bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel hypothesis‐generating computational workflow utilizing reverse pharmacophore mapping—A drug repurposing perspective of istradefylline towards major depressive disorder
Authors: van der Walt Mietha Magdalena , Smith Arnold Petrus 
Published: October 2024

Background and PurposeDrug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource‐intensive process. DR is the process of identifying alternative clinical applications for pre‐approved drugs as a low‐risk and low‐cost strategy. Computational approaches are crucial during the early hypothesis‐generating stage of DR. However, ‘large‐scale’ data retrieval remains a significant challenge. A computational workflow addressing such limitations might improve hypothesis generation, ultimately benefit patients and advance DR research.Experimental ApproachWe introduce a novel computational workflow (combining free‐accessible computational platforms) to provide ‘proof‐of‐concept’ of the pre‐approved drug's suitability for repurposing. Three key phases are included: target fishing (via reverse pharmacophore mapping), target identification (via disease‐ and drug‐target pathway identification) and retrospective literature and drug‐like analysis (via in silico ADMET properties determination). Istradefylline is a Parkinson's disease‐approved drug with literature‐attributed antidepressant properties remaining unclear. Practically applied, istradefylline's antidepressant activity was assessed in the context of major depressive disorder (MDD).Key ResultsData mining aided by target identification resulted in istradefylline potentially representing a novel antidepressant drug class. Retrieved drug targets (KYNU, MAO‐B, ALOX12 and PLCB2) associated with selected MDD pathways (tryptophan metabolism and serotonergic synapse) generated a hypothesis that istradefylline increased extracellular 5‐HT levels (MAO‐B inhibition) and reduced inflammation (KYNU, ALOX12 and PLCB2 inhibition).Conclusion and ImplicationsThe practically applied workflow's generated hypothesis aligns with known experimental data, validating the effectiveness of this novel computational workflow. It is a low‐risk and low‐cost DR computational tool providing a bird's‐eye view for exploring alternative clinical applications of pre‐approved drugs.
Reduction in mutualistic ant aggressive behavior upon sugar supplementation
Authors: Hoffman Sarah G. , Benson Luke R. , Philson Conner S. , Chock Rachel Y. , Curti Joseph N. , Flores‐Negrón César F. , Grether Gregory F. 
Published: October 2024

AbstractMutualistic interactions between species are widespread and important for community structure and ecosystem function. In a changing environment, the proximate mechanisms that maintain mutualisms affect their stability and susceptibility to perturbation. In ant‐plant mutualisms, ants defend their host plants against herbivores or competing plants in exchange for housing or food. While the phenomenon of species exchanging services for resources is well documented, how such arrangements are maintained is not. There are at least four hypothesized mechanisms through which plants use sugar to induce ant defense against herbivores. Three such hypotheses (“deficit”, “fuel for foraging”, “predictable rewards”) predict that the appearance of a new sugar source near the host plant would increase the rate of ant attacks against herbivores, but the fourth hypothesis (“attract and distract”) predicts the opposite. To examine how the mutualism between Triplaris americana and Pseudomyrmex dendroicus would be affected, we simulated the appearance of a novel sugar source at a random half of 34 T. americana trees with P. dendroicus colonies. Compared to control colonies, those with access to the sugar source were less likely to attack herbivorous insects (Nasutitermes sp. termites). Thus, our findings support the “attract and distract” hypothesis. We infer that this ant‐plant mutualism could be destabilized by the appearance of an alternative sugar source, such as a nectar‐producing plant or honeydew‐excreting insect. More broadly, we conclude that the mechanisms responsible for maintaining mutualistic relationships are relevant for understanding how ecological communities are affected by environmental change.Abstract in Spanish is available with online material.
Tyramine Derivatives as Versatile Pharmacophores With Potent Biological Properties: Sex Hormone–Binding Globulin Inhibition, Colon Cancer Antimigration, and Antimicrobial Activity
Authors: Marjanović Jovana S. , Arsenijević Dejan , Kosanić Marijana , Matić Jovana , Bogdanović Goran A. , Kostić Marina D. , Divac Vera M. 
Published: October 2024

ABSTRACTGuided by the idea that the presence of a heterocyclic aromatic core and tyramine moiety, under the umbrella of a single molecular scaffold could bring interesting biological properties, herein we present synthesis, characterization, with two crystal structures reported, and biological evaluation of some tyramine derivates. Cytotoxic and antimigratory potential was addressed by using a colorectal cancer cell line as a model system. Although possessing no cytotoxic effects, two compounds have shown strong antimigratory potential in low doses, with no effect on healthy MRC‐5 cells. Evaluation of their antimicrobial activities suggested prominent antimicrobial activity, where Compound 4 outperformed streptomycin against Escherichia coli and Proteus mirabilis. Hormone‐dependent types of cancer, such as prostate, ovary, and breast, are highly dependent on human sex hormone–binding globulin (SHBG) blood levels. A molecular docking study has shown that 1 has high affinity to bind and therefore compete with natural steroids for the SHBG steroid‐binding site. DNA‐binding study have shown that 4 interacts with CT‐DNA in a groove‐binding mode. In silico ADME/T study revealed that all compounds have suitable physicochemical properties for oral bioavailability and druglikeness, while toxicity tests for 1, 4, and 6 suggested potential for mutagenicity (4, 6), hepatotoxicity (6), and skin sensation (1).
Insulin‐Like Growth Factor Binding Protein 2 Drives Neurodegeneration in Parkinson's Disease: Insights From In Vivo and In Vitro Studies
Authors: An Jing , Wen Lulu , Yu Haiyang , Bu Zhongqi , Feng Juan 
Published: October 2024

ABSTRACTAimsInsulin‐like growth factor binding protein 2 (IGFBP2) is implicated in various neurodegenerative diseases. However, its role in Parkinson's disease (PD) is unclear.MethodsPD rat model was established by 6‐OHDA injection. After 3 weeks, mRNA‐seq was conducted. Rats received rIGFBP2 via intra‐MFB injection 6 h prior to 6‐OHDA infusion, and the effect of IGFBP2 in PD rats was investigated by western blotting, IHC, specific kits, JC‐1 staining, and TUNEL analysis. In vitro, PC12 cells were treated with 6‐OHDA, and CCK‐8, specific kits, Hoechst 33258 staining, Western blotting, and JC‐1 staining were performed to assess the IGFBP2's role.ResultsmRNA‐seq revealed DEGs in PD, with attention to downregulated IGFBP2. rIGFBP2 treatment aggravated neurobehavioral deficits, decreased TH expression, Ψm, ATP level and SOD, GSH‐Px activities but increased α‐synuclein, ROS, MDA, mitochondrial cytochrome c contents, cell apoptosis in 6‐OHDA‐lesioned rats, which might be mediated through inactivating IGF‐1R/AKT pathway. In 6‐OHDA‐treated PC12 cells, rIGFBP2 aggravated cell injury, demonstrated by decreased cell viability and increased apoptosis, oxidative stress, and mitochondrial dysfunction. Co‐treatment with rIGFBP2 and rIGF‐1 partially reversed the effect of rIGFBP2 on cell damage.ConclusionIGFBP2 exacerbates neurodegeneration in PD through increasing oxidative stress, mitochondrial dysfunction, and apoptosis via inhibiting IGF‐1R/AKT pathway.
Progress in Noninvasive Surveillance for Acute Rejection in Pediatric Heart Transplant Recipients: A Real‐World Analysis of Donor‐Derived Cell‐Free DNA‐Based Surveillance Protocol
Authors: Akabas Leor , Bravo Stephen A. , Zhang Yun , Simonelli Anna , Zuckerman Warren A. , Richmond Marc E. , Lytrivi Irene D. 
Published: October 2024

ABSTRACTPurposeAcute cellular (ACR) and antibody‐mediated (AMR) rejection are risk factors for allograft loss in heart transplant (HT) recipients. Endomyocardial biopsy (EMB), although considered the gold standard for rejection surveillance, is invasive and has high interobserver variability. Noninvasive donor‐derived cell‐free DNA (dd‐cfDNA) sampling has a high negative predictive value (NPV) for rejection in adults and is increasingly used in pediatrics. This single center study aimed to test the performance of dd‐cfDNA in screening for acute rejection (AR) and donor‐specific antibodies (DSAs) in pediatric HT recipients.MethodsBlood samples for dd‐cfDNA were obtained per clinical protocol for all eligible HT recipients in our center from July 1, 2022 to December 31, 2023. Primary endpoints were episodes of AR, pathology grading of EMBs temporally related to ddcfDNA sampling (0–150 days), and presence of DSAs.ResultsThere were 471 interpretable samples, in 192 unique patients. Of those, 199 dd‐cfDNA tests were paired with EMB ± DSA in 152 patients. Abnormal dd‐cfDNA (> 0.2%) was found in 77 samples (median 0.48%, range 0.21%–11%) and led to EMB, where one sample was positive for ACR (grade 2R), 13 for AMR, yielding an NPV of 97% for AMR. After excluding abnormal ddcfDNA testing associated with AR, 65 abnormal dd‐cfDNA tests were paired with DSA testing. The NPV of the test for detection of DSAs was 93%.ConclusionImplementation of noninvasive rejection surveillance with dd‐cfDNA in a pediatric cohort demonstrates high NPV for AR and high DSAs, making it an ideal screening tool for long‐term monitoring of allograft health in pediatrics.
The impact of Scotland's minimum unit pricing for alcohol policy on people accessing services for alcohol dependence: A difference‐in‐difference structured interview study
Authors: Buykx Penny , Perkins Andy , Hughes Jane , Livingston Wulf , Boyd Jennifer , Perman‐Howe Parvati , Johnston Allan , McCarthy Trevor , McLean Alex , Wright Alex , Little Simon , Holmes John 
Published: October 2024

AbstractIntroductionA minimum unit price (MUP) for alcohol of £0.50 per unit (1 UK unit = 10 mL/8 g alcohol) was introduced in Scotland in May 2018. Few previous studies have examined the impact of alcohol pricing policies on people who are alcohol dependent. This study aimed to evaluate the effect of MUP on people who are alcohol dependent including changes in alcohol consumption and health status, as well as potential unintended consequences.MethodsThree waves of cross‐sectional data were collected in Scotland (intervention) and Northern England (control) at 0–6 months pre‐implementation then 3–9 months and 18–22 months post‐implementation. The sample was N = 706 people receiving treatment related to their alcohol use. We collected structured interview data including recent drinking information via a 7‐day timeline‐follow‐back drinking diary. Difference‐in‐difference analyses estimated change in indicators in Scotland compared to England at both post‐implementation timepoints.ResultsThe proportion of participants consuming alcohol costing on average <£0.50 per unit in Scotland decreased from 60.6% at 0–6 months prior to MUP implementation to 6.3% at 3–9 months post‐implementation (p < 0.0004). There was no significant change in the indicators for alcohol consumption, severity of dependence, health status, other substance use, deprivation level or parenting.Discussion and ConclusionsThe introduction of MUP in Scotland was associated with increases in the prices paid for alcohol by people with dependence and presenting to treatment services. There was no evidence of changes in their alcohol consumption or health status. There was also no evidence of harmful unintended consequences for this population.
In vitro diagnostics of drug allergies
Authors: Glässner Andreas , Weßollek Katharina , Yazdi Amir S. , Sachs Bernhardt 
Published: October 2024

SummaryIn vitro diagnostics for drug hypersensitivity reactions distinguish between serological and cellular‐based tests. A serological test used for the diagnosis of immediate type reactions is the detection of specific IgE antibodies. The cellular tests include the basophil activation test for immediate type reactions and the lymphocyte transformation test, which is mainly used to detect delayed type hypersensitivity reactions. Further cellular‐based tests are the CAST‐ELISA and the mast cell activation test. None of the above‐mentioned tests can definitively exclude an allergy if the result is negative. In addition, it is important to note that even a positive test result is not necessarily associated with an allergy but has to be interpreted in the clinical context.
Thermal Tolerance and Species Distributions: Interactions Between Latitude, Elevation and Arboreality in Ants
Authors: Camara Talita , N. Andersen Alan , Nascimento Geraldo , Arnan Xavier 
Published: October 2024

ABSTRACTAimGlobal warming has highlighted the importance of understanding the role of thermal tolerance as a driver of species distributions, especially for ectotherms. Here we analyse interactions between latitude, elevation and arboreality as predictors of geographic patterns of thermal tolerance in ants.LocationThe collected data are distributed globally.MethodsWe first tested the effect of latitude, elevation and its interactive effect on ant CTmax and CTmin. Second, we tested whether CTmax and CTmin are phylogenetic clustering. Finally, we tested whether CTmax and CTmin can be explained by nesting microhabitat (ground vs. tree‐nesting species) and whether the probability of occurrence of tree‐nesting species along thermal gradients helps explain the global pattern in ant CTmax.ResultsCTmax and CTmin displayed high and low phylogenetic signals respectively and therefore showed different responses to geographic gradients. Notably, we found that CTmax was higher in higher latitudes. This was explained by a lack of elevational turnover at high latitudes among tree‐nesting species, which are exposed to warmer microclimates and have higher CTmax compared with ground‐nesting species. CTmin decreased with elevation at low latitudes, but did not vary with elevation at higher latitudes.Main ConclusionsOur findings highlight the important influence of arboreality on the macroecology of thermal tolerance, substantially modifying traditional notions of variation along latitudinal and elevation gradients.
More Than Just Treats? Effects of Grandparental Support for Children Growing up in Adversity
Authors: Riem Madelon M. E. , Hasselman Fred , Psyllou Constantina , van Harmelen Anne‐Laura , Pearce Anna , Minnis Helen , Lodder Paul , Cima Maaike 
Published: October 2024

ABSTRACTThis study examined whether grandparental support is a protective factor for children's socio‐emotional development in the context of adversity. Using longitudinal data from the Millennium Cohort Study, we investigated the effects of grandparental support across development in children with and without adverse childhood experiences (ACEs). Socio‐emotional development was assessed with the Strengths and Difficulties Questionnaire when children were aged 3 years (N = 10,186), 5 years (N = 10,412) and 7 years (N = 10,551). Parent‐reported grandparental childcare, coresidence and financial help were assessed and parents reported on the occurrence of five ACEs: physical and emotional abuse assessed with the Straus’ Conflict Tactics Scale, parental mental illness assessed with the Kessler scale, domestic violence and parental separation. We found that children with relatively higher levels of ACEs showed more prosocial behaviour and less externalizing problems when they received grandparental care compared to non‐grandparental (in)formal care, but only at age 3. By age 7, children with higher levels of ACEs receiving grandparental care showed less prosocial behaviour and more externalizing problems. In addition, grandparental financial support at age 3 was related to more externalizing problems. Post‐hoc analyses showed that internalizing and externalizing behaviours at age 5 were related to an increased probability of grandparental childcare at age 7, indicating that children's socio‐emotional problems trigger grandparental support. Our findings point to a protective effect of grandparental care on children's socio‐emotional development at age 3. Our results highlight the importance of going beyond the nuclear family towards the impact of the wider family network when examining children's socio‐emotional development.Research Highlights
Three‐year‐old children with high levels of adverse childhood experiences (ACEs) show more prosocial behaviour and less externalizing behaviour when they receive grandparental care.
Grandparental care has therefore protective effects on young children's socio‐emotional development in the context of family adversity.
Grandparents respond to children's socio‐emotional problems and family adversity by increasing financial support and involvement in care.
These findings underscore the importance of going beyond the nuclear family towards the impact of the wider family network when examining children's socio‐emotional development.
Transmitral Pressure Gradients in Patients With Degenerative Mitral Regurgitation After Robotic Mitral Valve Repair With Leaflet Preservation Techniques
Authors: Goldberger Madison I. , Pollak Angela , Fuller Matthew , Sun Katherine , Alenezi Fawaz , Glower Donald , Nicoara Alina 
Published: October 2024

ABSTRACTIntroductionThe hemodynamic effects of mitral valve repair (MVr) with respect to transmitral pressure gradients (TMPGs) have not been described well in patients undergoing leaflet preservation techniques. In a population of patients undergoing robotic MVr with leaflet preservation, we investigate the expected change of the postrepair intraoperative TMPG in the postoperative follow‐up period.MethodsWe retrospectively studied 144 adult patients who underwent robotic MVr. Demographic, clinical, procedural, and echocardiographic data were collected and analyzed.ResultsWe found a slight increase in the mean TMPG from the intraoperative postrepair to the immediate postoperative period (intraoperative 3.3 ± 1.4 mmHg vs. first postoperative transthoracic echocardiography [TTE] follow‐up 3.6 ± 1.9 mmHg, p = 0.016) with a gradual decline in the long‐term follow‐up (mean TMPG at last follow‐up TTE 2.4+2.1 mmHg). When dichotomizing the patient population using a cutoff of 3 mmHg for the intraoperative mean TMPG, patients with an intraoperative mean TMPG > 3 mmHg had higher mean TMPG gradients at first TTE (4.5 ± 2.4 vs. 3.1 ± 1.3 mmHg, p < 0.001) as well as at last TTE (3.0± 2.2 vs. 2.1 ± 2.0 mmHg, p = 0.01) when compared with patients with an intraoperative mean TMPG ≤ 3 mmHg. There was no difference in clinical outcomes.ConclusionsAlthough the hemodynamic effect of MVr seems to be small, patients with an intraoperative TMPG > 3 mmHg have a higher mean TMPG at follow‐up. The hemodynamic effect does not seem to have an impact on clinical outcome.
Microbial Evolution Drives Adaptation of Substrate Degradation on Decadal to Centennial Time Scales Relevant to Global Change
Authors: Abs Elsa , Coulette David , Ciais Philippe , Allison Steven D. 
Published: October 2024

ABSTRACTUnderstanding microbial adaptation is crucial for predicting how soil carbon dynamics and global biogeochemical cycles will respond to climate change. This study employs the DEMENT model of microbial decomposition, along with empirical mutation and dispersal rates, to explore the roles of mutation and dispersal in the adaptation of soil microbial populations to shifts in litter chemistry, changes that are anticipated with climate‐driven vegetation dynamics. Following a change in litter chemistry, mutation generally allows for a higher rate of litter decomposition than dispersal, especially when dispersal predominantly introduces genotypes already present in the population. These findings challenge the common idea that mutation rates are too low to affect ecosystem processes on ecological timescales. These results demonstrate that evolutionary processes, such as mutation, can help maintain ecosystem functioning as the climate changes.
Vagus nerve stimulation for epilepsy: A narrative review of factors predictive of response
Authors: Clifford Harry J. , Paranathala Menaka P. , Wang Yujiang , Thomas Rhys H. , da Silva Costa Tiago , Duncan John S. , Taylor Peter N. 
Published: October 2024

AbstractVagus nerve stimulation (VNS) is an established therapy for drug‐resistant epilepsy. However, there is a lack of reliable predictors of VNS response in clinical use. The identification of factors predictive of VNS response is important for patient selection and stratification as well as tailored stimulation programming. We conducted a narrative review of the existing literature on prognostic markers for VNS response using clinical, demographic, biochemical, and modality‐specific information such as from electroencephalography (EEG), magnetoencephalography, and magnetic resonance imaging (MRI). No individual marker demonstrated sufficient predictive power for individual patients, although several have been suggested, with some promising initial findings. Combining markers from underresearched modalities such as T1‐weighted MRI morphometrics and EEG may provide better strategies for treatment optimization.
Biochar Production From Plastic‐Contaminated Biomass
Authors: Hilber Isabel , Hagemann Nikolas , de la Rosa José María , Knicker Heike , Bucheli Thomas D. , Schmidt Hans‐Peter 
Published: October 2024

ABSTRACTAnaerobic digestion and composting of biowastes are vital pathways to recycle carbon and nutrients for agriculture. However, plastic contamination of soil amendments and fertilizers made from biowastes is a relevant source of (micro‐) plastics in (agricultural) ecosystems. To avoid this contamination, plastic containing biowastes could be pyrolyzed to eliminate the plastic, recycle most of the nutrients, and create carbon sinks when the resulting biochar is applied to soil. Literature suggests plastic elimination mainly by devolatilization at co‐pyrolysis temperatures of > 520°C. However, it is uncertain if the presence of plastic during biomass pyrolysis induces the formation of organic contaminants or has any other adverse effects on biochar properties. Here, we produced biochar from wood residues (WR) obtained from sieving of biowaste derived digestate. The plastic content was artificially enriched to 10%, and this mixture was pyrolyzed at 450°C and 600°C. Beech wood (BW) chips and the purified, that is, (macro‐) plastic‐free WR served as controls. All biochars produced were below limit values of the European Biochar Certificate (EBC) regarding trace element content and organic contaminants. Under study conditions, pyrolysis of biowaste, even when contaminated with plastic, can produce a biochar suitable for agricultural use. However, thermogravimetric and nuclear magnetic resonance spectroscopic analysis of the WR + 10% plastics biochar suggested the presence of plastic residues at pyrolysis temperatures of 450°C. More research is needed to define minimum requirements for the pyrolysis of plastic containing biowaste and to cope with the automated identification and determination of plastic types in biowaste at large scales.