bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity
Authors: Brehmer Dirk , Beke Lijs , Wu Tongfei , Millar Hillary J. , Moy Christopher , Sun Weimei , Mannens Geert , Pande Vineet , Boeckx An , van Heerde Erika , Nys Thomas , Gustin Emmanuel M. , Verbist Bie , Zhou Longen , Fan Yue , Bhargava Vipul , Safabakhsh Pegah , Vinken Petra , Verhulst Tinne , Gilbert Angelique , Rai Sumit , Graubert Timothy A. , Pastore Friederike , Fiore Danilo , Gu Junchen , Johnson Amy , Philippar Ulrike , Morschhäuser Barbara , Walker David , De Lange Desiree , Keersmaekers Vikki , Viellevoye Marcel , Diels Gaston , Schepens Wim , Thuring Jan Willem , Meerpoel Lieven , Packman Kathryn , Lorenzi Matthew V. , Laquerre Sylvie 
Published: September 2021

Abstract
The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity–driven tumors.
Ketone Ester D‐β‐Hydroxybutyrate‐(R)‐1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice
Authors: Thai Phung N. , Miller Charles V. , King M. Todd , Schaefer Saul , Veech Richard L. , Chiamvimonvat Nipavan , Bers Donald M. , Dedkova Elena N. 
Published: September 2021

Background
Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D‐β‐hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus.

Methods and Results
Type 2 diabetic (db/db) and their corresponding wild‐type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D‐β‐hydroxybutyrate‐(R)‐1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl‐CoA:3‐oxoacid‐CoA transferase and restored decreased expression of mitochondrial β‐hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP‐mediated oxygen consumption in cardiac mitochondria from both wild‐type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule‐associated protein 1 light chain 3–mediated autophagosome formation.

Conclusions
Moderate elevation in circulating D‐β‐hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.
Risk‐Attributable Burden of Ischemic Heart Disease in 137 Low‐ and Middle‐Income Countries From 2000 to 2019
Authors: Wang Chenran , Sun Yanghua , Jiang Di , Wang Chunping , Liu Shiwei 
Published: September 2021

Background
Ischemic heart disease (IHD) imposes the greatest disease burden globally, especially in low‐ and middle‐income countries (LMICs). We aim to examine the population‐attributable fraction and risk‐attributable death and disability‐adjusted life years (DALYs) for IHD in 137 low‐ and middle‐income countries.

Methods and Results
Using comparative risk assessment framework from the 2019 Global Burden of Disease study, the population‐attributable fraction and IHD burden (death and DALYs) attributable to risk factors in low‐income countries, lower‐middle‐income countries (LMCs), and upper‐middle‐income countries were assessed from 2000 to 2019. In 2019, the population‐attributable fraction (%) of IHD deaths in relation to all modifiable risk factors combined was highest in lower‐middle‐income countries (94.2; 95% uncertainty interval, 91.9–96.2), followed by upper‐middle‐income countries (93.5; 90.4–95.8) and low‐income countries (92.5; 90.0–94.7). There was a >13‐fold difference between Peru and Uzbekistan in age‐standardized rates (per 100 000) of attributable death (44.3 versus 660.4) and DALYs (786.7 versus 10506.1). Dietary risks accounted for the largest proportion of IHD’s behavioral burden in low‐ and middle‐income countries, primarily attributable to diets low in whole grains. High systolic blood pressure and high low‐density lipoprotein cholesterol remained the 2 leading causes of DALYs, with the former topping the list in 116 countries, while the latter led in 21 of the 137 countries. Compared with 2000 to 2010, the increases in risk‐attributable deaths and DALYs among upper‐middle income countries were slower from 2010 to 2019, while the trends in low‐income countries and lower‐middle income countries were opposite.

Conclusions
IHD’s attributable burden remains high in low‐ and middle‐income countries. Considerable heterogeneity was observed among different income‐classified regions and countries.
Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study
Authors: Lee Jungsoo , Chang Won Hyuk , Chung Jong-Won , Kim Suk Jae , Kim Soo-Kyoung , Lee Jin Soo , Sohn Sung-Il , Kim Yun-Hee , Bang Oh Young , Kim Suk Jae , Cho Yeon Hee , Sung Ji Hee , Kim Eun Hee , Son Jeong Pyo , Kim Dong Hee , Choi Eun-Hyeok , Ryoo Sookyung , Kang Yoon Mi , Kim Yong Man , Kim Hyun Soo , Jang Jun Ho 
Published: September 2021

Background and Purpose:
Stem cell–based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell–based therapy in patients with ischemic stroke.

Methods:
In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging.

Results:
For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference.

Conclusions:
Stem cell–based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01716481.
Musth and sexual selection in elephants: a review of signalling properties and potential fitness consequences
Authors: LaDue Chase A. , Schulte Bruce A. , Kiso Wendy K. , Freeman Elizabeth W. 
Published: September 2021

Abstract
Sexual selection mediated by multimodal signals is common among polygynous species, including seasonally breeding mammals. Indirect benefit models provide plausible explanations for how and why mate selection can occur in the absence of direct benefits. Musth — an asynchronous reproductive state in male elephants — facilitates both inter- and intrasexual selection via indirect benefits, and it is further communicated through a multimodal signal. In this review, we synthesise existing evidence that supports the hypothesis that musth is a multimodal signal subject to sexual selection and that male elephants increase their direct fitness by propagating this signal while females accrue indirect benefits. Musth is characterised by a suite of physiological and behavioural changes, serving to facilitate copulation between the sexes, and via multisensory modalities musth conveys honest information about the condition of a male. Female elephants mate preferentially with musth males, increasing their own fitness in the absence of direct benefits. In addition, musth resolves dynamic dominance hierarchies among male elephants and often eliminates the need for costly physical combat. Future work in this field should investigate potential postcopulatory selection mechanisms in elephants, including sperm competition and cryptic female choice. These topics join other fundamental questions related to sexual selection, signalling, and indirect benefits that are still unanswered in elephants.
Urban-nesting mountain chickadees have a reduced response to a simulated predator
Authors: Smith Blaire L. , Snell Cara L. , Reudink Matthew W. , Otter Ken A. 
Published: September 2021

Abstract
Anti-predator behaviour is common among birds, but little research exists on whether differences in the predator landscape between urban and rural habitats results in differential anti-predator behaviour. We compared nest-defence behaviour of mountain chickadees (Poecile gambeli) in urban and rural habitats in Kamloops, BC, Canada to a simulated predator model (snake) on top of nest boxes while incubating females were away from nests on foraging bouts. Upon their return, we recorded proximity to the predator model, latency to contact the nest box and enter the nest, and number of gargle and chick-a-dee calls as measures of anti-predator behaviour and compared multivariate “predator aversion scores” across birds occupying either rural or urban landscapes. Rural-nesting birds had more aversive reactions to the predator model than the urban-nesting birds, which may suggest differences in perceived threat of the model, in combination with increased boldness associated with urban-nesting birds.
On the applicability of eye movement desensitization and reprocessing (EMDR) as an intervention in dogs with fear and anxiety disorders after a traumatic event
Authors: Kapteijn C.M. , van der Borg J.A.M. , Vinke C.M. , Endenburg N. 
Published: September 2021

Abstract
Fear and anxiety disorders are prevalent in dogs. These disorders are not adequately resolved by current interventions, which urges exploration of additional interventions. In humans, fear and anxiety disorders such as post-traumatic stress disorder (PTSD), are effectively treated by Eye Movement Desensitization and Reprocessing (EMDR). EMDR is a non-invasive and non-pharmacological intervention involving bilateral sensory stimulation while memorizing the traumatic event, resulting in decreased emotionality of the memory. We argue EMDR might be applied as an intervention for fear and anxiety disorders in dogs, adding to the currently available interventions for the field of Clinical Ethology. Particularly nonverbal EMDR protocols used in preverbal children can be applied and the setup can be adapted for dogs. Future research should focus on the development of nonverbal EMDR protocols including proper controls, and on clinical effectiveness of such EMDR protocols for dogs. Apart from behavioural measures, psychophysiological variables should be incorporated as well.
The Role of Religious Experiences and Religious Institutions: Comparing Peter L. Berger’s and Hans Joas’ Approach to Religion
Authors: Deman Isaak 
Published: September 2021

Abstract
Hans Joas (born 1948) has repeatedly criticized Peter L. Berger (1929–2017) for placing religious experiences in the cognitive realm, where it runs the risk of being “contaminated” by secularization and pluralism. Instead, Joas has proposed to locate religious experiences in the “deeper layers” of the human person, where it is protected against mere cognitive reductionism and against contamination by secularization and pluralism. Despite his critique, Joas follows a similar path of Berger, as he explains the phenomenon of religion from an inductive point of view that originates in the experiential realm. This article demonstrates how Joas’ approach operates on a similar methodology like the one of Berger and ultimately results in similar theoretical conclusions despite their differing theoretical foundations. Moreover, this article illuminates an implicit methodological similarity between Joas and Berger that, on the one hand, differs from one of the taken-for-granted methodologies in the discipline of sociology (of religion), and, on the other hand, strongly influences the disposition of religious institutions in their definition of religion.
An Indigenous Jesus: Methodological and Theoretical Intersections in the Comparative Study of Religion
Authors: Joseph Simon J. 
Published: September 2021

Abstract
Indigeneity is a relational category that is predominantly, albeit not exclusively, applicable to Indigenous peoples. As a central theoretical site of discourse in Native Studies, indigeneity tends to be characterized by politicized relationships and provides powerful rhetorical strategies and counter-narratives. Facilitating decolonization as well as illuminating the structural and systemic relationships between the indigenous and the colonial, Indigenous theory recognizes the often complex inter-relationships attending the delineation of ethnic, social, and religious identity. The historical Black Elk, for example, illustrates how Lakota and Catholic religious identities co-exist in an ongoing site of discursive tension. This article argues that the historical figure of Jesus can be re-cognized as an indigenous Judean, complicating contemporary efforts in which the quest for the historical Jesus occurs in a predominantly Christian discursive context.
Space and Transformation: The Struggle for Architecture in Post Apartheid South Africa
Authors: Low Iain 
Published: September 2021

The title and this essay, ‘Space and Transformation – the struggle for architecture in post-apartheid South Africa’ derive from the 2nd Annual Nelson Mandela Lecture delivered in Ghent in 2015. Its source as my topic is located in the intersection of three interrelated trajectories. The most obvious is the issue of my disciplinary grounding and the locus of intellectual thought, that of architecture and the complexity associated with the production of space, particularly under conditions of change. The other is the life work and philosophical teaching of this extraordinary man Nelson Rolihlahla Mandela and the third is the condition of the world, and South Africa in particular, as we experience it today at what appears to be this unique historic intersectional moment of globalization and expansive technological shift within our nations’ democratic emergence.
The essay draws on texts derived from other disciplines, such as literature and philosophy, particularly those that have relevance to conditions of the South, but resorts to the spatial disciplining associated with design. In so doing it reflects on architectural projects produced during the first decades of democratic rule. Most of these projects fall within the realm of human settlement, and have been selected in order to demonstrate transformation relative to the lived reality of ordinary South Africans, especially those marginalised and dispossessed by apartheid legislation. A semi structured longitudinal analysis has been conducted so as to reflect on the relations between the agency of design and the instrumentation of architecture as practice in determining spatial transformation.
Identification of Drought Tolerant Mutant Lines of Tef [Eragrostis Tef (Zucc.) Trotter]
Authors: Blösch Regula , Rindisbacher Abiel , Plaza-Wüthrich Sonia , Röckel Nora , Weichert Annett , Cannarozzi Gina , Tadele Zerihun 
Published: September 2021

Introduction: Tef [Eragrostis tef (Zucc.) Trotter] is the major food crop in Ethiopia where it is annually cultivated on about 30% of the total area allocated to cereals. The productivity of tef is, however, significantly reduced by drought which can occur at either the early or the late developmental stage of the crop.
Methodology: A total of 10,000 EMS (ethyl methane sulfonate) mutagenized M2 tef populations were screened first for early and second for terminal drought tolerance. The performance of candidate lines was investigated using diverse agronomical and physiological parameters.
Results and discussion: Several promising lines were obtained for both early and terminal drought tolerance. Among these, genotypes with outstanding performance were found for two drought tolerant tef lines targeting early drought tolerance (dtt2 and dtt13) and three terminal drought tolerant lines targeting terminal drought tolerance (tdt9, tdt15 and tdt19).
Conclusions: Candidate lines for both early and terminal drought tolerance will play vital roles in developing drought tolerance in tef improvement.
Whole-body and muscle responses to aerobic exercise training and withdrawal in ageing and COPD
Authors: Latimer Lorna E. , Constantin-Teodosiu Dumitru , Popat Bhavesh , Constantin Despina , Houchen-Wolloff Linzy , Bolton Charlotte E. , Steiner Michael C. , Greenhaff Paul L. 
Published: September 2021

BackgroundChronic obstructive pulmonary disease (COPD) patients exhibit lower peak oxygen uptake (V′O2peak), altered muscle metabolism and impaired exercise tolerance compared with age-matched controls. Whether these traits reflect muscle-level deconditioning (impacted by ventilatory constraints) and/or dysfunction in mitochondrial ATP production capacity is debated. By studying aerobic exercise training (AET) at a matched relative intensity and subsequent exercise withdrawal period we aimed to elucidate the whole-body and muscle mitochondrial responsiveness of healthy young (HY), healthy older (HO) and COPD volunteers to whole-body exercise.MethodsHY (n=10), HO (n=10) and COPD (n=20) volunteers were studied before and after 8 weeks of AET (65%V′O2peak) and after 4 weeks of exercise withdrawal.V′O2peak, muscle maximal mitochondrial ATP production rate (MAPR), mitochondrial content, mitochondrial DNA (mtDNA) copy number and abundance of 59 targeted fuel metabolism mRNAs were determined at all time-points.ResultsMuscle MAPR (normalised for mitochondrial content) was not different for any substrate combination in HO, HY and COPD at baseline, but mtDNA copy number relative to a nuclear-encoded housekeeping gene (mean±sd) was greater in HY (804±67) than in HO (631±69; p=0.041). AET increasedV′O2peakin HO (17%; p=0.002) and HY (21%; p<0.001), but not COPD (p=0.603). Muscle MAPR for palmitate increased with training in HO (57%; p=0.041) and HY (56%; p=0.003), and decreased with exercise withdrawal in HO (−45%; p=0.036) and HY (−30%; p=0.016), but was unchanged in COPD (p=0.594). mtDNA copy number increased with AET in HY (66%; p=0.001), but not HO (p=0.081) or COPD (p=0.132). The observed changes in muscle mRNA abundance were similar in all groups after AET and exercise withdrawal.ConclusionsIntrinsic mitochondrial function was not impaired by ageing or COPD in the untrained state. Whole-body and muscle mitochondrial responses to AET were robust in HY, evident in HO, but deficient in COPD. All groups showed robust muscle mRNA responses. Higher relative exercise intensities during whole-body training may be needed to maximise whole-body and muscle mitochondrial adaptation in COPD.
Violence-related distress and lung function in two longitudinal studies of youth
Authors: Gaietto Kristina , Han Yueh-Ying , Forno Erick , Bacharier Leonard B. , Phipatanakul Wanda , Guilbert Theresa W. , Cabana Michael D. , Ross Kristie , Blatter Joshua , Acosta-Pérez Edna , Miller Gregory E. , de la Hoz Rafael E. , Rosser Franziska J. , Durrani Sandy , Canino Glorisa , Wisniewski Stephen R. , Celedón Juan C. 
Published: September 2021

BackgroundExposure to violence has been associated with lower lung function in cross-sectional studies.MethodsWe examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9–16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)).ResultsIn a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI −6.44– −0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI −4.86– −0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI −0.50– −0.10 points; p<0.01). Similar findings for FEV1and FVC were obtained in the prospective study of Puerto Rican youth.ConclusionsOur findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.