak Alison , Sondheimer Neal , Warman‐Chardon Jodi , Bhola Priya T. , Bourque Danielle K. , Chacon Inara J. , Chad Lauren , Chakraborty Pranesh , Chong Karen , Doja Asif , Goh Elaine Suk‐Ying , Saleh Maha ,   Care4Rare Canada, Potter Beth K. , Marshall Christian R. , Dyment David A. , Kernohan Kristin , Boycott Kym M. 
Published: November 2022

AbstractWe examined the utility of clinical and research processes in the reanalysis of publicly‐funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically‐relevant genes is modest, and the highest yield comes from validation of novel disease‐gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses.
Comparison of P‐glycoprotein function in peripheral blood mononuclear cells ex vivo in stable Black and White male and female kidney transplant recipients
Authors: Tornatore Kathleen M. , Attwood Kris , Brazeau Daniel , Sprowl Jason , Chang Shirley , Gundroo Aijaz , Minderman Hans , Venuto Rocco C. 
Published: November 2022

AbstractKidney allograft survival remains poorer in Black compared to White recipients due to racial differences in calcineurin inhibitor (CNI) pharmacology. P‐glycoprotein (P‐gp), an ABC efflux transporter expressed in peripheral blood mononuclear cells (PBMCs), modulates CNI pharmacokinetics and intracellular pharmacology. This study investigated P‐gp function in PBMC ex vivo at 0 (trough), 4, 8, and 12 h in stable Black and White male and female kidney transplant recipients (n = 67) receiving tacrolimus and mycophenolic acid. Tacrolimus doses were adjusted to troughs of 4–10 ng/ml. P‐gp function was quantified with flow cytometric measurement of cyclosporine (CYA; 2.5 μM)‐reversible efflux of P‐gp substrate, 3,3′‐Diethyloxacarbocyanine iodide by determining the percentage change of mean fluorescent intensity (MFI) with CYA (% ΔMFI). The composite parameter of area under the concentration versus time (AUC)0–12h % ΔMFI estimated P‐gp function. Data analysis examined race, sex, and race‐sex associations to P‐gp function. A secondary aim analyzed ABCB1 genotypes: 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), and P‐gp function. P‐gp function (% ΔMFI) was higher in White patients at troughs (p = 0.031) compared to Black counterparts with similar trends at 4 and 8 h. Reduced AUC0–12h % ΔMFI was noted in Black recipients (N = 32) compared with Whites (N = 35, p = 0.029) with notable pairwise adjusted differences between Black and White women (p = 0.021). Higher AUC0–12h % ΔMFI was associated with ABCB1 2677 TT compared to GG variants (p = 0.035). The AUC0–12h % ΔMFI was greater in White than Black subjects. P‐gp function was higher at troughs in White subjects and differed between race‐sex groups. P‐gp function in PBMC may influence intracellular tacrolimus exposure and inter‐relating pharmacodynamic responses which may support race and sex pharmacologic differences.
Holding together after disaster: The role of social skills in strengthening family cohesion and resilience
Authors: Bogdan Eva A. , McDonald‐Harker Caroline , Bassi Emilie M. , Haney Timothy J. 
Published: November 2022

AbstractObjectiveThis study investigated how a flooding disaster impacted family cohesion and resilience.BackgroundDisasters present challenges for families, often threatening family cohesion. Although there is extensive research on the impacts of disasters on mental health at the individual level, less is known about how family units recover from disasters, and how parental relationship dynamics and parent–child dynamics influence family functioning during and after such traumatic events.MethodQualitative face‐to‐face interviews were conducted 1 year after the 2013 southern Alberta flood with 105 parents of children ages 17 years and under.ResultsFindings reveal that families who experienced more loss were not necessarily more negatively impacted overall. Some families reported the flood caused them to grow further apart, whereas for others it brought them closer together. Those who reported that the flood brought them closer together demonstrated the following three main social skills: (a) communication, (b) conflict resolution, and (c) coping. Findings also reveal that families have higher levels of cohesiveness and resilience post‐disaster when they exhibit these important skills.ConclusionThis research concludes that coming together as a family unit created a supportive space for families to process and reduce the stress generated by the flood event. Families who demonstrate and practice communication, conflict resolution, and coping in the face of challenging events like disasters are more cohesive and resilient.ImplicationsUnderstanding how key social skills influence family members' functioning post‐disaster in terms of cohesion and resilience provides important insight into strategies, services, and resources that can be adopted and utilized to support families in disaster contexts.
Stress corrosion cracking behavior of AZ80 magnesium alloy with different orientations in simulated body fluid
Authors: Xiong Ying , Zhang Aoxuan , Zhu Tao 
Published: November 2022

AbstractSlow strain rate tensile (SSRT) testing was performed on AZ80 magnesium alloy plate along different orientation at a nominal stain rate, viz., 1 × 10−6/s and 5.3 × 10−7/s, in a simulated body fluid (SBF). Two types of orientation specimens were machined from the rolled plate with the loading axes of testing specimens along 0° (RD) and 30° (RD30) with respect to the rolled direction. The stress corrosion cracking (SCC) behavior of specimens with different orientation was studied by a combination of electrochemical impedance spectroscopy (EIS) and SSRT analysis. The fracture surface of the specimens was observed by scanning electron microscope (SEM). The initiation and propagation of cracking are analyzed by the EIS information recorded during the SSRT loading. Based on the experimental observations, the stress corrosion mechanism of AZ80 Mg alloy with different initial texture was revealed.
Pan‐Arctic soil moisture control on tundra carbon sequestration and plant productivity
Authors: Zona Donatella , Lafleur Peter M. , Hufkens Koen , Gioli Beniamino , Bailey Barbara , Burba George , Euskirchen Eugénie S. , Watts Jennifer D. , Arndt Kyle A. , Farina Mary , Kimball John S. , Heimann Martin , Göckede Mathias , Pallandt Martijn , Christensen Torben R. , Mastepanov Mikhail , López‐Blanco Efrén , Dolman Albertus J. , Commane Roisin , Miller Charles E. , Hashemi Josh , Kutzbach Lars , Holl David , Boike Julia , Wille Christian , Sachs Torsten , Kalhori Aram , Humphreys Elyn R. , Sonnentag Oliver , Meyer Gesa , Gosselin Gabriel H. , Marsh Philip , Oechel Walter C. 
Published: November 2022

AbstractLong‐term atmospheric CO2 concentration records have suggested a reduction in the positive effect of warming on high‐latitude carbon uptake since the 1990s. A variety of mechanisms have been proposed to explain the reduced net carbon sink of northern ecosystems with increased air temperature, including water stress on vegetation and increased respiration over recent decades. However, the lack of consistent long‐term carbon flux and in situ soil moisture data has severely limited our ability to identify the mechanisms responsible for the recent reduced carbon sink strength. In this study, we used a record of nearly 100 site‐years of eddy covariance data from 11 continuous permafrost tundra sites distributed across the circumpolar Arctic to test the temperature (expressed as growing degree days, GDD) responses of gross primary production (GPP), net ecosystem exchange (NEE), and ecosystem respiration (ER) at different periods of the summer (early, peak, and late summer) including dominant tundra vegetation classes (graminoids and mosses, and shrubs). We further tested GPP, NEE, and ER relationships with soil moisture and vapor pressure deficit to identify potential moisture limitations on plant productivity and net carbon exchange. Our results show a decrease in GPP with rising GDD during the peak summer (July) for both vegetation classes, and a significant relationship between the peak summer GPP and soil moisture after statistically controlling for GDD in a partial correlation analysis. These results suggest that tundra ecosystems might not benefit from increased temperature as much as suggested by several terrestrial biosphere models, if decreased soil moisture limits the peak summer plant productivity, reducing the ability of these ecosystems to sequester carbon during the summer.
A systematic review of research on immigrant parenting of young children in the 21st century (2000–2020)
Authors: Guo Karen 
Published: November 2022

AbstractAs the immigrant population grows in many countries, immigrant parenting has become a prominent research topic and generated an extensive body of literature. This bibliometric study conducted a systematic review of 1090 articles published from 2000–2020 within the field of immigrant parenting (IP) of young children. Using the citation and co‐citation data, the study delineated the developing trends of IP research, explored the significant shifts, and mapped the future directions. The analysis identified remarkable evolutions and revealed the future of the IP field in both optimistic and problematic lights. This was attributed to a combination of factors, in particular to the diverse topics, increased recognition of the gaps between immigration and parenting, limited methodological choices, a lack of theoretical underpinnings and the influence of the intensification of digitalization upon many dimensions of people's lives. Future studies should broaden the field's understanding of underlying reasons that properly account for IP varieties.
Positional cloning and characterization reveal the role of a miRNA precursor gene ZmLRT in the regulation of lateral root number and drought tolerance in maize
Authors: Zhang Ming , Chen Yanhong , Xing Hongyan , Ke Wensheng , Shi Yunlu , Sui Zhipeng , Xu Ruibin , Gao Lulu , Guo Ganggang , Li Jiansheng , Xing Jiewen , Zhang Yirong 
Published: November 2022

AbstractLateral roots play essential roles in drought tolerance in maize (Zea mays L.). However, the genetic basis for the variation in the number of lateral roots in maize remains elusive. Here, we identified a major quantitative trait locus (QTL), qLRT5‐1, controlling lateral root number using a recombinant inbred population from a cross between the maize lines Zong3 (with many lateral roots) and 87‐1 (with few lateral roots). Fine‐mapping and functional analysis determined that the candidate gene for qLRT5‐1, ZmLRT, expresses the primary transcript for the microRNA miR166a. ZmLRT was highly expressed in root tips and lateral root primordia, and knockout and overexpression of ZmLRT increased and decreased lateral root number, respectively. Compared with 87‐1, the ZmLRT gene model of Zong3 lacked the second and third exons and contained a 14 bp deletion at the junction between the first exon and intron, which altered the splicing site. In addition, ZmLRT expression was significantly lower in Zong3 than in 87‐1, which might be attributed to the insertions of a transposon and over large DNA fragments in the Zong3 ZmLRT promoter region. These mutations decreased the abundance of mature miR166a in Zong3, resulting in increased lateral roots at the seedling stage. Furthermore, miR166a post‐transcriptionally repressed five development‐related class‐III homeodomain‐leucine zipper genes. Moreover, knockout of ZmLRT enhanced drought tolerance of maize seedlings. Our study furthers our understanding of the genetic basis of lateral root number variation in maize and highlights ZmLRT as a target for improving drought tolerance in maize.
Episodic memory effects of gamma frequency precuneus transcranial magnetic stimulation in Alzheimer's disease: A randomized multiple baseline study
Authors: Traikapi Artemis , Kalli Ioanna , Kyriakou Andrea , Stylianou Elena , Symeou Rafaella Tereza , Kardama Akrivi , Christou Yiolanda Panayiota , Phylactou Phivos , Konstantinou Nikos 
Published: November 2022

AbstractEpisodic memory decline is the prominent neuropsychological feature of typical Alzheimer's Disease (AD), for which current treatments have a limited clinical response. Recently, gamma entrainment therapy has been used as a non‐invasive treatment in AD, providing evidence that it may have the potential to alleviate brain pathology and improve cognitive function in AD patients. At the same time, the precuneus (PC) has been recognized as a key area involved in AD related memory deficits and as a key node of the Default Mode Network. This study aimed to investigate the effectiveness of a 40 Hz Transcranial Magnetic Stimulation (TMS) intervention, delivered bilaterally to the precuneus for 10 days, in improving the patients' episodic memory performance. Secondary outcome variables investigated included general cognitive function, semantic and spatial memory, as well as attention and executive function. A concurrent multiple baseline design across five cases was employed. Four patients completed the study. Visual analysis combined with effect size indices were used to evaluate changes across phases. An increase in the average level of immediate recalled words was observed in three out of four patients. Effect size indices indicated significant improvement of attention skills in two patients. No treatment effect was observed for semantic and visual memory, or for executive function. An immediate treatment effect was observed in all patients' general cognitive function as assessed with the Alzheimer's Disease Assessment Scale (mean reduction of 5 points), which was maintained and improved further three months post‐treatment. The neuropsychological evaluations indicated improved performance three months post‐treatment in immediate and delayed recall, attention, phonological verbal fluency, anxiety, and neuropsychiatric symptoms. This study provides preliminary evidence for the efficacy of a novel non‐pharmacological treatment using gamma‐band TMS in addressing cognitive dysfunction in AD.
Managerial delegation, network externalities and loan commitment
Authors: Lian Xubei , Zhang Kai , Wang Leonard F. S. 
Published: November 2022

AbstractIn this paper, we show that, compared with no network externalities, firms always obtain higher profits and social welfare in the presence of positive network externalities, irrespective of the managerial delegation contracts. Furthermore, we show that whether the owner chooses market share delegation or sales delegation contracts relies on the type and strength of network externalities. If the network externalities are positive and strong enough, sales delegation dominates the market share delegation; otherwise, the owner will choose market share delegation. More importantly, we find that, if the network externalities are positive, the optimal interest rate of a loan commitment decreases with an increase of network externalities, and the firm's delegation behavior will benefit society regardless of the delegation contract types. On the contrary, the optimal interest rate increases with an increase of network externalities, and the firm's delegation behavior will harm social welfare in the presence of negative network externalities.
The Nature and Limits of Theology: A Response to Rowan Williams
Authors: DeSantis Cole 
Published: November 2022

AbstractTheology is both a human endeavor and something of Divine origin, insofar as it is a human attempt to make sense of certain Divinely revealed propositions. How does one reconcile these two elements? One attempt to do so was on the part of the Anglican theologian Rowan Williams. In sections I and II of chapter 1 of his work ‘On Christian Theology’, Williams speaks of the nature of authentic theological discourse, that is, theological discourse that has integrity. In his work on theological integrity, Williams explores how human intentions or hidden agendas can potentially warp our attempt to make sense of the truths contained within Divine Revelation. He then goes on to speak of how to avoid such pitfalls. In this article, I will respond to the epistemological implications of William's thoughts on this topic. I will use various ideas from Catholic theology, including the development of doctrines and the notion that faith has both a subjective and objective element, to explore both the strengths and weaknesses of Williams's thought.
Knowledge of the Heart: Notes on the Definition of the Sensus Fidei in the Personal Life of the Believer
Authors: Tóth Beáta 
Published: November 2022

AbstractThe sensus fidei is a crucial concept which has assumed growing importance during recent years of theological enquiry, however, it is not so easily defined. This article examines a section of the document. Sensus Fidei in the Life of the Church. (ITC, 2014, Chapter 2, no. 48-65) and explores the underlying anthropological-epistemological assumptions which seem to be inherently shaping the idea of the sensus fidei fidelis (the sense of faith of the individual believer). What is the site of such a sense of faith in the personal life of the believer? Is there an adequate theological anthropological framework for imagining the operation of this special ‘faculty’? After commenting on the various definitions of the concept, I focus on the four classical theological key elements the document draws on in articulating a modern account: the Thomistic understanding of faith, virtue, connaturality and instinct. The third section of the article highlights inherent tensions between the traditional Thomistic scheme and a post-Enlightenment, anti-rationalist agenda which call for a more systematic elaboration of an adequate current anthropology of the human person.
Competition between Colletotrichum species reduces anthracnose symptom development in Dioscorea alata yams: Potential for biopriming and breeding
Authors: Dentika Pauline , Ninsseu Achille , Pétro Dalila , Ozier‐Lafontaine Harry , Penet Laurent 
Published: November 2022

AbstractEcological interactions are a fairly overlooked component in agriculture, despite their known potential in productivity, pest and disease regulation. In this study, we assessed whether a potential low pathogenic congeneric competitor of Colletotrichum gloeosporioides could decrease disease onset in yams. We set up an experiment with artificial drop inoculation on detached leaves, with individual controls and treatments as either co‐inoculation or inoculation with a harmless competitor 24 h prior to inoculating the pathogen. Our results demonstrate that direct admixing translated into accrued competition and disease symptoms, while prior inoculation of the competitor tended to decrease symptom development. There was variation in how varieties responded to treatments and in strain competitive ability altering the protective effect, but nevertheless these results suggest that incorporating such interactions in breeding programmes or working towards increased use of commensals in agriculture might confer improved disease control for crops.