bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials
Authors: Haney Margaret , Vallée Monique , Fabre Sandy , Collins Reed Stephanie , Zanese Marion , Campistron Ghislaine , Arout Caroline A. , Foltin Richard W. , Cooper Ziva D. , Kearney-Ramos Tonisha , Metna Mathilde , Justinova Zuzana , Schindler Charles , Hebert-Chatelain Etienne , Bellocchio Luigi , Cathala Adeline , Bari Andrea , Serrat Roman , Finlay David B. , Caraci Filippo , Redon Bastien , Martín-García Elena , Busquets-Garcia Arnau , Matias Isabelle , Levin Frances R. , Felpin François-Xavier , Simon Nicolas , Cota Daniela , Spampinato Umberto , Maldonado Rafael , Shaham Yavin , Glass Michelle , Thomsen Lars Lykke , Mengel Helle , Marsicano Giovanni , Monlezun Stéphanie , Revest Jean-Michel , Piazza Pier Vincenzo 
Published: June 2023

AbstractCannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB1-SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ9-tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing significant adverse effects. In single-ascending-dose (0.2 mg, 0.6 mg, 2 mg and 6 mg; n = 40) and multiple-ascending-dose (0.6 mg, 2 mg and 6 mg; n = 24) phase 1 trials, healthy volunteers were randomized to ascending-dose cohorts (n = 8 per cohort; 6:2 AEF0117 to placebo randomization). In both studies, AEF0117 was safe and well tolerated (primary outcome measurements). In a double-blind, placebo-controlled, crossover phase 2a trial, volunteers with CUD were randomized to two ascending-dose cohorts (0.06 mg, n = 14; 1 mg, n = 15). AEF0117 significantly reduced cannabis’ positive subjective effects (primary outcome measurement, assessed by visual analog scales) by 19% (0.06 mg) and 38% (1 mg) compared to placebo (P < 0.04). AEF0117 (1 mg) also reduced cannabis self-administration (P < 0.05). In volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efficacious treatment for CUD.ClinicalTrials.gov identifiers: NCT03325595, NCT03443895 and NCT03717272.
Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study
Authors: Neul Jeffrey L. , Percy Alan K. , Benke Timothy A. , Berry-Kravis Elizabeth M. , Glaze Daniel G. , Marsh Eric D. , Lin Tim , Stankovic Serge , Bishop Kathie M. , Youakim James M. 
Published: June 2023

AbstractRett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study (https://clinicaltrials.govidentifierNCT04181723), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was −4.9 versus −1.7 (P = 0.0175; Cohen’sdeffect size, 0.37), and LSM Clinical Global Impression–Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist Social Composite score was −0.1 versus −1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.
Microcalcification crystallography as a potential marker of DCIS recurrence
Authors: Gosling Sarah B. , Arnold Emily L. , Davies Samantha K. , Cross Hannah , Bouybayoune Ihssane , Calabrese Doriana , Nallala Jayakrupakar , Pinder Sarah E. , Fu Liping , Lips Esther H. , King Lorraine , Marks Jeffrey , Hall Allison , Grimm Lars J. , Lynch Thomas , Pinto Donna , Stobart Hilary , Hwang E. Shelley , Wesseling Jelle , Geraki Kalotina , Stone Nicholas , Lyburn Iain D. , Greenwood Charlene , Rogers Keith D. ,   Grand Challenge PRECISION Consortium, Thompson Alastair , Nik-Zainal Serena , Sawyer Elinor J. , Davies Helen , Futreal Andrew , Navin Nicholas , Jonkers Jos , van Rheenen Jacco , Behbod Fariba , Schmidt Marjanka , Wessels Lodewyk F. A. , Rea Daniel , Bhattacharjee Proteeti , Collyar Deborah , Verschuur Ellen , van Oirsouw Marja 
Published: June 2023

AbstractDuctal carcinoma in-situ (DCIS) accounts for 20–25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.
4-Methylumbelliferone enhances the effects of chemotherapy on both temozolomide-sensitive and resistant glioblastoma cells
Authors: Pibuel Matías A. , Poodts Daniela , Sias Sofía A. , Byrne Agustín , Hajos Silvia E. , Franco Paula G. , Lompardía Silvina L. 
Published: June 2023

AbstractGlioblastoma (GBM) is the most frequent malignant primary tumor of the CNS in adults, with a median survival of 14.6 months after diagnosis. The effectiveness of GBM therapies remains poor, highlighting the need for new therapeutic alternatives. In this work, we evaluated the effect of 4-methylumbelliferone (4MU), a coumarin derivative without adverse effects reported, in combination with temozolomide (TMZ) or vincristine (VCR) on U251, LN229, U251-TMZ resistant (U251-R) and LN229-TMZ resistant (LN229-R) human GBM cells. We determined cell proliferation by BrdU incorporation, migration through wound healing assay, metabolic and MMP activity by XTT and zymography assays, respectively, and cell death by PI staining and flow cytometry. 4MU sensitizes GBM cell lines to the effect of TMZ and VCR and inhibits metabolic activity and cell proliferation on U251-R cells. Interestingly, the lowest doses of TMZ enhance U251-R and LN229-R cell proliferation, while 4MU reverts this and even sensitizes both cell lines to TMZ and VCR effects. We showed a marked antitumor effect of 4MU on GBM cells alone and in combination with chemotherapy and proved, for the first time, the effect of 4MU on TMZ-resistant models, demonstrating that 4MU would be a potential therapeutic alternative for improving GBM therapy even on TMZ-refractory patients.
Broad anti-pathogen potential of DEAD box RNA helicase eIF4A-targeting rocaglates
Authors: Obermann Wiebke , Azri Mohammad Farhan Darin , Konopka Leonie , Schmidt Nina , Magari Francesca , Sherman Julian , Silva Liliana M. R. , Hermosilla Carlos , Ludewig Andreas H. , Houhou Hicham , Haeberlein Simone , Luo Mona Yiting , Häcker Irina , Schetelig Marc F. , Grevelding Christoph G. , Schroeder Frank C. , Lau Gilbert Sei Kung , Taubert Anja , Rodriguez Ana , Heine Andreas , Yeo Tiong Chia , Grünweller Arnold , Taroncher-Oldenburg Gaspar 
Published: June 2023

AbstractInhibition of eukaryotic initiation factor 4A has been proposed as a strategy to fight pathogens. Rocaglates exhibit the highest specificities among eIF4A inhibitors, but their anti-pathogenic potential has not been comprehensively assessed across eukaryotes. In silico analysis of the substitution patterns of six eIF4A1 aa residues critical to rocaglate binding, uncovered 35 variants. Molecular docking of eIF4A:RNA:rocaglate complexes, and in vitro thermal shift assays with select recombinantly expressed eIF4A variants, revealed that sensitivity correlated with low inferred binding energies and high melting temperature shifts. In vitro testing with silvestrol validated predicted resistance in Caenorhabditiselegans and Leishmaniaamazonensis and predicted sensitivity in Aedes sp., Schistosomamansoni, Trypanosomabrucei, Plasmodiumfalciparum, and Toxoplasmagondii. Our analysis further revealed the possibility of targeting important insect, plant, animal, and human pathogens with rocaglates. Finally, our findings might help design novel synthetic rocaglate derivatives or alternative eIF4A inhibitors to fight pathogens.
Climate analogs can catalyze cross-regional dialogs for US specialty crop adaptation
Authors: Chaudhary Siddharth , Rajagopalan Kirti , Kruger Chad E. , Brady Michael P. , Fraisse Clyde W. , Gustafson David I , Hall Sonia A. , Hoogenboom Gerrit , Melnick Rachel L. , Reyes Julian , Stöckle Claudio O. , Sulser Timothy B. 
Published: June 2023

AbstractCommunication theory suggests that interactive dialog rather than information transmission is necessary for climate change action, especially for complex systems like agriculture. Climate analogs—locations whose current climate is similar to a target location’s future climate—have garnered recent interest as transmitting more relatable information; however, they have unexplored potential in facilitating meaningful dialogs, and whether the way the analogs are developed could make a difference. We developed climate context-specific analogs based on agriculturally-relevant climate metrics for US specialty crop production, and explored their potential for facilitating dialogs on climate adaptation options. Over 80% of US specialty crop counties had acceptable US analogs for the mid-twenty-first century, especially in the West and Northeast which had greater similarities in the crops produced across target-analog pairs. Western counties generally had analogs to the south, and those in other regions had them to the west. A pilot dialog of target-analog pairs showed promise in eliciting actionable adaptation insights, indicating potential value in incorporating analog-driven dialogs more broadly in climate change communication.
Explaining population booms and busts in Mid-Holocene Europe
Authors: Kondor Dániel , Bennett James S. , Gronenborn Detlef , Antunes Nicolas , Hoyer Daniel , Turchin Peter 
Published: June 2023

AbstractArchaeological evidence suggests that the population dynamics of Mid-Holocene (Late Mesolithic to Initial Bronze Age, ca. 7000–3000 BCE) Europe are characterized by recurrent booms and busts of regional settlement and occupation density. These boom-bust patterns are documented in the temporal distribution of 14C dates and in archaeological settlement data from regional studies. We test two competing hypotheses attempting to explain these dynamics: climate forcing and social dynamics leading to inter-group conflict. Using the framework of spatially-explicit agent-based models, we translated these hypotheses into a suite of explicit computational models, derived quantitative predictions for population fluctuations, and compared these predictions to data. We demonstrate that climate variation during the European Mid-Holocene is unable to explain the quantitative features (average periodicities and amplitudes) of observed boom-bust dynamics. In contrast, scenarios with social dynamics encompassing density-dependent conflict produce population patterns with time scales and amplitudes similar to those observed in the data. These results suggest that social processes, including violent conflict, played a crucial role in the shaping of population dynamics of European Mid-Holocene societies.
Acute effects of transcranial direct current stimulation (tDCS) on peak torque and 5000 m running performance: a randomized controlled trial
Authors: dos Santos Leila Fernanda , dos Santos Silva Devisson , de Jesus Alves Micael Deivison , Moura Pereira Erika Vitoria , do Nascimento Hortência Reis , de Sousa Fernandes Matheus Santos , de Freitas Zanona Aristela , Knechtle Beat , Weiss Katja , Aidar Felipe J. , de Souza Raphael Fabricio 
Published: June 2023

AbstractThe benefits of transcranial direct current stimulation (tDCS) on brain function, cognitive response, and motor ability are well described in scientific literature. Nevertheless, the effects of tDCS on athletes’ performance remain unclear. To compare the acute effects of tDCS on the running performance of 5000 m (m) runners. Eighteen athletes were randomized into Anodal (n = 9) groups that received tDCS for 20 min and 2 mA, and Sham (n = 9), in the motor cortex region (M1). Running time in 5000 m, speed, perceived exertion (RPE), internal load and peak torque (Pt) were evaluated. The Shapiro–Wilk test followed by a paired Student’s t-test was used to compare Pt and total time to complete the run between the groups. The running time and speed of the Anodal group (p = 0.02; 95% CI 0.11–2.32; d = 1.24) was lower than the Sham group (p = 0.02, 95% CI 0.05–2.20; d = 1.15). However, no difference was found in Pt (p = 0.70; 95% CI − 0.75 to 1.11; d = 0.18), RPE (p = 0.23; 95% CI − 1.55 to 0.39; d = 0.60) and internal charge (p = 0.73; 95% CI − 0.77 to 1.09; d = 0.17). Our data indicate that tDCS can acutely optimize the time and speed of 5000 m runners. However, no alterations were found for Pt and RPE.
Early-life adversities and later-life reproductive patterns in women with fully traced reproductive history
Authors: Klimek Magdalena , Entringer Sonja , Matras Agnieszka , Blukacz Mateusz , Nenko Ilona , Galbarczyk Andrzej , Jasienska Grazyna 
Published: June 2023

AbstractOne of the most crucial determinants of early-life development is the experience of childhood adversities. However, limited evidence is available for how these experiences shape later-life reproductive outcomes in women. Here we test the association between early-life adversities and reproductive parameters in women. Post-reproductive women (N = 105; mean age = 59.7; SD = 10.09) were recruited at the Mogielica Human Ecology Study Site in Poland within a traditional population with a low prevalence of birth control usage and fully traced reproductive histories. Reproductive parameters, as well as exposure to early-life abuse and neglect, were assessed using questionnaires. Childhood adversity was associated negatively with age at menarche (p = 0.009). Analyses on specific subtypes revealed that compared to women who did not experience any kind of early-life adversities in childhood, those who were exposed to emotional (p = 0.007) and physical (p = 0.023) neglect had an earlier age at menarche, those who experienced emotional abuse reported an earlier age at first birth (p = 0.035), and those who were exposed to physical abuse gave birth to fewer number of sons (p = 0.010). Our results suggest that women exposed to childhood adversities experience earlier physiological reproductive readiness and timing of the first birth, but their overall biological condition might be impaired as they bear fewer sons.
The feasibility of enhanced pore space utilization in CO2 storage reservoirs using an artificially emplaced Si-gel flow barrier
Authors: Cossins Teya , Mishra Achyut , Haese Ralf R. 
Published: June 2023

AbstractCarbon capture and storage is a key technology to abate CO2 emissions. One of the challenges towards ensuring the efficiency and the security of CO2 storage in reservoirs, such as open saline aquifers, is the low pore space utilization. This study investigates the feasibility of using an artificial Si-gel barrier to enhance pore space utilisation in such reservoirs under variable geological conditions. Conceptually, enhanced CO2 capillary trapping is achieved by emplacing a disk-shaped, low-permeability barrier above the CO2 injection point forcing the injected CO2 to migrate laterally underneath the barrier before transitioning to buoyancy-controlled migration. Multiphase fluid flow simulations were conducted to test the feasibility of this concept. Sensitivity analysis revealed that the barrier exhibits a strong control on CO2 plume geometry. Specifically, the relative impact of the barrier diameter on increasing the CO2 plume width, reducing the plume height and enhancing trapping varied between 67 and 86%. Capillary trapping was enhanced by 40–60% with a 20 m increase in barrier diameter in low permeability reservoirs. Additionally, the results indicate that the barrier can enhance the security of trapping CO2 in high permeability reservoirs. Results were tested for the South-West Hub reservoir, a case study area in Western Australia.
Assessment of goal-directed behavior and prospective memory in adult ADHD with an online 3D videogame simulating everyday tasks
Authors: Jylkkä Jussi , Ritakallio Liisa , Merzon Liya , Kangas Suvi , Kliegel Matthias , Zuber Sascha , Hering Alexandra , Laine Matti , Salmi Juha 
Published: June 2023

AbstractThe diagnosis of ADHD is based on real-life attentional-executive deficits, but they are harder to detect in adults than in children and objective quantitative measures reflecting these everyday problems are lacking. We developed an online version of EPELI 3D videogame for naturalistic and scalable assessment of goal-directed action and prospective memory in adult ADHD. In EPELI, participants perform instructed everyday chores in a virtual apartment from memory. Our pre-registered hypothesis predicted weaker EPELI performances in adult ADHD compared to controls. The sample comprised 112 adults with ADHD and 255 neurotypical controls comparable in age (mean 31, SD = 8 years), gender distribution (71% females) and educational level. Using web-browser, the participants performed EPELI and other cognitive tasks, including Conner’s Continuous Performance Test (CPT). They also filled out questionnaires probing everyday executive performance and kept a 5-day diary of everyday prospective memory errors. Self-reported strategy use in the EPELI game was also examined. The ADHD participants’ self-ratings indicated clearly more everyday executive problems than in the controls. Differences in the EPELI game were mostly seen in the ADHD participants’ higher rates of task-irrelevant actions. Gender differences and a group × gender interaction was found in the number of correctly performed tasks, indicating poorer performance particularly in ADHD males. Discriminant validity of EPELI was similar to CPT. Strategy use strongly predicted EPELI performance in both groups. The results demonstrate the feasibility of EPELI for online assessment and highlight the role of impulsivity as a distinctive everyday life problem in adult ADHD.
Spatial–temporal variation of extreme precipitation in the Yellow–Huai–Hai–Yangtze Basin of China
Authors: Wang Lichuan , Wang Jianhua , He Fan , Wang Qingming , Zhao Yong , Lu Peiyi , Huang Ya , Cui Hao , Deng Haodong , Jia Xinran 
Published: June 2023

AbstractClimate warming leads to frequent extreme precipitation events, which is a prominent manifestation of the variation of the global water cycle. In this study, data from 1842 meteorological stations in the Huang–Huai–Hai–Yangtze River Basin and 7 climate models of CMIP6 were used to obtain the historical and future precipitation data using the Anusplin interpolation, BMA method, and a non-stationary deviation correction technique. The temporal and spatial variations of extreme precipitation in the four basins were analysed from 1960 to 2100. The correlation between extreme precipitation indices and their relationship with geographical factors was also analysed. The result of the study indicates that: (1) in the historical period, CDD and R99pTOT showed an upward trend, with growth rates of 14.14% and 4.78%, respectively. PRCPTOT showed a downward trend, with a decreasing rate of 9.72%. Other indices showed minimal change. (2) Based on SSP1-2.6, the intensity, frequency, and duration of extreme precipitation changed by approximately 5% at SSP3-7.0 and 10% at SSP5-8.5. The sensitivity to climate change was found to be highest in spring and autumn. The drought risk decreased, while the flood risk increased in spring. The drought risk increased in autumn and winter, and the flood risk increased in the alpine climate area of the plateau in summer. (3) Extreme precipitation index is significantly correlated with PRCPTOT in the future period. Different atmospheric circulation factors significantly affected different extreme precipitation indices of FMB. (4) CDD, CWD, R95pD, R99pD, and PRCPTOT are affected by latitude. On the other hand, RX1day and RX5day are affected by longitude. The extreme precipitation index is significantly correlated with geographical factors, and areas above 3000 m above sea level are more sensitive to climate change.
Buckling critical pressures in collapsible tubes relevant for biomedical flows
Authors: Laudato Marco , Mosca Roberto , Mihaescu Mihai 
Published: June 2023

AbstractThe behaviour of collapsed or stenotic vessels in the human body can be studied by means of simplified geometries like a collapsible tube. The objective of this work is to determine the value of the buckling critical pressure of a collapsible tube by employing Landau’s theory of phase transition. The methodology is based on the implementation of an experimentally validated 3D numerical model of a collapsible tube. The buckling critical pressure is estimated for different values of geometric parameters of the system by treating the relation between the intramural pressure and the area of the central cross-section as the order parameter function of the system. The results show the dependence of the buckling critical pressures on the geometric parameters of a collapsible tube. General non-dimensional equations for the buckling critical pressures are derived. The advantage of this method is that it does not require any geometric assumption, but it is solely based on the observation that the buckling of a collapsible tube can be treated as a second-order phase transition. The investigated geometric and elastic parameters are sensible for biomedical application, with particular interest to the study of the bronchial tree under pathophysiological conditions like asthma.